Journal articles: 'Pathobionte'

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Gilliland, A., Y. Chen, D. Tertigas, M. Surette, B. Bressler, and B. Vallance. "A24 AN ULCERATIVE COLITIS-ISOLATED PATHOBIONT CAN DEGRADE MUCUS PRODUCED BY UC PATIENT-DERIVED COLONOIDS." Journal of the Canadian Association of Gastroenterology 7, Supplement_1 (February 14, 2024): 13–14. http://dx.doi.org/10.1093/jcag/gwad061.024.

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Abstract Background Inflammatory bowel disease (IBD) pathobionts are commensal microbes with pathogenic potential that may cause or exacerbate IBD symptoms. Some pathobionts (ex. Escherichia coli) reside at low levels in the lumen of a healthy gut but can rapidly grow in the inflamed colons of ulcerative colitis (UC) patients. To promote disease, these pathobionts must cross the colonic mucus barrier (comprised of MUC2) that separates the epithelium from luminal microbes. It is currently unclear how bacterial pathobionts cross the mucus barrier of UC patients. Aims Using healthy and UC patient biopsy-derived colonic organoids (colonoids) and an air liquid interface (ALI) monolayer model, we investigated how the UC-isolated E. coli pathobiont p19A crosses the mucus barrier. Methods Apical out healthy and UC patient biopsy-derived colonoids were infected with p19A to confirm this pathobiont exerts direct cytopathic effects on human colonocytes. Sequencing p19A’s genome, we found it contains two mucus degrading proteins (mucinases). Healthy human and UC colonoids, as well as mouse colonoids, were used to generate mucus-producing ALI monolayers. To detect p19A-mediated mucus degradation, concentrated p19A supernatant was incubated with ALI-derived mucus and degraded MUC2 proteins were detected by protein gel and MUC2 Western blot. MUC2 glycosylation was analyzed by protein gel and PAS staining. ALI monolayers were infected with p19A to evaluate mucus degradation and p19A localization by immunostaining. Results The UC-isolated pathobiont p19A infected and exerted cytotoxic effects on apical out healthy and UC patient colonoids. By day 14, ALI monolayers were differentiated and covered by a thick mucus layer as assessed using brightfield microscopy. Mucus removed for mucinase assays was replenished within 7 days. p19A harbours proteins capable of degrading human ALI-, but not mouse ALI-derived mucus, in vitro, suggesting the presence of host-specific mucinases. Mucus produced by UC ALI monolayers showed reduced glycosylation and increased degradation both over time and by p19A proteins. Day 21 ALI-monolayers infected with p19A for 18 hours exhibited overt mucus degradation allowing p19A to infect the underlying epithelium. Conclusions Patient-derived ALI monolayers produce a thick mucus layer that can be used to study pathobiont-mucus interactions. The UC pathobiont p19A disrupts apical out organoids and produces proteins that degrade ALI-derived mucus in vitro, with UC mucus being more susceptible to degradation than mucus from healthy controls. The results from our model suggest a potential mechanism for pathobiont-mediated mucosal barrier disruption in UC patients. Patient-derived ALI monolayer (blue/white) produces a thick mucus layer (green) that can be degraded by the pathobiont p19A (red). Funding Agencies CCC, CIHR

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Jones, Josh, Qiaojuan Shi, Rahul R. Nath, and Ilana L. Brito. "Keystone pathobionts associated with colorectal cancer promote oncogenic reprograming." PLOS ONE 19, no. 2 (February 16, 2024): e0297897. http://dx.doi.org/10.1371/journal.pone.0297897.

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Fusobacterium nucleatum (Fn) and enterotoxigenic Bacteroides fragilis (ETBF) are two pathobionts consistently enriched in the gut microbiomes of patients with colorectal cancer (CRC) compared to healthy counterparts and frequently observed for their direct association within tumors. Although several molecular mechanisms have been identified that directly link these organisms to features of CRC in specific cell types, their specific effects on the epithelium and local immune compartment are not well-understood. To fill this gap, we leveraged single-cell RNA sequencing (scRNA-seq) on wildtype mice and mouse model of CRC. We find that Fn and ETBF exacerbate cancer-like transcriptional phenotypes in transit-amplifying and mature enterocytes in a mouse model of CRC. We also observed increased T cells in the pathobiont-exposed mice, but these pathobiont-specific differences observed in wildtype mice were abrogated in the mouse model of CRC. Although there are similarities in the responses provoked by each organism, we find pathobiont-specific effects in Myc-signaling and fatty acid metabolism. These findings support a role for Fn and ETBF in potentiating tumorigenesis via the induction of a cancer stem cell-like transit-amplifying and enterocyte population and the disruption of CTL cytotoxic function.

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Yang, H., H. Mirsepasi-Lauridsen, C. Struve, J. M. Allaire, A. Sivignon, W. Vogl, E. S. Bosman, et al. "A21 ULCERATIVE COLITIS-ASSOCIATED E. COLI PATHOBIONTS POTENTIATE COLITIS IN SUSCEPTIBEL HOSTS." Journal of the Canadian Association of Gastroenterology 4, Supplement_1 (March 1, 2021): 142–44. http://dx.doi.org/10.1093/jcag/gwab002.020.

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Abstract Background Ulcerative colitis (UC) is a chronic inflammatory condition linked to intestinal microbial dysbiosis, including the expansion of E. coli strains related to extra-intestinal pathogenic E. coli. These “pathobionts” exhibit pathogenic properties, but their potential to promote UC is unclear due to the lack of relevant animal models. Aims We explored the potential to establish a mouse model of GI infection by the UC-associated E. coli strain p19A, as well as characterize the pathogenic features of p19A. Methods We used a representative UC pathobiont strain (p19A), and mice lacking single immunoglobulin and toll-interleukin 1 receptor domain (SIGIRR), a deficiency increasing susceptibility to gut infections. Vancomycin-pretreated Sigirr-/- mice were subsequently gavaged with the control E. coli DH10B (a derivative of commensal strain K-12) or p19A. One day after infection, mice were exposed to 2.5% dextran sodium sulfate (DSS) in their drinking water for another 4 days. Results Strain p19A was found to adhere to the cecal mucosa of Sigirr-/- mice, causing modest inflammation. Moreover, it dramatically worsened DSS-induced colitis. This potentiation was attenuated using a p19A strain lacking α-hemolysin genes, or when we targeted pathobiont adherence using a p19A strain lacking the adhesin FimH, or following treatment with FimH antagonists. Conclusions Thus, UC pathobionts adhere to the intestinal mucosa, and worsen the course of colitis in susceptible hosts in a manner dependent on specific virulence factors, including α-hemolysin and FimH. Funding Agencies CCC, CIHR

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Chapman, Timothy J., Matthew C. Morris, Lei Xu, and Michael E. Pichichero. "Nasopharyngeal colonization with pathobionts is associated with susceptibility to respiratory illnesses in young children." PLOS ONE 15, no. 12 (December 11, 2020): e0243942. http://dx.doi.org/10.1371/journal.pone.0243942.

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Some children are more susceptible to viral and bacterial respiratory infections in the first few years of life than others. However, the factors contributing to this susceptibility are incompletely understood. In a retrospective analysis of clinical samples collected from a prospectively-enrolled cohort of 358 children we sought associations between physician-attended illness visits and bacterial colonization in the first five years of life. A subset of children was identified by unsupervised clustering analysis as infection and allergy prone (IAP). Several respiratory infection- and allergy-mediated illnesses co-occurred at higher rates in IAP children, while the rates of other illnesses were not significantly different between the groups. Analyses of nasopharyngeal (NP) pathobionts and microbiota commensals showed that early age of first colonization with pathobionts Streptococcus pneumonia, non-typeable Haemophilus influenzae, and Moraxella catarrhalis was associated with IAP children, and particularly Moraxella abundance was negatively associated with NP microbiome diversity. We conclude that mucosal pathobiont exposures in early life can influence susceptibility to respiratory illnesses in children.

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Yang, Hyungjun, Hengameh Chloé Mirsepasi-Lauridsen, Carsten Struve, Joannie M. Allaire, Else Bosman, Adeline Sivignon, Wayne Vogl, et al. "Ulcerative Colitis-associated E. coli pathobionts potentiate colitis in susceptible hosts." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 192.3. http://dx.doi.org/10.4049/jimmunol.202.supp.192.3.

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Abstract Ulcerative colitis (UC) is chronic inflammatory condition linked to intestinal microbial dysbiosis, including the expansion of E. coli strains related to extra-intestinal E. coli. These “pathobionts” exhibit pathogenic properties, but their potential to promote UC is unclear due to the lack of suitable animal models. Here, we established a mouse model using a representative UC pathobiont strain (p19A), and mice lacking single immunoglobulin and toll-interleukin 1 receptor domain (SIGIRR), a deficiency increasing susceptibility to gut infections. p19A was found to adhere to the cecal mucosa of Sigirr−/− mice, causing modest inflammation. Moreover, it dramatically worsened DSS induced colitis, in concert with adherence to, and penetration of the inflamed mucosa. This pathogenicity was lost in a p19A strain lacking the adhesin FimH; following treatment with FimH antagonists, or was attenuated when using a p19A strain lacking a-hemolysin genes. Thus UC pathobionts can worsen the course of colitis in susceptible hosts.

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Clayton, C., K. Ng, and C. Tropini. "A38 EXPLORING HOW BOWEL PREPARATION CAN AFFECT INFLAMMATORY BOWEL DISEASE VIA THE GUT MICROBIOTA." Journal of the Canadian Association of Gastroenterology 7, Supplement_1 (February 14, 2024): 21–22. http://dx.doi.org/10.1093/jcag/gwad061.038.

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Abstract Background Inflammatory bowel disease (IBD) is a debilitating disorder that targets the gastrointestinal (GI) tract. Although its causes remain unknown, recent studies have identified changes to the gut microbiota associated with IBD. While most gut bacteria are essential for GI health, pathobionts are bacteria that are prevalent in IBD patients and that can act as pathogens and induce inflammation. IBD patients undergo routine endoscopies which require the administration of laxative-based bowel prep to clear out the luminal contents of the GI for the endoscope. It has been found that after bowel prep some IBD patients experience inflammatory flareups. IBD patients may experience adverse reactions following bowel prep, including increased inflammation, emergency room visits, and medication adjustments. Importantly, bowel prep perturbs the gut microbiota, depleting beneficial microorganisms, while allowing pathobiont strains to thrive, which could be the cause for worsened symptoms post-bowel prep in some patients. Aims We hypothesize that the altered intestinal microenvironment during bowel prep causes commensal bacteria depletion and favours osmotolerant pathogenic species that lead to increased inflammation in two systems: 1) in a model disease-causing microorganism, Salmonella enterica 2) in an IBD microbiota. Methods To investigate pathogen expansion after bowel prep a Salmonella mouse model was established. Microbiota changes were determined by 16S rRNA sequencing and spot plating. Changes to the gut environment and the mechanism for pathogen colonization were characterized using Salmonella mutants and confocal imaging. To identify changes to the IBD microbiota, a humanized mouse model was established, and microbiota changes were investigated as done in the Salmonella model. IBD-associated pathobiont growth was also characterized in in vitro conditions that were identified in our in vivo model. Results We have demonstrated that bowel prep increases GI osmolality and leads to increased Salmonella colonization in the gut and systemic organs following bowel prep unlike mice treated with vehicle, supporting our hypothesis. We then explored the effects of bowel prep in a humanized mouse model of IBD, which showed increased translocation of bacteria from the gut to internal organs post-prep. Additionally, IBD-associated pathobionts were able to grow much greater than commensal strains highlighting that IBD pathobionts can persist in the gut after bowel prep. Conclusions Our study highlights that bowel prep disrupts the gut microbiota and the intestinal environment allowing for pathogen colonization and bacterial translocation. Therefore, bacterial translocation could provide mechanistic insight for inflammatory flareups following bowel prep. Ultimately, our research underscores the importance of the gut environment in facilitating pathobiont exacerbation of IBD. Funding Agencies CIHR

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Yang, H., X. Han, C. Ma, H. Yu, and B. Vallance. "A15 GENETIC OR DIET-ASSOCIATED DEFECTS IN MUCUS FACILITATE ULCERATIVE COLITIS PATHOBIONT-DRIVEN COLITIS." Journal of the Canadian Association of Gastroenterology 6, Supplement_1 (March 1, 2023): 8–9. http://dx.doi.org/10.1093/jcag/gwac036.015.

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Abstract Background The Inflammatory Bowel Diseases (IBD), Crohn’s Disease (CD) and ulcerative colitis (UC) affect > 270,000 Canadians and are increasing in incidence. Ileal CD has been linked to the overgrowth of mucosal adherent E. coli. Recent studies have also implicated the adherence of Escherichia coli pathobionts to the colonic mucosa of UC patients. Using the representative UC E. coli pathobiont p19A, we recently demonstrated it aggravated chemical-induced colitis in susceptible mice, through the actions of the toxin alpha-hemolysin, and by adhering to the inflamed colonic mucosa via the adhesin FimH. It is less clear what host factors control susceptibility to the UC pathobionts. One of the potential candidates is the glycosylated mucin (Muc2) which forms the mucus layer that covers the colonic epithelium and is often impaired in UC patients. Purpose To define the role of mucus structure and function in determining susceptibility to the p19A pathobiont, and its ability to cause colitis in mice. Method In vitro growth was assessed to test p19A’s ability to utilize mucin-derived sugars as nutrients. Susceptibility to p19A was tested in two mouse models of colonic mucus impairment. The first is a mouse strain deficient in core 1 derived O-glycans in their intestinal epithelial cells (IEC C1galt1-/-), resulting in reduced Muc2 glycosylation, and thus a thin and impaired mucus barrier. The second model involves feeding wildtype (WT) C57BL/6CR mice a fiber-free (FF) diet, resulting in a significantly thinner colonic mucus layer. The mice were subsequently orally gavaged with p19A and their susceptibility determined by p19A burdens, intestinal histopathology, inflammatory cytokine and short chain fatty acid (SCFA) production. Result(s) When tested in vitro, the p19A pathobiont was found to use an array of mucin-derived sugars as sole carbon source to proliferate. Following oral gavage of WT mice fed a normal diet, immunostaining identified p19A within the colonic mucus but it did not reach the colonic mucosa or cause disease. In contrast, p19A was found at the colonic mucosal surface of mucus-defective IEC C1galt1-/- mice (as compared to IEC C1galt1flox/flox mice) and in WT mice fed a fiber-free diet. This mucosal adherence was associated with increased body weight loss during the course of infection, as well as increased p19A burdens, colonic pathology and pro-inflammatory cytokine expression. Especially fiber-free diet-fed mice showed reduced SCFA levels in their feces at baseline. When the mice were given exogenous SCFA (tributyrin) orally, p19A infection was reduced. Conclusion(s) Our results indicate that UC E. coli pathobionts are able to dwell within colonic mucus and utilize mucin sugars as nutrients. Moreover, they can reach the mucosal surface and induce colitis in hosts suffering genetic or diet-based mucus dysfunction. In part, this susceptibility reflects the important role played by mucus in the production of SCFA, suggesting potential therapeutic approaches for patients suffering UC. Please acknowledge all funding agencies by checking the applicable boxes below CCC, CIHR Disclosure of Interest None Declared

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Doonan, James M., Martin Broberg, Sandra Denman, and James E. McDonald. "Host–microbiota–insect interactions drive emergent virulence in a complex tree disease." Proceedings of the Royal Society B: Biological Sciences 287, no. 1933 (August 19, 2020): 20200956. http://dx.doi.org/10.1098/rspb.2020.0956.

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Forest declines caused by climate disturbance, insect pests and microbial pathogens threaten the global landscape, and tree diseases are increasingly attributed to the emergent properties of complex ecological interactions between the host, microbiota and insects. To address this hypothesis, we combined reductionist approaches (single and polyspecies bacterial cultures) with emergentist approaches (bacterial inoculations in an oak infection model with the addition of insect larvae) to unravel the gene expression landscape and symptom severity of host–microbiota–insect interactions in the acute oak decline (AOD) pathosystem. AOD is a complex decline disease characterized by predisposing abiotic factors, inner bark lesions driven by a bacterial pathobiome, and larval galleries of the bark-boring beetle Agrilus biguttatus . We identified expression of key pathogenicity genes in Brenneria goodwinii , the dominant member of the AOD pathobiome, tissue-specific gene expression profiles, cooperation with other bacterial pathobiome members in sugar catabolism, and demonstrated amplification of pathogenic gene expression in the presence of Agrilus larvae. This study highlights the emergent properties of complex host–pathobiota–insect interactions that underlie the pathology of diseases that threaten global forest biomes.

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Meghil, Mohamed M., and Christopher W. Cutler. "Oral Microbes and Mucosal Dendritic Cells, “Spark and Flame” of Local and Distant Inflammatory Diseases." International Journal of Molecular Sciences 21, no. 5 (February 28, 2020): 1643. http://dx.doi.org/10.3390/ijms21051643.

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Mucosal health and disease is mediated by a complex interplay between the microbiota (“spark”) and the inflammatory response (“flame”). Pathobionts, a specific class of microbes, exemplified by the oral microbe Porphyromonas gingivalis, live mostly “under the radar” in their human hosts, in a cooperative relationship with the indigenous microbiota. Dendritic cells (DCs), mucosal immune sentinels, often remain undisturbed by such microbes and do not alert adaptive immunity to danger. At a certain tipping point of inflammation, an “awakening” of pathobionts occurs, wherein their active growth and virulence are stimulated, leading to a dysbiosis. Pathobiont becomes pathogen, and commensal becomes accessory pathogen. The local inflammatory outcome is the Th17-mediated degenerative bone disease, periodontitis (PD). In systemic circulation of PD subjects, inflammatory DCs expand, carrying an oral microbiome and promoting Treg and Th17 responses. At distant peripheral sites, comorbid diseases including atherosclerosis, Alzheimer’s disease, macular degeneration, chronic kidney disease, and others are reportedly induced. This review will review the immunobiology of DCs, examine the complex interplay of microbes and DCs in the pathogenesis of PD and its comorbid inflammatory diseases, and discuss the role of apoptosis and autophagy in this regard. Overall, the pathophysiological mechanisms of DC-mediated chronic inflammation and tissue destruction will be summarized.

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Minton, Kirsty. "Pathobiont peacekeepers." Nature Reviews Immunology 18, no. 3 (February 16, 2018): 152. http://dx.doi.org/10.1038/nri.2018.11.

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A. James, Stephen, Sarah Phillips, Andrea Telatin, David Baker, Rebecca Ansorge, Paul Clarke, Lindsay J. Hall, and Simon R. Carding. "Preterm Infants Harbour a Rapidly Changing Mycobiota That Includes Candida Pathobionts." Journal of Fungi 6, no. 4 (November 9, 2020): 273. http://dx.doi.org/10.3390/jof6040273.

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Fungi and the mycobiome are a fundamental part of the human microbiome that contributes to human health and development. Despite this, relatively little is known about the mycobiome of the preterm infant gut. Here, we have characterised faecal fungal communities present in 11 premature infants born with differing degrees of prematurity and mapped how the mycobiome develops during early infancy. Using an ITS1 sequencing-based approach, the preterm infant gut mycobiome was found to be often dominated by a single species, typically a yeast. Candida was the most abundant genus, with the pathobionts C.albicans and C.parapsilosis highly prevalent and persistent in these infants. Gestational maturity at birth affected the distribution and abundance of these Candida, with hospital-associated C.parapsilosis more prevalent and abundant in infants born at less than 31 weeks. Fungal diversity was lowest at 6 months, but increased with age and change of diet, with food-associated Saccharomycescerevisiae most abundant in infants post weaning. This study provides a first insight into the fungal communities present within the preterm infant gut, identifying distinctive features including the prominence of pathobiont species, and the influence age and environmental factors play in shaping the development of the mycobiome.

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Devkota, Suzanne, and Eugene B. Chang. "Interactions between Diet, Bile Acid Metabolism, Gut Microbiota, and Inflammatory Bowel Diseases." Digestive Diseases 33, no. 3 (2015): 351–56. http://dx.doi.org/10.1159/000371687.

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The composite human gut microbiomes of Western populations have changed over the past century, brought on by new environmental triggers that often have a negative impact on human health. Diets high in saturated fats and refined sugars and low in fiber are leading candidates for these events and for triggering the increased prevalence of immune-mediated diseases like inflammatory bowel disease (IBD). Our studies have shown that consumption of a ‘Western' diet high in saturated (milk-derived) fat (MF) or n-6 polyunsaturated (safflower oil) fat have similar effects on the structure of the colonic microbiome of wild-type and IL- 10-/- mice, characterized by increased Bacteroidetes and decreased Firmicutes. However, the MF diet uniquely promotes the expansion of an immunogenic sulfite-reducing pathobiont, Bilophila wadsworthia, a member of the Deltaproteobacteria and minor component of the gut microbiome. This bacterial bloom results from a MF diet-induced shift in hepatic conjugation of bile acids, from glycocholic to taurocholic (TC) acid, which is important for solubilizing the more hydrophobic MF diet. However, it is also responsible for delivery of taurine-derived sulfur to the distal bowel, promoting the assemblage of bile-tolerant microbes such as B. wadsworthia. The bloom of this species promotes a Th1-mediated immune response and the development of colitis in IL-10-/- mice. A similar bloom of B. wadsworthia is seen when IL-10-/- mice are fed a low-fat diet supplemented with TC. B. wadsworthia colonization of monoassociated germ-free IL-10-/- mice was dependent on the host consuming either a high-saturated MF diet or the gavage with TC. Together, these data provide a plausible explanation for the link between diseases such as IBD and dietary-mediated selection of gut microbial pathobionts in genetically susceptible hosts. With this knowledge, it may be possible to mitigate the bloom of these types of pathobionts by modifying the conjugation states of bile acids.

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Zeng, Melody. "Regulation of the gut microbiota and intestinal homeostasis by phagocyte NADPH oxdiase (INC1P.351)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 54.8. http://dx.doi.org/10.4049/jimmunol.194.supp.54.8.

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Abstract The phagocyte NADPH oxidase generates reactive oxygen species (ROS) for microbial killing, and its impairment gives rise to Chronic Granulomatous Disease (CGD), a primary immunodeficiency characterized by recurrent infections and granulomatous lesions. Mutations in Nox2 (Cybb), a critical subunit of the oxidase, contribute 66% of CGD. In our study, we found spontaneous inflammation in the intestine of naïve Cybb-/- mice, indicated by higher levels of IL-1b, IL-6 and TNFα in lamina propria macrophages, as well as increased levels of IFNγ and IL-17A in CD4+ T cells. In addition, Klebsiella pneumoniae, a bacterium frequently found in granulomatous lesions in CGD patients, were detected in the spleens and mesenteric lymph nodes (MLNs) of naïve Cybb-/- mice, and IP administration of this pathobiont strain of K. pneumonia led to rapid mortality of wild-type mice. Oral administration of this K. pneumoniae induced intestinal inflammation in wild-type and Cybb-/- mice, but translocation of K. pneumoniae to MLNs was drastically enhanced in Cybb-/- mice and bone marrow chimeras with a neutrophil-specific deficiency in NOX2. Thus, our results demonstrate the importance of neutrophil-derived ROS in restricting dissemination of pathobionts from the intestine under steady-state conditions. Therefore, our study underscores a critical role for the NADPH oxidase in regulating intestinal homeostasis and provides insights into intestinal complications in CGD patients.

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Bording-Jorgensen, M., K. Chea, T. Gartke, C. Cheng, H. Armstrong, and E. Wine. "A50 THE EFFECTS OF SHORT-CHAIN FATTY ACIDS ON EPITHELIAL AND MACROPHAGE RESPONSE TO BACTEROIDES FRAGILIS." Journal of the Canadian Association of Gastroenterology 6, Supplement_1 (March 1, 2023): 28. http://dx.doi.org/10.1093/jcag/gwac036.050.

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Abstract Background Patients with IBD have an altered microbiome and gut microenvironment leading to changes in their Short-Chain Fatty Acid (SCFA) profile. Pathobionts are commensal organisms that become pathogenic under specific conditions, likely related to microenvironmental gut changes. This is especially relevant to children given that early life exposures are critical to microbiome development and impact immune response. Purpose The objectives of our study were to: 1) determine if microbes from IBD patients are more proinflammatory compared to non-IBD microbes; and 2) define how SCFAs affect host-response to potential pathobionts. Method Fructooligosaccharide (FOS) fermentation and SCFA production were assessed by HPLC-RID using whole-intestinal microbe culture collected as mucosal washes from pIBD (n=10) and non-IBD patients (n=8). Individual anaerobic bacteria were isolated from individual patients and screened for proinflammatory response [interleukin (IL)-1ß] using THP-1 macrophages. Caco-2 (epithelial) or THP-1 cells were pre-exposed to individual SCFAs (50 mM acetate or formate; 10 mM succinate; or 1 mM butyrate or propionate), then infected with Bacteroides fragilis, isolated from patients. Microscopy (bacterial staining with HEMA 3), qPCR, ELISA, TransEpithelial Electrical Resistance (TEER), and culturing were used to determine invasion potential, cytokine expression, barrier, and secretion. Result(s) FOS fermentation by microbes from IBD patients led to increased acetate and decreased butyrate production. Microbes from IBD patients were more proinflammatory, with increased IL-1ß secretion and reactive oxygen species generation, compared to those from non-IBD patients. B. fragilis isolated from an IBD patient was found to be a potential pathobiont with increased invasion and cytokine production in both epithelial and macrophage cells. Invasion was further increased when cells were exposed to SCFAs, particularly acetate and butyrate. Furthermore, the strain isolated from the IBD patient was observed (by microscopy) to be more adherent to the epithelial barrier, causing a loss of membrane integrity (TEER). The inflammasome pathway were significantly upregulated in Caco-2 cells infected with IBD-isolated B. fragilis and incubated with acetate or butyrate. Conclusion(s) The altered microbiome in IBD patients leads to an increased acetate and decreased butyrate, which likely affects host response to microbes and promotes inflammation. This changed microenvironment promotes the development of pathobionts, such as the identified B. fragilis strain we isolated from an IBD patient. The observation that acetate and butyrate increased host susceptibility to this strain indicates that understanding diet and SCFA production are instrumental in treating chronic conditions such as IBD. The role of diet as both a treatment and potential cause of inflammation in IBD is becoming more apparent; therefore, it is crucial that we understand the complex role diet has in host-microbe interactions. Please acknowledge all funding agencies by checking the applicable boxes below CIHR, Other Please indicate your source of funding; Mitacs- Weston Foundation Disclosure of Interest None Declared

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Meisner, Jeffrey, Toni Bransford, Kelsey Miller, Jackson Lee, Adarsh Jose, Michael Giuggio, Megan McComb, et al. "THE SYNTHETIC GLYCAN KB295 OPTIMIZES MICROBIOME COMPOSITION AND FUNCTION IN ULCERATIVE COLITIS – RESULTS FROM A PROOF OF PRINCIPLE HUMAN STUDY." Inflammatory Bowel Diseases 28, Supplement_1 (January 22, 2022): S70—S71. http://dx.doi.org/10.1093/ibd/izac015.114.

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Abstract The pathogenesis of ulcerative colitis (UC) involves genetic susceptibility, immune-mediated tissue injury and environmental factors including disturbances of the gut microbiota. Nearly all current approved therapies modify host immunity, rather than directly targeting the microbiota. Fecal microbiota transplantation provides encouraging evidence for the therapeutic potential of gut microbiome modulation. Bacteria in the GI tract are ecologically differentiated by their ability to use specific glycans as growth substrates, making glycans a promising and safe alternative to target the microbiome. To explore this, we used an ex vivo fecal microbiota culture system to identify a synthetic glycan (KB295) with desirable microbiological activity and conducted a proof of principle study of safety and tolerability of KB295 in patients with UC. Fecal microbial communities from healthy subjects were incubated anaerobically with and without (negative control) KB295. KB295 increased short chain fatty acid (SCFA) production across ten fecal samples to a median concentration of 47.0 mM compared to 15.2 mM with the negative control in culture supernatants, including increases in acetate, propionate, and butyrate in all cases. Metagenomic sequencing of the ex vivo fecal pellets revealed that KB295 depleted pathobionts in the family Enterobacteriaceae to a median relative abundance of 10.8% compared to 38.2% with the negative control. Pathobiont depletion was associated with enrichments of diverse genera in the phyla Bacteroidetes and Firmicutes. Twelve patients with mild to moderate UC were enrolled in an open-label single-arm study with an 8-week intake of KB295. KB295 was well tolerated with generally mild adverse events, and only one AE resulted in discontinuation. The most frequently occurring adverse events were changes in bowel habit, flatulence, and headache. Fecal calprotectin and lactoferrin decreased by median values of 69.0% (n=11) and 86.0% (n=6), respectively, from screening to the end of the KB295 intake. Consistent with the ex vivo preclinical findings, of the subjects for whom we have data to date, the relative abundance of the fecal pathobiont family Enterobacteriaceae decreased from five participants, and the commensal genus Parabacteroides was enriched in four of five participants. These results establish a proof of principle for the glycobiological modulation of gut microbiome composition and function and provide insight into the potential utility of this strategy in patients with ulcerative colitis. The safety, tolerability, and encouraging evidence for reduced inflammation with KB295 call for a Phase 2 study, which is planned.

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Li, Liang, Micheál Mac Aogáin, Tengfei Xu, Tavleen Kaur Jaggi, Louisa L. Y. Chan, Jing Qu, Lan Wei, et al. "Neisseria species as pathobionts in bronchiectasis." Cell Host & Microbe 30, no. 9 (September 2022): 1311–27. http://dx.doi.org/10.1016/j.chom.2022.08.005.

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Alegre, Maria‐Luisa. "Immune impact of commensals versus pathobionts." American Journal of Transplantation 20, no. 4 (March 28, 2020): 913. http://dx.doi.org/10.1111/ajt.15840.

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Zechner, Ellen L. "Inflammatory disease caused by intestinal pathobionts." Current Opinion in Microbiology 35 (February 2017): 64–69. http://dx.doi.org/10.1016/j.mib.2017.01.011.

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Hazime, Hajar, Julia Fritsch, Ana Santander, Nivis Brito, Irina Fernandez, Judith Pignac-Kobinger, Gregory Conner, Maria Abreu, and Juan Burgueno. "INFLAMMATORY CYTOKINES AND MICROBIAL LIGANDS AND METABOLITES INTERACT TO MODULATE DUOX2 EXPRESSION AND ACTIVITY." Inflammatory Bowel Diseases 27, Supplement_1 (January 1, 2021): S26—S27. http://dx.doi.org/10.1093/ibd/izaa347.059.

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Abstract Background The pathogenesis of inflammatory bowel diseases (IBD) is characterized by a dysregulated crosstalk between the host and the microbiome that leads to the development of inflammation and dysbiosis. Dysbiosis in IBD involves an expansion of Proteobacteria and a reduction of Firmicutes, particularly of butyrate-producing species such as Faecalibacterium prausnitzii. The epithelial NADPH oxidase dual oxidase 2 (DUOX2), which prevents bacterial colonization of the mucosa through the production of hydrogen peroxide (H2O2), is the only gene consistently altered in IBD patients before the onset of disease. However, the involvement of DUOX2 in IBD is not well understood. We aimed to define how inflammation and the microbiota regulate DUOX2 activity. Methods C57BI/6J males raised in specific-pathogen free (SPF) and germ-free (GF) conditions underwent a model of dextran sulfate sodium (DSS)-induced colitis for 6 days. We obtained colon specimens for histopathology and isolation of colon epithelial cells (CEC). We stimulated colonoids from wild-type (WT), toll-like receptor 4-KO (Tlr4-KO), and Duox2-KO mice with IFNγ, heat-killed adherent invasive Escherichia coli (AIEC) strain LF82, and heat-killed F. prausnitzii strain A2-165 and determined expression of Duox2, Duoxa2, and production of H2O2. We also treated colonoids with butyrate, a microbial metabolite with anti-inflammatory properties. Extracellular H2O2 production was analyzed by means of the Amplex Red assay, whereas gene expression was determined by qPCR. Results SPF mice undergoing DSS-induced colitis developed overt inflammation that was accompanied by upregulation of Duox2 and Duoxa2, as well as increased production of H2O2 in freshly isolated CECs. DSS-treated GF mice developed a mild inflammation that also caused increased H2O2 production and Duoxa2 upregulation. WT colonoid stimulation with IFNγ and the Crohn’s disease-associated pathobiont AIEC induced Duox2 and Duoxa2 expression, whereas heat-killed F. prausnitzii did not. Similarly, both IFNγ and AIEC promoted epithelial production of H2O2 in WT colonoids but not Duox2-KO colonoids, indicating that epithelial release of H2O2 in response to these stimuli is mediated by DUOX2. Response to AIEC additionally required functional TLR4. Although heat-killed F. prausnitzii did not alter H2O2 production, its metabolite butyrate caused a significant blockade in the release of H2O2 in response to both IFNγ and AIEC. Conclusions Our results show that both inflammation and pathobionts induce the expression and activity of DUOX2, which begets more inflammation. We posit that specific depletion of pathobionts or restitution with butyrate-producing bacteria such as F. prausnitzii may be beneficial in IBD.

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Fickert, Peter, and Hanns-Ulrich Marschall. "Gut pathobionts as triggers for liver diseases." Nature Microbiology 4, no. 3 (February 20, 2019): 380–81. http://dx.doi.org/10.1038/s41564-019-0388-7.

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Purcell, Rachel V., Nadeem O. Kaakoush, Hazel M. Mitchell, John F. Pearson, and Jacqueline I. Keenan. "Gastrointestinal Pathobionts in Pediatric Crohn’s Disease Patients." International Journal of Microbiology 2018 (July 17, 2018): 1–5. http://dx.doi.org/10.1155/2018/9203908.

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Crohn’s disease (CD) is an inflammatory disease of the gastrointestinal tract, with a rising incidence worldwide, particularly in children. CD is thought to arise due to an immune response to environmental factors. The role of bacteria in CD has recently been highlighted, and here, we examine the prevalence of two bacterial species, enterotoxigenicBacteroides fragilis(ETBF) andFusobacterium nucleatum, implicated in gastrointestinal pathologies, in a pediatric CD cohort. Stool samples from 30 children with treatment-naïve CD and 30 age- and sex-matched controls were collected, and DNA was extracted. Quantitative PCR was used to determine the levels of ETBF andF. nucleatumin stool samples. Bacterial positivity and relative abundance were assessed between cases and controls and in relation to disease severity. No associations were found between colonization with ETBF and CD, or between colonization with either ETBF orF. nucleatumand disease severity or presence ofC. concisus. However, a strong association was observed between positivity forF. nucleatumin the stool samples and the occurrence of CD in patients (25/30) as compared to controls (8/30) (P=0.003).F. nucleatumis more prevalent in the stool samples of pediatric CD patients, compared to healthy controls, and may have potential use as a biomarker of pediatric CD.

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Cordell, Barbara J. "Shifting microbiomes: pathobionts hiding in our guts." eBioMedicine 92 (June 2023): 104592. http://dx.doi.org/10.1016/j.ebiom.2023.104592.

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Jochum, Lara, and Bärbel Stecher. "Label or Concept – What Is a Pathobiont?" Trends in Microbiology 28, no. 10 (October 2020): 789–92. http://dx.doi.org/10.1016/j.tim.2020.04.011.

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Chassaing, Benoit, and Andrew T. Gewirtz. "Pathobiont hypnotises enterocytes to promote tumour development." Gut 63, no. 12 (April 29, 2014): 1837–38. http://dx.doi.org/10.1136/gutjnl-2014-306890.

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Fine, Rebecca, Silvio Manfredo Vieira, Daniel Fernando Zegarra Ruiz, and Martin A. Kriegel. "Gut pathobiont translocation induces lymphocyte migration to internal organs in autoimmunity." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 102.16. http://dx.doi.org/10.4049/jimmunol.200.supp.102.16.

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Abstract Gut commensal translocation to distant sites can drive autoimmunity. We have evidence that a gut pathobiont, Enterococcus gallinarum, translocates spontaneously to internal organs in the lupus-prone (NZWxBXSB)F1 mouse model to induce systemic autoimmune disease. Lymphocyte migration during commensal translocation to secondary lymphoid organs is not well characterized but may contribute to understanding host-microbiota interactions in autoimmunity. We thus investigated if gut-imprinted lymphocytes migrate to non-gut organs that are progressively colonized by a pathobiont in the (NZWxBXSB)F1 model. We longitudinally characterized gut homing markers on lymphocytes isolated from various tissues of autoimmune-prone F1 mice and monocolonized C57BL/6 mice. In F1 males, circulating CD4+α4β7+ and CD4+CCR9+ cells were increased with age. These subpopulations were reduced after administration of oral antibiotics that deplete the microbiota including E. gallinarum. Next, we monocolonized non-autoimmune prone C57BL/6 mice with E. gallinarum to track lymphocyte migration specifically due to this pathobiont that we have shown to translocate to liver and spleen, induce Th17 responses and autoantibody production. Aged monocolonized C57BL/6 mice harbored greater Peyer’s patch and splenic CD4+ T cells as well as splenic CD4+α4β7+ T cells, supporting that gut-imprinted lymphocytes follow E. gallinarum to non-gut sites. In summary, we linked gut-imprinted lymphocyte migration to internal organs in the setting of systemic autoimmunity that is induced by a translocating pathobiont. Ongoing studies are aimed at determining if these T cells are commensal-reactive and if blockade of gut homing can abrogate autoimmunity.

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Devkota, Suzanne, and Eugene B. Chang. "Diet-induced expansion of pathobionts in experimental colitis." Gut Microbes 4, no. 2 (January 2013): 172–74. http://dx.doi.org/10.4161/gmic.23589.

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Chow, Janet, Haiqing Tang, and Sarkis K. Mazmanian. "Pathobionts of the gastrointestinal microbiota and inflammatory disease." Current Opinion in Immunology 23, no. 4 (August 2011): 473–80. http://dx.doi.org/10.1016/j.coi.2011.07.010.

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Hecht, Aaron, and Juliane Bubeck Wardenburg. "975 Pathobiont Colonization Resistance by Type VI Secretion." Gastroenterology 150, no. 4 (April 2016): S198. http://dx.doi.org/10.1016/s0016-5085(16)30743-0.

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Pereira, Márcia S., and Martin A. Kriegel. "Evolving concepts of host–pathobiont interactions in autoimmunity." Current Opinion in Immunology 80 (February 2023): 102265. http://dx.doi.org/10.1016/j.coi.2022.102265.

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Siak, Jay, Anthony St. Leger, Kumarkrishna Raychaudhuri, Mary Mattapallil, Ivan J. Fuss, Raphaela Goldbach-Mansky, Warren Strober, and Rachel R. Caspi. "Commensal microbiota as possible pathobiont in autoinflammatory disease." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 120.26. http://dx.doi.org/10.4049/jimmunol.202.supp.120.26.

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Abstract The ocular surface has an associated microbiome that contributes to maintenance of local immune homeostasis and protects the ocular surface from fungal and bacterial infections. However, in individuals with a dysregulated immune response, commensal flora could cause pathology. In this study, we seek to understand how an ocular commensal colonizing humans and mice, C. mastitidis (C. mast), stimulates immunity in the immunologically perturbed host. Cryopyrin Associated Periodic Syndrome (CAPS) patients suffer from systemic and ocular autoinflammatory disease caused by a hyperactive NLRP3 inflammasome. Knock-in mice bearing a mutated NLRP3 gene cloned from a CAPS patient responded to ocular colonization with C. mast by increased conjunctival neutrophilia, which progressed to overt ocular surface disease. Compared to wild type (WT) controls, their BM dendritic cells produced elevated IL-1 in response to C. mast. Additionally, gd T cells, which were primarily the Vg4 subset, isolated from eye-draining lymph nodes of C. mast-associated mutant mice were more activated and produced more IL-17, suggesting a qualitatively analogous but quantitatively amplified response compared to WT. Importantly, the same commensal elicited strongly elevated IL-17 production from leukocytes of inflammasome disease patients when compared with healthy controls. Our results suggest that C. mast induces an abnormal immune response in the NLRP3 mutant and acts as a pathobiont, in contrast to its behavior in the immunologically normal host. Based on these data, we hypothesize that the recurrent non-infectious conjunctivitis observed in CAPS patients may be driven by a hyperactive immune response to their own ocular surface bacteria.

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Juliana, Naomi C. A., Saikat Deb, Mohamed H. Juma, Linda Poort, Andries E. Budding, Abdalla Mbarouk, Said M. Ali, et al. "The Vaginal Microbiota Composition and Genital Infections during and after Pregnancy among Women in Pemba Island, Tanzania." Microorganisms 10, no. 3 (February 25, 2022): 509. http://dx.doi.org/10.3390/microorganisms10030509.

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We investigated the vaginal microbiota (VMB) composition, prevalence of genital pathogens and their association among pregnant and post-delivery women in Pemba Island, Tanzania. Vaginal swabs were collected from 90 women, at two time points during pregnancy (<20 weeks of gestational age [GA] and ≥20 weeks GA) and once after delivery, when possible. IS-pro assay was used for VMB characterization. Chlamydia trachomatis (CT), Neisseria gonorrhea (NG), Trichomonas vaginalis (TV), Mycoplasma genitalium (MG) and human papillomavirus (HPV) were detected by qPCRs. VMB were mostly Lactobacillus dominant during pregnancy and non-Lactobacillus dominant post-delivery. A significant decrease in VMB richness was observed during pregnancy among paired and unpaired samples. Shannon diversity was significantly lower during pregnancy than post-delivery among unpaired samples. Klebsiella species and Streptococcus anginosus were the most commonly identified pathobionts at all timepoints. A high abundance of pathobionts was mostly seen in women with non-Lactobacillus dominant VMB. At ≥20 weeks GA timepoint during pregnancy, 63.0% of the women carrying one or more genital pathogen (either HPV, CT, TV, or MG) had L. iners dominant VMB. NG was not detected pre-delivery. This study contributes evidence on VMB composition, its changes during pregnancy and post-delivery, and their association with pathobionts and genital pathogens.

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Chernevskaya, E. A., M. L. Getsina, R. A. Cherpakov, E. A. Sorokina, A. K. Shabanov, V. V. Moroz, and N. V. Beloborodova. "Sepsis-Associated Metabolites and Their Biotransformation by Intestinal Microbiota." General Reanimatology 19, no. 6 (December 21, 2023): 4–12. http://dx.doi.org/10.15360/1813-9779-2023-6-4-12.

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High concentration of sepsis-associated aromatic microbial metabolites (AMM) stands as a prognostically unfavorable factor, indicating the progression of multiple organ dysfunction and an increased risk of death in patients with sepsis and septic shock. This study is based on a hypothesis that excess of sepsis-associated AMM in patients with sepsis is caused by metabolic alterations (dysfunction) in the intestinal microbiota.The aim of this study was to compare the potential of normobiota and pathobiota to bio-transform sepsis-associated metabolites of aromatic amino acids tyrosine and phenylalanine, such as phenyllactic acid(PhLA) and 4-hydroxyphenyllactic acid (4-HPhLA).Materials and methods. Samples of intestinal contents of patients with septic shock (N=10, pathobiota) and healthy volunteers (N=9, normobiota) were placed in test tubes with the omnipurpose thioglycol medium. The clinical model of excessive inflow of sepsis-associated AMM into the intestine (for example, from blood or sites of inflammation) was reproduced in the in vitro experiment by adding PhLA or 4-HPhLA in clinically significant concentrations (25 mkM) into each test tube with pathobiota and normobiota. After incubation in a thermostat (37°, 24 hours), AMМ concentrations were measured in the samples with pathobiota and normobiota using GC-MS analysis.Results. Concentration of AMM decreased within 24 hours in the tubes with normobiota after PhLA or 4-HPhLA were added. In the tubes with pathobiota, no decrease in AMM concentrations was documented after loading with PhLA or 4-HPhLA. Concentrations of PhLA (P=0.002) and 4-HPhLA (P0.001) were statistically significantly higher in pathobiota samples compared to normobiota.Conclusion. The in vitro experiment demonstrates that after excessive load with sepsis-associated metabolites (PhLA, 4-HPhLA), the microbiota of healthy people is capable to bio-transform such metabolites to the end products of microbial metabolism, while pathobiota of septic patients exhibits altered biotransformational potential. This data demonstrate that microbiota dysfunction may contribute to the pathogenesis of sepsis.

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Kamada, Nobuhiko, Grace Y. Chen, Naohiro Inohara, and Gabriel Núñez. "Control of pathogens and pathobionts by the gut microbiota." Nature Immunology 14, no. 7 (June 18, 2013): 685–90. http://dx.doi.org/10.1038/ni.2608.

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Hajishengallis, George. "Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response." Trends in Immunology 35, no. 1 (January 2014): 3–11. http://dx.doi.org/10.1016/j.it.2013.09.001.

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Howard, Kaitlind C., Octavio A. Gonzalez, and Sylvie Garneau-Tsodikova. "Porphyromonas gingivalis: where do we stand in our battle against this oral pathogen?" RSC Medicinal Chemistry 12, no. 5 (2021): 666–704. http://dx.doi.org/10.1039/d0md00424c.

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Local and/or systemic antibacterial therapy has been extensively studied and suggested to control periodontopathogens like P. gingivalis. However, more effective and specific antibacterial agents against oral pathobionts remain to be developed.

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Capparelli, Rosanna, Paola Cuomo, Antonio Gentile, and Domenico Iannelli. "Microbiota–Liver Diseases Interactions." International Journal of Molecular Sciences 24, no. 4 (February 15, 2023): 3883. http://dx.doi.org/10.3390/ijms24043883.

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Gut microbiota regulates essential processes of host metabolism and physiology: synthesis of vitamins, digestion of foods non-digestible by the host (such as fibers), and—most important—protects the digestive tract from pathogens. In this study, we focus on the CRISPR/Cas9 technology, which is extensively used to correct multiple diseases, including liver diseases. Then, we discuss the non-alcoholic fatty liver disease (NAFLD), affecting more than 25% of the global population; colorectal cancer (CRC) is second in mortality. We give space to rarely discussed topics, such as pathobionts and multiple mutations. Pathobionts help to understand the origin and complexity of the microbiota. Since several types of cancers have as target the gut, it is vital extending the research of multiple mutations to the type of cancers affecting the gut–liver axis.

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Guerrini, Matteo M., Alexis Vogelzang, and Sidonia Fagarasan. "A Hen in the Wolf Den: A Pathobiont Tale." Immunity 48, no. 4 (April 2018): 628–31. http://dx.doi.org/10.1016/j.immuni.2018.04.003.

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Kim, Donghyun, and Wan-Uk Kim. "Editorial: CanPrevotella copriBe a Causative Pathobiont in Rheumatoid Arthritis?" Arthritis & Rheumatology 68, no. 11 (October 27, 2016): 2565–67. http://dx.doi.org/10.1002/art.39807.

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Jiao, Y., M. Hasegawa, and N. Inohara. "The Role of Oral Pathobionts in Dysbiosis during Periodontitis Development." Journal of Dental Research 93, no. 6 (March 19, 2014): 539–46. http://dx.doi.org/10.1177/0022034514528212.

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Lang, Sonja, Münevver Demir, and Bernd Schnabl. "Targeting pathobionts for the treatment of alcohol‐associated liver disease." Liver International 41, no. 1 (November 17, 2020): 239–40. http://dx.doi.org/10.1111/liv.14723.

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Singh, Shivani, and Leopoldo N. Segal. "A lung pathobiont story: Thinking outside the Koch’s postulate box." Cell Host & Microbe 30, no. 9 (September 2022): 1196–98. http://dx.doi.org/10.1016/j.chom.2022.08.012.

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Jellbauer, Stefan, and Manuela Raffatellu. "An intestinal arsonist: pathobiont ignites IBD and flees the scene." Gut 63, no. 7 (September 11, 2013): 1034–35. http://dx.doi.org/10.1136/gutjnl-2013-305589.

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Bass, David, Grant D. Stentiford, Han-Ching Wang, Britt Koskella, and Charles R. Tyler. "The Pathobiome in Animal and Plant Diseases." Trends in Ecology & Evolution 34, no. 11 (November 2019): 996–1008. http://dx.doi.org/10.1016/j.tree.2019.07.012.

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Lau, Trevor C., Aline A. Fiebig-Comyn, Christopher R. Shaler, Joseph B. McPhee, Brian K. Coombes, and Jonathan D. Schertzer. "Low dietary fiber promotes enteric expansion of a Crohn’s disease-associated pathobiont independent of obesity." American Journal of Physiology-Endocrinology and Metabolism 321, no. 3 (September 1, 2021): E338—E350. http://dx.doi.org/10.1152/ajpendo.00134.2021.

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It is commonly thought that obesity or a high-fat diet alters pathogenic bacteria and promotes inflammatory gut diseases. We found that lower dietary fiber is a key factor that expands a gut pathobiont linked to Crohn’s disease, independent of obesity status in mice.

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Amend, L., B. Gilbert, A. Finckh, and T. Strowig. "AB0018 SERUM ANTIBODIES AGAINST ORAL AND INTESTINAL BACTERIA IN INDIVIDUALS AT RISK FOR RHEUMATOID ARTHRITIS, CHRONIC RA PATIENTS, AND NEW ONSET PATIENTS WITH DIFFERENT RHEUMATIC DISEASES." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1144.1–1144. http://dx.doi.org/10.1136/annrheumdis-2022-eular.498.

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BackgroundEvidence about the influence of microbes in autoimmune diseases such as rheumatoid arthritis (RA) has grown in recent years. However, the precise role of specific bacteria remains largely unknown. Previous investigations identified several oral pathobionts to be specifically targeted by serum antibodies in RA patients.1 In addition, Pianta et al.2 identified recognition of Prevotella copri by the immune system of RA patients. It has to be noted, however, that such findings have neither been reproduced, nor studied in different disease stages. Also, the assumptions made for P. copri relied on a single strain, the type strain DSM18205, isolated from a healthy individual.3 However, there is recent evidence suggesting P. copri to be a non-monotypic species, meaning it clusters into several subspecies displaying geno- and phenotypic differences4.ObjectivesThis study aimed to quantify serum antibodies targeting different P. copri strains, as well as known oral pathobionts in patients with different rheumatic diseases or in various stages of RA development.MethodsWe used custom-made ELISA assays measuring pathogen-specific IgG levels in patient’s serum. Samples were tested against P. copri strains isolated from stool samples of healthy donors and RA patients, as well as the following oral pathobionts: Porphyromonas gingivalis, Prevotella intermedia and Prevotella melaninogenica. We analyzed 120 samples from a Swiss cohort of first-degree relatives, individuals in various pre-clinical RA stages (SCREEN-RA), and 45 samples of patients with established RA (SCQM cohort). These participants were categorized as asymptomatic seronegative individuals (FDR), individuals with ‘systemic autoimmunity associated with RA’ (ACPA and/or RF autoantibodies) (preRA 1), individuals with ’clinically suspect arthralgia’ or ‘undifferentiated arthritis’ with/without autoantibodies (preRA 2) and chronic RA patients (cRA). Additionally, we included 92 serum samples from new-onset patients diagnosed with RA, psoriatic arthritis (PsA) axial spondyloarthritis (SpA), or other non-rheumatic diseases (NRD) recruited via the german RheumaVOR cohort (Table 1).Table 1.Overview human cohort studiescohortSCREEN-RASCQMRheumaVORpatient groupFDRpreRA 1preRA 2cRANRDRAPsAaxSpAtotal numbers4240384532143016age median5454595643.551.550.533sex (F/M)32/1035/534/435/1019/139/515/1510/6ACPA positivity0259310700RF positivity0198340700ResultsOverall, there were no significant differences in the IgG reactivity profiles between the patient groups against the distinct P. copri strains or oral pathobionts (Figure 1). However, performing this assay with P. copri strains from distinct subspecies identified clear differences and revealed important variability in the IgG reactivity.Figure 1.Serum IgG responses against different microbes from individuals recruited via SCREEN-RA, SCQM or RheumaVOR cohortConclusionOur study failed to reproduce previous results and could confirm neither P. copri nor the three oral pathobionts to be particularly targeted by systemic IgG immune reactions in RA patients. However, we identified strain-specific differences in the IgG reactivity against P. copri, regardless of disease type or state. The latter suggests that the overall immunostimulatory potential of P. copri might be dependent on its strain/subspecies level. Our findings underline the necessity of P. copri strain-level characterization when studying host-microbiota immune interactions.References[1]Ogrendik et al. MedGenMed (2005)[2]Pianta et al. Arthritis Rheumatol. (2017)[3]Hayashi et al. Int. J. Syst. Evol. Microbiol. (2007)[4]Tett et al. Cell Host & Microbe (2019)Disclosure of InterestsNone declared

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Taku, Ongeziwe, Adrian Brink, Tracy L. Meiring, Keletso Phohlo, Charles B. Businge, Zizipho Z. A. Mbulawa, and Anna-Lise Williamson. "Detection of sexually transmitted pathogens and co-infection with human papillomavirus in women residing in rural Eastern Cape, South Africa." PeerJ 9 (March 3, 2021): e10793. http://dx.doi.org/10.7717/peerj.10793.

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Background South African women of reproductive age have a high burden of sexually transmitted infections (STIs), including human papillomavirus (HPV) infection. However, there is limited information on the prevalence of sexually transmitted pathogens in women from rural Eastern Cape Province, South Africa. The study aims at determining the prevalence of sexually transmitted pathogens and co-infection with high-risk (HR) HPV among women from rural Eastern Cape Province, South Africa. Methods A total of 205 cervical specimens were collected from women aged ≥ 30 years from a rural community-based clinic. The samples were tested for a panel of pathogenic STIs [Chlamydia trachomatis (serovars A-K & L1-L3), Haemophilus ducreyi, Herpes Simplex Virus (Types 1 & 2), Neisseria gonorrhoeae, Treponema pallidum, Trichomonas vaginalis (TV), and pathobionts [Mycoplasma genitalium (MG), Mycoplasma hominis (MH) and Ureaplasma spp. (UP)] using a multiplex PCR STD direct flow chip assay through a manual Hybrispot platform (Master Diagnostica, Granada, Spain). HR-HPV detection was performed by Hybrid Capture-2 assay. Results High-risk HPV prevalence was 32.2% (66/205) and HIV-1 prevalence was 38.5% (79/205). The overall prevalence of six pathogenic STIs was 22.9% (47/205), with TV having the highest prevalence (15.6%; 32/205). UP (70.2%, 144/205) and MH (36.6%, 75/205) were the most frequently detected pathobionts. Co-infection with ≥ 2 pathogens pathobionts was observed among 52.7% (108/205) participants. Of the six pathogenic STIs, three participants had more than one STI (1.46%) with the presence of MH and UP. HSV-2 (OR: 4.17, CI [1.184–14.690]) and HIV infection (OR: 2.11, CI [1.145–3.873]) were independent STIs associated with HR-HPV infection. Conclusions The high prevalence of pathogenic STIs underscores the need to improve syndromic management policy by implementing effective strategies of prevention, screening tests, and management. HSV-2 and HIV positive remain strongly associated with HR-HPV infection.

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Saquib, Shahabe Abullais, Nabeeh Abdullah AlQahtani, Irfan Ahmad, Mohammed Abdul Kader, Sami Saeed Al Shahrani, and Elyas Ali Asiri. "Evaluation and Comparison of Antibacterial Efficacy of Herbal Extracts in Combination with Antibiotics on Periodontal pathobionts: An in vitro Microbiological Study." Antibiotics 8, no. 3 (July 1, 2019): 89. http://dx.doi.org/10.3390/antibiotics8030089.

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Background: In the past few decades focus of research has been toward herbal medicines because of growing bacterial resistance and side effects of antimicrobial agents. The extract derived from the plants may increase the efficacy of antibiotics when used in combination against pathogenic bacteria. In the current study, the synergistic antibacterial efficacy of plant extracts in combination with antibiotics has been assessed on selected periodontal pathogens. Methods: Ethanolic extracts were prepared from Salvadora persica (Miswak) and Cinnamomum zeylanicum (Ceylon cinnamon), by the soxhalate method. Plaque samples were collected from clinical periodontitis patients to isolate and grow the periodontal pathobionts under favorable conditions. Susceptibility of bacteria to the extracts was assessed by gauging the diameter of the inhibition zones. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of plant extracts were determined against each bacterium. Synergistic activity of plants extract in combination with antibiotics against the bacteria was also assessed by measuring the diameter of the inhibition zones. Results: Ethanolic extract of both the plants showed an inhibitory effect on the proliferation and growth of all four strains of periodontal pathobionts. Maximum antibacterial activity was exhibited by C. zeylanicum against Tannerella forsythia (MIC = 1.56 ± 0.24 mg/mL, MBC = 6.25 ± 0.68 mg/mL), whereas among all the studied groups the minimum activity was reported by C. zeylanicum against Aggregatibacter actinomycetemcomitans the (MIC = 12.5 ± 3.25 mg/mL, MBC = 75 ± 8.23 mg/mL). Combination of herbal extracts with different antibiotics revealed a synergistic antibacterial effect. The best synergism was exhibited by S. persica with metronidazole against A. actinomycetemcomitans (27 ± 1.78). Conclusions: Current in vitro study showed variable antibacterial activity by experimented herbal extracts against periodontal pathobionts. The synergistic test showed significant antibacterial activity when plant extracts were combined with antibiotics.

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Franz, Mathias, Roland R. Regoes, and Jens Rolff. "How infection-triggered pathobionts influence virulence evolution." Philosophical Transactions of the Royal Society B: Biological Sciences 379, no. 1901 (March 18, 2024). http://dx.doi.org/10.1098/rstb.2023.0067.

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Host–pathogen interactions can be influenced by the host microbiota, as the microbiota can facilitate or prevent pathogen infections. In addition, members of the microbiota can become virulent. Such pathobionts can cause co-infections when a pathogen infection alters the host immune system and triggers dysbiosis. Here we performed a theoretical investigation of how pathobiont co-infections affect the evolution of pathogen virulence. We explored the possibility that the likelihood of pathobiont co-infection depends on the evolving virulence of the pathogen. We found that, in contrast to the expectation from classical theory, increased virulence is not always selected for. For an increasing likelihood of co-infection with increasing pathogen virulence, we found scenario-specific selection for either increased or decreased virulence. Evolutionary changes, however, in pathogen virulence do not always translate into similar changes in combined virulence of the pathogen and the pathobiont. Only in one of the scenarios where pathobiont co-infection is triggered above a specific virulence level we found a reduction in combined virulence. This was not the case when the probability of pathobiont co-infection linearly increased with pathogen virulence. Taken together, our study draws attention to the possibility that host–microbiota interactions can be both the driver and the target of pathogen evolution. This article is part of the theme issue ‘Sculpting the microbiome: how host factors determine and respond to microbial colonization’.

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Joshi, C., A. Mezincescu, M. Gunasekara, A. Rudd, H. Botchorichvili, S. Sabir, C. Dospinescu, et al. "Myocardial infarction risk is increased by periodontal pathobionts: a cross-sectional study." Scientific Reports 12, no. 1 (November 3, 2022). http://dx.doi.org/10.1038/s41598-022-19154-z.

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AbstractTo establish the role of periodontal pathobionts as a risk factor for myocardial infarction, we examined the contribution of five periodontal pathobionts and their virulence genes’ expressions to myocardial injury (Troponin-I) and coronary artery disease burden (SYNTAX-I scores) using hierarchical linear regression. Pathobiont loads in subgingival-plaques and intra-coronary-thrombi were compared. Troponin-I release increased with one 16S rRNA gene copy/ng DNA of Porphyromonas gingivalis (β = 6.8 × 10–6, 95% CI = 1.1 × 10–7–2.1 × 10–5), one-fold increased expressions of fimA (β = 14.3, 95% CI = 1.5–27.1), bioF-3 (β = 7.8, 95% CI = 1.1–12.3), prtH (β = 1107.8, 95% CI = 235.6–2451.3), prtP (β = 6772.8, 95% CI = 2418.7–11,126.9), ltxA (β = 1811.8, 95% CI = 217.1–3840.8), cdtB (β = 568.3, 95% CI = 113.4–1250.1), all p < 0.05. SYNTAX-I score increased with one 16S rRNA gene copy/ng DNA of Porphyromonas gingivalis (β = 3.8 × 10–9, 95% CI = 3.6 × 10–10-1.8 × 10–8), one-fold increased expressions of fimA (β = 1.2, 95% CI = 1.1–2.1), bioF-3 (β = 1.1, 95% CI = 1–5.2), prtP (β = 3, 95% CI = 1.3–4.6), ltxA (β = 1.5, 95% CI = 1.2–2.5), all p < 0.05. Within-subject Porphyromonas gingivalis and Tannerella forsythia from intra-coronary-thrombi and subgingival-plaques correlated (rho = 0.6, p < 0.05). Higher pathobiont load and/or upregulated virulence are risk factors for myocardial infarction.Trial registration: ClinicalTrials.gov Identifier: NCT04719026.

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Green, Sabrina I., Carmen Gu Liu, Xue Yu, Shelley Gibson, Wilhem Salmen, Anubama Rajan, Hannah E. Carter, et al. "Targeting of Mammalian Glycans Enhances Phage Predation in the Gastrointestinal Tract." mBio 12, no. 1 (February 9, 2021). http://dx.doi.org/10.1128/mbio.03474-20.

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ABSTRACT The human gastrointestinal mucosal surface consists of a eukaryotic epithelium, a prokaryotic microbiota, and a carbohydrate-rich interface that separates them. In the gastrointestinal tract, the interaction of bacteriophages (phages) and their prokaryotic hosts influences the health of the mammalian host, especially colonization with invasive pathobionts. Antibiotics may be used, but they also kill protective commensals. Here, we report a novel phage whose lytic cycle is enhanced in intestinal environments. The tail fiber gene, whose protein product binds human heparan sulfated proteoglycans and localizes the phage to the epithelial cell surface, positions it near its bacterial host, a type of locational targeting mechanism. This finding offers the prospect of developing mucosal targeting phage to selectively remove invasive pathobiont species from mucosal surfaces. IMPORTANCE Invasive pathobionts or microbes capable of causing disease can reside deep within the mucosal epithelium of our gastrointestinal tract. Targeted effective antibacterial therapies are needed to combat these disease-causing organisms, many of which may be multidrug resistant. Here, we isolated a lytic bacteriophage (phage) that can localize to the epithelial surface by binding heparan sulfated glycans, positioning it near its host, Escherichia coli. This targeted therapy can be used to selectively remove invasive pathobionts from the gastrointestinal tract, preventing the development of disease.

Journal articles on the topic 'Pathobionte'

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