Artykuły w czasopismach: „CANCER-ASSOCIATED MICROBE”

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Gnanasekar, Aditi, Neil Shende, Jaideep Chakladar, Wei T. Li, Lindsay M. Wong, Michael Karin i Weg M. Ongkeko. "Abstract 3528: Influence of obesity-associated intra-tumor microbes on exacerbating cancer severity". Cancer Research 82, nr 12_Supplement (15.06.2022): 3528. http://dx.doi.org/10.1158/1538-7445.am2022-3528.

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Abstract Background: Despite there being a well-established connection between the gut microbiome and metabolic disease in humans, intra-tumor microbes and the mechanisms by which they regulate cell signaling, inflammation, and adipocyte growth to exacerbate disease severity in cancer patients also suffering from obesity remains largely unclear. In this study, we identified microbes to be distinctly abundant in cancer patients who are obese and correlated microbe abundance to patient survival, clinical variables, and immunological genes and pathways, in order to mechanistically explain how differential microbe abundance may influence clinical outcome. Methods: Microbial reads were aligned and extracted from raw whole-transcriptome RNA-sequencing data of cancer patient samples using Pathoscope 2.0 software. The Kruskal-Wallis test was used to correlate body mass index (BMI)-associated microbes to clinical variables. Reactome FIViz and Gene Set Enrichment Analysis were used to calculate pathway enrichment. Results: We identified specific microbes, including Pseudomonas fluorescens SBW25 and Enterobacter cloacae, and chemokine and interleukin-related genes to be potential determining factors of disease severity among cancer patients in BMI-associated groups. Gene set enrichment analysis revealed that microbes abundant in cancer tissue in obese patient samples, including Pseudomonas baetica in liver cancer patients, were significantly associated with the upregulation oncogenic, cell migration-related signaling pathways. Intra-tumor microbes from obese patient samples were also found to correlate with chemokine signaling and TFR2/NFkB-related genes, both of which have well-established roles in inflammatory activity. Conclusions: Our study significantly advances the understanding of the microbiome composition of the tumor microenvironment in patients who are obese and microbes’ relationship with clinical and immunologic variables, particularly inflammatory-related genes and pathways. We uncovered unknown mechanisms of the microbiome-immune interaction and obtained definitive data on microbiome dysbiosis in patients with obesity as a key determinant of severity of cancer, including microbe regulation of inflammasome activity. While deeper sequencing, more rigorous contamination correction, and in vitro and in vivo experiments are necessary to fully elucidate how microbe species can effectively act as therapeutic agents in probiotic and prebiotic therapies to reduce insulin resistance, inflammation, and glucose levels, our results are essential for guiding this future research. Citation Format: Aditi Gnanasekar, Neil Shende, Jaideep Chakladar, Wei T. Li, Lindsay M. Wong, Michael Karin, Weg M. Ongkeko. Influence of obesity-associated intra-tumor microbes on exacerbating cancer severity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3528.

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Bose, Mukulika, i Pinku Mukherjee. "Microbe–MUC1 Crosstalk in Cancer-Associated Infections". Trends in Molecular Medicine 26, nr 3 (marzec 2020): 324–36. http://dx.doi.org/10.1016/j.molmed.2019.10.003.

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Li, Wei Tse, Anjali S. Iyangar, Rohan Reddy, Jaideep Chakladar, Valmik Bhargava, Kyoko Sakamoto, Weg M. Ongkeko i Mahadevan Rajasekaran. "The Bladder Microbiome Is Associated with Epithelial–Mesenchymal Transition in Muscle Invasive Urothelial Bladder Carcinoma". Cancers 13, nr 15 (21.07.2021): 3649. http://dx.doi.org/10.3390/cancers13153649.

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The intra-tumor microbiome has recently been linked to epithelial–mesenchymal transition (EMT) in a number of cancers. However, the relationship between EMT and microbes in bladder cancer has not been explored. In this study, we profiled the abundance of individual microbe species in the tumor samples of over 400 muscle invasive bladder carcinoma (MIBC) patients. We then correlated microbe abundance to the expression of EMT-associated genes and genes in the extracellular matrix (ECM), which are key players in EMT. We discovered that a variety of microbes, including E. coli, butyrate-producing bacterium SM4/1, and a species of Oscillatoria, were associated with expression of classical EMT-associated genes, including E-cadherin, vimentin, SNAI2, SNAI3, and TWIST1. We also found significant correlations between microbial abundance and the expression of genes in the ECM, specifically collagens and elastin. Lastly, we found that a large number of microbes exhibiting significant correlations to EMT are also associated with clinical prognosis and outcomes. We further determined that the microbes we profiled were likely not environmental contaminants. In conclusion, we discovered that the intra-tumoral microbiome could potentially play a significant role in the regulation of EMT in MIBC.

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Malik, Hafiza Iqra, i Muhammad Imran Qadir. "Relation between Gut Microbiota and Cancer". JOURNAL OF MICROBIOLOGY AND MOLECULAR GENETICS 2, nr 1 (21.03.2021): 45–54. http://dx.doi.org/10.52700/jmmg.v2i1.28.

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Human has about 100 trillion symbiotic microbes in the gut with 300-1000 different species. Gut microbiota is associated with host metabolism, obesity, diabetes, hepatic disorder, and cancer. Nowadays, studies are focusing on the role of gut microbiota in cancer. Evidence shows that Fusobacterium is associated with colorectal cancer when its genome was confirmed by 16SRNA analysis and PCR technique in cancerous cell. The complete mechanism of gut microbe involvement in cancer is still unknown. There may be some association of toxic metabolites of gut microbes, dietary substances, and the immune response. This review will help to attain the brief knowledge about the research till now in the regard of gut microbiota with cancer. The study will also reveal the research of using gut microbes for anticancer therapy. It is examined that Lactobacillus rhamnosus in the form of probiotics has a significant role in anticancer therapy. The anticancerous therapeutic and immunogenic role of gut microbiota must be further studied.

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Ponath, Falk, Caroline Tawk, Yan Zhu, Lars Barquist, Franziska Faber i Jörg Vogel. "RNA landscape of the emerging cancer-associated microbe Fusobacterium nucleatum". Nature Microbiology 6, nr 8 (8.07.2021): 1007–20. http://dx.doi.org/10.1038/s41564-021-00927-7.

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Sayed, Ibrahim M., Anirban Chakraborty, Amer Ali Abd El-Hafeez, Aditi Sharma, Ayse Z. Sahan, Wendy Jia Men Huang, Debashis Sahoo, Pradipta Ghosh, Tapas K. Hazra i Soumita Das. "The DNA Glycosylase NEIL2 Suppresses Fusobacterium-Infection-Induced Inflammation and DNA Damage in Colonic Epithelial Cells". Cells 9, nr 9 (28.08.2020): 1980. http://dx.doi.org/10.3390/cells9091980.

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Colorectal cancer (CRC) is the third most prevalent cancer, while the majority (80–85%) of CRCs are sporadic and are microsatellite stable (MSS), and approximately 15–20% of them display microsatellite instability (MSI). Infection and chronic inflammation are known to induce DNA damage in host tissues and can lead to oncogenic transformation of cells, but the role of DNA repair proteins in microbe-associated CRCs remains unknown. Using CRC-associated microbes such as Fusobacterium nucleatum (Fn) in a coculture with murine and human enteroid-derived monolayers (EDMs), here, we show that, among all the key DNA repair proteins, NEIL2, an oxidized base-specific DNA glycosylase, is significantly downregulated after Fn infection. Fn infection of NEIL2-null mouse-derived EDMs showed a significantly higher level of DNA damage, including double-strand breaks and inflammatory cytokines. Several CRC-associated microbes, but not the commensal bacteria, induced the accumulation of DNA damage in EDMs derived from a murine CRC model, and Fn had the most pronounced effect. An analysis of publicly available transcriptomic datasets showed that the downregulation of NEIL2 is often encountered in MSS compared to MSI CRCs. We conclude that the CRC-associated microbe Fn induced the downregulation of NEIL2 and consequent accumulation of DNA damage and played critical roles in the progression of CRCs.

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Uzelac, Matthew, Wei Tse Li, Jaideep Chakladar, Daniel John i Weg M. Ongkeko. "Abstract LB110: Racial and ethnic disparities associated with the intratumor microbiome in female cancers". Cancer Research 83, nr 8_Supplement (14.04.2023): LB110. http://dx.doi.org/10.1158/1538-7445.am2023-lb110.

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Abstract Background: The intratumor microbiome is implicated in tumor initiation, progression, and altered immune response to cancer therapies. Furthermore, recent studies have revealed correlations between microbial abundance and racial disparities in cancer. While these investigations provide novel insights into cancer disparities research, few have investigated which racial and ethnic disparities exist for patients with female malignancies. In this study, we characterized the intratumor microbiome according to racial and ethnic disparities in common female malignancies including breast, cervical, uterine, and ovarian cancers. Methods: We examined the intra-tumoral microbiome in the breasts, cervix, uterus, and ovaries (n = 2630). Raw tumor RNA sequencing data were downloaded from The Cancer Genome Atlas (TCGA) and aligned to bacterial genomes using the PathoScope 2.0 framework and references genomes provided by the NCBI nucleotide database. Potential contaminants were identified and removed from downstream analyses by associating individual microbe abundance with total microbe abundance in each sample. Microbial abundance was correlated to race, ethnicity, and prognostic variables (Kruskal-Wallis test or Cox regression, p < 0.05). Finally, we validated our results using transcriptomic sequencing data downloaded from the GEO NCBI data portal. Results: Significant dysregulation of bacterial microbes according to race and ethnicity was observed in these cancers, but most notably in breast cancer in which 6 species correlated strongly with survival. Of particular significance were Veillonella Parvula and Mycobacteroides chelonae, which were both significantly dysregulated in Black breast cancer patients, with low abundance of both species correlating to poor survival. Cupriavidus Taiwanensis and Delftia Acidovorans were more abundant in Black breast cancer patients, with high abundance correlating to poorer prognosis. Black patients were also diagnosed at significantly later cancer stages in cervical cancer. We also observed significant correlations of bacterial microbe abundance with prognostic and treatment variables in these cancers, including pathologic TNM staging, neoplasm presence, therapy outcome, and more. Conclusion: Our study is the most comprehensive to date investigating racial differences in the intra-tumoral microbiome in common female cancers. We found that differences in intratumoral microbial abundance may account in part for observed racial and ethnic disparities in cancer prevalence and progression in these cancers. Further studies are needed to investigate the specific mechanisms by which these microbes contribute to these observed cancer disparities within the tumor microenvironment. Citation Format: Matthew Uzelac, Wei Tse Li, Jaideep Chakladar, Daniel John, Weg M. Ongkeko. Racial and ethnic disparities associated with the intratumor microbiome in female cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB110.

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Armstrong, Heather, Michael Bording-Jorgensen, Stephanie Dijk i Eytan Wine. "The Complex Interplay between Chronic Inflammation, the Microbiome, and Cancer: Understanding Disease Progression and What We Can Do to Prevent It". Cancers 10, nr 3 (20.03.2018): 83. http://dx.doi.org/10.3390/cancers10030083.

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Cancer is a multifaceted condition, in which a senescent cell begins dividing in an irregular manner due to various factors such as DNA damage, growth factors and inflammation. Inflammation is not typically discussed as carcinogenic; however, a significant percentage of cancers arise from chronic microbial infections and damage brought on by chronic inflammation. A hallmark cancer-inducing microbe is Helicobacter pylori and its causation of peptic ulcers and potentially gastric cancer. This review discusses the recent developments in understanding microbes in health and disease and their potential role in the progression of cancer. To date, microbes can be linked to almost every cancer, including colon, pancreatic, gastric, and even prostate. We discuss the known mechanisms by which these microbes can induce cancer growth and development and how inflammatory cells may contribute to cancer progression. We also discuss new treatments that target the chronic inflammatory conditions and their associated cancers, and the impact microbes have on treatment success. Finally, we examine common dietary misconceptions in relation to microbes and cancer and how to avoid getting caught up in the misinterpretation and over inflation of the results.

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Wang, Di, Yan Cui, Yuxuan Cao, Yuehan He i Hui Chen. "Human Microbe-Disease Association Prediction by a Novel Double-Ended Random Walk with Restart". BioMed Research International 2020 (11.08.2020): 1–8. http://dx.doi.org/10.1155/2020/3978702.

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Microorganisms in the human body play a vital role in metabolism, immune defense, nutrient absorption, cancer control, and prevention of pathogen colonization. More and more biological and clinical studies have shown that the imbalance of microbial communities is closely related to the occurrence and development of various complex human diseases. Finding potential microbial-disease associations is critical for understanding the pathology of a few diseases and thus further improving disease diagnosis and prognosis. In this study, we proposed a novel computational model to predict disease-associated microbes. Specifically, we first constructed a heterogeneous interconnection network based on known microbe-disease associations deposited in a few databases, the similarity between diseases, and the similarity between microorganisms. We then predicted novel microbe-disease associations by a new method called the double-ended restart random walk model (DRWHMDA) implemented on the interconnection network. In addition, we performed case studies of colon cancer and asthma for further evaluation. The results indicate that 10 and 9 of the top 10 microorganisms predicted to be associated with colorectal cancer and asthma were validated by relevant literatures, respectively. Our method is expected to be effective in identifying disease-related microorganisms and will help to reveal the relationship between microorganisms and complex human diseases.

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Liu, Yunjie, Yao-zhong Zhang i Seiya Imoto. "Microbial Gene Ontology informed deep neural network for microbe functionality discovery in human diseases". PLOS ONE 18, nr 8 (21.08.2023): e0290307. http://dx.doi.org/10.1371/journal.pone.0290307.

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The human microbiome plays a crucial role in human health and is associated with a number of human diseases. Determining microbiome functional roles in human diseases remains a biological challenge due to the high dimensionality of metagenome gene features. However, existing models were limited in providing biological interpretability, where the functional role of microbes in human diseases is unexplored. Here we propose to utilize a neural network-based model incorporating Gene Ontology (GO) relationship network to discover the microbe functionality in human diseases. We use four benchmark datasets, including diabetes, liver cirrhosis, inflammatory bowel disease, and colorectal cancer, to explore the microbe functionality in the human diseases. Our model discovered and visualized the novel candidates’ important microbiome genes and their functions by calculating the important score of each gene and GO term in the network. Furthermore, we demonstrate that our model achieves a competitive performance in predicting the disease by comparison with other non-Gene Ontology informed models. The discovered candidates’ important microbiome genes and their functions provide novel insights into microbe functional contribution.

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Wei, Yu-Feng, Ming-Shyan Huang, Cheng-Hsieh Huang, Yao-Tsung Yeh i Chih-Hsin Hung. "Impact of Gut Dysbiosis on the Risk of Non-Small-Cell Lung Cancer". International Journal of Environmental Research and Public Health 19, nr 23 (30.11.2022): 15991. http://dx.doi.org/10.3390/ijerph192315991.

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Background: The imbalance of gut microbiota, dysbiosis, is associated with various malignant diseases. This study aimed to identify the characteristics of gut microbiota in age-matched treatment-naïve non-small-cell lung cancer (NSCLC) patients and healthy individuals to investigate possible gut-microbe-related pathways involved in the development of NSCLC. Methods: We enrolled 34 age-matched NSCLC patients and 268 healthy individuals. Hypervariable V3–V4 amplicons of 16S rRNA in freshly collected fecal samples were sequenced. Diversity, microbial composition, functional pathways, smoking history, and gut-microbe-related comorbidities were analyzed to assess the factors associated with the risk of NSCLC. Results: Microbial alpha diversity was decreased in the patients with NSCLC, and beta diversity was significantly different between the patients and controls (p < 0.001). After adjustments for sex, smoking history, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, and 11 abundant microbes with significant differences between the patients and controls, the enrichment of Anaerotruncus spp. and Bacteroides caccae was associated with an increased risk of NSCLC (p = 0.003 and 0.007, respectively). The areas under receiver operating characteristic curves were 71.4% and 66.9% for Anaerotruncus spp. and Bacteroides caccae, respectively (both p < 0.001). Furthermore, the abundance of Bacteroides caccae was positively correlated with steroid hormone biosynthesis (p < 0.001), N-glycan biosynthesis (p = 0.023), glycosaminoglycan degradation (p < 0.001), lipoic acid metabolism (p = 0.039), peroxisome (p < 0.001), and apoptosis (p < 0.001), but inversely related to glycerolipid metabolism (p < 0.001). Anaerotruncus spp. was positively associated with decreased biosynthesis of ansamycin only (p = 0.001). No overlapping signaling pathways were modulated by Bacteroides caccae or Anaerotruncus spp. Conclusions: Our results revealed that fecal Anaerotruncus spp. and Bacteroides caccae were abundant and may be associated with the risk of NSCLC regardless of sex, smoking history, and gut-microbe-related comorbidities. Further investigations on the mechanism underlying the potential association between gut dysbiosis and the development of NSCLC are warranted.

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Chakladar, Jaideep, Daniel John, Shruti Magesh, Matthew Uzelac, Wei Tse Li, Kypros Dereschuk, Lauren Apostol, Kevin T. Brumund, Jessica-Wang Rodriguez i Weg M. Ongkeko. "The Intratumor Bacterial and Fungal Microbiome Is Characterized by HPV, Smoking, and Alcohol Consumption in Head and Neck Squamous Cell Carcinoma". International Journal of Molecular Sciences 23, nr 21 (31.10.2022): 13250. http://dx.doi.org/10.3390/ijms232113250.

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Head and neck squamous cell carcinoma (HNSCC) tumor phenotypes and clinical outcomes are significantly influenced by etiological agents, such as HPV infection, smoking, and alcohol consumption. Accordingly, the intratumor microbiome has been increasingly implicated in cancer progression and metastasis. However, few studies characterize the intratumor microbial landscape of HNSCC with respect to these etiological agents. In this study, we aimed to investigate the bacterial and fungal landscape of HNSCC in association with HPV infection, smoking, and alcohol consumption. RNA-sequencing data were extracted from The Cancer Genome Atlas (TCGA) regarding 449 tissue samples and 44 normal samples. Pathoscope 2.0 was used to extract the microbial reads. Microbe abundance was compared to clinical variables, oncogenic signatures, and immune-associated pathways. Our results demonstrated that a similar number of dysregulated microbes was overabundant in smokers and nonsmokers, while heavy drinkers were characterized by an underabundance of dysregulated microbes. Conversely, the majority of dysregulated microbes were overabundant in HPV+ tumor samples when compared to HPV- tumor samples. Moreover, we observed that many dysregulated microbes were associated with oncogenic and metastatic pathways, suggesting their roles in influencing carcinogenesis. These microbes provide insights regarding potential mechanisms for tumor pathogenesis and progression with respect to the three etiological agents.

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Wang, Yen-Chieh, Wei-Chi Ku, Chih-Yi Liu, Yu-Che Cheng, Chih-Cheng Chien, Kang-Wei Chang i Chi-Jung Huang. "Supplementation of Probiotic Butyricicoccus pullicaecorum Mediates Anticancer Effect on Bladder Urothelial Cells by Regulating Butyrate-Responsive Molecular Signatures". Diagnostics 11, nr 12 (4.12.2021): 2270. http://dx.doi.org/10.3390/diagnostics11122270.

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In bladder cancer, urothelial carcinoma is the most common histologic subtype, accounting for more than 90% of cases. Pathogenic effects due to the dysbiosis of gut microbiota are localized not only in the colon, but also in regulating bladder cancer distally. Butyrate, a short-chain fatty acid produced by gut microbial metabolism, is mainly studied in colon diseases. Therefore, the resolution of the anti-cancer effects of butyrate-producing microbes on bladder urothelial cells and knowledge of the butyrate-responsive molecules must have clinical significance. Here, we demonstrate a correlation between urothelial cancer of the bladder and Butyricicoccus pullicaecorum. This butyrate-producing microbe or their metabolite, butyrate, mediated anti-cancer effects on bladder urothelial cells by regulating cell cycle, cell growth, apoptosis, and gene expression. For example, a tumor suppressor against urothelial cancer of the bladder, bladder cancer-associated protein, was induced in butyrate-treated HT1376 cells, a human urinary bladder cancer cell line. In conclusion, urothelial cancer of the bladder is a significant health problem. To improve the health of bladder urothelial cells, supplementation of B. pullicaecorum may be necessary and can further regulate butyrate-responsive molecular signatures.

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Kim, Boram, Eun Ju Cho, Jung-Hwan Yoon, Soon Sun Kim, Jae Youn Cheong, Sung Won Cho i Taesung Park. "Pathway-Based Integrative Analysis of Metabolome and Microbiome Data from Hepatocellular Carcinoma and Liver Cirrhosis Patients". Cancers 12, nr 9 (21.09.2020): 2705. http://dx.doi.org/10.3390/cancers12092705.

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Aberrations of the human microbiome are associated with diverse liver diseases, including hepatocellular carcinoma (HCC). Even if we can associate specific microbes with particular diseases, it is difficult to know mechanistically how the microbe contributes to the pathophysiology. Here, we sought to reveal the functional potential of the HCC-associated microbiome with the human metabolome which is known to play a role in connecting host phenotype to microbiome function. To utilize both microbiome and metabolomic data sets, we propose an innovative, pathway-based analysis, Hierarchical structural Component Model for pathway analysis of Microbiome and Metabolome (HisCoM-MnM), for integrating microbiome and metabolomic data. In particular, we used pathway information to integrate these two omics data sets, thus providing insight into biological interactions between different biological layers, with regard to the host’s phenotype. The application of HisCoM-MnM to data sets from 103 and 97 patients with HCC and liver cirrhosis (LC), respectively, showed that this approach could identify HCC-related pathways related to cancer metabolic reprogramming, in addition to the significant metabolome and metagenome that make up those pathways.

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Hoyd, Rebecca, Caroline E. Wheeler, Samuel Coleman, Louis Denko, Carlos Chan, Yousef Zakharia, Rebecca Dodd i in. "Abstract 5907: The tumor microbiome associates with features of the tumor microenvironment, treatment outcomes, and histologies: A national collaboration of the exORIEN Consortium". Cancer Research 83, nr 7_Supplement (4.04.2023): 5907. http://dx.doi.org/10.1158/1538-7445.am2023-5907.

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Abstract A tumor microbiome has recently been established as present in many cancer types. Further study is needed to define the scope of its role in cancer tumorigenesis, progression, and treatment outcomes. The Oncology Research Information Exchange Network (ORIEN) established a collaboration among eight member institutions to study the tumor microbiome and clinical features across several cancers. We evaluated RNAseq data from n = 2,892 tumors, including colorectal adenocarcinomas, lung adeno- and squamous cell carcinomas, pancreatic adenocarcinomas, sarcomas, melanomas, and thyroid carcinomas, using the tool {exotic}. Matched cancers from the Cancer Genome Atlas were processed by the same method (n = 2,720 samples). Clinical data, including treatment information, lab values, detailed histology, and long-term follow-up, were collected and harmonized across sites. Microbe abundances (bacteria, fungi, and viruses) were associated with clinical features and human gene expression, which was deconvolved into immune cell composition using {CIBERSORT} and {TIMEx}, and aggregated into expression signatures using {tmesig} and {IOSig}. Microbes were found in all tumors and associated with treatment outcomes for all modalities tested, including radiation in colorectal cancer, chemotherapy in pancreatic cancer, and immunotherapy in melanoma. In the case of radiation treatment in colorectal cancer, the microbes also affected outcomes in preclinical model systems and were modified by altering hypoxia levels with the drug atovaquone. Virus prevalence associated with histological subtypes in lung cancer. Similar microbes in ORIEN and TCGA tumors associated with overall survival in subtypes of sarcoma (dedifferentiated liposarcoma, leiomyosarcoma, and others). Finally, microbes associated with expression-based indicators of the tumor microenvironment across cancer types. These results suggest that the tumor microbiome may have broad clinical utility as a biomarker of treatment outcomes and as a target for rational manipulation. Citation Format: Rebecca Hoyd, Caroline E. Wheeler, Samuel Coleman, Louis Denko, Carlos Chan, Yousef Zakharia, Rebecca Dodd, Cornelia M. Ulrich, Sheetal Hardikar, Jennifer Ose, Michelle Churchman, Ahmad Tarhini, Lary A. Robinson, Eric Singer, Alexandra P. Ikeguchi, Martin McCarter, Kyra Anderson, John Carpten, Gabriel Tinoco, Marium Hussain, Nicolas Denko, YunZhou Liu, Ning Jin, Youngchul Kim, Asgeir Masson, Naomi Fei, Martin Benej, McKenzie Kreamer, Dennis Dennis Grencewicz, Ahmed Hussein, Aik Choon Tan, Daniel Spakowicz. The tumor microbiome associates with features of the tumor microenvironment, treatment outcomes, and histologies: A national collaboration of the exORIEN Consortium. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5907.

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Spakowicz, Daniel, Rebecca Hoyd, Caroline E. Wheeler, Yousef Zakharia, Rebecca D. Dodd, Jennifer Ose, Sheetal Hardikar i in. "Pan-cancer analysis of exogenous (microbial) sequences in tumor transcriptome data from the ORIEN consortium and their association with cancer and tumor microenvironment." Journal of Clinical Oncology 40, nr 16_suppl (1.06.2022): 3113. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3113.

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3113 Background: The tumor microbiome holds great potential for its ability to characterize various aspects of cancer biology and as a target for rational manipulation. For many cancer types, little is known about the role of microbes and in what contexts they affect clinical outcomes. Non-human (i.e. exogenous) sequences can be observed in low abundance within high throughput sequencing data of tumors. Here, we describe a collaboration among members of The Oncology Research Information Exchange Network (ORIEN) to leverage tumor biopsy RNAseq data collected under a shared protocol and generated at a single site to better understand the tumor microbiome, its association with prognostic features of the tumor microenvironment (TME) such as hypoxia, and how it may be used to improve clinical outcomes. Methods: Tumor RNAseq samples from 10 primary source locations including the tissues colon, lung, pancreas, and skin from ORIEN and similar cancers from The Cancer Genome Atlas (TCGA) were processed through the exoTIC (exogenous sequencing in tumors and immune cells) pipeline to identify and count exogenous sequences, filter contaminants, and normalize across datasets. Gene expression signatures of the TME, such as hypoxia, were calculated using ‘tmesig’. Microbe relative abundances were modeled with primary tumor location and hypoxia score using a gamma-distributed generalized linear regression via the stats package in R. Results: We analyzed RNAseq data of 2892 and 2720 tumors from ORIEN and TCGA, respectively. Patients’ ages were significantly greater in the ORIEN than the TCGA dataset (62 vs 58 yo, t-test p<0.001). The ORIEN data contained more sarcoma samples than TCGA (n = 691 vs 259) with roughly equivalent numbers in other cancer types. Fewer microbes were significantly associated with the hypoxia score than with cancer type (n = 32 vs 210). This trend was observed in both the ORIEN and TCGA datasets. The largest effect sizes were observed between microbes and small cell lung cancer. Conclusions: We found microbial sequences in all ORIEN and TCGA tumor RNAseq samples tested. Cancer type showed more significant associations with microbes than a hypoxia signature. These observations merit further investigation into the interaction between microbes and the TME. [Table: see text]

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Pani, Giovambattista. "Fusobacterium & Co. at the Stem of Cancer: Microbe–Cancer Stem Cell Interactions in Colorectal Carcinogenesis". Cancers 15, nr 9 (30.04.2023): 2583. http://dx.doi.org/10.3390/cancers15092583.

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Adult stem cells lie at the crossroads of tissue repair, inflammation, and malignancy. Intestinal microbiota and microbe–host interactions are pivotal to maintaining gut homeostasis and response to injury, and participate in colorectal carcinogenesis. Yet, limited knowledge is available on whether and how bacteria directly crosstalk with intestinal stem cells (ISC), particularly cancerous stem-like cells (CR-CSC), as engines for colorectal cancer initiation, maintenance, and metastatic dissemination. Among several bacterial species alleged to initiate or promote colorectal cancer (CRC), the pathobiont Fusobacterium Nucleatum has recently drawn significant attention for its epidemiologic association and mechanistic linkage with the disease. We will therefore focus on current evidence for an F. nucleatum-CRCSC axis in tumor development, highlighting the commonalities and differences between F. nucleatum-associated colorectal carcinogenesis and gastric cancer driven by Helicobacter Pylori. We will explore the diverse facets of the bacteria–CSC interaction, analyzing the signals and pathways whereby bacteria either confer “stemness” properties to tumor cells or primarily target stem-like elements within the heterogeneous tumor cell populations. We will also discuss the extent to which CR-CSC cells are competent for innate immune responses and participate in establishing a tumor-promoting microenvironment. Finally, by capitalizing on the expanding knowledge of how the microbiota and ISC crosstalk in intestinal homeostasis and response to injury, we will speculate on the possibility that CRC arises as an aberrant repair response promoted by pathogenic bacteria upon direct stimulation of intestinal stem cells.

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Spakowicz, Daniel, Rebecca Hoyd, Caroline E. Wheeler, Nyelia Williams, Amna Bibi, Marium Husain, Srichandhana Rajamouli i in. "Abstract PR004: Older adult-specific microbes correlate with treatment response and markers of T-cell senescence in NSCLC". Cancer Research 83, nr 2_Supplement_1 (15.01.2023): PR004. http://dx.doi.org/10.1158/1538-7445.agca22-pr004.

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Abstract The gut microbiome changes with age and affects many aspects of human health, including response to cancer treatments. Cancer survival rates have improved with new treatment options, including immune checkpoint blockade (ICB); however, the objective response rate remains low. Manipulation of the microbiome is a promising approach to improving cancer outcomes, but the effect of age is understudied. Here, we sought to understand whether (1) specific microbes are associated with treatment response in older adults with non-small cell lung cancer (NSCLC) and (2) whether these microbes are the same as for younger adults. Next, we explored the causal effects of the microbiome on ICB response in mouse models and the relationship with blood-based markers of T-cell senescence. We conducted a prospective cohort study of adults ≥60 years with a new diagnosis of NSCLC who received any treatment modality. Stool was collected, and metagenomic whole-genome shotgun sequencing was performed. Blood T-cells were isolated, the RNA purified and then assessed for markers of senescence by nanostring. Response to treatment was determined by RECIST v1.1 criteria. Generalized linear regression was used to relate baseline microbiome abundances to treatment response and non-parametric correlations associated with CDKN2A (p16) expression to microbe abundances. To assess the causal role of the gut microbiome in ICB response, we gavaged gut microbiome samples from responders and non-responders into C57BL/6 mice to create human-microbiome avatar models. The mice were then injected with MC38 cancer cells and treated with anti-PD1 or isotype control antibodies, and tumor volume was measured over time. Biospecimens and best response data at three months were captured from 23 patients, of which five had a complete response, eight had a partial response, eight had stable disease, and two had progressive disease. Over 50 microbes were associated with a response after p-value adjustment. Responder stool was enriched for microbes associated with youth and ICB response (Bifidobacterium adolescentis, p = 2.64e-20). However, microbial taxa associated with response differed from those reported in younger populations (Firmicutes sp. CAG 145, p = 1.58e-20, Oscillibacter sp. 57-20, p = 7.96e-24). Stool from non-responders (NRs) was enriched in taxa previously linked to treatment-related toxicities and shorter progression-free survival (Streptococcus lutetiensis, p = 4.55E-24) but also contained microbes previously linked to response in younger adults (e.g., Roseburia sp. CAG 309, p = 5.16e-15). The T cell senescence marker, p16, correlated with the most enriched taxon in non-responders NRs (Streptococcus thermophilus, r = 0.45, p = 0.02), suggesting a connection between immune aging and the microbiome. Preliminary fecal transplant studies in mice showed improved ICB response in mice engrafted with stool from responders versus non-responders. Together, these data identify potential differences in the gut microbiomes of young and older adult NSCLC patients who respond to ICB. Citation Format: Daniel Spakowicz, Rebecca Hoyd, Caroline E. Wheeler, Nyelia Williams, Amna Bibi, Marium Husain, Srichandhana Rajamouli, Shankar Suman, Joseph Amann, Madison Grogan, Pooja Vibhakar, Dwight H. Owen, David P. Carbone, Ashley Rosko, Christin E. Burd, Carolyn J. Presley. Older adult-specific microbes correlate with treatment response and markers of T-cell senescence in NSCLC [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR004.

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Williams, Nyelia, Rebecca Hoyd, Caroline E. Wheeler, Mari Lynn, Amna Bibi, Shannon Gray, Michael Bodner i in. "The effect of the microbiome on immune checkpoint inhibitor toxicity in patients with melanoma." Journal of Clinical Oncology 40, nr 16_suppl (1.06.2022): 9568. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.9568.

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9568 Background: Immune-checkpoint inhibitor (ICI) immunotherapy has increased survival in patients with melanoma. However, only half of the patients respond, and many experience immune-related adverse events (irAEs). Recent evidence suggests that modification of the gut microbiome may increase response to ICIs and decrease toxicity. Here we describe the first results of a clinical trial to determine if the microbiome can predict the response or toxicity during the first 16 weeks of ICI treatment. Methods: We enrolled patients aged 18 or older in a prospective observational cohort study at The Ohio State University Comprehensive Cancer Center Skin Cancer Clinic (OSUCCC-SCC) who were to receive treatment with pembrolizumab or nivolumab alone or in combination with other treatments (e.g. nivolumab and ipilimumab) for melanoma. Patients receiving systemic or oral corticosteroids at the start of ICI cycle 1 were excluded but were eligible if receiving adrenal physiologic replacement. Patients collected stool samples at baseline, within 2 days of an adverse event (if applicable), and at 12 weeks. The response to ICIs was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) at a 12-week computed tomography scan. Metagenomic whole-genome shotgun sequencing was performed on an Illumina NovaSeq 6000 and then classified using HUMAnN3. The effect of microbe relative abundances on potential irAEs was modeled by logistic regression with the R package glmm. Results: In total, 88 patients consented to the trial. Pre-treatment microbiome samples were collected from 49 patients. Potential irAEs were observed in 16 out of the 49 patients for whom pre-treatment microbiome samples were collected. There was no significant difference in the ages (p = 0.150, genders (p = 0.2), stages (p = 0.2) or treatments (p = 0.07) of those who developed potential irAEs. Pretreatment abundance of the family Ruminococaceae was most strongly associated with the development of a potential irAE (p = 0.03), followed by a taxon in an unclassified order within the phylum Firmicutes (p = 0.05). The family Bacteroidaceae was most strongly associated with no potential irAE (p = 0.05). Conclusions: Longitudinal and event-driven biospecimen collection in the context of treatment with immunotherapies was feasible in the OSUCCC-SCC. The abundance of the two high-taxonomic rank microbe groups was significantly associated with potential irAEs. The association with Ruminococaceae is consistent with previous studies where it was associated with response to ICIs and, in separate studies, development of an irAE was associated with a better response. The unclassified taxon is potentially a new biomarker for the prediction of toxicity and a therapeutic target to reduce treatment side effects. Future analyses will associate microbes with treatment response and test for consistent microbiome changes at the time of irAE development. Clinical trial information: NCT05102773.

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Luo, Wenhao, Zhe Cao, Jiangdong Qiu, Yueze Liu, Lianfang Zheng i Taiping Zhang. "Novel Discoveries Targeting Pathogenic Gut Microbes and New Therapies in Pancreatic Cancer: Does Pathogenic E. coli Infection Cause Pancreatic Cancer Progression Modulated by TUBB/Rho/ROCK Signaling Pathway? A Bioinformatic Analysis". BioMed Research International 2020 (11.05.2020): 1–12. http://dx.doi.org/10.1155/2020/2340124.

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Pancreatic cancer (PC) is a pernicious cancer of the digestive system which remains a high degree of malignancy. Increasing studies demonstrated that regulating the gut microbiome may become a brand new strategy to improve the therapeutic outcomes of PC. This study is aimed at obtaining the pathway in the microbial tumorigenesis of PC. Microarray datasets GSE27890, GSE46234, and GSE17610 were downloaded from the GEO (Gene Expression Omnibus) database. Differential analysis was performed for every single gene chip using the R software package (“Limma” package), and functional enrichment analyses were carried out by DAVID (Database for Annotation, Visualization and Integrated Discovery). The PPI (protein-protein interaction) network was constructed with the Search Tool for the Retrieval of Interacting Genes (STRING). The survival analysis was performed by GEPIA and USCS. A total of 84 differentially expressed genes (DEGs) were identified, and 3 of them were extracted (TUBB, TUBA4A, and TLR5). Biological process analysis revealed that these 3 genes were mainly enriched in pathogenic Escherichia coli (E. coli) infection. Survival analysis and pathway analysis revealed that TUBB (tubulin, beta class I) may be associated with the pathogenic E. coli infection, which may be involved in the carcinogenesis and progression of PC by activating the TUBB/Rho/ROCK signaling pathway. Elevated evidence indicated that a specific gut microbe could affect the progression of PC by suppressing immune response. However, little attention has been paid to the relationship and crosstalk between TUBB/Rho/ROCK signaling, microbes, and PC. This article is aimed at deducing that gut and tumor microbes are related to the development of PC by stimulating TUBB/Rho/ROCK signaling, while ablation of microbes by antibiotics cotreated with inhibitors of TUBB/Rho/ROCK signaling were identified as a novel target for PC therapy.

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Vadhwana, Bhamini, Munir Tarazi, Piers R. Boshier i George B. Hanna. "Evaluation of the Oesophagogastric Cancer-Associated Microbiome: A Systematic Review and Quality Assessment". Cancers 15, nr 10 (9.05.2023): 2668. http://dx.doi.org/10.3390/cancers15102668.

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Objective. Oesophagogastric cancer is the fifth most common cancer worldwide, with poor survival outcomes. The role of bacteria in the pathogenesis of oesophagogastric cancer remains poorly understood. Design. A systematic search identified studies assessing the oesophagogastric cancer microbiome. The primary outcome was to identify bacterial enrichment specific to oesophagogastric cancer. Secondary outcomes included appraisal of the methodology, diagnostic performance of cancer bacteria and the relationship between oral and tissue microbiome. Results. A total of 9295 articles were identified, and 87 studies were selected for analysis. Five genera were enriched in gastric cancer: Lactobacillus, Streptococcus, Prevotella, Fusobacterium and Veillonella. No clear trends were observed in oesophageal adenocarcinoma. Streptococcus, Prevotella and Fusobacterium were abundant in oesophageal squamous cell carcinoma. Functional analysis supports the role of immune cells, localised inflammation and cancer-specific pathways mediating carcinogenesis. STORMS reporting assessment identified experimental deficiencies, considering batch effects and sources of contamination prevalent in low-biomass samples. Conclusions. Functional analysis of cancer pathways can infer tumorigenesis within the cancer–microbe–immune axis. There is evidence that study design, experimental protocols and analytical techniques could be improved to achieve more accurate and representative results. Whole-genome sequencing is recommended to identify key metabolic and functional capabilities of candidate bacteria biomarkers.

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Oliva, Marc, Nuria Mulet-Margalef, Maria Ochoa-De-Olza, Stefania Napoli, Joan Mas, Berta Laquente, Laia Alemany, Eric Duell, Paolo Nuciforo i Victor Moreno. "Tumor-Associated Microbiome: Where Do We Stand?" International Journal of Molecular Sciences 22, nr 3 (1.02.2021): 1446. http://dx.doi.org/10.3390/ijms22031446.

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The study of the human microbiome in oncology is a growing and rapidly evolving field. In the past few years, there has been an exponential increase in the number of studies investigating associations of microbiome and cancer, from oncogenesis and cancer progression to resistance or sensitivity to specific anticancer therapies. The gut microbiome is now known to play a significant role in antitumor immune responses and in predicting the efficacy of immune-checkpoint inhibitors in cancer patients. Beyond the gut, the tumor-associated microbiome—microbe communities located either in the tumor or within its body compartment—seems to interact with the local microenvironment and the tumor immune contexture, ultimately impacting cancer progression and treatment outcome. However, pre-clinical research focusing on causality and mechanistic pathways as well as proof-of-concept studies are still needed to fully understand the potential clinical utility of microbiome in cancer patients. Moreover, there is a need for the standardization of methodology and the implementation of quality control across microbiome studies to allow for a better interpretation and greater comparability of the results reported between them. This review summarizes the accumulating evidence in the field and discusses the current and upcoming challenges of microbiome studies.

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Cavallucci, Virve, Ivana Palucci, Marco Fidaleo, Antonella Mercuri, Letizia Masi, Valeria Emoli, Giada Bianchetti i in. "Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells". Biomolecules 12, nr 9 (7.09.2022): 1256. http://dx.doi.org/10.3390/biom12091256.

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Intestinal bacterial communities participate in gut homeostasis and are recognized as crucial in bowel inflammation and colorectal cancer (CRC). Fusobacterium nucleatum (Fn), a pathobiont of the oral microflora, has recently emerged as a CRC-associated microbe linked to disease progression, metastasis, and a poor clinical outcome; however, the primary cellular and/or microenvironmental targets of this agent remain elusive. We report here that Fn directly targets putative colorectal cancer stem cells (CR-CSCs), a tumor cell subset endowed with cancer re-initiating capacity after surgery and chemotherapy. A patient-derived CSC line, highly enriched (70%) for the stem marker CD133, was expanded as tumor spheroids, dissociated, and exposed in vitro to varying amounts (range 100–500 MOI) of Fn. We found that Fn stably adheres to CSCs, likely by multiple interactions involving the tumor-associated Gal-GalNac disaccharide and the Fn-docking protein CEA-family cell adhesion molecule 1 (CEACAM-1), robustly expressed on CSCs. Importantly, Fn elicited innate immune responses in CSCs and triggered a growth factor-like, protein tyrosine phosphorylation cascade largely dependent on CEACAM-1 and culminating in the activation of p42/44 MAP kinase. Thus, the direct stimulation of CSCs by Fn may contribute to microbiota-driven colorectal carcinogenesis and represent a target for innovative therapies.

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Williams, Nyelia, Caroline E. Wheeler, Marium Husain, Rebecca Hoyd, Alexa Simon Meara, Mari Lynn, Amna Bibi i in. "De-correlating immune checkpoint inhibitor toxicity and response in melanoma via the microbiome." Journal of Clinical Oncology 41, nr 16_suppl (1.06.2023): 9569. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.9569.

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9569 Background: Immune-checkpoint inhibitor (ICI) immunotherapy increases survival in patients with melanoma. Yet only half of the patients respond, and 10-40% of patients experience immune-related adverse events (irAEs). Previous studies have found a correlation between the development of an irAE and treatment response. Modifying the gut microbiome could positively affect response to ICIs and reduce toxicities. We sought to determine if the microbiome at the onset of treatment, during an irAE, and at 12 weeks, can predict the response or toxicity during ICI treatment for metastatic melanoma. Methods: Melanoma patients (pts) > 18 yo treated with ICI enrolled in a prospective observational cohort study at The Ohio State University Comprehensive Cancer Center Skin Cancer Clinic. Excluded were patients on corticosteroids at the start of ICI cycle 1, except for adrenal physiologic replacement. Stools were collected at baseline, within 2 days of an adverse event assessed by physician chart review using CTCAE (Common Terminology Criteria for Adverse Events) v5.0, and at 12 weeks. Response (ORR) to ICIs was assessed by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) q12 weeks and progression-free survival recorded. Metagenomic whole-genome shotgun sequencing was performed on an Illumina NovaSeq 6000 and classified using HUMAnN3. The effect of microbe relative abundances on irAEs was modeled by logistic regression with the R package glmm. Results: Of the 88 patients enrolled, 48 had metastatic disease with 32 assessable for response. ORR at 12 weeks was 28% (1 CR, 8 PR, 17 SD, and 6 PD) and 24 patients showed PFS at 12 months. Grade > 2 irAEs were observed in 11/48 pts. Abundance of Bacteroides dorei (False Discovery Rate Corrected p-value = 9.5E-07) and Blautia species CAG:257 (padj = 0.001) were enriched in responders, Prevotella Stercorea (padj = 1.1E-07) and a phage with a predicted target of Salmonella (padj = 8.3E-09) in non-responders. Responders with an irAE had enrichment of Bacteroides plebeius (padj = 4.2E-13) and Bacteroides coprophilus (padj = 0.0002) whereas responders without irAE had enrichment of Eubacterium siraeum (padj = 7.2E-05). Conclusions: Longitudinal and event-driven biospecimen collection in patients treated with ICIs showed several bacteria and viruses but no fungi associated with response, with and without the development of an irAE. The abundance of the two high-taxonomic rank microbe groups is significantly associated with irAEs. The association with the Bacteroides Genus is consistent with previous studies and is associated with response to ICIs. A microbiome abundant in Bacteroides and lacking Prevotella is associated with response to ICI. An abundance of Bacteroides could be a biomarker for irAEs, and an abundance of Eubacterium, a biomarker for response without irAEs. Future analyses are necessary to assign causal roles for microbe biomarkers with specific irAEs. Clinical trial information: NCT05102773 .

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Wheeler, Caroline E., Samuel Coleman, Rebecca Hoyd, Afaf Osman, Louis Denko, Aik Choon Tan, Daniel Spakowicz i Ahmad Tarhini. "Abstract 5904: Intra-tumor microbes identified by RNAseq associated with response to immune checkpoint blockade in metastatic melanoma". Cancer Research 83, nr 7_Supplement (4.04.2023): 5904. http://dx.doi.org/10.1158/1538-7445.am2023-5904.

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Abstract The tumor microbiome has recently been shown to play a key role in the context of oncogenesis, cancer immune phenotype, cancer progression and treatment outcomes in a variety of cancers. We investigated the possible associations between tumor microbiome and successful treatment outcomes with immune checkpoint blockade (ICB) in patients with metastatic melanoma. We evaluated RNAseq from tumor samples, collected prior to the start of treatment with ICB, from 71 patients with metastatic melanoma. Samples were provided by eight members of the Oncology Research Information Exchange Network (ORIEN). Non-response was determined as change in treatment after less than 12 months. Patients maintaining the same treatment regimen for greater than 12 months were classified as responders. We applied our custom tool, {exotic} (Exogenous sequences in Tumor and Immune Cells), to carefully identify non-human sequences within the RNAseq data. After filtering reads aligning to the human reference genome, reads were further filtered of common laboratory contaminants, taxa inversely correlated with input RNA quantity, and taxa frequently found in the negative controls of microbiome experiments. A differential abundance analysis was performed on the response groups at every taxonomic level utilizing DESeq2. We calculated expression signatures using {tmesig}, and related them to ICB response using {IOSig}. We observed significantly enriched taxa (p-value < 0.05) with a high (>1.00) fold-difference in abundance between responders and non-responders found within the tumor RNAseq data, including Fusobacterium nucleatum and several viruses in responders, and Delftia lacustris and Fungi in non-responders. These microbes were associated with immune cell expression signatures, including Th17 cells and CD8+ T-cells. We calculated the gene expression scores of 30 signatures with literature precedence for the ability to predict ICB treatment outcomes in melanoma. The receiver operator characteristic (ROC) curve of the random forest classification model for prediction of response to ICB using the combined expression signature scores resulted in an AUC of 0.8750. Combining expression signature scores with microbe relative abundances at the genus level improved the ability to predict ICB response (AUC = 0.8958). Combining tumor expression signatures with curated tumor microbiome relative abundances improves the performance of predictive models for treatment outcomes with ICB in melanoma. Citation Format: Caroline E. Wheeler, Samuel Coleman, Rebecca Hoyd, Afaf Osman, Louis Denko, Aik Choon Tan, Daniel Spakowicz, Ahmad Tarhini. Intra-tumor microbes identified by RNAseq associated with response to immune checkpoint blockade in metastatic melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5904.

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Nandi, Deeptashree, Sheetal Parida, Sowjanya Thatikonda, Jackson Foley, Tracy Stewart, Cynthia L. Sears, Robert A. Casero i Dipali Sharma. "Abstract 5905: Enterotoxigenic Bacteroides fragilis, a colon microbe, dysregulates polyamine catabolism to promote breast cancer progression". Cancer Research 83, nr 7_Supplement (4.04.2023): 5905. http://dx.doi.org/10.1158/1538-7445.am2023-5905.

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Abstract Background: With more than 2.3 million cases worldwide, breast cancer persists as a major health burden and warrants a greater understanding of the molecular triggers underlying this disease. Focusing on microbial dysbiosis, our lab discovered the pivotal role of the enterotoxigenic Bacteroides fragilis (ETBF) in promoting breast tumorigenesis through activation of key oncogenic pathways. A gap in knowledge exists regarding how microbes/microbial toxins modulate the oncogenic pathways in cancer cells. Polyamines are imperative for various physiological processes, including cell growth, survival, differentiation and apoptosis and are strongly associated with breast cancer. We questioned the involvement of polyamine pathway in mediating the oncogenic effects of microbial dysbiosis on breast cancer. Methods: Human Her2 expressing spontaneous breast cancer model, MMTV.f.HuHer2 mice, were infected with ETBF and tumor incidence and progression were monitored for 18 months. We used qRT-PCR, western blotting, immunocytochemistry and immunohistochemistry to examine expression of key nodes of polyamine pathway. Various growth, migration and invasion assays were performed to assess carcinogenic properties in breast cancer cells. We employed a colorimetric-based assay to analyze enzymatic activities of key polyamine metabolic members. ROS generation was examined via DCFA staining. Results: Our in vivo data showed that ETBF colonization in mice led to a considerable increase in the level of spermine oxidase (SMOX) in breast tumors, hinting at a correlation between ETBF and polyamine metabolism. Moreover, a marked rise in expression of γH2AX foci was observed in these tumors and in breast cancer cells, suggesting a critical role of ETBF in SMOX-related DNA damage. In agreement, we found SMOX upregulation in breast cancer cells. Our findings displayed a substantial increase in SMOX enzymatic activity in the presence of ETBF toxin, BFT, in breast tumor cells. BFT caused a marked rise in ROS generation of breast tumor cells, suggesting a plausible association of ETBF in SMOX-mediated oxidative stress. Interestingly, we noted a significant induction of ornithine decarboxylase (ODC) expression and activity in response to ETBF or BFT in breast cancer cells. Treatment of BFT-exposed breast cancer cells with SMOX inhibitors led to a sharp inhibition of neoplastic transformations, like cellular migration and γH2AX induction. Conclusion: Our collated evidences suggest the existence of an important cross-talk between key polyamine metabolic enzymes and ETBF that aids in exacerbating breast tumorigenesis. Of importance, therapeutic inhibition of SMOX dramatically impeded BFT-related breast tumorigenesis. Collectively, our results demonstrated the attractive potential of intervening the polyamine catabolic pathway for the management of breast cancer. Citation Format: Deeptashree Nandi, Sheetal Parida, Sowjanya Thatikonda, Jackson Foley, Tracy Stewart, Cynthia L. Sears, Robert A. Casero, Dipali Sharma. Enterotoxigenic Bacteroides fragilis, a colon microbe, dysregulates polyamine catabolism to promote breast cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5905.

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Yusuf, Kafayat, Venkatesh Sampath i Shahid Umar. "Bacterial Infections and Cancer: Exploring This Association And Its Implications for Cancer Patients". International Journal of Molecular Sciences 24, nr 4 (4.02.2023): 3110. http://dx.doi.org/10.3390/ijms24043110.

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Bacterial infections are common in the etiology of human diseases owing to the ubiquity of bacteria. Such infections promote the development of periodontal disease, bacterial pneumonia, typhoid, acute gastroenteritis, and diarrhea in susceptible hosts. These diseases may be resolved using antibiotics/antimicrobial therapy in some hosts. However, other hosts may be unable to eliminate the bacteria, allowing them to persist for long durations and significantly increasing the carrier's risk of developing cancer over time. Indeed, infectious pathogens are modifiable cancer risk factors, and through this comprehensive review, we highlight the complex relationship between bacterial infections and the development of several cancer types. For this review, searches were performed on the PubMed, Embase, and Web of Science databases encompassing the entirety of 2022. Based on our investigation, we found several critical associations, of which some are causative: Porphyromonas gingivalis and Fusobacterium nucleatum are associated with periodontal disease, Salmonella spp., Clostridium perfringens, Escherichia coli, Campylobacter spp., and Shigella are associated with gastroenteritis. Helicobacter pylori infection is implicated in the etiology of gastric cancer, and persistent Chlamydia infections present a risk factor for the development of cervical carcinoma, especially in patients with the human papillomavirus (HPV) coinfection. Salmonella typhi infections are linked with gallbladder cancer, and Chlamydia pneumoniae infection is implicated in lung cancer, etc. This knowledge helps identify the adaptation strategies used by bacteria to evade antibiotic/antimicrobial therapy. The article also sheds light on the role of antibiotics in cancer treatment, the consequences of their use, and strategies for limiting antibiotic resistance. Finally, the dual role of bacteria in cancer development as well as in cancer therapy is briefly discussed, as this is an area that may help to facilitate the development of novel microbe-based therapeutics as a means of securing improved outcomes.

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Zeng, Huawei, Shahid Umar, Bret Rust, Darina Lazarova i Michael Bordonaro. "Secondary Bile Acids and Short Chain Fatty Acids in the Colon: A Focus on Colonic Microbiome, Cell Proliferation, Inflammation, and Cancer". International Journal of Molecular Sciences 20, nr 5 (11.03.2019): 1214. http://dx.doi.org/10.3390/ijms20051214.

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Secondary bile acids (BAs) and short chain fatty acids (SCFAs), two major types of bacterial metabolites in the colon, cause opposing effects on colonic inflammation at chronically high physiological levels. Primary BAs play critical roles in cholesterol metabolism, lipid digestion, and host–microbe interaction. Although BAs are reabsorbed via enterohepatic circulation, primary BAs serve as substrates for bacterial biotransformation to secondary BAs in the colon. High-fat diets increase secondary BAs, such as deoxycholic acid (DCA) and lithocholic acid (LCA), which are risk factors for colonic inflammation and cancer. In contrast, increased dietary fiber intake is associated with anti-inflammatory and anticancer effects. These effects may be due to the increased production of the SCFAs acetate, propionate, and butyrate during dietary fiber fermentation in the colon. Elucidation of the molecular events by which secondary BAs and SCFAs regulate colonic cell proliferation and inflammation will lead to a better understanding of the anticancer potential of dietary fiber in the context of high-fat diet-related colon cancer. This article reviews the current knowledge concerning the effects of secondary BAs and SCFAs on the proliferation of colon epithelial cells, inflammation, cancer, and the associated microbiome.

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Banerjee, Anik, Christina Roland, Sarah Johnson, Nadim Ajami i Jennifer Wargo. "Abstract 5906: Gut microbiota signatures are associated with immunotherapy induced cognitive decline and neurotoxicity". Cancer Research 83, nr 7_Supplement (4.04.2023): 5906. http://dx.doi.org/10.1158/1538-7445.am2023-5906.

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Abstract Studies have demonstrated promising outcomes of combined immune checkpoint blockade (CICB) modulating tumor cytotoxicity via targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 (PD-1). The emergence of long-term patient management has been transformed among health care professionals as patient survival rates are increasing significantly. Despite promising advances, patient outcomes are heterogenic and are correlative to host intrinsic and extrinsic factors. Multiple reports have highlighted the negative effects of cancer treatments towards inducing cognitive impairment and neurotoxicity often referred to as “chemofog”. More recently, the gut microbiome has been increasingly recognized to regulate antitumor immunity and further distinct microbiome signatures can confer favorable outcomes in the context of CICB. Interestingly, specific microbes within the gut microbiome have been shown to regulate social behavior and cognition via the bidirectional communication along the gut-brain axis though changes in microbiota-derived metabolites and vagal afferent fibers. Insights into mechanisms of immunotherapy induced cognitive decline are warranted. Thus, we hypothesize CICB exacerbates cognitive impairment and neurotoxicity via the detrimental alterations to the gut microbiome. To address this, we profiled the gut microbiome, through 16S rRNA gene and metagenomic sequencing of fecal samples from patients (n=146) with advanced melanoma treated with CICB stratified based on severity of cognitive dissonance. Beta-diversity, incorporating weighted UniFrac distances by principal coordinate analysis (PCoA), revealed a cluster of samples from patients with cognitive impairment as compared to samples from those with minimal to absent cognitive decline. Further, taxonomical analysis showed significant alterations in relative abundances of microbial candidates (e.g., L. intestinalis, A. muciniphila, F. prausnitizii, and R. hominis). These results suggests that CICB patients with cognitive impairments and neurotoxicity have altered microbiome signatures which may potentially exacerbate downstream neuroinflammatory signaling. Further studies investigating specific host-microbe pathways and profiling microbiota-derived metabolites which are implicated in these detrimental effects are essential for biomarker discovery and mechanistic insight. Citation Format: Anik Banerjee, Christina Roland, Sarah Johnson, Nadim Ajami, Jennifer Wargo. Gut microbiota signatures are associated with immunotherapy induced cognitive decline and neurotoxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5906.

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Rodríguez, Eduardo Lemuel Tosado, Anelisse Dominicci-Maura, Loyda Mendez, Stephanie Dorta, Josefina Romaguera i Filipa Godoy-Vitorino. "Abstract 712: Cytokine and TGF-β levels are associated with changes in cervicovaginal microbiota in a cohort of Caribbean women". Cancer Research 82, nr 12_Supplement (15.06.2022): 712. http://dx.doi.org/10.1158/1538-7445.am2022-712.

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Abstract Recent studies suggest that the cervical microbiome can strongly influence inflammation and pre-cancerous lesion progression. However, research focused on understanding the role of microbial communities in the progression of pre-cancerous lesions to cancer in Latino women is scarce. We aimed to investigate the relationship between the cervicovaginal microbiome and inflammation while considering cervical neoplasia and HPV infection in Puerto Rican women. We collected cervical swabs and lavages from 142 participants coming to colposcopy clinics in San Juan, Puerto Rico. Genomic DNA was extracted from swabs, and 16S rDNA V4 region genes were amplified and sequenced by Illumina MiSeq. Inflammatory (IL-1β, TNFa, IFNg, IL-6), anti-inflammatory (IL-4, IL-10, TGFβ1), and trafficking (IL-8, MIP1a, MCP1, IP10) cytokines were measured from cervical lavages, using Luminex MAGPIX technology. Cytokines were related to microbes via an inflammation scoring index based on the quartile and tercile distribution of the cytokine’s concentration. IL-10 (p value= 0.0455) was significantly different when evaluating HPV risk, while IL1-β (p value= 0.0005) and INF-γ (p value= 0.0258) were significant when evaluating cervical disease. We found significant differences in diversity and composition of the microbiota among HPV risk, cervical disease, pro-inflammatory, anti-inflammatory, and trafficking cytokine abundances. The increasing concentration of IL1-β, IL-10, and INF-γ, associated with a decrease in Lactobacillus communities. While contrarily, bacteria associated with dysbiosis such as Gardnerella, Prevotella, Atopobium increased. This study also revealed that the most dominant community state types (CST) among Puerto Rican women regardless of lesion or HPV status, are CST3 and 4 featuring high diversity and anaerobic bacteria typical of vaginosis in Caucasians. These CSTs are especially abundant with ~ 90% dominance in participants with high grade disease (HGSIL) and high-risk HPV. Our study evidence that the cervical microbiota of Puerto Ricans is characteristically diverse and that the joint host-microbe interaction analyses via cytokine signaling and microbiota in pre-cancerous lesions has great translational potential. Citation Format: Eduardo Lemuel Tosado Rodríguez, Anelisse Dominicci-Maura, Loyda Mendez, Stephanie Dorta, Josefina Romaguera, Filipa Godoy-Vitorino. Cytokine and TGF-β levels are associated with changes in cervicovaginal microbiota in a cohort of Caribbean women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 712.

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Panneerselvam, Janani, Venkateshwar Madka, Rajani Rai, Katherine T. Morris, Courtney W. Houchen, Parthasarathy Chandrakesan i Chinthalapally V. Rao. "Inflammatory Mediators and Gut Microbial Toxins Drive Colon Tumorigenesis by IL-23 Dependent Mechanism". Cancers 13, nr 20 (14.10.2021): 5159. http://dx.doi.org/10.3390/cancers13205159.

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Obesity-associated chronic inflammation predisposes colon cancer risk development. Interleukin-23 (IL-23) is a potential inflammatory mediator linking obesity to chronic colonic inflammation, altered gut microbiome, and colon carcinogenesis. We aimed to elucidate the role of pro-inflammatory eicosanoids and gut bacterial toxins in priming dendritic cells and macrophages for IL-23 secretion to promote colon tumor progression. To investigate the association of IL-23 with obesity and colon tumorigenesis, we utilized TCGA data set and colonic tumors from humans and preclinical models. To understand IL-23 production by inflammatory mediators and gut microbial toxins, we performed several in vitro mechanistic studies to mimic the tumor microenvironment. Colonic tumors were utilized to perform the ex vivo experiments. Our findings showed that IL-23 is elevated in obese individuals, colonic tumors and correlated with reduced disease-free survival. In vitro studies showed that IL-23 treatment increased the colon tumor cell self-renewal, migration, and invasion while disrupting epithelial barrier permeability. Co-culture experiments of educated dendritic cells/macrophages with colon cancer cells significantly increased the tumor aggression by increasing the secretory levels of IL-23, and these observations are further supported by ex vivo rat colonic tumor organotypic experiments. Our results demonstrate gut microbe toxins and eicosanoids facilitate IL-23 production, which plays an important role in obesity-associated colonic tumor progression. This newly identified nexus represents a potential target for the prevention and treatment of obesity-associated colon cancer.

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Holmes, Laurens, Jasmine Rios, Betyna Berice, Jacqueline Benson, Nastocia Bafford, Kadedrah Parson i Daniel Halloran. "Predictive Effect of Helicobacter pylori in Gastric Carcinoma Development: Systematic Review and Quantitative Evidence Synthesis". Medicines 8, nr 1 (5.01.2021): 1. http://dx.doi.org/10.3390/medicines8010001.

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Helicobacter pylori (H. pylori) is a bacterial pathogen implicated in gastritis, gastric ulceration, and gastric carcinoma. This study aimed to synthesize literature in providing evidence on the causative role of H. pylori in gastric carcinoma development. This study is based on assessing public literature using an applied meta-analysis, namely, quantitative evidence synthesis (QES). The analytic procedure uses DerSimonian-Laird, including assessing heterogeneity. The QES also utilizes meta-regression and the environmental effect associated with H. pylori in gastric cancer development. Eighteen studies are included in the QES. There is increased prevalence of H. pylori exposure among the cases. The heterogeneity between the CES and individual effect sizes is also significant. Despite controlling for the confoundings, there is increased exposure to H. pylori among the gastric cancer cases, regardless of the differences in the geographic location. H. pylori in this synthesized literature illustrates the contributory role of this microbe in gastric carcinoma. Additionally, regardless of geographic locale, namely, South Korea or Spain, H. pylori is implicated in gastric cancer development.

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Shi, Zhongcheng, Robert S. Fultz, Melinda A. Engevik, Chunxu Gao, Anne Hall, Angela Major, Yuko Mori-Akiyama i James Versalovic. "Distinct roles of histamine H1- and H2-receptor signaling pathways in inflammation-associated colonic tumorigenesis". American Journal of Physiology-Gastrointestinal and Liver Physiology 316, nr 1 (1.01.2019): G205—G216. http://dx.doi.org/10.1152/ajpgi.00212.2018.

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Inflammatory bowel disease (IBD) is a well-known risk factor for the development of colorectal cancer. Prior studies have demonstrated that microbial histamine can ameliorate intestinal inflammation in mice. We tested the hypothesis whether microbe-derived luminal histamine suppresses inflammation-associated colon cancer in Apcmin/+ mice. Mice were colonized with the human-derived Lactobacillus reuteri. Chronic inflammation was induced by repeated cycles of low-dose dextran sulfate sodium (DSS). Mice that were given histamine-producing L. reuteri via oral gavage developed fewer colonic tumors, despite the presence of a complex mouse gut microbiome. We further demonstrated that administration of a histamine H1-receptor (H1R) antagonist suppressed tumorigenesis, while administration of histamine H2-receptor (H2R) antagonist significantly increased both tumor number and size. The bimodal functions of histamine include protumorigenic effects through H1R and antitumorigenic effects via H2R, and these results were supported by gene expression profiling studies on tumor specimens of patients with colorectal cancer. Greater ratios of gene expression of H2R ( HRH2) vs. H1R ( HRH1) were correlated with improved overall survival outcomes in patients with colorectal cancer. Additionally, activation of H2R suppressed phosphorylation of mitogen-activated protein kinases (MAPKs) and inhibited chemokine gene expression induced by H1R activation in colorectal cancer cells. Moreover, the combination of a H1R antagonist and a H2R agonist yielded potent suppression of lipopolysaccharide-induced MAPK signaling in macrophages. Given the impact on intestinal epithelial and immune cells, simultaneous modulation of H1R and H2R signaling pathways may be a promising therapeutic target for the prevention and treatment of inflammation-associated colorectal cancer. NEW & NOTEWORTHY Histamine-producing Lactobacillus reuteri can suppress development of inflammation-associated colon cancer in an established mouse model. The net effects of histamine may depend on the relative activity of H1R and H2R signaling pathways in the intestinal mucosa. Our findings suggest that treatment with H1R or H2R antagonists could yield opposite effects. However, by harnessing the ability to block H1R signaling while stimulating H2R signaling, novel strategies for suppression of intestinal inflammation and colorectal neoplasia could be developed.

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Parisi, Alessandro, Giampiero Porzio, Fanny Pulcini, Katia Cannita, Corrado Ficorella, Vincenzo Mattei i Simona Delle Monache. "What Is Known about Theragnostic Strategies in Colorectal Cancer". Biomedicines 9, nr 2 (1.02.2021): 140. http://dx.doi.org/10.3390/biomedicines9020140.

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Despite the paradigmatic shift occurred in recent years for defined molecular subtypes in the metastatic setting treatment, colorectal cancer (CRC) still remains an incurable disease in most of the cases. Therefore, there is an urgent need for new tools and biomarkers for both early tumor diagnosis and to improve personalized treatment. Thus, liquid biopsy has emerged as a minimally invasive tool that is capable of detecting genomic alterations from primary or metastatic tumors, allowing the prognostic stratification of patients, the detection of the minimal residual disease after surgical or systemic treatments, the monitoring of therapeutic response, and the development of resistance, establishing an opportunity for early intervention before imaging detection or worsening of clinical symptoms. On the other hand, preclinical and clinical evidence demonstrated the role of gut microbiota dysbiosis in promoting inflammatory responses and cancer initiation. Altered gut microbiota is associated with resistance to chemo drugs and immune checkpoint inhibitors, whereas the use of microbe-targeted therapies including antibiotics, pre-probiotics, and fecal microbiota transplantation can restore response to anticancer drugs, promote immune response, and therefore support current treatment strategies in CRC. In this review, we aim to summarize preclinical and clinical evidence for the utilization of liquid biopsy and gut microbiota in CRC.

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Cavadas, Bruno, Rui Camacho, Joana C. Ferreira, Rui M. Ferreira, Ceu Figueiredo, Alvis Brazma, Nuno A. Fonseca i Luísa Pereira. "Gastric Microbiome Diversities in Gastric Cancer Patients from Europe and Asia Mimic the Human Population Structure and Are Partly Driven by Microbiome Quantitative Trait Loci". Microorganisms 8, nr 8 (6.08.2020): 1196. http://dx.doi.org/10.3390/microorganisms8081196.

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The human gastrointestinal tract harbors approximately 100 trillion microorganisms with different microbial compositions across geographic locations. In this work, we used RNASeq data from stomach samples of non-disease (164 individuals from European ancestry) and gastric cancer patients (137 from Europe and Asia) from public databases. Although these data were intended to characterize the human expression profiles, they allowed for a reliable inference of the microbiome composition, as confirmed from measures such as the genus coverage, richness and evenness. The microbiome diversity (weighted UniFrac distances) in gastric cancer mimics host diversity across the world, with European gastric microbiome profiles clustering together, distinct from Asian ones. Despite the confirmed loss of microbiome diversity from a healthy status to a cancer status, the structured profile was still recognized in the disease condition. In concordance with the parallel host-bacteria population structure, we found 16 human loci (non-synonymous variants) in the European-descendent cohorts that were significantly associated with specific genera abundance. These microbiome quantitative trait loci display heterogeneity between population groups, being mainly linked to the immune system or cellular features that may play a role in enabling microbe colonization and inflammation.

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Seya, Tsukasa, Megumi Tatematsu i Misako Matsumoto. "Toward Establishing an Ideal Adjuvant for Non-Inflammatory Immune Enhancement". Cells 11, nr 24 (11.12.2022): 4006. http://dx.doi.org/10.3390/cells11244006.

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The vertebrate immune system functions to eliminate invading foreign nucleic acids and foreign proteins from infectious diseases and malignant tumors. Because pathogens and cancer cells have unique amino acid sequences and motifs (e.g., microbe-associated molecular patterns, MAMPs) that are recognized as “non-self” to the host, immune enhancement is one strategy to eliminate invading cells. MAMPs contain nucleic acids specific or characteristic of the microbe and are potential candidates for immunostimulants or adjuvants. Adjuvants are included in many vaccines and are a way to boost immunity by deliberately administering them along with antigens. Although adjuvants are an important component of vaccines, it is difficult to evaluate their efficacy ex vivo and in vivo on their own (without antigens). In addition, inflammation induced by currently candidate adjuvants may cause adverse events, which is a hurdle to their approval as drugs. In addition, the lack of guidelines for evaluating the safety and efficacy of adjuvants in drug discovery research also makes regulatory approval difficult. Viral double-stranded (ds) RNA mimics have been reported as potent adjuvants, but the safety barrier remains unresolved. Here we present ARNAX, a noninflammatory nucleic acid adjuvant that selectively targets Toll-like receptor 3 (TLR3) in antigen-presenting dendritic cells (APCs) to safely induce antigen cross-presentation and subsequently induce an acquired immune response independent of inflammation. This review discusses the challenges faced in the clinical development of novel adjuvants.

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Uzelac, Matthew, Yuxiang Li, Jaideep Chakladar, Wei Tse Li i Weg M. Ongkeko. "Archaea Microbiome Dysregulated Genes and Pathways as Molecular Targets for Lung Adenocarcinoma and Squamous Cell Carcinoma". International Journal of Molecular Sciences 23, nr 19 (30.09.2022): 11566. http://dx.doi.org/10.3390/ijms231911566.

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The human microbiome is a vast collection of microbial species that exist throughout the human body and regulate various bodily functions and phenomena. Of the microbial species that exist in the human microbiome, those within the archaea domain have not been characterized to the extent of those in more common domains, despite their potential for unique metabolic interaction with host cells. Research has correlated tumoral presence of bacterial microbial species to the development and progression of lung cancer; however, the impacts and influences of archaea in the microbiome remain heavily unexplored. Within the United States lung cancer remains highly fatal, responsible for over 100,000 deaths every year with a 5-year survival rate of roughly 22.9%. This project attempts to investigate specific archaeal species’ correlation to lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) incidence, patient staging, death rates across individuals of varying ages, races, genders, and smoking-statuses, and potential molecular targets associated with archaea microbiome. Archaeal species abundance was assessed across lung tissue samples of 527 LUAD patients, 479 LUSC patients, and 99 healthy individuals. Nine archaeal species were found to be of significantly altered abundance in cancerous samples as compared to normal counterparts, 6 of which are common to both LUAD and LUSC subgroups. Several of these species are of the taxonomic class Thermoprotei or the phylum Euryarchaeota, both known to contain metabolic processes distinct from most bacterial species. Host-microbe metabolic interactions may be responsible for the observed correlation of these species’ abundance with cancer incidence. Significant microbes were correlated to patient gene expression to reveal genes of altered abundance with respect to high and low archaeal presence. With these genes, cellular oncogenic signaling pathways were analyzed for enrichment across cancer and normal samples. In comparing gene expression between LUAD and adjacent normal samples, 2 gene sets were found to be significantly enriched in cancers. In LUSC comparison, 6 sets were significantly enriched in cancer, and 34 were enriched in normals. Microbial counts across healthy and cancerous patients were then used to develop a machine-learning based predictive algorithm, capable of distinguishing lung cancer patients from healthy normal with 99% accuracy.

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Nagatake, Takahiro, i Jun Kunisawa. "Emerging roles of metabolites of ω3 and ω6 essential fatty acids in the control of intestinal inflammation". International Immunology 31, nr 9 (5.02.2019): 569–77. http://dx.doi.org/10.1093/intimm/dxy086.

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AbstractThe gastrointestinal tract is continuously exposed to the external environment, which contains numerous non-self antigens, including food materials and commensal micro-organisms. For the maintenance of mucosal homeostasis, the intestinal epithelial layer and mucosal immune system simultaneously provide the first line of defense against pathogens and are tightly regulated to prevent their induction of inflammatory responses to non-pathogenic antigens. Defects in mucosal homeostasis lead to the development of inflammatory and associated intestinal diseases, such as Crohn’s disease, ulcerative colitis, food allergy and colorectal cancer. The recent discovery of novel dietary ω3 and ω6 lipid-derived metabolites—such as resolvin, protectin, maresin, 17,18-epoxy-eicosatetraenoic acid and microbe-dependent 10-hydroxy-cis-12-octadecenoic acid—and their potent biologic effects on the regulation of inflammation have initiated a new era of nutritional immunology. In this review, we update our understanding of the role of lipid metabolites in intestinal inflammation.

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Koti, Madhuri, Alvaro Morales, Charles H. Graham i David Robert Siemens. "BCG vaccine and COVID-19: implications for infection prophylaxis and cancer immunotherapy". Journal for ImmunoTherapy of Cancer 8, nr 2 (lipiec 2020): e001119. http://dx.doi.org/10.1136/jitc-2020-001119.

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The COVID-19 pandemic has killed over 400 000 people globally. Ecological evidence indicates that countries with national universal BCG vaccination programs for tuberculosis (TB) prevention have a much lower incidence of severe COVID-19 and mortality compared with those that do not have such programs. BCG is a century old vaccine used for TB prevention via infant/childhood vaccination in lowto middle-income countries with high infection prevalence rate and is known to reduce all-cause neonatal mortality. BCG remains the standard immunotherapy treatment for patients with high-risk non-muscle invasive bladder cancer globally for more than 44 years. Several trials are, therefore, investigating BCG as a prophylactic against COVID-19 in healthcare workers and the elderly. In this commentary, we discuss the potential mechanisms that may underlie BCG associated heterologous protection with a focus on tertiary lymphoid structure (TLS) organogenesis. Given the significance of TLSs in mucosal immunity, their association with positive prognosis and response to immune checkpoint blockade with a critical role of Type I interferon (IFN-1) in inducing these, we also discuss potentiating TLS formation as a promising approach to enhance anti-tumor immunity. We propose that lessons learned from BCG immunotherapy success could be applied to not only augment such microbe-based therapeutics but also lead to similar adjunctive IFN-1 activating approaches to improve response to immune checkpoint blockade therapy in cancer.

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Mirji, Gauri, Alison Worth, Sajad Bhat, Mohamed Sayed, Toshitha Kannan, Aaron Goldman, Hsin-Yao Tang i in. "Abstract C023: A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer". Cancer Research 82, nr 22_Supplement (15.11.2022): C023. http://dx.doi.org/10.1158/1538-7445.panca22-c023.

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Abstract The composition of the gut microbiome controls innate and adaptive immunity and has emerged as a key regulator of tumor growth and the success of immune checkpoint blockade (ICB) therapy. However, the underlying mechanisms remain unclear. Pancreatic ductal adenocarcinoma (PDAC) tends to be refractory to therapy, including ICB. We found that the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) enhances anti-tumor immunity to PDAC. Delivery of TMAO given intraperitoneally or via dietary choline supplement to PDAC-bearing mice reduces tumor growth and is associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype and activated effector T cell response in the tumor microenvironment. Mechanistically, TMAO signals through potentiating type-I interferon (IFN) pathway and confers anti-tumor effects in a type-I IFN dependent manner. Notably, delivering TMAO-primed macrophages alone produced similar anti-tumor effects. Combining TMAO with ICB (anti-PD1 and/or anti-Tim3) significantly reduced tumor burden and improved survival beyond TMAO or ICB alone. Finally, the levels of trimethylamine (TMA)-producing bacteria and of CutC gene expression correlate with improved survivorship and response to anti-PD1 in cancer patients. Together, our study identifies the gut microbial metabolite TMAO as an important driver of anti-tumor immunity and lays the groundwork for new therapeutic strategies. Citation Format: Gauri Mirji, Alison Worth, Sajad Bhat, Mohamed Sayed, Toshitha Kannan, Aaron Goldman, Hsin-Yao Tang, Qin Liu, Noam Auslander, Chi Dang, Mohamed Abdel-Mohsen, Andrew Kossenkov, Ben Stanger, Rahul Shinde. A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C023.

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O’Day, Danton. "Proteins of the Nucleolus of Dictyostelium discoideum: Nucleolar Compartmentalization, Targeting Sequences, Protein Translocations and Binding Partners". Cells 8, nr 2 (17.02.2019): 167. http://dx.doi.org/10.3390/cells8020167.

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The nucleoli of Dictyostelium discoideum have a comparatively unique, non-canonical, localization adjacent to the inner nuclear membrane. The verified nucleolar proteins of this eukaryotic microbe are detailed while other potential proteins are introduced. Heat shock protein 32 (Hsp32), eukaryotic translation initiation factor 6 (eIF6), and tumour necrosis factor receptor-associated protein 1 (TRAP1) are essential for cell survival. NumA1, a breast cancer type 1 susceptibility protein-C Terminus domain-containing protein linked to cell cycle, functions in the regulation of nuclear number. The cell cycle checkpoint kinase 2 homologue forkhead-associated kinase A (FhkA) and BRG1-associated factor 60a homologue Snf12 are also discussed. While nucleoli appear homogeneous ultrastructurally, evidence for nucleolar subcompartments exists. Nucleolar localization sequences (NoLS) have been defined that target proteins to either the general nucleolar area or to a specific intranucleolar domain. Protein translocations during mitosis are protein-specific and support the multiple functions of the Dictyostelium nucleolus. To enrich the picture, binding partners of NumA1, the most well-characterized nucleolar protein, are examined: nucleolar Ca2+-binding protein 4a (CBP4a), nuclear puromycin-sensitive aminopeptidase A (PsaA) and Snf12. The role of Dictyostelium as a model for understanding the contribution of nucleolar proteins to various diseases and cellular stress is discussed throughout the review.

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Özdirik, Burcin, Tobias Müller, Alexander Wree, Frank Tacke i Michael Sigal. "The Role of Microbiota in Primary Sclerosing Cholangitis and Related Biliary Malignancies". International Journal of Molecular Sciences 22, nr 13 (28.06.2021): 6975. http://dx.doi.org/10.3390/ijms22136975.

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Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy characterized by biliary inflammation, cholestasis, and multifocal bile duct strictures. It is associated with high rates of progression to end-stage liver disease as well as a significant risk of cholangiocarcinoma (CCA), gallbladder cancer, and colorectal carcinoma. Currently, no effective medical treatment with an impact on the overall survival is available, and liver transplantation is the only curative treatment option. Emerging evidence indicates that gut microbiota is associated with disease pathogenesis. Several studies analyzing fecal and mucosal samples demonstrate a distinct gut microbiome in individuals with PSC compared to healthy controls and individuals with inflammatory bowel disease (IBD) without PSC. Experimental mouse and observational human data suggest that a diverse set of microbial functions may be relevant, including microbial metabolites and bacterial processing of pharmacological agents, bile acids, or dietary compounds, altogether driving the intrahepatic inflammation. Despite critical progress in this field over the past years, further functional characterization of the role of the microbiota in PSC and related malignancies is needed. In this review, we discuss the available data on the role of the gut microbiome and elucidate important insights into underlying pathogenic mechanisms and possible microbe-altering interventions.

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Caproni, Elena, Riccardo Corbellari, Michele Tomasi, Samine J. Isaac, Silvia Tamburini, Ilaria Zanella, Martina Grigolato i in. "Anti-Tumor Efficacy of In Situ Vaccination Using Bacterial Outer Membrane Vesicles". Cancers 15, nr 13 (24.06.2023): 3328. http://dx.doi.org/10.3390/cancers15133328.

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In situ vaccination (ISV) is a promising cancer immunotherapy strategy that consists of the intratumoral administration of immunostimulatory molecules (adjuvants). The rationale is that tumor antigens are abundant at the tumor site, and therefore, to elicit an effective anti-tumor immune response, all that is needed is an adjuvant, which can turn the immunosuppressive environment into an immunologically active one. Bacterial outer membrane vesicles (OMVs) are potent adjuvants since they contain several microbe-associated molecular patterns (MAMPs) naturally present in the outer membrane and in the periplasmic space of Gram-negative bacteria. Therefore, they appear particularly indicted for ISV. In this work, we first show that the OMVs from E. coli BL21(DE3)Δ60 strain promote a strong anti-tumor activity when intratumorally injected into the tumors of three different mouse models. Tumor inhibition correlates with a rapid infiltration of DCs and NK cells. We also show that the addition of neo-epitopes to OMVs synergizes with the vesicle adjuvanticity, as judged by a two-tumor mouse model. Overall, our data support the use of the OMVs in ISV and indicate that ISV efficacy can benefit from the addition of properly selected tumor-specific neo-antigens.

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Yang, Zhongzhou, Ye Zhang, Araceli Stubbe-Espejel, Yumei Zhao, Mengping Liu, Jianjun Li, Yanping Zhao i in. "Vaginal microbiota and personal risk factors associated with HPV status conversion—A new approach to reduce the risk of cervical cancer?" PLOS ONE 17, nr 8 (9.08.2022): e0270521. http://dx.doi.org/10.1371/journal.pone.0270521.

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Vaginal microbiota (VMB) is associated with changes in Human papilloma virus (HPV) status, which consequently influences the risk of cervical cancer. This association was often confounded by personal risk factors. This pilot research aimed to explore the relationship between vaginal microbiota, personal risk factors and their interactions with HPV status conversion to identify the vaginal microbiota that was associated with HPV clearance under heterogeneous personal risk factors. A total of 38 women participated by self-collecting a cervicovaginal mucus (CVM) sample that was sent for metagenomics sequencing. Most of the participants also filled in personal risk factors questionnaire through an eHealth platform and authorized the use of their previous HPV genotyping results stored in this eHealth platform. Based on the two HPV results, the participants were grouped into three cohorts, namely HPV negative, HPV persistent infection, and HPV status conversion. The relative abundance of VMB and personal factors were compared among these three cohorts. A correlation investigation was performed between VMB and the significant personal factors to characterize a robustness of the panel for HPV status change using R programming. At baseline, 12 participants were HPV-negative, and 22 were HPV-positive. Within one year, 18 women remained HPV-positive, 12 were HPV-negative and 4 participants showed HPV clearance. The factors in the eHealth questionnaire were systematically evaluated which identified several factors significantly associated with persistent HPV infection, including age, salary, history of reproductive tract infection, and the total number of sexual partners. Concurrent vaginal microbiome samples suggest that a candidate biomarker panel consisting of Lactobacillus gasseri, Streptococcus agalactiae, and Timona prevotella bacteria, which may be associated with HPV clearance. This pilot study indicates a stable HPV status-related vaginal microbe environment. To establish a robust biomarker panel for clinical use, larger cohorts will be recruited into follow-up studies.

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Chen, Zigui, Po Yee Wong, Cherrie W. K. Ng, Linlin Lan, Sherwood Fung, Jing W. Li, Liuyang Cai i in. "The Intersection between Oral Microbiota, Host Gene Methylation and Patient Outcomes in Head and Neck Squamous Cell Carcinoma". Cancers 12, nr 11 (18.11.2020): 3425. http://dx.doi.org/10.3390/cancers12113425.

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The role of oral microbiota in head and neck squamous cell carcinoma (HNSCC) is poorly understood. Here we sought to evaluate the association of the bacterial microbiome with host gene methylation and patient outcomes, and to explore its potential as a biomarker for early detection or intervention. Here we performed 16S rRNA gene amplicon sequencing in sixty-eight HNSCC patients across both tissue and oral rinse samples to identify oral bacteria with differential abundance between HNSCC and controls. A subset of thirty-one pairs of HNSCC tumor tissues and the adjacent normal tissues were characterized for host gene methylation profile using bisulfite capture sequencing. We observed significant enrichments of Fusobacterium and Peptostreptococcus in HNSCC tumor tissues when compared to the adjacent normal tissues, and in HNSCC oral rinses when compared to healthy subjects, while ten other bacterial genera were largely depleted. These HNSCC-related bacteria were discriminative for HNSCC and controls with area under the receiver operating curves (AUCs) of 0.84 and 0.86 in tissue and oral rinse samples, respectively. Moreover, Fusobacterium nucleatum abundance in HNSCC cases was strongly associated with non-smokers, lower tumor stage, lower rate of recurrence, and improved disease-specific survival. An integrative analysis identified that enrichment of F. nucleatum was associated with host gene promoter methylation, including hypermethylation of tumor suppressor genes LXN and SMARCA2, for which gene expressions were downregulated in the HNSCC cohort from The Cancer Genome Atlas. In conclusion, we identified a taxonomically defined microbial consortium associated with HNSCC that may have clinical potential regarding biomarkers for early detection or intervention. Host–microbe interactions between F. nucleatum enrichment and clinical outcomes or host gene methylation imply a potential role of F. nucleatum as a pro-inflammatory driver in initiating HNSCC without traditional risk factors, which warrants further investigation for the underlying mechanisms.

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Masi, L., V. Petito, M. Fidaleo, I. Palucci, F. Del Chierico, V. Ivagnes, A. Mercuri i in. "P005 The solute carrier LC22A4/Organic Cation Transporter (OCTN)-1 as a novel Inflammatory Bowel Disease determinant at the microbe-host interface". Journal of Crohn's and Colitis 16, Supplement_1 (1.01.2022): i136—i139. http://dx.doi.org/10.1093/ecco-jcc/jjab232.134.

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Abstract Background The putative Ergothioneine Transporter, SLC22A4/OCTN1, is expressed in the intestine and monocytes/macrophages, and its widely represented missense variant L503F (0.4 Minor Allele Frequency in Caucasians) has been found to be associated with Crohn’s disease, sporadic colorectal cancer in early age and ulcerative colitis (UC) patients. The leucine-to-phenylalanine substitution at amino acid 503 affects OCTN1 capacity to transport ergothioneine, acetylcholine and likely other substrates of endogenous or microbial origin; however, whether this defect contributes to inflammatory bowel disease (IBD) pathogenesis, and the mechanistic underpinnings, remain elusive. Methods In order to gain mechanistic insight on the role of SLC22A4 in IBD, we first analyzed primary monocytes from healthy donors and UC patients of varying OCTN1 genotypes. Then we stably knocked down or overexpressed OCTN1 and its disease-associated variant in the monocytic cell line THP-1. Finally, we compared wild-type and OCTN1 knockout C57BL/6 mice in a chemical colitis paradigm in vivo. Results Primary adherent monocytes from healthy donors homozygous for the IBD-associated allele (TT) displayed a significant enhancement of interleukin 1 beta (IL-1β) response to peptidoglycan (PGN) compared to the other genotypes. Likewise, cells from UC patients bearing the 503F variant released more IL-1β in response to live bacteria and displayed reduced expression of autophagy markers (e.g. p62, LC3), compared to patients negative for the variant. In agreement with these findings, OCTN1-deficient THP-1 macrophages secreted reduced amounts of IL-1β when challenged in vitro with PGN or live bacteria. Most relevant, THP1 cells engineered to overexpress the 503F variant of OCTN1 displayed a much stronger IL-1β response to muramyl dipeptide and PGN challenge, compared to cells transduced with the “wild type” transporter. Also consistent with a role for OCTN1 variants in inflammatory cascades relevant to IBD, in vivo studies revealed milder DSS-induced colitis in OCTN1 knockout mice compared to wild-type animals, both at the peak of disease severity and at the end of the recovery period. Conclusion Collectively our initial evidence supports the view that OCTN1 may have a causative role in IBD via deranged bacterial sensing and cytokine production, with 503F likely behaving as a gain-of-function variant. Thus, targeting OCTN1 variant may provide unprecedented opportunities for the personalized treatment of IBD patients and a better understanding of disease pathogenesis.

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47

Taketomi, Yoshitaka, Yoshimi Miki i Makoto Murakami. "Old but New: Group IIA Phospholipase A2 as a Modulator of Gut Microbiota". Metabolites 12, nr 4 (14.04.2022): 352. http://dx.doi.org/10.3390/metabo12040352.

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Among the phospholipase A2 (PLA2) superfamily, the secreted PLA2 (sPLA2) family contains 11 mammalian isoforms that exhibit unique tissue or cellular distributions and enzymatic properties. Current studies using sPLA2-deficient or -overexpressed mouse strains, along with mass spectrometric lipidomics to determine sPLA2-driven lipid pathways, have revealed the diverse pathophysiological roles of sPLA2s in various biological events. In general, individual sPLA2s exert their specific functions within tissue microenvironments, where they are intrinsically expressed through hydrolysis of extracellular phospholipids. Recent studies have uncovered a new aspect of group IIA sPLA2 (sPLA2-IIA), a prototypic sPLA2 with the oldest research history among the mammalian PLA2s, as a modulator of the gut microbiota. In the intestine, Paneth cell-derived sPLA2-IIA acts as an antimicrobial protein to shape the gut microbiota, thereby secondarily affecting inflammation, allergy, and cancer in proximal and distal tissues. Knockout of intestinal sPLA2-IIA in BALB/c mice leads to alterations in skin cancer, psoriasis, and anaphylaxis, while overexpression of sPLA2-IIA in Pla2g2a-null C57BL/6 mice induces systemic inflammation and exacerbates arthritis. These phenotypes are associated with notable changes in gut microbiota and fecal metabolites, are variable in different animal facilities, and are abrogated after antibiotic treatment, co-housing, or fecal transfer. These studies open a new mechanistic action of this old sPLA2 and add the sPLA2 family to the growing list of endogenous factors capable of affecting the microbe–host interaction and thereby systemic homeostasis and diseases.

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48

Paley, Elena L. "Diet-Related Metabolic Perturbations of Gut Microbial Shikimate Pathway-Tryptamine-tRNA Aminoacylation-Protein Synthesis in Human Health and Disease". International Journal of Tryptophan Research 12 (styczeń 2019): 117864691983455. http://dx.doi.org/10.1177/1178646919834550.

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Human gut bacterial Na(+)-transporting NADH:ubiquinone reductase (NQR) sequence is associated with Alzheimer disease (AD). Here, Alzheimer disease-associated sequence (ADAS) is further characterized in cultured spore-forming Clostridium sp. Tryptophan and NQR substrate ubiquinone have common precursor chorismate in microbial shikimate pathway. Tryptophan-derived tryptamine presents in human diet and gut microbiome. Tryptamine inhibits tryptophanyl-tRNA synthetase (TrpRS) with consequent neurodegeneration in cell and animal models. Tryptophanyl-tRNA synthetase inhibition causes protein biosynthesis impairment similar to that revealed in AD. Tryptamine-induced TrpRS gene-dose reduction is associated with TrpRS protein deficiency and cell death. In animals, tryptamine treatment results in toxicity, weight gain, and prediabetes-related hypoglycemia. Sequence analysis of gut microbiome database reveals 89% to 100% ADAS nucleotide identity in American Indian (Cheyenne and Arapaho [C&A]) Oklahomans, of which ~93% being overweight or obese and 50% self-reporting type 2 diabetes (T2D). Alzheimer disease-associated sequence occurs in 10.8% of C&A vs 1.3% of healthy American population. This observation is of considerable interest because T2D links to AD and obesity. Alzheimer disease-associated sequence prevails in gut microbiome of colorectal cancer, which linked to AD. Metabolomics revealed that tryptamine, chorismate precursor quinate, and chorismate product 4-hydroxybenzoate (ubiquinone precursor) are significantly higher, while tryptophan-containing dipeptides are lower due to tRNA aminoacylation deficiency in C&A compared with non-native Oklahoman who showed no ADAS. Thus, gut microbial tryptamine overproduction correlates with ADAS occurrence. Antibiotic and diet additives induce ADAS and tryptamine. Mitogenic/cytotoxic tryptamine cause microbial and human cell death, gut dysbiosis, and consequent disruption of host-microbe homeostasis. Present analysis of 1246 participants from 17 human gut metagenomics studies revealed ADAS in cell death diseases.

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49

Kumar, Robin, Akhilendra K. Maurya, Lakshmi S. Bugata, Md I. Kabir, Munendra Tomar, Rajesh Agarwal, Elizabeth P. Ryan i Komal Raina. "Abstract 4229: Differential impact of rice bran based dietary interventions during inflammation-associated colorectal cancer on distinct immune infiltrates and their spatial distribution signature". Cancer Research 83, nr 7_Supplement (4.04.2023): 4229. http://dx.doi.org/10.1158/1538-7445.am2023-4229.

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Abstract Modulating the immune cell infiltrates in the colonic tissue via dietary intervention or modulation of the gut microbiota and its crosstalk with the components of the diet is now recognized as an effective strategy to protect against inflammation-associated colorectal cancer (CRC). In this regard, we recently reported, both gut microbiota-dependent and independent mechanisms for dietary rice bran (RB) meditated protective efficacy against inflammation-associated azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC. We also reported that ex vivo fermentation of RB with beneficial microbe ‘Bifidobacterium longum’ did not exhibit similar protective benefits as RB in damaged colonic tissues in the absence of gut microbiota [germ-free (gf) mice]. The role of rice bran (RB) constituents as prebiotics and in preserving gut barrier and a healthy gut microbiota led to in-depth investigation into the protective efficacy of RB against CRC. Accordingly, in the present study, we performed multiplex imaging (9 color panel) to assess immune sub-typing and spatial phenotypic signature of the colonic tissue/tumor microenvironment in the AOM/DSSgf mice [following RB and fermented RB (FRB) dietary intervention]. Briefly, we determined the presence of T cells [CD3+], cytotoxic T cells [CD3+ CD8+], helper T cells [CD3+ CD8−], regulatory T (Treg) cells [CD3+CD8−FoxP3+), natural killer (NK) cells [CD49b+], NKT cells [CD3+CD49b+], macrophage (MΦ) [F4/80 +], M1 [F4/80+iNOS+CD206−] and M2 [F4/80+CD206+] subtypes and B cells [B220+]. Results indicated an overall high infiltration of immune cells in female AOM/DSSgf mice on control diet compared to males, which was positively correlated with severe pathological changes observed in the female colon tissues. Notably, RB and FRB diets showed a differential impact on the sub-type of immune cells and their spatial localization. Protective efficacy of RB was associated with decrease in infiltration of T cells (including their subtypes). Interestingly, while cytotoxic T cells were lower in FRB (AOM/DSSgf) female mice, there was a significant increase in pro-inflammatory M1 MΦ sub-types in colon tissue of mice marred by epithelial erosion which compromised FRB potential. Spatial distance analysis also indicated that immune cells were distantly spaced in RB intervention groups compared to FRB and AOM/DSSgf controls. Though, M2 MΦ were relatively higher in number in AOM/DSSgf controls, their presence did not have influence on protective efficacy or lack thereof. In general, it was inferenced that the protective efficacy of the RB diets in the absence of gut microbiota was positively correlated with modulation of T cell infiltration while inflammation-associated CRC and epithelial erosion in FRB diet groups were associated with skewed MΦ sub-types-with increased presence of M1MΦ. Citation Format: Robin Kumar, Akhilendra K. Maurya, Lakshmi S. Bugata, Md. I. Kabir, Munendra Tomar, Rajesh Agarwal, Elizabeth P. Ryan, Komal Raina. Differential impact of rice bran based dietary interventions during inflammation-associated colorectal cancer on distinct immune infiltrates and their spatial distribution signature. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4229.

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Gutiérrez-Escobar, Andrés J., María M. Bravo, Orlando Acevedo i Steffen Backert. "Molecular evolution of the VacA p55 binding domain of Helicobacter pylori in mestizos from a high gastric cancer region of Colombia". PeerJ 7 (6.05.2019): e6634. http://dx.doi.org/10.7717/peerj.6634.

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The stomach bacterium Helicobacter pylori is one of the most prevalent pathogens in humans, closely linked with serious diseases such as gastric cancer. The microbe has been associated with its host for more than 100,000 years and escorted modern humans out of Africa. H. pylori is predominantly transmitted within families and dispersed globally, resulting in distinct phylogeographic patterns, which can be utilized to investigate migrations and bioturbation events in human history. Latin America was affected by several human migratory waves due to the Spanish colonisation that drastically changed the genetic load and composition of the bacteria and its host. Genetic evidence indicates that independent evolutionary lines of H. pylori have evolved in mestizos from Colombia and other countries in the region during more than 500 years since colonisation. The vacuolating cytotoxin VacA represents a major virulence factor of the pathogen comprising two domains, p33 and p55, the latter of which is essential for binding to the host epithelial cell. The evolution of the VacA toxin in Colombia has been strongly biased due to the effects of Spanish colonization. However, the variation patterns and microevolution of the p55 domain have not yet been described for this population. In the present study, we determined the genetic polymorphisms and deviations in the neutral model of molecular evolution in the p55 domain of 101 clinical H. pylori isolates collected in Bogotá, a city located in Andean mountains characterized by its high gastric cancer risk and its dominant mestizo population. The microevolutionary patterns of the p55 domain were shaped by recombination, purifying and episodic diversifying positive selection. Furthermore, amino acid positions 261 and 321 in the p55 domain of VacA show a high variability among mestizos clinical subsets, suggesting that natural selection in H. pylori may operate differentially in patients with different gastric diseases.

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