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1
Meyerholz, David K., Thomas J. Stabel, and Norman F. Cheville. "Segmented Filamentous Bacteria Interact with Intraepithelial Mononuclear Cells." Infection and Immunity 70, no. 6 (June 2002): 3277–80. http://dx.doi.org/10.1128/iai.70.6.3277-3280.2002.
Повний текст джерелаАнотація:
ABSTRACT Segmented filamentous bacteria (SFB) are found in multiple species and play an important role in the development of mucosal immunity. The mechanism by which the bacteria interact with the immune system has not been well defined. We provide morphologic evidence of direct interaction between SFB and intraepithelial mononuclear cells.
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Wilmore, Joel, Gregory Sonnenberg, David Artis, and David Allman. "Segmented filamentous bacteria induce systemic IgA responses to commensal bacteria (MUC4P.854)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 133.30. http://dx.doi.org/10.4049/jimmunol.192.supp.133.30.
Повний текст джерелаАнотація:
Abstract IgA is a component of the mucosal barrier surface and plays an important part in maintaining separation between the host and the commensal microbiota. Mucosal IgA responses are considered short-lived and restricted to mucosal sites with no systemic dissemination. However, there is little known about the regulation and maintenance of IgA secreting plasma cells (PCs) and how they compare to bone marrow PCs. Interestingly, we find that IgA secreting PCs make up a large proportion of the bone marrow PC pool in mice colonized with segmented filamentous bacteria (SFB), but not in germ-free or conventional SFB free mice. The increase in IgA PCs in the bone marrow correlates with a large increase in serum IgA. The co-housing of SFB free mice with SFB colonized mice results in significantly increased levels of IgA in the serum and higher numbers of IgA+ PCs in the bone marrow. This process is dependent upon T cells, because SFB colonized TCRβ-/-δ-/- mice have similar levels of IgA bone marrow PCs as wild-type SFB free mice. The SFB associated increase of IgA antibody titers coincides with the ability to detect commensal bacteria specific IgA in the serum. These data suggest that the induction of systemic IgA is influenced by the composition of the commensal microbiota. These results highlight the need for greater understanding of the role commensal bacteria play in systemic immunity, which could impact oral vaccine development and autoimmunity.
3
Snel, J., C. C. Hermsen, H. J. Smits, N. A. Bos, WMC Eling, J. J. Cebra, and P. J. Heidt. "Interactions between gut-associated lymphoid tissue and colonization levels of indigenous, segmented, filamentous bacteria in the small intestine of mice." Canadian Journal of Microbiology 44, no. 12 (December 1, 1998): 1177–82. http://dx.doi.org/10.1139/w98-122.
Повний текст джерелаАнотація:
Unlike most other indigenous bacteria, segmented filamentous bacteria (SFB) are potent activators of the mucosal immune system. SFB are strongly anchored to the epithelial cells of the small intestine where they have a preference for mucosal lymphoid epithelium. Since SFB are only present in high numbers shortly after weaning, it was investigated whether an SFB-induced immune reaction results in the removal of these bacteria from the small intestine. A correlation was found between age and colonization levels in the small intestines of SFB monoassociated Swiss mice. Five-week-old athymic BALB/c (nu/nu) mice showed lower colonization levels than their heterozygous littermates, but the opposite was found at the age of 12 weeks. However, SFB inoculation of germfree Swiss mice resulted in higher colonization levels in 5-week-old mice when compared with 4-month-old mice. We conclude that SFB colonization levels in the small intestine are likely influenced by the activity of the mucosal immune system. However, an additional age-dependent factor that modulates SFB colonization levels cannot be excluded.Key words: segmented filamentous bacteria, small intestine, gut-associated lymphoid tissue.
4
Grześkowiak, Łukasz, Beatriz Martínez-Vallespín, Jürgen Zentek, and Wilfried Vahjen. "A Preliminary Survey of the Distribution of Segmented Filamentous Bacteria in the Porcine Gastrointestinal Tract." Current Microbiology 78, no. 10 (September 3, 2021): 3757–61. http://dx.doi.org/10.1007/s00284-021-02636-0.
Повний текст джерелаАнотація:
AbstractSegmented filamentous bacteria (SFB) are present in various animal species including pigs. The aim of this work was to analyze the occurrence of SFB in different parts of the gastrointestinal tract of piglets of different ages. A total of 377 DNA extracts from stomach, jejunum, ileum, cecum and colon digesta, and from feces collected on different time points, originating from 155 animals, were screened by qPCR method with primers specific for the SFB. SFB sequences were detected in 74 of 377 samples (19.6%) from 155 animals in total. SFB were most abundant in ileum (50.0%), cecum (45.0%), and colon (37.0%), followed by feces (14.6%). SFB prevalence in sows was 12.9% (13/101) and 75.9% (41/54) in individual piglets. Of the 41 SFB-positive piglets, only two samples were from pre-weaning animals, while the rest of samples originated from post-weaning piglets. SFB sequences are abundant in post-weaning piglets, but not in suckling or adult animals. They are most abundant in the ileum and cecum of pigs. Further studies are warranted to reveal the role of SFB in pigs.
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Metwaly, A., J. Calasan, N. Waldschmitt, S. Khaloian, D. Häcker, M. Ahmed, L. F. Butto, et al. "P059 Diet controls segmented filamentous bacteria in driving Crohn’s disease-like inflammation in TNFdeltaARE mice." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i168. http://dx.doi.org/10.1093/ecco-jcc/jjab232.188.
Повний текст джерелаАнотація:
Abstract Background Crohn’s disease (CD)-like inflammation in TNFdeltaARE mice (ARE) mice is triggered by dysbiotic gut microbial communities. Similar to the therapeutic effect of exclusive enteral nutrition in CD, dietary intervention using semi-synthetic experimental diet prevents disease development in ARE mice. The aim of this study is to identify the causal microbial cues responsible for CD-like inflammation and to dissect the protective role of diet in ARE mice. Methods Bacterial communities in ARE and wildtype (WT) mice were profiled by 16S rRNA gene sequencing, FISH and qPCR. Germfree WT and ARE mice were colonized with segmented filamentous bacteria (SFB) from dysbiotic ARE mice. Disease activity, cytokine expression, mucosal immune cell infiltrates as well as Paneth and goblet cells phenotypes were assessed in murine ileal and colonic tissue. To assess the influence of diet on disease development, ARE mice were fed either chow, purified semi-synthetic experimental diet (SED) or fiber-rich diet. Impact of SFB on ileo-colonic inflammation was tested in additional mouse models (XIAP-/- and IL10 -/-). Mucosal biopsies from adult and pediatric IBD patients (N=407) were screened for the presence of human SFB using SFB-specific PCR primers. Results Under specific pathogen-free (SPF) conditions, ARE mice developed CD-like ileal inflammation which correlated strongly with increasing abundance of SFB. Mono-colonization of germfree ARE mice with SFB resulted in severe enterocolitis. Parallel to high tissue levels of TNF and IL-17, SPF-mediated inflammation was associated with neutrophil infiltration and the expansion of IFNγ expressing Th1 cells in the mucosa. Loss of Paneth and goblet cell function allowed SFB to penetrate mucus layers towards the epithelium. SED eradicated SFB and completely abolished inflammation in ARE mice. In contrast, fiber-rich diet partially restored SFB colonization and led to increased levels of inflammatory cytokines. SFB mono-colonization of GF XIAP-/- and IL10 -/- failed to induce inflammation, emphasizing host specificity to the mucosa-adherent SFB. Presence of SFB was confirmed in 12 ileal and 11 colonic mucosal biopsies from IBD patients with active or inactive disease. Conclusion We identified a novel pathogenic role of SFB in driving severe CD-like ileo-colonic inflammation characterized by loss of Paneth and goblet cell functions in ARE mice. Detection of SFB in mucosal biopsies of patients with IBD opens new perspectives about therapeutic strategies targeting SFB-mediated processes. Purified diet antagonized SFB colonization and prevented disease development in ARE mice in contrast to fiber-rich diet, clearly demonstrating the important role of diet in modulating a novel IBD-relevant pathobiont.
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Sano, Teruyuki, Yi Yang, Gretchen Diehl, Alessandra Chen, Daniel H. Kaplan, and Dan R. Littman. "Multi-step Th17 differentiation in response to segmented filamentous bacteria in the mouse intestine." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 67.1. http://dx.doi.org/10.4049/jimmunol.196.supp.67.1.
Повний текст джерелаАнотація:
Abstract Th17 cells have significant roles in maintaining homeostasis and regulating host defense against various pathogens in our bodies. Our laboratory initially identified segmented filamentous bacteria (SFB) as a unique commensal that is sufficient for Th17 cell differentiation and promotion of Th17-dependent autoimmune diseases such as a mouse model of spontaneous arthritis. The molecular and cellular requirements of SFB-induced Th17 cell differentiation are still unclear. To understand the whole process of Th17 cells differentiation in vivo, we developed SFB-specific T cell receptor transgenic (7B8) mice. We can trace SFB-specific Th17 cell differentiation and response by transferring fluorescently-labeled 7B8 naïve T cells into SFB-gavaged host mice. Using this approach, we have elucidated the requirements for cytokines and antigen presenting cells (APCs) to understand the process of Th17 cell differentiation. Here, we describe that initial induction and expansion of Th17 cells occurs in mesenteric lymph nodes (MLN), and their subsequent migration to intestine is integrin β7-dependent. Although RORγt expression in Th17 cells is mainly dependent on IL-6 signaling in the MLN, IL-23R signaling also contributes to RORγt expression in Th17 cells in the ileum in the absence of IL-6. CD103+ CD11b+ APCs are not important for induction and initial expansion of SFB-specific Th17 cells in MLN, but play important roles in maintenance of SFB-specific Th17 cells in the ileum. Taken together, these results indicate that Th17 cell differentiation proceeds in multiple discrete stages.
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Kumar, Pawan, Jeremy McAleer, Waleed Elsegeiny, Rachel Armentrout, Derek Pociask, and Jay Kolls. "Hyper Th17 responses in IL-17R knockout is regulated by segmented filamentous bacteria (SFB) (MUC4P.857)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 133.33. http://dx.doi.org/10.4049/jimmunol.192.supp.133.33.
Повний текст джерелаАнотація:
Abstract Blockade or genetic deletion of IL-17RA resulted in marked increases in IL-17 response by T-cells. We hypothesize that the hyper Th17 response in IL-17 deficient mice is due to alterations of the gut microbiome particularly overgrowth of segmented filamentous bacteria (SFB). Our data shows that Il17ra-/- and Il17rc-/- mice have overgrowth of SFB (10 fold higher than WT.Taconic), suggesting a critical role of IL-17 signaling in SFB colonization. Higher SFB colonization in Il17ra-/- and Il17rc-/- mice results in expansion of IL-17A and IL-22 producing Th17 cells. As further evidence that this expansion was not T-cell intrinsic, we observed similar frequencies of IL-17 producing cells in WT and Il17ra-/- when naïve T-cells were polarized in vitro to Th17 cells. Furthermore, vancomycin depletion of SFB in Il17ra-/- mice resulted into fewer Th17 cells in the lamina propria and spleen, suggesting gut microflora responsible for hyper Th17 response. SFB-colony free WT mice with intact IL-17 signaling can control SFB overgrowth but IL-17 deficient mice could not following SFB inoculation. To further define the role of IL-17 in SFB colonization, we have generated SFB-free Il17ra conditional knockout (Il17rafl/flxe2a cre) mice. SFB-free Il17rafl/flxe2a cre mice are devoid of hyper Th17 responses, and SFB inoculation resulted into acquisition of hyper Th17 phenotype as observed in Il17ra-/-. Our data suggest that IL-17 signaling regulates SFB colonization and associated Th17 responses.
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Umesaki, Yoshinori, Hiromi Setoyama, Satoshi Matsumoto, Akemi Imaoka, and Kikuji Itoh. "Differential Roles of Segmented Filamentous Bacteria and Clostridia in Development of the Intestinal Immune System." Infection and Immunity 67, no. 7 (July 1, 1999): 3504–11. http://dx.doi.org/10.1128/iai.67.7.3504-3511.1999.
Повний текст джерелаАнотація:
ABSTRACT The presence of microflora in the digestive tract promotes the development of the intestinal immune system. In this study, to evaluate the roles of two types of indigenous microbe, segmented filamentous bacteria (SFB) and clostridia, whose habitats are the small and large intestines, respectively, in this immunological development, we analyzed three kinds of gnotobiotic mice contaminated with SFB, clostridia, and both SFB and clostridia, respectively, in comparison with germfree (GF) or conventionalized (Cvd) mice associated with specific-pathogen-free flora. In the small intestine, the number of αβ T-cell receptor-bearing intraepithelial lymphocytes (αβIEL) increased in SFB-associated mice (SFB-mice) but not in clostridium-associated mice (Clost-mice). There was no great difference in Vβ usage among GF mice, Cvd mice, and these gnotobiotic mice, although the association with SFB decreased the proportion of Vβ6+ cells in CD8β− subsets to some extent, compared to that in GF mice. The expression of major histocompatibility complex class II molecules on the epithelial cells was observed in SFB-mice but not in Clost-mice. On the other hand, in the large intestine, the ratio of the number of CD4−CD8+ cells to that of CD4+ CD8−cells in αβIEL increased in Clost-mice but not in SFB-mice. On association with both SFB and clostridia, the numbers and phenotypes of IEL in the small and large intestines changed to become similar to those in Cvd mice. In particular, the ratio of the number of CD8αβ+ cells to that of CD8αα+ cells in αβIEL, unusually elevated in the small intestines of SFB-mice, decreased to the level in Cvd mice on contamination with both SFB and clostridia. The number of immunoglobulin A (IgA)-producing cells in the lamina propria was more elevated in SFB-mice than in Clost-mice, not only in the ileum but also in the colon. The number of IgA-producing cells in the colons of Clost-mice was a little increased compared to that in GF mice. Taken together, SFB and clostridia promoted the development of both IEL and IgA-producing cells in the small intestine and that of only IEL in the large intestine, respectively, suggesting the occurrence of compartmentalization of the immunological responses to the indigenous bacteria between the small and large intestines.
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Tan, Tze Guan, Esen Sefik, Naama Geva-Zatorsky, Lindsay Kua, Debdut Naskar, Fei Teng, Lesley Pasman, et al. "Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice." Proceedings of the National Academy of Sciences 113, no. 50 (November 23, 2016): E8141—E8150. http://dx.doi.org/10.1073/pnas.1617460113.
Повний текст джерелаАнотація:
Th17 cells accrue in the intestine in response to particular microbes. In rodents, segmented filamentous bacteria (SFB) induce intestinal Th17 cells, but analogously functioning microbes in humans remain undefined. Here, we identified human symbiont bacterial species, in particularBifidobacterium adolescentis, that could, alone, induce Th17 cells in the murine intestine. Similar to SFB,B. adolescentiswas closely associated with the gut epithelium and engendered cognate Th17 cells without attendant inflammation. However,B. adolescentiselicited a transcriptional program clearly distinct from that of SFB, suggesting an alternative mechanism of promoting Th17 cell accumulation. Inoculation of mice withB. adolescentisexacerbated autoimmune arthritis in the K/BxN mouse model. Several off-the-shelf probiotic preparations that includeBifidobacteriumstrains also drove intestinal Th17 cell accumulation.
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Klaasen, H. L. B. M., J. P. Koopman, M. E. Van Den Brink, M. H. Bakker, F. G. J. Poelma, and A. C. Beynen. "Intestinal, segmented, filamentous bacteria in a wide range of vertebrate species." Laboratory Animals 27, no. 2 (April 1, 1993): 141–50. http://dx.doi.org/10.1258/002367793780810441.
Повний текст джерелаАнотація:
Segmented, filamentous bacteria (SFBs) form a group of bacteria with similar morphology and are identified on the basis of their morphology only. The relationships of these organisms are unclear as the application of formal taxonomic criteria is impossible currently due to the lack of an in vitro technique to culture SFBs. The intestine of laboratory animals such as mice, rats, chickens, dogs, cats and pigs is known to harbour SFBs. To see whether this extends to other animal species, intestines from 18 vertebrate species, including man, were examined. SFBs were detected with light microscopy in the cat, dog, rhesus monkey, crab-eating macaque, domestic fowl, South African claw-footed toad, carp, man, laboratory mouse and rat, wood mouse, jackdaw and magpie. These results suggest that non-pathogenic SFBs are ubiquitous in the animal kingdom. Among apparently identical animals, there was considerable variation in the degree of SFB colonization. It is suggested that SFB colonization could serve as a criterion of standardization of laboratory animals.
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Kang, Byunghyun, Eun-Do Kim, Bong-Hyun Kim, Tomohiro Tomachi, Jianping He, and Brian L. Kelsall. "Segmented filamentous bacteria (SFB) drives enhanced T cell-dependent IgA and IgG2b responses in Peyer’s patches." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 218.10. http://dx.doi.org/10.4049/jimmunol.210.supp.218.10.
Повний текст джерелаАнотація:
Abstract Peyer’s patches (PPs) are the major site for T-cell dependent IgA B-cell differentiation. Segmented filamentous bacteria (SFB) are commensal bacteria that preferentially colonize the ileum, mainly over PPs. SFB colonization of germ-free mice induces polyclonal IgA responses by unclear mechanisms. Using scmRNAseq and flow cytometry we found SFB colonization of SPF mice induced an increase in the size and overall cell number in PPs that includes enhanced numbers of naïve, follicular, and germinal center B-cells as well as Th 17 and Tfh cells. SFB colonization increased the numbers of IgA +and IgG2b +, but not IgG1 +B-cells in PPs. Enhanced class-switching to IgA and IgG2b was dependent on T-cells, CCR6, CD40-CD40L and DC-expression of MHCII, as well as to some degree on IL-6. An increased number of activated CD11c +SIRPa +BST2 −CD11b +DCs with CCR6 +Th17 of SFB +compared to SFB −mice suggests increased initiation of IgA class switching in the PP subepithelial dome (SED). SFB colonization increased the conversion of Th17 into Tfh cells, however unlike previous reports, SFB-colonized IL-17R −/−and CD4 CRE-RORg tfl/flmice indicated that neither IL-17, nor the enhanced Tfh conversion from Th17 cells is required for increased IgA and IgG2b responses. Finally, B cell repertoire analysis from IgA +, IgG1 +and IgG2b +PP B cells showed SFB colonization affected the B-cell repertoire qualitatively as well as quantitatively. Together, these data indicate that SFB colonization enhances the recruitment of naïve B cells, as well as drives IgA and IgG2b antibody responses through enhanced T cell-dependent class switching in PPs, and contribute to our understanding of how commensal microbes affect humoral immune responses to infection and vaccination. This work was supported by the Division of Intramural Research, NIAID, NIH
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Kitagami, Y., N. Kanzaki, and Y. Matsuda. "First report of segmented filamentous bacteria associated with Rhigonema sp. (Nematoda: Rhigonematidae) dwelling in hindgut of Riukiaria sp. (Diplopoda: Xystodesmidae)." Helminthologia 56, no. 3 (September 1, 2019): 219–28. http://dx.doi.org/10.2478/helm-2019-0018.
Повний текст джерелаАнотація:
SummaryWe morphologically and molecularly characterized segmented filamentous bacteria (SFB) associated with Rhigonema sp. nematodes in millipede hindguts. Seventy-three Riukiaria sp. millipedes were collected from a broad-leaf forest in Japan, and nematodes were excised from the millipede’s hindguts. The occurrence rate of SFB associated with nematodes was 24 % (10/41) for males, 47 % (14/30) for females, and 100 % (2/2) for juveniles. Genomic DNA was extracted from four SFB-rich nematode heads, and we obtained 40 bacterial clones via analysis of nearly full-length 16S rDNA gene sequences. At the phylum level, Firmicutes, Proteobacteria, and Verrucomicrobia accounted for 55 %, 40 %, and 5 % of SFB, respectively. In Firmicutes, Clostridiaceae (28 %) and Lachnospiraceae (15 %) were the dominant groups. Our sequences were divided into seven and three subclades between Firmicutes and Proteobacteria in the phylogenetic tree. In the Firmicutes clade, eight sequences were classified as Lachnospiraceae with a bootstrap value >83 %. A phylogenetic tree involving known uncultured Lachnospiraceae sequences characterized the phylogenetic position of SFB associated with nematodes. Our results suggest that the association of SFB with nematode bodies was probably incidental and that SFB are not always present in millipede hindguts. Our bacterial groups corresponded to those of arthropod hindgut, and SFB associated with nematodes were inferred to belong to Lachnospiraceae. Because the Lachnospiraceae sequences obtained in this study showed specific lineages that differed from all the known deposited sequence data, these groups may be unique to Riukiaria sp.
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Talham, Gwen L., Han-Qing Jiang, Nicolaas A. Bos, and John J. Cebra. "Segmented Filamentous Bacteria Are Potent Stimuli of a Physiologically Normal State of the Murine Gut Mucosal Immune System." Infection and Immunity 67, no. 4 (April 1, 1999): 1992–2000. http://dx.doi.org/10.1128/iai.67.4.1992-2000.1999.
Повний текст джерелаАнотація:
ABSTRACT Segmented filamentous bacteria (SFB) are autochthonous bacteria inhabiting the intestinal tracts of many species, including humans. We studied the effect of SFB on the mucosal immune system by monoassociating formerly germfree C3H/HeN mice with SFB. At various time points during 190 days of colonization, fragment cultures of small intestine and Peyer’s patches (PP) were analyzed for total immunoglobulin A (IgA) and SFB-specific IgA production. Also, phenotypic changes indicating germinal center reactions (GCRs) and the activation of CD4+ T cells in PP were determined by using fluorescence-activated cell sorter analyses. A second group of SFB-monoassociated mice was colonized with a gram-negative commensal,Morganella morganii, to determine if the mucosal immune system was again stimulated and to evaluate the effect of prior colonization with SFB on the ability of M. morganii to translocate to the spleen and mesenteric lymph nodes. We found that SFB stimulated GCRs in PP from day 6 after monoassociation, that GCRs only gradually waned over the entire length of colonization, that natural IgA production was increased to levels 24 to 63% of that of conventionally reared mice, and that SFB-specific IgA was produced but accounted for less than 1.4% of total IgA. Also, the proportion of CD4+, CD45RBlow T cells, indicative of activated cells, gradually increased in the PP to the level found in conventionally reared mice. Secondary colonization with M. morganii was able to stimulate GCRs anew, leading to a specific IgA antibody response. Previous stimulation of mucosal immunity by SFB did not prevent the translocation of M. morganii in the double-colonized mice. Our findings generally indicate that SFB are one of the single most potent microbial stimuli of the gut mucosal immune system.
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Goto, Yoshiyuki, Yoshinori Umesaki, Yoshimi Benno, and Hiroshi Kiyono. "Specific comensal bacteria modulate epithelial glycosylaion (59.5)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 59.5. http://dx.doi.org/10.4049/jimmunol.186.supp.59.5.
Повний текст джерелаАнотація:
Abstract Commensal bacteria constantly reside in our mucosal sites, especially in the intestine and create a mutually beneficial condition of symbiosis with the host. The physical and molecular crosstalk between host and gut microbiota is established at the surface of intestinal epithelial layer. It has been reported that specific epithelial carbohydrate chains, fucoses, are involved in the attachment of bacteria and viruses and ablation of these fucoses seems to be associated with the onset of Crohn’s disease. In spite of this important role, the mechanism of the induction and regulation of epithelial fucoses is not fully understood. Here, we show that specific commensal bacteria, segmented filamentous bacteria (SFB), physiologically induce fucoses on the ileal epithelial cells. To analyze the role of commensal bacteria in the induction of fucosylated epithelial cells (F-ECs), we firstly checked germfree mice. F-ECs were not found in germfree mice, while a large number of F-ECs were observed in the ileum of SPF mice. When we analyzed the ileal bacterial population to identify bacteria responsible for the induction of F-ECs, SFB were dominant in the ileum. Mono-colonization of SFB led to the development of F-ECs in germfree mice. Furthermore, F-ECs were abolished in SFB deficient mice bred in Jackson laboratory, indicating that SFB physiologically induce F-ECs. Our findings provide the basis of mutually beneficial system between the host and commensal bacteria.
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Yamauchi, Koh-En, and Johannes Snel. "Transmission Electron Microscopic Demonstration of Phagocytosis and Intracellular Processing of Segmented Filamentous Bacteria by Intestinal Epithelial Cells of the Chick Ileum." Infection and Immunity 68, no. 11 (November 1, 2000): 6496–504. http://dx.doi.org/10.1128/iai.68.11.6496-6504.2000.
Повний текст джерелаАнотація:
ABSTRACT Segmented filamentous bacteria (SFB) are autochthonous bacteria colonizing the ileum of many young animals by attaching to intestinal epithelial cells. These nonpathogenic bacteria strongly stimulate the mucosal immune system and induce intestinal epithelial cells to express major histocompatibility complex class II molecules. We tried to discover whether SFB are phagocytized and intracellularly processed by the host cells, which is indicative of antigen processing. The middle part of the ileum was extracted from 10- and 20-day-old broiler chicks (Gallus gallus domesticus). Samples were processed and examined by scanning and transmission electron microscopy (SEM and TEM, respectively). In SEM, no, few, medium, and dense SFB colonization levels were classified. In TEM of cells from animals with medium or dense SFB colonization levels, we could observe extracellular particles ranging from those only indenting the cell membrane to particles found in the cytoplasmatic area beyond the terminal web. These particles had a structural similarity with SFB that were floating freely in the intestinal lumen. Furthermore, we observed unlacing of the membrane and septum surrounding the extracellular particles and their incorporation into host cytoplasmatic components, which strongly suggests that these particles are phagocytized and intracellularly processed SFB. This conclusion is supported by TEM analysis of samples with no or few SFB, in which we failed to find these characteristic morphologies. The phagocytosis process described here could be an important trigger for the stimulating effect of SFB on the mucosal immune system.
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McCarthy, Ú., R. Pettinello, L. Feehan, YM Ho, and P. White. "Experimental transmission of segmented filamentous bacteria (SFB) in rainbow trout Oncorhynchus mykiss." Diseases of Aquatic Organisms 119, no. 1 (April 12, 2016): 45–57. http://dx.doi.org/10.3354/dao02977.
Повний текст джерела
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Griffith, Thomas, Javier Cabrera, Jeffrey Babcock, and Vladimir Badovinac. "Differential function of Ag-specific CD4 T cells from sepsis-induced lymphopenia is influenced by gut microbiota (MPF2P.744)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 63.3. http://dx.doi.org/10.4049/jimmunol.194.supp.63.3.
Повний текст джерелаАнотація:
Abstract Sepsis changes the composition and functional potential of the naïve CD4 T cell repertoire, but the mechanism(s) that control such changes are unknown. We posited that the constituents of the gut flora play an important role in defining the responsiveness of CD4 T cell populations specific for Ag present in the commensal bacterial species that establish polymicrobial sepsis after cecal-ligation and puncture (CLP) versus those CD4 T cells undergoing sepsis-induced Ag-independent homeostatic proliferation. To test this hypothesis, we tracked the loss/recovery and function of CD4 T cells specific for an Ag present in segmented filamentous bacteria (SFB) in mice containing or devoid of this bacteria in their gut. SFB-specific CD4 T cells underwent Ag-driven proliferation in CLP-treated SFB+ mice, but not in SFB- mice. This correlated with their functional ability after secondary infection with SFB Ag-expressing Listeria. Interestingly, we found that a second CD4 T cell population specific for the influenza NP311 epitope underwent differential recovery and function depending on the mouse vendor, suggesting antigenic stimulation as a result of cross-reactivity with some yet-to-be defined epitope expressed by the gut commensal bacteria. Our data suggest the extent of recovery and function of a particular Ag-specific T cell population during sepsis can determined by the intestinal “health” of the individual, regardless of possible genetic similarities.
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Gauguet, Stefanie, Samantha D'Ortona, Kathryn Ahnger-Pier, Biyan Duan, Neeraj K. Surana, Roger Lu, Colette Cywes-Bentley, et al. "Intestinal Microbiota of Mice Influences Resistance to Staphylococcus aureus Pneumonia." Infection and Immunity 83, no. 10 (July 27, 2015): 4003–14. http://dx.doi.org/10.1128/iai.00037-15.
Повний текст джерелаАнотація:
Th17 immunity in the gastrointestinal tract is regulated by the intestinal microbiota composition, particularly the presence of segmented filamentous bacteria (sfb), but the role of the intestinal microbiota in pulmonary host defense is not well explored. We tested whether altering the gut microbiota by acquiring sfb influences the susceptibility to staphylococcal pneumonia via induction of type 17 immunity. Groups of C57BL/6 mice which differed in their intestinal colonization with sfb were challenged with methicillin-resistantStaphylococcus aureusin an acute lung infection model. Bacterial burdens, bronchoalveolar lavage fluid (BALF) cell counts, cell types, and cytokine levels were compared between mice from different vendors, mice from both vendors after cohousing, mice given sfb orally prior to infection, and mice with and without exogenous interleukin-22 (IL-22) or anti-IL-22 antibodies. Mice lacking sfb developed more severeS. aureuspneumonia than mice colonized with sfb, as indicated by higher bacterial burdens in the lungs, lung inflammation, and mortality. This difference was reduced when sfb-negative mice acquired sfb in their gut microbiota through cohousing with sfb-positive mice or when given sfb orally. Levels of type 17 immune effectors in the lung were higher after infection in sfb-positive mice and increased in sfb-negative mice after acquisition of sfb, as demonstrated by higher levels of IL-22 and larger numbers of IL-22+TCRβ+cells and neutrophils in BALF. Exogenous IL-22 protected mice fromS. aureuspneumonia. The murine gut microbiota, particularly the presence of sfb, promotes pulmonary type 17 immunity and resistance toS. aureuspneumonia, and IL-22 protects against severe pulmonary staphylococcal infection.
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Ladinsky, Mark S., Leandro P. Araujo, Xiao Zhang, John Veltri, Marta Galan-Diez, Salima Soualhi, Carolyn Lee, et al. "Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis." Science 363, no. 6431 (March 7, 2019): eaat4042. http://dx.doi.org/10.1126/science.aat4042.
Повний текст джерелаАнотація:
Commensal bacteria influence host physiology, without invading host tissues. We show that proteins from segmented filamentous bacteria (SFB) are transferred into intestinal epithelial cells (IECs) through adhesion-directed endocytosis that is distinct from the clathrin-dependent endocytosis of invasive pathogens. This process transfers microbial cell wall–associated proteins, including an antigen that stimulates mucosal T helper 17 (TH17) cell differentiation, into the cytosol of IECs in a cell division control protein 42 homolog (CDC42)–dependent manner. Removal of CDC42 activity in vivo led to disruption of endocytosis induced by SFB and decreased epithelial antigen acquisition, with consequent loss of mucosal TH17 cells. Our findings demonstrate direct communication between a resident gut microbe and the host and show that under physiological conditions, IECs acquire antigens from commensal bacteria for generation of T cell responses to the resident microbiota.
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Burgess, Stacey L., Mahmoud Saleh, Carrie A. Cowardin, Erica Buonomo, Zannatun Noor, Koji Watanabe, Mayuresh Abhyankar, Stephane Lajoie, Marsha Wills-Karp, and William A. Petri. "Role of Serum Amyloid A, Granulocyte-Macrophage Colony-Stimulating Factor, and Bone Marrow Granulocyte-Monocyte Precursor Expansion in Segmented Filamentous Bacterium-Mediated Protection from Entamoeba histolytica." Infection and Immunity 84, no. 10 (July 25, 2016): 2824–32. http://dx.doi.org/10.1128/iai.00316-16.
Повний текст джерелаАнотація:
Intestinal segmented filamentous bacteria (SFB) protect from ameba infection, and protection is transferable with bone marrow dendritic cells (BMDCs). SFB cause an increase in serum amyloid A (SAA), suggesting that SAA might mediate SFB's effects on BMDCs. Here we further explored the role of bone marrow in SFB-mediated protection. Transient gut colonization with SFB or SAA administration alone transiently increased the H3K27 histone demethylase Jmjd3, persistently increased bone marrowCsf2raexpression and granulocyte monocyte precursors (GMPs), and protected from ameba infection. Pharmacologic inhibition of Jmjd3 H3K27 demethylase activity during SAA treatment or blockade of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling in SFB-colonized mice prevented GMP expansion, decreased gut neutrophils, and blocked protection from ameba infection. These results indicate that alteration of the microbiota and systemic exposure to SAA can influence myelopoiesis and susceptibility to amebiasis via epigenetic mechanisms. Gut microbiota-marrow communication is a previously unrecognized mechanism of innate protection from infection.
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Marino, Naomi Claudette Rodriguez, Dormarie E. Rivera-Rodriguez, Charlotte J. Royer, Madelyn Yaceczko та Luisa Cervantes-Barragan. "Dietary fiber and Segmented Filamentous Bacteria interaction with intestinal epithelial cells supports the development of CD4 +CD8αα +intraepithelial T cells". Journal of Immunology 210, № 1_Supplement (1 травня 2023): 150.02. http://dx.doi.org/10.4049/jimmunol.210.supp.150.02.
Повний текст джерелаАнотація:
Abstract Double positive intraepithelial lymphocytes (DP IELs) are microbiome induced CD4 +CD8αα +T cells that play a role in maintaining homeostasis and reducing inflammation in the small intestine. While the impact of the microbiome on the intestinal immune system has been extensively studied, little is known about how changes in macronutrients, such as dietary fiber, affect the development of important immune cell populations through changes in the microbiome. Here we show that a diet low in fermentable fiber (LFF) impairs development of DP IELs by reducing MHC-II expression on intestinal epithelial cells (IECs). Bulk RNA sequencing of ileal IECs revealed that LFF fed mice had lower expression of genes associated with the antigen presentation machinery. Subsequently, flow cytometry analysis confirmed increased expression of MHC-II on IECs in standard chow fed mice, which is required for DP IEL development. 16s rRNA sequencing of the microbiota of LFF mice showed that SFB is reduced in these animals. We found that colonizing mice with SFB induces MHC-II expression on IECs and restores development of DP IELs in a fiber-dependent manner. Finally, using the offspring of mice that naturally harbor SFB, we show that MHC-II expression on IECs and IFN-γ levels in the ileum increase gradually over time and correlate with SFB colonization. These results suggest that dietary fiber is required for the development of DP IELs through supporting SFB colonization and increasing expression of MHC-II on small intestinal epithelial cells. Supported by grants from NIH (1R011DK129950) and startup funds from Emory University
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Jiang, Han-Qing, Nicolaas A. Bos, and John J. Cebra. "Timing, Localization, and Persistence of Colonization by Segmented Filamentous Bacteria in the Neonatal Mouse Gut Depend on Immune Status of Mothers and Pups." Infection and Immunity 69, no. 6 (June 1, 2001): 3611–17. http://dx.doi.org/10.1128/iai.69.6.3611-3617.2001.
Повний текст джерелаАнотація:
ABSTRACT As a member of the indigenous gut mucosal microbiota, segmented filamentous bacteria (SFB) colonize the guts of a variety of vertebrates and invertebrates. They are potent microbial stimuli of the gut mucosal immune system. In the small intestines of mice and rats, it has been observed that SFB are absent during the suckling period and appear in high numbers shortly after weaning, then quickly retreat to the cecum and large intestine. In this study, we explored whether this microecological phenomenon resulted from the interaction between SFB and the passively acquired maternal mucosal immunity and/or the actively acquired mucosal immunity. We set up a mouse model by reciprocal crossings and backcrossings of SFB-monoassociated, formerly germ-free, immunocompetent (+/+) BALB/c mice and immunodeficient (scid/scid) mice to produce pups which are either immunocompetent (scid/+) or immunodeficient (scid/scid) and are born either to immunocompetent (scid/+) mothers or to immunodeficient (scid/scid) mothers. We monitored the number of SFB on the mucosa of the small intestine in the four different groups of mice after birth, as well as the level of passively acquired antibodies, the active gut mucosal immune responses, and immunoglobulin A (IgA) coating of SFB in the gut. The results showed that, irrespective of whether the pups were scid/scid or scid/+, SFB could be found earlier on the mucosa of the small intestine in pups born to scid/scid mothers, appearing from day 13 and rapidly reaching a climax around weaning time on day 28, compared to the significantly delayed colonization in the pups of scid/+ mothers, starting from day 16 and peaking around days 28 to 32. After the climax, SFB quickly declined to very low levels in the small intestines of scid/+ pups of either scid/scid mothers or scid/+ mothers, whereas they remained at high levels in scid/scid pups at least until day 70, the last observation time in this study. The dynamic changes in SFB colonization of the small intestines of the different groups of pups may be related to the dynamic changes in the levels of SFB coated with secretory IgA (sIgA), which resulted from the significantly different levels of sIgA obtained from the mothers' milk during the suckling period and, later, of self-produced sIgA in the small intestine. Nevertheless, it is evident that the timing, localization, and persistence of colonization of the neonatal gut by SFB depends on the immune status of both mothers and pups.
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Pamp, Sünje J., Eoghan D. Harrington, Stephen R. Quake, David A. Relman, and Paul C. Blainey. "Single-cell sequencing provides clues about the host interactions of segmented filamentous bacteria (SFB)." Genome Research 22, no. 6 (March 20, 2012): 1107–19. http://dx.doi.org/10.1101/gr.131482.111.
Повний текст джерела
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Ghilardi, Nico, Jennifer Cox, and Vincent Shih. "Homeostatic IL-23R signaling limits TH17 response through IL-22-mediated containment of commensal microbiota (MUC9P.818)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 199.5. http://dx.doi.org/10.4049/jimmunol.192.supp.199.5.
Повний текст джерелаАнотація:
Abstract Mammalian hosts are colonized with commensal microbes in various mucosal and epithelial tissues, including the intestinal tract. In mice, the presence of segmented filamentous bacteria (SFB) is required for TH17 differentiation and the development of autoimmune disease. Here we demonstrate that the IL-23 pathway dynamically regulates the abundance of SFB as well as mucosal barrier function in the adult animal. Genetic or pharmacological inactivation of the pathway selectively perturbs abundance of a small group of commensals, including SFB, and results in an impaired mucosal barrier, leading to systemic microbial dissemination. Conversely, microbial dissemination leads to induction of the IL-23 pathway with dual consequences: IL-23 drives IL-22 production to reinforce mucosal barrier function and elicit antimicrobial activities. It also drives the differentiation of TH17 cells in an attempt to combat escaped microbes in the lamina propria and in distal tissues. Thus barrier defects generate a systemic environment that facilitates TH17 development.
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McAleer, Jeremy, Nikki Nguyen, Kong Chen, Rachel Armentrout, Derek Pociask, David Ricks, Matthew Binnie, et al. "Pulmonary Th17 immunity is regulated by regenerating islet-derived III-gamma and the gut microbiome (MUC4P.826)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 133.2. http://dx.doi.org/10.4049/jimmunol.192.supp.133.2.
Повний текст джерелаАнотація:
Abstract Antimicrobial proteins provide an innate immune barrier against pathogen invasion. Here we identify a function for the bactericidal lectin regenerating islet-derived III-gamma (RegIIIγ) in shaping CD4 T cell polarization. Gram-positive bacteria in the intestine induce RegIIIγ expression, which modulates the immune tone of the gut, resulting in decreased Th17-type immunity during pulmonary fungal infection. This was associated with RegIIIγ inhibiting intestinal colonization with segmented filamentous bacteria (SFB), a pro-inflammatory commensal that augments Th17 differentiation. Vancomycin drinking water inhibited IL-17 production in lungs of RegIIIγ-/- and Il22-/- mice, demonstrating that intestinal Gram-positive commensals contribute to systemic inflammation. Reconstituting Il22-/- mice with IL-22 decreased the SFB/Clostridium ratio, while gastrointestinal delivery of recombinant RegIIIγ decreased inflammatory gene expression in lung tissue and protected Il22-/- mice from weight-loss during Aspergillus fumigatus infection. Therefore, intestinal antimicrobial proteins influence the development of adaptive immunity by altering the balance of pro- and anti-inflammatory intestinal commensal species.
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McKarns, Susan, and Patrick Miller. "TNFR2 regulates gut commensal microbiota tocontrol sex-biased spontaneous experimental autoimmune encephalomyelitis (BA6P.138)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 114.19. http://dx.doi.org/10.4049/jimmunol.194.supp.114.19.
Повний текст джерелаАнотація:
Abstract Host-commensal interactions influence the development and plasticity of gut-associated T helper (Th) and T regulatory (Treg) cells. In mice, the gut commensal segmented filamentous bacteria (SFB) modulate TH17 and FoxP3+ Treg differentiation to enhance host protection against external pathogens. However, in the context of a susceptible genetic background, SFB has the potential to augment the development of autoimmunity, including multiple sclerosis (MS). We have previously demonstrated that greater than 90% of female, but few male, tumor necrosis alpha receptor type 2 (TNFR2)-deficient mice crossed onto the myelin oligodendrocyte glycoprotein peptide fragment 35-55 (MOG35-55)-specific T cell receptor (TCR) transgenic background rapidly develop spontaneous experimental autoimmune encephalomyelitis (EAE). We now report that oral administration of trimethoprim/sulfamethoxazole, an antibiotic which has broad spectrum of activity against a variety of bacteria prevents the development of spontaneous EAE in TNFR2-deficient 2D2 TCR Tg mice. We have further combined Illumina MiSeq sequencing and RT-PCR to demonstrate a sex-biased microbiome profile in TNFR2-deficient MOG35-55-specific TCR mice, including increased SFB expression in the females relative to their male cohorts. Collectively, these findings suggest a role for TNFR2 in regulating commensal microbiota in the context of myelin autoantigen to control autoreactive T cells and autoimmune demyelination.
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Seo, Goo-Young, Jr-Wen Shui, Zbigniew Mikulski, Qingyang Wang, Daisuke Takahashi, Daniel A. Giles, Hitoshi Iwaya, et al. "CD160-HVEM signaling in intestinal epithelial cells modulates gut microbial homeostasis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 191.11. http://dx.doi.org/10.4049/jimmunol.202.supp.191.11.
Повний текст джерелаАнотація:
Abstract Intestinal epithelial cells (IEC) are a first barrier that segregates host and commensal bacteria to maintain intestinal homeostasis. Intestinal intraepithelial lymphocytes (IEL) are located beneath or between adjacent IEC and directly contact IEC. The herpes virus entry mediator (HVEM), a member of the tumor necrosis factor receptor superfamily (TNFRSF), is highly expressed by IEC. Epithelial HVEM expression was previously reported as a regulator of innate immune defense during acute infections in the intestine (Shui et al., Nature, 2012). Here, we identify that HVEM signaling in IEC is important for the regulation of the gut microbiota at steady state. Mice with an epithelial-specific deletion of the gene encoding HVEM (HvemΔIEC) had significantly increased segmented filamentous bacteria (SFB) which caused an increase in Th17 cells in the ileum. Treatment with the antibiotic vancomycin eliminated SFB and decreased Th17 cells in HvemΔIEC mice. Additionally, mice with a deletion of the gene encoding CD160, which is a ligand for HVEM and is highly expressed by IEL, including intraepithelial innate lymphoid cells (ILC) and intraepithelial T cells, had increased SFB in the ileum. Our findings suggest that the interaction of CD160 expressed by IEL with HVEM expressed by IEC is important at steady state for shaping the microbiota in the intestine.
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Felix, Krysta M., Ivan Jaimez, Thuy-Vi Nguyen, Heqing Ma, Walid Raslan, Christina Klinger, Kristian Doyle, and Hsin-Jung Joyce Wu. "Gut microbiota enhances neutrophil resolution in immunocompromised hosts to improve response to pneumococcal pneumonia." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 173.10. http://dx.doi.org/10.4049/jimmunol.200.supp.173.10.
Повний текст джерелаАнотація:
Abstract Streptococcus pneumoniae is a major cause of disease and death worldwide, particularly in neonatal, elderly, and immunodeficient patients. We examined the impact of the gut microbiota on lung disease (known as the gut-lung axis) using traditional immunocompetent as well as novel immunocompromised mouse models of S. pneumoniae lung infection. Adaptive immunity against S. pneumoniae depends largely on T-independent II (TI-II) antibodies against the bacterial polysaccharide capsule. We found that colonization with the gut commensal Segmented Filamentous Bacteria (SFB) increased anti-S. pneumoniae TI-II antibodies, but did not further enhance protection against S. pneumoniae in wild type mice. Indeed, basal B cell activity in the absence of SFB colonization was sufficient to provide essential protection against S. pneumoniae. However, in adaptive immune-compromised mice, we demonstrated a gut-lung axis of communication, as SFB colonization modulated the innate immune response to enhance protection against S. pneumoniae lung infection. Neutrophils are important first responders during pneumonia, but proper neutrophil resolution is essential to prevent excessive tissue damage. We found that SFB colonization led to more efficient clearance of lung neutrophils at 3 days after infection, which correlated with a decrease in CD47, a transmembrane glycoprotein that inhibits clearance of apoptotic cells, on lung neutrophils in SFB+ immunocompromised mice. This accompanied a shift in lung neutrophils from CD18hiCD62L−/lo inflammatory neutrophils to CD18−/loCD62Lhi pro-resolution neutrophils. These data demonstrate that a gut commensal modulates the innate immune response to enhance protection against a lung infection.
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Kumar, Pawan, Leticia Monin, Paticia Castillo, Waleed Abdel Wahab Elsegeiny, William Horne, Taylor John Eddens, Misty Good, et al. "Intestinal IL-17R signaling modulates commensal microbiota by regulating expression of Nox1 and Pigr." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 207.2. http://dx.doi.org/10.4049/jimmunol.196.supp.207.2.
Повний текст джерелаАнотація:
Abstract Despite recent advances in understanding the role of IL-17 in host immunity, its role in regulating enteric immune responses as well as its impact on the commensal microbiome has not been well studied. To further understand this, we have generated intestinal epithelial cell specific IL-17R knockout mice. Our data shows that global and intestinal epithelial cell specific Il17r−/− mice have overgrowth of segmented filamentous bacteria (SFB), suggesting a critical role of IL-17 signaling in SFB colonization. Higher SFB colonization in Il17rafl/fl x villin cre+ mice resulted in expansion of IL-17A and IL-22 producing Th17 cells. The expansion of SFB was also confirmed by 16S rRNA. Furthermore this analysis also showed higher abundance of S24-7 and the Clostridiales family in Il17rafl/fl x villin cre+ mice. RNA sequencing data from the distal small intestine of SFB-colonized Il17ra−/− and Il17rafl/fl x villin cre+ mice revealed substantial reduction of Nox1 (an apical NADPH oxidase) and Pigr genes. Mouse and human primary intestinal organoid culture further confirmed a direct role of IL-17 in regulating Nox1 and Pigr expression. Reduced Nox1 expression correlated with significant reduction in H202 levels in the terminal ileum of Il17rcfl/fl x villin cre+ mice. Furthermore, Nox1−/− and IgA−/− mice showed a higher degree of SFB colonization in the feces and terminal ileum as compared to cohoused control WT mice. We have evidence that Il17rafl/fl x villin cre+ mice are more susceptible to autoimmune inflammation. Collectively, our data indicate IL-17R-dependent intestinal signaling controls commensal bacteria by regulating the expression of Nox1 and Pigr which regulates lumenal H202 and sIgA concentrations respectively.
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Cebra, John J., Sangeeta Bhargava Periwal, Gwen Lee, Fan Lee, and Khushroo E. Shroff. "Development and Maintenance of the Gut-Associated Lymphoid Tissue (Galt): the Roles of Enteric Bacteria and Viruses." Developmental Immunology 6, no. 1-2 (1998): 13–18. http://dx.doi.org/10.1155/1998/68382.
Повний текст джерелаАнотація:
GALT can be subdivided into several compartments: (a) Peyer's patches (PP); (b) lamina propria (LP); and (c) intraepithelial leukocyte (IEL) spaces. The B-cell follicles of PP are quiescent in neonatal and germ-free (GF) adult mice. Germinal centers (GC), including sIgA+blasts, appear in the B follicles of formerly GF adult mice about 10-14 days after monoassociation with various gut commensal bacteria. The GC wax and wane over about a 3-week period, although the bacterial colonizers remain in the gut at high density. Neonatal mice, born of conventionally reared (CV), immunocompetent mothers, display GC reactions in PP postweaning, although pups of SCID mothers display precocious GC reactions at about 14 days of life. Normally, gut colonization of neonates with segmented filamentous bacteria (SFB) leads to explosive development of IgA plasmablasts in LP shortly after weaning. Commensal gut bacteria and the immunocompetency of mothers also appears to control the rate of accumulation of primary B cells from “virgin” B cells in neonates.Enteric reovirus infection by the oral route can cause the activation of CD8+T cells in the interfollicular regions of PP and the appearance of virus-specific precursor cytotoxic T lymphocytes (pCTL) in the IEL spaces. Such oral stimulation can also lead to “activation” of both CTL and natural killer (NK) cells in the IEL spaces. More normally, colonization of the gut with SFB also leads to similar activations of NK cells and “constitutively” cytotoxic T cells.
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Aggor, Felix E. Y., Chunsheng Zhou, Darryl Abbott, Javonn Musgrove, Vincent Bruno, Timothy W. Hand, and Sarah L. Gaffen. "Th17-driven immunity to oral candidiasis is dependent on the microbiome and can be triggered by mono-colonization with segmented filamentous bacteria." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 115.18. http://dx.doi.org/10.4049/jimmunol.208.supp.115.18.
Повний текст джерелаАнотація:
Abstract The opportunistic infection oropharyngeal candidiasis (OPC; oral thrush) is a common oral infection among the immunocompromised. The oral cavity is a major entry portal to the body and oral health impacts several aspects of host immunity. While much is now known about microbiome dependent Th17 induction and protection against intestinal candidiasis and other Th17 driven responses, our understanding of the role of the microbiome in oral Th17 induction and oral antifungal immunity is rather rudimentary. We demonstrate a direct role for the microbiome in triggering protection against OPC. While wildtype (WT) mice raised under specific pathogen free (SPF) conditions are resistant to OPC, WT germ free (GF) mice succumbed to infection. Reconstitution of WT-GF mice with segmented filamentous bacteria (SFB) was sufficient to restore protection against OPC with associated increase in Th17 cells, neutrophils, and antimicrobial responses in the oral mucosa. Thus, SFB mono-colonization in WT-GF mice triggers oral mucosal Th17 induction to protect against oral thrush and reveals a role of the microbiome in promoting oral mucosal immunity. Supported by R37-DE022550
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Sano, Teruyuki, Zachary White, and Ivan Cabrera. "Commensal-specific CD4 T cells can promote inflammation in the central nervous system via molecular mimicry." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 227.09. http://dx.doi.org/10.4049/jimmunol.210.supp.227.09.
Повний текст джерелаАнотація:
Abstract Commensal bacteria are critical regulators of both tissue homeostasis and the development and exacerbation of autoimmunity. However, it remains unclear how the intestinal microbiota contributes to inflammation in tissues such as the central nervous system (CNS) where these microbes are typically absent and whether T cell receptor (TCR) specificity for commensal-derived antigens is important to the development of tissue inflammation-related outcomes. Here, we found that ileum- and cecum-colonizing segmented filamentous bacteria (SFB)-specific T cells (clone TCR 7B8) can infiltrate the CNS wherein they can be reactivated and produce high levels of inflammatory cytokines including IFNγ, IL-17A, TNFα, and GM-CSF in the absence of regulatory T cells. In contrast, other SFB-specific T cells (clone TCR 1A2) recognizing an epitope in which 8/9 amino acids overlap with those recognized by TCR 7B8failed to induce such neuroinflammation. Despite their similar SFB-derived peptide antigen targets, TCR 7B8was found to recognize peptides derived from host proteins including receptor tyrosine-protein kinase ErbB2, trophinin 1, and anaphase-promoting complex subunit 2 in vitro, whereas TCR 1A2did not, indicating that TCR 7B8induces CNS inflammation via molecular mimicry. Immune checkpoint blockade accelerated TCR 7B8-mediated CNS inflammation. Together, our findings reveal a potential mechanism whereby gut commensal-specific T cells are dysregulated, infiltrate into the CNS, and contribute to extraintestinal inflammation. Supported by grants from UIC start-up funds and UIC COVID Relief Funding.
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Bukina, Yu V., L. Ya Fedoniuk, G. D. Koval, Yu O. Shekhovtsova, A. M. Kamyshnyi, A. O. Gubar, and V. O. Gubka. "Salmonella-induced changes in the level of key immunoregulatory bacteria affect the transcriptional activity of the Foxp3 and RORgt genes in the gut-associated lymphoid tissue of rats." Russian Journal of Infection and Immunity 10, no. 4 (November 27, 2020): 671–85. http://dx.doi.org/10.15789/2220-7619-sic-1151.
Повний текст джерелаАнотація:
Intestinal microbes involved in many physiological processes owner, contributes to the formation and maintenance of immune homeostasis by regulating immune responses to protect against colonization by pathogens. A special role in the differentiation of various subpopulations of T-lymphocytes play the segmental filamentous bacteria (Segmented filamentous bacteria, SFB), capable of inducing a gut-associated lymphoid tissue (GALT) differentiation proinflammatory Th17-cells and members of the genus Clostridium (cluster IV and XIVa) and Bacteroides fragilis (polysaccharide A [PSA]), stimulating the formation of regulatory T-cells (Treg) and production of suppressor of cytokine IL-10. Important metabolites of B. fragilis are short-chain fatty acids (SCFA), which are able to activate GALT cells through the FFAR2 receptor. Lowering of the SCFA concentration leads to the reduction of the number of Treg in the intestine and breaks Th17/Treg balance. These changes lead to direct reducing of mRNA FFAR2, Foxp3 expression and increasing in RORyt GALT. Therefore, the goal was to determine the level of the key in the edge immunoregulatory bacteria intestinal microflora rats and their effects on the transcriptional activity of the genes Foxp3 and RORyt in GALT with Salmonella-induced inflammation and during administration of vancomycin and B. fragilis. To determine the genus and species of bacteria, as well as their number in the microflora of rats, was used the method of polymerase chain reaction (PCR-RV) with their identification by 16S rDNA genes. To study the transcriptional activity of genes using polymerase chain reaction reverse transcription real-time (RT-PCR). During the experiment with the introduction of animals vancomycin and Salmonella there was an increase in the level of SFB and a decrease in A. muciniphila, F. prausnitzii. Also, during infecting rats with S. Enteritidis and S. Typhimurium on the background of pre-treatment with vancomycin, there was an increase in the number of SFBs against the background of a pronounced decrease in Bacteroides—Prevotela group, A. muciniphila, Clostridium spp. clusters XIV, IV, and F. prausnitzii, which led to a decrease in the expression level of Foxp3+ mRNA and an increase in RORyt+, respectively. However, administration of B. fragilis to animals receiving S. Enteritidis or S. Typhimurium against pretreatment with vancomycin caused a decrease in the level of SFB and mRNA RORyt+, and, conversely, increased the number of Bacteroides—Prevotela group, A. muciniphila, Clostridium spp. clusters XIV, IV, F. prausnitzii and expression of Foxp3+ genes, which indicates the restoration of the homeostasis of the intestinal microbiome. The obtained results showed that B. fragilis can be successfully used in the treatment of inflammatory bowel diseases or diseases with impaired intestinal barrier function.
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Block, Katharine, and Haochu Huang. "The gut microbiota regulates K/BxN autoimmune arthritis independent of Th17 and IL-17 (BA6P.121)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 114.2. http://dx.doi.org/10.4049/jimmunol.194.supp.114.2.
Повний текст джерелаАнотація:
Abstract The bacterial community that colonizes mucosal surfaces helps shape the development and function of the immune system. The effect of the microbiota on autoimmunity has important implications, although the mechanisms are not well understood. The K/BxN mouse model of rheumatoid arthritis is dependent on the microbiota, and particularly on segmented filamentous bacteria (SFB), for the autoimmune phenotype. Because SFB potently induce Th17 cell differentiation, previous studies have suggested Th17 cells as the link between microbiota and arthritis. In this study we sought to test directly the functional significance of Th17 and IL-17 in arthritis development by genetic approaches. We utilized mice deficient for either transcription factor RORγt (which controls the Th17 program), or the cytokine IL-17A (the major cytokine of the IL-17 family) in both cell transfer and spontaneous disease models. Unexpectedly, mice without Th17 or IL-17 were not protected from disease. Germinal center B and follicular helper T cell (Tfh) populations were normal, as were levels of serum IgG against self antigen. We found no evidence for compensation in production of the related cytokine IL-17F in IL-17A deficient mice. However, antibiotic treatment prevented disease in both IL-17 deficient and sufficient K/BxN mice, and resulted in defective Tfh and germinal center B cell differentiation. We conclude that the gut microbiota promotes autoimmune development by mechanisms independent of Th17 or IL-17.
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Liao, Ningbo, Yeshi Yin, Guochang Sun, Charlie Xiang, Donghong Liu, Hongwei D. Yu, and Xin Wang. "Colonization and distribution of segmented filamentous bacteria (SFB) in chicken gastrointestinal tract and their relationship with host immunity." FEMS Microbiology Ecology 81, no. 2 (April 18, 2012): 395–406. http://dx.doi.org/10.1111/j.1574-6941.2012.01362.x.
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Seo, Goo-Young, Jr-Wen Shui, Zbigniew Mikulski, Hilde Cheroutre, Pyeung-Hyeun Kim, and Mitchell Kronenberg. "HVEM expression by intestinal epithelial cells modulates the microbiome and epithelial immunity." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 200.10. http://dx.doi.org/10.4049/jimmunol.198.supp.200.10.
Повний текст джерелаАнотація:
Abstract The herpes virus entry mediator (HVEM), a member of the tumor necrosis factor receptor superfamily (TNFRSF), is highly expressed by intestinal epithelial cells (IEC). Previously, we reported that HVEM expression by epithelial cells was required for innate immune defense from acute infections in the lung and the intestine (Nature 488:222,2012). Here, we demonstrate a novel, constitutive role of HVEM expression by IEC in microbial homeostasis and epithelial immunity. Mice with an epithelial-specific deletion of the gene encoding HVEM (HvemΔIEC) had significantly increased segmented filamentous bacteria (SFB). This caused an increase in Th17 cells and IL-22+ILC3s in the intestine lamina propria. HvemΔIEC mice also exhibited increased goblet cell hypertrophy and hyperplasia, crypt hyperplasia, villous atrophy as they aged, and they showed a severe defect in fucosylation of cell surface proteins, even at younger ages. Treatment with the antibiotic vancomycin eliminated SFB and decreased Th17 cells and ILC3, but did not reverse the defect in fucosylation. Our findings suggest that epithelial cell expression of HVEM is important at steady state both for shaping the intestinal microbiota and for the homeostasis of IEC in the intestine.
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Barin, Jobert, Nicola Diny, Elizabeth Gebremariam, Monica Talor, Djahida Bedja, David Kass, Daniel Peterson, Noel Rose, and Daniela Cihakova. "Commensal microbiota regulate inflammatory cardiac remodeling (BA6P.126)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 114.7. http://dx.doi.org/10.4049/jimmunol.194.supp.114.7.
Повний текст джерелаАнотація:
Abstract In this study, we sought to understand how the microbiota regulates inflammatory mechanisms underlying cardiac autoimmunity. We employ an autoimmunization model of heart disease in mice, termed experimental autoimmune myocarditis (EAM). This disease model depends on CD4+ T cells for pathogenesis, immediately implying a cytokine product of these cells as a critical mediator of disease pathogenesis, and an attractive target for therapeutic intervention. Our laboratory has previously reported that Th17 cells are critical for the disease process. In order to establish a role for the commensal microbiota in autoimmune heart disease, we treated animals with a comprehensive polyantibiotic cocktail to induce antibiotic dysbiosis. Treating BALB/cJ animals with antibiotic limited the development of myocarditis, and furthermore prevented their progression to later heart failure. Segmented filamentous bacteria (SFB) represent a clade of Clostridia that have been found to elicit intestinal Th17 differentiation upon colonization, and subsequently modulate susceptibility to Th17-associated autoimmune disease. We colonized BALB/cJ mice with SFB and observed that these animals progress to diminished cardiac function following the induction of EAM. Microbiota manipulations were associated with differences in canonical Th17-associated programs, pointing to these pathways as an important mechanism in coupling commensal sensing to the progression of heart disease.
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Sofi, Mohammed, Radhika Gudi, Subha Karumuthil-Melethil, Nicolas Perez, Benjamin Johnson, and Chenthamarakshan Vasu. "Influence of drinking water pH on gut microbiota and type 1 diabetes (P4069)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 127.6. http://dx.doi.org/10.4049/jimmunol.190.supp.127.6.
Повний текст джерелаАнотація:
Abstract Type 1 diabetes (T1D) is an autoimmune disease which occurs due to the interaction of genetically determined and environmental factors. T1D is characterized by progressive destruction of insulin secreting beta-cells by T cells leading to hyperglycemia. The non-obese diabetic (NOD) mouse spontaneously develops T1D similar to that in humans and thus widely used as a model for understanding the immunological basis and treatment of the disease. Incidence of TID in NOD mice is thought to be influenced by the degree of cleanliness of the mouse colony. Recent studies have shown a role for gut microbiota in promoting as well as preventing the disease. In this study, we show that pH of drinking water can have a profound influence not only on the type of commensal bacteria colonized in the gut, but also on the rate of disease progression. NOD mice that were on acidic pH water developed insulitis and hyperglycemia rapidly compared to those on neutral water. Interestingly, segmented filamentous bacteria (SFB) positive fecal transplant resulted in a profoundly suppressed insulitis and T1D incidence in NOD mice that are on acidic pH water. Microbial community analysis by pyrosequencing shows a significant difference in the type of gut microflora among the mice that were on acidic and neutral pH drinking water and this profile was altered by SFB+ fecal transplant. Our study shows that T1D incidence in NOD mice is influenced by the type of gut flora, but not the degree of cleanness alone.
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Flannigan, K. L., M. Johnston, S. L. Erickson, K. Nieves, H. Jijon, M. Gallo, K. McCoy, and S. A. Hirota. "A14 GUT-RESIDING BACTERIA CAN SHAPE HOST DRUG METABOLISM IN THE SMALL INTESTINE THROUGH AN INNATE LYMPHOID CELL-IL-22 DRIVEN AXIS." Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (February 2020): 16–17. http://dx.doi.org/10.1093/jcag/gwz047.013.
Повний текст джерелаАнотація:
Abstract Background The ability of the intestinal microbiota to influence drug metabolism has been recognized, however the mechanisms through which this occurs remain unexplored. Recent work in germ-free mice showed that conventionalization with specific pathogen free (SPF) microbiota influences the expression of cytochrome P450 (CYP) enzymes in the liver and small intestine (SI), two important sites of drug metabolism. Given that CYP enzymes, including CYP3A11 in mice, account for roughly 70% of total drug metabolism, we hypothesized that commensal gut bacteria can shape the CYP landscape to influence drug metabolism and therapeutic outcomes. Aims To investigate the role of specific gut-residing microbes in shaping the expression and activity of host drug metabolism enzymes. Methods Segmented filamentous bacteria (SFB)-free mice were obtained from Jackson Lab (Jax) and colonized with feces from SFB-mono-associated mice via oral gavage. 14 days later, expression of drug metabolism enzymes in the SI were probed using PCR arrays, and lamina propria cells isolated for flow cytometry. A monoclonal antibody for Thy1.2 was used to deplete innate lymphoid cells (ILCs) in RAG1-/- mice (lacking T- and B-cells). CYP3A11 activity was determined through the colorimetric breakdown of the CYP3A11-specific substrate 7-benzyloxyresorufin. SI organoids were generated from mice and humans, and treated with IL-22 to further assess the dynamics of CYP3A11/CYP3A4 expression and activity. Results Colonization of Jax mice with immunomodulatory SFB altered the expression of various CYP enzymes in the SI (but not liver), with Cyp3a11 being the most downregulated gene. Further analysis showed that SFB-induced IL-22 production by type 3 ILCs (ILC3) correlated with reduced SI Cyp3a11 expression. Additionally, SFB colonization had no effect on the expression of Cyp3a11 in the SI of mice in which ILCs were depleted. Both SFB colonization and administration of IL-23, to induce IL-22 from ILC3, increased the ability of the CYP3A11-metabolized drug glyburide to decrease blood glucose levels when given orally. In mouse SI enteroid cultures, IL-22 dose-dependently reduced the expression of Cyp3a11 and decreased the ability of enteroids to metabolize CYP3A11-specific substrates. Finally, IL-22 induced wide changes in the transcriptome of human SI enteroids, with substantial effects on a drug metabolism pathway centred around CYP3A. Conclusions Our data suggest that a gut-resident microbe (SFB) can influence the expression and activity of the drug metabolising enzyme CYP3A11 in the SI through an ILC3-IL-22 dependent mechanism. These findings provide an understanding of how the intestinal microbiota may modulate host drug metabolism to influence the efficacy and toxicity of various pharmaceutical compounds. Funding Agencies CAG, CIHRAbbvie, Lloyd Sutherland Investigatorship
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Xu, Mo, Yi Yang, Maria Pokrovskii, Carolina Galan та Dan R. Littman. "Balance of Commensal Bacteria-Specific Th17 and RORγt+ Treg Cells in Intestinal Homeostasis and Inflammation". Journal of Immunology 196, № 1_Supplement (1 травня 2016): 137.3. http://dx.doi.org/10.4049/jimmunol.196.supp.137.3.
Повний текст джерелаАнотація:
Abstract A number of Helicobacter species, including Helicobacter hepaticus, have been isolated as the etiological agents of ulcerative inflammatory bowel disease and cancer in their respective hosts. H. hepaticus induces severe Th17-Th1 mediated colitis in a number of immuno-compromised mouse strains, but does not usually cause disease in most wild-type mouse strains. However, how the inflammatory response is carefully contained to be harmless under homeostatic conditions and how perturbations lead to pathogenicity remain elusive questions. To understand this, we developed new research tools, including TCR transgenic mice, as well as MHCII tetramers to interrogate the regulation of H. hepaticus-specific CD4+ T cell function. Interestingly, in contrast to Segmented Filamentous Bacteria (SFB), which induces Th17 cells in the small intestinal lamina propria (SILP) of both IL10+/− and IL-10−/− mice, H. hepaticus mainly induces RORgt+ Treg cells in the large intestinal lamina propria (LILP) of IL-10-sufficient mice, but induces a Th17-Th1 response in the absence of IL-10. We propose that the balance between self/commensal antigen-induced RORgt+ Treg and Th17 cells may be a general strategy to control autoimmune inflammation.
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Jellbauer, Stefan, Araceli Perez Lopez, Judith Behnsen, Nina Gao, Thao Nguyen, Clodagh Murphy, Robert A. Edwards, and Manuela Raffatellu. "Beneficial Effects of Sodium Phenylbutyrate Administration during Infection with Salmonella enterica Serovar Typhimurium." Infection and Immunity 84, no. 9 (July 5, 2016): 2639–52. http://dx.doi.org/10.1128/iai.00132-16.
Повний текст джерелаАнотація:
Sodium phenylbutyrate (PBA) is a derivative of the short-chain fatty acid butyrate and is approved for treatment of urea cycle disorders and progressive familial intrahepatic cholestasis type 2. Previously known functions include histone deacetylase inhibitor, endoplasmic reticulum stress inhibitor, ammonia sink, and chemical chaperone. Here, we show that PBA has a previously undiscovered protective role in host mucosal defense during infection. Administration of PBA to Taconic mice resulted in the increase of intestinalLactobacillalesand segmented filamentous bacteria (SFB), as well as an increase of interleukin 17 (IL-17) production by intestinal cells. This effect was not observed in Jackson Laboratory mice, which are not colonized with SFB. Because previous studies showed that IL-17 plays a protective role during infection with mucosal pathogens, we hypothesized that Taconic mice treated with PBA would be more resistant to infection withSalmonella entericaserovar Typhimurium (S. Typhimurium). By using the streptomycin-treated mouse model, we found that Taconic mice treated with PBA exhibited significantly lowerS. Typhimurium intestinal colonization and dissemination to the reticuloendothelial system, as well as lower levels of inflammation. The lower levels ofS. Typhimurium gut colonization and intestinal inflammation were not observed in Jackson Laboratory mice. Although PBA had no direct effect on bacterial replication, its administration reducedS. Typhimurium epithelial cell invasion and lowered the induction of the proinflammatory cytokine IL-23 in macrophage-like cells. These effects likely contributed to the better outcome of infection in PBA-treated mice. Overall, our results suggest that PBA induces changes in the microbiota and in the mucosal immune response that can be beneficial to the host during infection withS. Typhimurium and possibly other enteric pathogens.
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Salvador, Ryan S., Reiko Horai, Jihong Tang, Carlos Zárate-Bladés, Yingyos Jittayasothorn, Kikuji Itoh, Yoshinori Umesaki, and Rachel R. Caspi. "Gut microbiota as a source of signals that trigger spontaneous ocular autoimmunity." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 218.10. http://dx.doi.org/10.4049/jimmunol.198.supp.218.10.
Повний текст джерелаАнотація:
Abstract Autoimmune uveitis, a major cause of blindness, is thought to be driven by T cells specific for unique retinal antigens that have been activated and acquired the ability to cross the blood-retinal barrier. However, it is unknown where and how they first become activated. The R161H mouse expresses a transgenic TCR specific for the retinal protein IRBP and develops spontaneous uveitis with 100% incidence, permitting to study natural triggers of disease. Retina-specific T cells were activated in the intestine of specific-pathogen-free (SPF) R161H mice. Elimination of gut commensals by oral treatment with antibiotics (ABX) or by rearing under germ-free conditions (GF) significantly attenuated uveitis and reduced Th17 cells in the gut lamina propria. Bacteria-rich extracts of intestinal contents from SPF, but not GF or ABX mice, activated retina-specific T cells in vitro, and R161H T cells signaled through the clonotypic TCR in the gut in vivo, suggesting a role for gut microbiota as a source of stimulating signals for retina-specific T cells. To dissect the contribution of adaptive vs innate microbial signals, gnotobiotic studies were performed: GF R161H mice exposed to SPF conditions developed full-blown uveitis, but mono-colonization with segmented filamentous bacteria (SFB) or a Turicibacter strain (T. H121) only partially restored disease. Unlike intestinal extracts from SPF mice, extracts from monocolonized mice failed to activate R161H T cells in vitro, suggesting lack of “antigen” activity, but SFB (not T. H121) restored gut Th17-producing cells, indicating presence of “adjuvant” activity. Thus, microbial-derived adaptive “antigen” and innate “adjuvant” signals are both required for full development of uveitis.
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Upadhyay, Vaibhav, and Yang-Xin Fu. "Lymphotoxin reduces commensal diversity to enable diet induced obesity (120.2)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 120.2. http://dx.doi.org/10.4049/jimmunol.188.supp.120.2.
Повний текст джерелаАнотація:
Abstract Commensal microbes exist in a state of symbiosis with host immunity and are essential for weight gain in diet induced obesity (DIO). Lymphotoxin α (LTα), a key molecule in mucosal defense, has been linked to obesity. We report that mice lacking LTα, LTβ, and LTβ-receptor (LTβR) resist DIO. The microbial communities of LTβR+/- mice and LTβR-/- mice differed on normal chow (NCD) and after high fat diet (HFD). The microbial community of LTβR+/- mice was less diverse after HFD, a hallmark of the “obese microbiome” in humans. On the contrary, LTβR-/- animals maintained similarly diverse communities to their NCD counterparts while on HFD. A specific microbe, Segmented Filamentous Bacteria (SFB), was cleared after HFD in LTβR+/- but not LTβR-/- mice and served as a marker of diversity loss. Transplantation of cecal contents from LTβR-/- animals conferred less weight gain than that of LTβR+/- mice to WT germ free mice, demonstrating a causal relationship between differing microbiota and weight gain. Housing LTβR-/- mice with their LTβR+/- siblings rescued weight gain, demonstrating horizontal transmissibility of the obese phenotype. HFD induced IL-23, an SFB associated cytokine, within the colon, but this induction was absent in LTβR-/- mice. Mice deficient in IL-23 (p19-/-) and the downstream cytokine IL-22 (RORγt-/-) also resisted DIO. Our data suggests that HFD induced inflammation reduces commensal diversity to enable weight gain, which may underlie the pathogenesis of obesity.
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Castillo, Patricia, Pawan Kumar, and Jay K. Kolls. "Dysregulation of intestinal IL17 signaling & the microbiome exacerbate autoimmune neuroinflammation." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 118.4. http://dx.doi.org/10.4049/jimmunol.196.supp.118.4.
Повний текст джерелаАнотація:
Abstract Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS). Studies in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, strongly indicate that both Th17 cells and the commensal microbiome modulate disease pathogenesis. The commensal, segmented filamentous bacteria (SFB), regulates Th17 responses. Given the relationship between commensals and Th17 cells and the role of each of these factors in EAE, we investigated the significance of enteric IL-17R signaling in EAE using intestinal specific IL-17 receptor knockouts (Il17ra/rcfl/flx villin cre+ mice). We hypothesized that disruption of the reciprocal regulatory relationship between enteric IL-17 signaling and the gut microbiota leads to dysbiosis, expansion of Th17 cells, and increased predisposition to autoimmune neuroinflammation. Our data suggested that Il17ra/rcfl/fl x villin cre+ mice, which have higher SFB levels, exhibit earlier EAE onset and increased EAE severity and incidence as compared to littermate cre− controls. Treatment with vancomycin ameliorated disease, further supporting our hypothesis. In addition, preliminary data indicated that cre+ mice have increased CCR2 and CCR6 gut expression at baseline. At day 9-post immunization in the same mice, there was increased expression of CCR2 and Nox2 in the spinal cord and Csf2 in the gut. Together, this suggested that there could be increased migration into the CNS of cre+ mice, contributing to exacerbated disease. These studies will make a significant conceptual advance by elucidating how dysregulation of enteric IL-17R signaling and the commensal microbiota contribute to the pathogenesis of autoimmune conditions such as Multiple Sclerosis.
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Manfredo Vieira, SILVIO, William Ruff, Michael Hiltensperger, Andrew Yu, Andrew Goodman, and Martin Kriegel. "Gut commensal dependence of autoreactivity and Th17 cells in systemic autoimmunity (MUC9P.740)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 205.4. http://dx.doi.org/10.4049/jimmunol.194.supp.205.4.
Повний текст джерелаАнотація:
Abstract Infectious triggers have been implicated in transient antiphospholipid antibody production but the cause of chronic antiphospholipid syndrome (APS) is unknown. We disrupted the gut microbiota composition in the (NZWxBXSB)F1 model of APS using antibiotics after maturation of the immune system. Targeting the microbiota with broad-spectrum antibiotics (ABX), vancomycin or ampicillin, but not neomycin or metronidazole, lowered pathogenic autoantibodies and mortality (p=0.014). On histology, manifestations of the autoimmune clotting disorder, i.e. myocardial infarctions, pulmonary emboli and strokes, were prevented. 16S rDNA sequencing on the MiSeq platform revealed preliminarily depletion of similar gram-positive anaerobic communities with vancomycin and ampicillin as were enriched in longitudinally collected human APS samples compared to controls. Systemic Th17 cells were detectable in our cohort in the absence of Th17-inducing segmented filamentous bacteria (SFB) but were reduced with ABX. IL-17 and Th17-differentiating factors IL-1b and IL-21 were diminished in serum whereas regulatory IL-10 was increased. Autoantigen- but not global anti-CD3-induced splenocyte proliferation was blunted after ABX (p=0.0012) supporting antigen-specific effects of the gut microbiota in systemic autoimmunity. In summary, gram-positive anaerobic gut microbiota are fundamentally involved in the pathogenesis of murine APS and systemic Th17 responses with broad implications for systemic autoimmunity.
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SINGH, AMIR KUMAR, Ritesh Kumar, John F. Brooks, Kevin P. Conlon, Venkatesha Basrur, Zhe Chen, Xialin Han, Lora Hooper, Ezra Burstein та Venuprasad K. "RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and intestinal inflammation." Journal of Immunology 210, № 1_Supplement (1 травня 2023): 154.03. http://dx.doi.org/10.4049/jimmunol.210.supp.154.03.
Повний текст джерелаАнотація:
Abstract Th17 cells that produce IL-17 are pathogenic in many human diseases, including inflammatory bowel disease (IBD), but are, paradoxically, essential for maintaining the integrity of the intestinal barrier in a non-inflammatory state. However, the intracellular mechanisms that regulate distinct transcriptional profiles and functional diversity of Th17 cells remain unclear. We have found that Raftlin1, a lipid raft protein, is specifically upregulated in and forms a complex with RORγt via its conserved LLNSL motif in pathogenic Th17 cells. Disruption of the RORγt-Raftlin1 complex in Raftlin1 ΔLLNSLknock-in mice resulted in attenuated pathogenic Th17 cells elicited by Citrobacter rodentium; however, there was no effect on nonpathogenic Th17 cells induced by commensal segmented filamentous bacteria (SFB). Mechanistically, we found that Raftlin1 recruits distinct phospholipids to RORγt and promotes the pathogenicity of Th17 cells. Thus, we have identified a fundamental mechanism that drives the pathogenic function of Th17 cells, which could provide a platform for new therapeutic strategies to dampen Th17-mediated inflammatory diseases. This work was supported by funds from the National Institutes of Health (R01-DK115668, R01-AI155786) and Cancer Prevention Research Institute of Texas (RP190527) and a stimulus grant from the Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center.
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Kowalczyk, Paulina, Anna Strzępa, and Marian Szczepanik. "Perinatal treatment of parents with the broad-spectrum antibiotic enrofloxacin aggravates contact sensitivity in adult offspring mice." Pharmacological Reports 73, no. 2 (January 22, 2021): 664–71. http://dx.doi.org/10.1007/s43440-021-00217-3.
Повний текст джерелаАнотація:
Abstract Background Antibiotics, while eliminating pathogens, also partially deplete commensal bacteria. Antibiotic-induced dysbiosis may contribute to the observed rise in “immune-mediated” diseases, including autoimmunity and allergy. The aim of this study is to investigate the impact of perinatal antibiotic treatment on T cell-mediated immune response in adult mice. Methods Oral treatment with broad-spectrum antibiotic enrofloxacin during gestation and breastfeeding or breastfeeding or gestation alone was used to evaluate whether antibiotic exposure early in life could modulate contact sensitivity (CS) in adult mice. Results Here, we demonstrated that enrofloxacin treatment during gestation and breastfeeding, but not during pregnancy or breastfeeding alone, aggravated CS reaction in adult mice measured by ear swelling. These data correlate with increased myeloperoxidase (MPO) activity in the ear extracts and elevated production of IL-6 and IL-17A by auricular lymph node cells (ELNC) and was not influenced by food consumption and body weight. In each dosing regimen, enrofloxacin treatment reduced the relative abundance of Enterococcus spp. but did not influence the relative abundances of Lactobacillus, Clostridium cluster XIVa, XIVab, I, Bacteroidetes, and segmented filamentous bacteria (SFB). However, prolonged enrofloxacin-treatment during both gestation and breastfeeding decreased the relative abundance of Clostridium cluster IV. Conclusion These data show that long-term perinatal enrofloxacin treatment induces intestinal dysbiosis, characterized by decreased levels of anti-inflammatory Clostridium cluster IV, and alters T cell-dependent immune responses, enhancing CS reaction in adult mice.
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Diehl, Gretchen, Andrea Hill-McAlester, Karina Ochoa, and Carolina Galan. "CX3CR1 mononuclear phagocytes utilize the microbiota to promote balanced intestinal immune responses." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 136.7. http://dx.doi.org/10.4049/jimmunol.196.supp.136.7.
Повний текст джерелаАнотація:
Abstract The development and proper functioning of the mammalian immune system relies on a reciprocal relationship between the host and the microbiota. These interactions shape both the composition of the microbiota along with the development and responsiveness of the immune system. Such a relationship requires mechanisms to reduce inflammatory immune responses within the intestine, which can damage the epithelial barrier and lead to the development of disorders such as inflammatory bowel disease. We find that CX3CR1 expressing mononuclear phagocytes (MNPs) are critical for maintaining this intestinal homeostasis. Using mice where we can selectively deplete CX3CR1+ MNPs in vivo, we demonstrate that CX3CR1+ MNPs in the lamina propria promote epithelial repair and, in models of colitis, limit TH1 responses against the microbiota itself. We also find they have functions in immune inductive sites such as the MLN where they limit the generation of inflammatory TH1 immune responses against pathogenic bacteria. Finally, we find they are required for the induction of antigen specific TH17 responses against members of the microbiota such as segmented filamentous bacteria (SFB). We find that the intact microbiota is critical for these homeostatic roles. After disruption of the microbiota with antibiotics, CX3CR1+ MNPs now promote inflammatory immune responses and are unable to promote epithelial barrier repair. Understanding this crucial relationship between the microbiota and intestinal immune cells will allow for selective targeting to modulate responsiveness of the intestinal immune system and promote homeostasis.
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Mao, Kairui, Antonio Baptista, Nicolas Bouladoux, Andrew J. Martins, Samira Tamoutounour, Jacquice Davis, Yuefeng Huang, Michael Y. Gerner, Yasmine Belkaid, and Ronald N. Germain. "Sequential activity of innate and adaptive lymphocytes supports non-inflammatory gut microbial commensalism." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 200.14. http://dx.doi.org/10.4049/jimmunol.198.supp.200.14.
Повний текст джерелаАнотація:
Abstract The mammalian gut is colonized by trillions of microorganisms termed the “microbiota”, which have a mutually beneficial relationship with their host. In normal individuals, the gut microbiota matures after birth to a state of balanced commensalism that is marked by the absence of adverse inflammation. Both innate lymphoid cells (ILCs) and antigen-specific conventional T cells contribute to containment and clearance of microbial pathogens. But how these two major lymphoid cell populations help shape the mature commensal (non-pathogenic) microbiome and maintain tissue homeostasis has not been determined. Using advanced multiplex quantitative imaging methods, here we show that in the absence of adaptive lymphocytes, IL-23 induced by specific commensal bacteria such as Segmented Filamentous Bacteria (SFB) persistently activates RORgt+ group 3 innate lymphoid cells (ILC3s) in the ileum to produce IL-22, which induces STAT3 activation in virtually all epithelial cells, contributing to production of molecules such as anti-microbial peptides that protect the tissue from microbial damage. The distinct roles of ILCs in handling gut microbes play out in normal mice during development. The pSTAT3 signature is absent after birth, which is followed by microbial colonization and strong ILC3 activation and an extensive epithelial pSTAT3 signature upon weaning. This innate immune activity is subsequently extinguished as adaptive CD4+ T cell immunity develops in response to the expanding commensal burden. Our findings provide new insights into how innate and adaptive lymphocytes sequentially operate during normal development to establish steady state commensalism.
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Xu, Chunliang, Sungkyun Lee, and Paul S. Frenette. "The Gut Microbiome Regulates Psychological Stress-Induced Inflammation in Sickle Cell Disease." Blood 134, Supplement_1 (November 13, 2019): 205. http://dx.doi.org/10.1182/blood-2019-122331.
Повний текст джерелаАнотація:
Psychological stress (PS) is reported to precipitate vaso-occlusive episides (VOE) in sickle cell disease (SCD), but the mechanisms by which it does, are largely unknown. We subjected humanized (Berkeley) SCD mice to restraint stress and analyzed VOE using intravital microscopy. We found that stress exacerbated VOE as shown by reduced venular blood flow rates (control: 494 ± 30 × 103 pL/s; stress: 380 ± 20 × 103 pL/s; n = 25 - 43; p = 0.009) and reduced survival time (median survival time in control and stress groups: 394 min and 175 min, respectively; p = 0.02, Log-rank test). As previous studies show that adherent polymorphonuclear neutrophils (PMNs), especially aged PMNs marked by low CD62L and high CXCR4 expression, contribute to VOEs, we evaluated the behavior of leukocytes in live mice and observed a robust PMN response manifested by significantly increased adhesion and interactions with sickle RBC in stressed SCD animals. Flow cytometry analysis revealed a striking increase in aged PMNs in stressed SCD mice (control: 0.7 ± 0.1 × 106/ml; stress: 2.9 ± 0.3 × 106/ml; n = 3 - 4; p = 0.001), suggesting that the aged PMN expansion induced by stress may lead to the exacerbation of VOE in stressed SCD mice. Since aged PMN numbers are regulated by microbiota under steady state, we investigated whether response to PS also required the presence of the microbiota. Depletion of microbiota with broad-spectrum antibiotics (ABX) in SCD mice significantly prevented stress-induced aged PMN expansion (control: 4.8 ± 1.2 × 106/ml; ABX: 1.2 ± 0.3× 106/ml; n = 4 - 5; p = 0.0006), which was further confirmed using C57BL/6 germ-free (GF) mice (control: 1.1 ± 0.3 × 106/ml; GF: 0.2 ± 0.1 × 106/ml; n = 4; p = 0.003). Interestingly, analysis of inflammatory cytokines revealed a microbiota-dependent augmentation of IL-17A in the stressed mice. To investigate the role of IL-17A in the stress response, we neutralized IL-17A using an antibody (Ab) in C57BL/6 mice and found that IL-17A inhibition significantly dampened the aged PMN expansion induced by stress (isotype control Ab: 0.6 ± 0.1 × 106/ml; anti-IL-17A: 0.1 ± 0.0 × 106/ml; n = 4 - 5; p = 0.0004), which was also confirmed using IL-17A-/- mice. Further analyses revealed that Th17 lymphocytes were the major IL-17A-producing cells contributing to the stress response. In addition, depletion of microbiota with ABX or neutralization of IL-17A significantly alleviated stress-exacerbated VOE as measured by reduced PMN activation, improved blood flow rate and prolonged SCD mouse survival. As segmented filamentous bacteria (SFB) commensals were previously found to induce a Th17 response, we next tested the hypothesis that SFB was the driving bacteria in the stress response. Indeed, we found that PS-induced aged PMN expansion was greater in SFB+ mice (from Taconic) than in SFB- mice (from Jackson lab) (Taconic: 0.64 ± 0.11× 106/ml; Jax: 0.13 ± 0.02 × 106/ml; n = 4 - 5; p = 0.005). Depletion of SFB using vancomycin, a drug that eliminates Gram+ bacteria (including SFB), significantly reduced stress-induced aged PMN expansion. Furthermore, colonization of GF mice with SFB augmented aged PMN expansion after stress compared to stress control GF mice (control GF: 0.08 ± 0.02 × 106/ml; GF + SFB: 0.34 ± 0.10× 106/ml; n = 4 - 5; p = 0.04), suggesting that SFB was the key bacteria promoting aged PMN expansion during stress. The stress mechanisms involved the hypothalamic-pituitary-adrenal (HPA) axis since the blockade of glucocorticoid (GC) production using metyrapone or following adrenalectomy significantly prevented aged PMN expansion in stressed mice (PBS: 0.5 ± 0.1 × 106/ml; metyrapone: 0.1 ± 0.1× 106/ml; n = 5; p = 0.02. sham: 1.2 ± 0.2 × 106/ml; adrenalectomy: 0.4 ± 0.2 × 106/ml; n = 4 - 5; p = 0.01). Moreover, PS and dexamethasone greatly increased the gut permeability. Blockade of GC synthesis using metyrapone significantly alleviated stress-induced exacerbation of VOE manifested by reduced inflammation, improved the blood flow rate and prolonged SCD mice survival (median survival time in control and metyrapone groups: 155 min and 200 min, respectively; p = 0.02, Log-rank test). Overall, our results suggest that stress activation of the HPA axis increases the intestinal permeability, thereby promoting exposure to commensals that stimulate Th17 cells to produce IL-17A, which enables the expansion of aged polymorphonuclear neutrophils driving vaso-occlusion in SCD. Disclosures Frenette: Albert Einstein College of Medicine, Inc: Patents & Royalties; Ironwood Pharmaceuticals: Research Funding; Cygnal Therapeutics: Equity Ownership; Pfizer: Consultancy.