Article

Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells

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Abstract

Intestinal Th17 cells are induced and accumulate in response to colonization with a subgroup of intestinal microbes such as segmented filamentous bacteria (SFB) and certain extracellular pathogens. Here, we show that adhesion of microbes to intestinal epithelial cells (ECs) is a critical cue for Th17 induction. Upon monocolonization of germ-free mice or rats with SFB indigenous to mice (M-SFB) or rats (R-SFB), M-SFB and R-SFB showed host-specific adhesion to small intestinal ECs, accompanied by host-specific induction of Th17 cells. Citrobacter rodentium and Escherichia coli O157 triggered similar Th17 responses, whereas adhesion-defective mutants of these microbes failed to do so. Moreover, a mixture of 20 bacterial strains, which were selected and isolated from fecal samples of a patient with ulcerative colitis on the basis of their ability to cause a robust induction of Th17 cells in the mouse colon, also exhibited EC-adhesive characteristics.

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... Similarly, lamina propria resident Th17 cells are induced by specific bacteria [161][162][163][164][165]. In particular, Th17 cells are induced by intestinal epithelial adhesive microbes, such as SFB [162][163][164][165], in a microbial antigen-dependent manner [40,166]. ...
... Similarly, lamina propria resident Th17 cells are induced by specific bacteria [161][162][163][164][165]. In particular, Th17 cells are induced by intestinal epithelial adhesive microbes, such as SFB [162][163][164][165], in a microbial antigen-dependent manner [40,166]. Interestingly, the functional profile of Th17 cells depends on bacterial stimuli. ...
... Th17 cells induced by SFB or other commensals are noninflammatory, while the opposite is true for the Th17 cells elicited by Citrobacter rodentium [167] or Helicobacter hepaticus in the condition of lacking IL-10 [168]. Homeostatic Th17 cell differentiation is promoted by IL-6 and TGF-β produced by microbiomestimulated epithelial cells and gut resident DCs [162][163][164][165]169]. On the other hand, it has been shown that IEC-derived serum amyloid A (SAA) proteins enhance differentiation of proinflam-matory Th17 cells [170]. ...
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Fundamental asymmetries between the host and its microbiome in enzymatic activities and nutrient storage capabilities have promoted mutualistic adaptations on both sides. As a result, the enteric immune system has evolved so as not to cause a zero-sum sterilization of non-self, but rather achieve a non-zero-sum self-reinforcing cooperation with its evolutionary partner the microbiome. In this review we attempt to integrate the accumulated knowledge of immune – microbiome interactions into an evolutionary framework and trace the pattern of positive immune – microbiome feedback loops across epithelial, enteric nervous system, innate and adaptive immune circuits. Indeed, the immune system requires commensal signals for its development and function, and reciprocally protects the microbiome from nutrient shortage and pathogen outgrowth. In turn, a healthy microbiome is the result of immune system curatorship as well as microbial ecology. The paradigms of host-microbiome asymmetry and the cooperative nature of their interactions identified in the gut are applicable across all tissues influenced by microbial activities. Incorporation of immune system influences into models of microbiome ecology will be a step forward towards defining what constitutes a healthy human microbiome and guide discoveries of novel host-microbiome mutualistic adaptations that may be harnessed for promotion of human health. This article is protected by copyright. All rights reserved
... SFB are Gram-positive members of the intestinal microbiota in rodents, non-human primates, and humans (Davis and Savage, 1974;Klaasen et al., 1993;Ley et al., 2008;Yin et al., 2013;Jonsson et al., 2020). SFB have a distinctive morphology characterized by long, segmented filaments and have a unique ability to attach tightly to intestinal epithelial cells (Davis and Savage, 1974) ( Figure S3A) and stimulate host gene expression (Ivanov et al., 2008;Ivanov et al., 2009;Sano et al., 2015;Atarashi et al., 2015). ...
... IL-22 activates epithelial cell STAT3 to drive Reg3g expression (Sano et al., 2015) ( Figure S5A). Epithelial attachment by SFB triggers the ILC3-STAT3 relay and stimulates expression of genes including Reg3g (Sano et al., 2015;Atarashi et al., 2015). ...
... First, SFB are a rare but detectable component of the gut microbiota of humans (Chen et al., 2018;Jonsson et al., 2020). Second, other members of the human microbiota adhere to the intestinal epithelium and thus shape immune responses in a manner similar to that of SFB (Yin et al., 2013;Atarashi et al., 2015). ...
Article
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Environmental light cycles entrain circadian feeding behaviors in animals that produce rhythms in exposure to foodborne bacteria. Here, we show that the intestinal microbiota generates diurnal rhythms in innate immunity that synchronize with feeding rhythms to anticipate microbial exposure. Rhythmic expression of antimicrobial proteins was driven by daily rhythms in epithelial attachment by segmented filamentous bacteria (SFB), members of the mouse intestinal microbiota. Rhythmic SFB attachment was driven by the circadian clock through control of feeding rhythms. Mechanistically, rhythmic SFB attachment activated an immunological circuit involving group 3 innate lymphoid cells. This circuit triggered oscillations in epithelial STAT3 expression and activation that produced rhythmic antimicrobial protein expression and caused resistance to Salmonella Typhimurium infection to vary across the day-night cycle. Thus, host feeding rhythms synchronize with the microbiota to promote rhythms in intestinal innate immunity that anticipate exogenous microbial exposure.
... Segmented filamentous bacteria (SFB) is an anaerobic grampositive spore-forming bacterium (123). SFB is essential for the proliferation and activation of Th17 cells, a process that cannot be separated from the adhesion of SFB to intestinal epithelial cells (124). The direct contact between SFB and intestinal epithelial cells induces the production of serum amyloid A proteins (SAA) and reactive oxygen species, creating an intestinal environment conducive to Th17 cell differentiation (124). ...
... SFB is essential for the proliferation and activation of Th17 cells, a process that cannot be separated from the adhesion of SFB to intestinal epithelial cells (124). The direct contact between SFB and intestinal epithelial cells induces the production of serum amyloid A proteins (SAA) and reactive oxygen species, creating an intestinal environment conducive to Th17 cell differentiation (124). SAA induces IL-23 production in DCs; subsequently, IL-23 triggers IL-22 secretion by type 3 innate lymphoid cells. ...
... SAA induces IL-23 production in DCs; subsequently, IL-23 triggers IL-22 secretion by type 3 innate lymphoid cells. IL-22 activates Stat3, which subsequently increases SAA expression (124,125). Moreover, various cytokines secreted by CD11c+ cells in response to SAA stimulation, including IL-1b, IL-6, and IL-23, can boost the differentiation of Th17 cells together with TGF-b and SAA, with the latter being a vector of high-density lipoprotein (HDL) and retinol; therefore, it is speculated that SAA can deliver these immunomodulatory molecules to antigenpresenting cells (APCs) and T cells to regulate the body's immune response. ...
Article
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Myasthenia gravis (MG) is an acquired neurological autoimmune disorder characterized by dysfunctional transmission at the neuromuscular junction, with its etiology associated with genetic and environmental factors. Anti-inflammatory regulatory T cells (Tregs) and pro-inflammatory T helper 17 (Th17) cells functionally antagonize each other, and the immune imbalance between them contributes to the pathogenesis of MG. Among the numerous factors influencing the balance of Th17/Treg cells, the gut microbiota have received attention from scholars. Gut microbial dysbiosis and altered microbial metabolites have been seen in patients with MG. Therefore, correcting Th17/Treg imbalances may be a novel therapeutic approach to MG by modifying the gut microbiota. In this review, we initially review the association between Treg/Th17 and the occurrence of MG and subsequently focus on recent findings on alterations of gut microbiota and microbial metabolites in patients with MG. We also explore the effects of gut microbiota on Th17/Treg balance in patients with MG, which may provide a new direction for the prevention and treatment of this disease.
... Additionally, some filamentous bacteria and Candida albicans induce the proliferation of bacterial and fungal antigen receptors on T cell helper 17 cells (TH17). The bacterial antigen receptors of the TH17 cells allow the immune system to distinguish commensals from antagonistic pathogens without eliciting immune detection to themselves (Atarashi et al., 2015;Romo and Kumamoto, 2020). The TH17 cells prevent inflammation from the innate immune response when pathogen-associated molecular patterns or PAMPS are detected (Atarashi et al., 2015). ...
... The bacterial antigen receptors of the TH17 cells allow the immune system to distinguish commensals from antagonistic pathogens without eliciting immune detection to themselves (Atarashi et al., 2015;Romo and Kumamoto, 2020). The TH17 cells prevent inflammation from the innate immune response when pathogen-associated molecular patterns or PAMPS are detected (Atarashi et al., 2015). Without functional TH17 immune cells, every PAMP is detected would cause an inflammatory response resulting in the unnecessary chronic flushing of the intestines or diarrhea, which is a common symptom of Crohn's disease (Brand, 2009). ...
... For example, an acidic environment will cause more PAMPs to be expressed on the cell surface, whereas a more basic environment does the opposite (Alves et al., 2020). As mentioned earlier, C. albicans induces the differentiation of TH17 fungal antigen receptors, which reduce inflammation caused by the innate immune system in response to PAMPs on the C. albicans cell surface (Atarashi et al., 2015;Romo & Kumamoto, 2020). ...
... [15,121,124]. Given their close association with the host epithelium, these microbes may act in a beneficial way by promoting appropriate immune responses to dampen inflammation [122,125]. Thus, improper MAB colonization during early lifedriven, for example, by dietary factors or overuse of antibioticsmight have implications for type 2 allergic immune responses later in life [126]. Perhaps the best-studied example of MABs are the segmented filamentous bacteria (SFBs). ...
... Perhaps the best-studied example of MABs are the segmented filamentous bacteria (SFBs). These have been identified in mouse and rat intestine as Gram-positive bacteria that can bind to the epithelium and induce a strong Th17 immune response [125]. SFBs primarily colonize the small intestine, where the mucus layer is thinner and looser than that in the large intestine. ...
... SFBs primarily colonize the small intestine, where the mucus layer is thinner and looser than that in the large intestine. Although SFB have not been identified in humans, a 20-strain community derived from humans was able to induce a Th17 response by adhering to the epithelium among colonization of germ-free mice and rats [125]. As research continues to shed light on this specific niche, functional characterization of its residents may allow us to better understand microbe-host communications. ...
Article
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The prevalence of food allergies has reached epidemic levels but the cause remains largely unknown. We discuss the clinical relevance of the gut mucosal barrier as a site for allergic sensitization to food. In this context, we focus on an important but overlooked part of the mucosal barrier in pathogenesis, the glycoprotein-rich mucus layer, and call attention to both beneficial and detrimental aspects of mucus–gut microbiome interactions. Studying the intricate links between the mucus barrier, the associated bacteria, and the mucosal immune system may advance our understanding of the mechanisms and inform prevention and treatment strategies in food allergy.
... Age-related intestinal dysbiosis is associated with immune dysregulation; impaired intestinal epithelial integrity causes transmucosal leakage of bacterial antigens (e.g., SCFA, neurotransmitters) into systemic circulation, leading to immunosenescence and the development of autoimmune disorders [126]. One mechanism by which the gut microbiota can impact immunity is through the induction of Th17 cells [127]. Th17 cells come from pro-inflammatory T helper cells and are characterized by their production of cytokines including IL-17, IL-22 and IL-21 [128]. ...
... Moreover, Th17 cells are known to be uniquely pathogenic in chronic inflammatory and autoimmune diseases, including those of the skin (e.g., psoriasis). In vivo experiments demonstrate an induction of Th17 cells in the host upon microbial adhesion to intestinal epithelial cells [127]. In particular, twenty bacterial strains were identified with adhesive characteristics that may lead to the induction and accumulation of Th17 cells. ...
Article
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The role of the microbiome in human aging is important: the microbiome directly impacts aging through the gastrointestinal system. However, the microbial impact on skin has yet to be fully understood. For example, cellular senescence is an intrinsic aging process that has been recently associated with microbial imbalance. With age, cells become senescent in response to stress wherein they undergo irreversible growth arrest while maintaining high metabolic activity. An accumulation of senescent cells has been linked to various aging and chronic pathologies due to an overexpression of the senescence-associated secretory phenotype (SASP) comprised of proinflammatory cytokines, chemokines, growth factors, proteases, lipids and extracellular matrix components. In particular, dermatological disorders may be promoted by senescence as the skin is a common site of accumulation. The gut microbiota influences cellular senescence and skin disruption through the gut-skin axis and secretion of microbial metabolites. Metabolomics can be used to identify and quantify metabolites involved in senescence. Moreover, novel anti-senescent therapeutics are warranted given the poor safety profiles of current pharmaceutical drugs. Probiotics and prebiotics may be effective alternatives, considering the relationship between the microbiome and healthy aging. However, further research on gut composition under a senescent status is needed to develop immunomodulatory therapies.
... Citrobacter rodentium is a natural mouse A/E pathogen that colonizes the colonic mucosa by a mechanism similar to those of EHEC and EPEC (4). It was reported that infection of germ-free mice with a C. rodentium strain lacking the eae gene for intimin induced mucosal IgA production at a level lower than that of the wild-type (WT) strain (10). These results suggest that adhesion of the A/E pathogens to the intestinal epithelial cells via the Tirintimin interaction is important for the induction of mucosal IgA responses. ...
... To determine the mechanisms underlying the reason why virulence factorspecific Ab production occurred only in Tir-F, we performed transcriptomic analysis, and it clearly showed that robust inflammatory and immune responses occurred only in the Tir-Finfected mice. Many of the genes elevated in the Tir-Finfected mice in our experiment were consistent with those elevated in germ-free mice infected with C. rodentium or segmented filamentous bacteria (10). Tir-Finfected mice showed strong enhancement of gene expression of Plet1, a recently characterized intestinal dendritic cell (DC) marker (26), suggesting that DC-mediated Ag presentation to T cells is enhanced in the Tir-Finfected mice. ...
Article
Citrobacter rodentium is a murine pathogenic bacterium that adheres to intestinal epithelial cells, resulting in loss of microvilli and pedestal formation, and alters multiple cellular processes, including actin dynamics. Translocated intimin receptor (Tir), one of its virulence factors, functions as receptor for intimin, a bacterial adhesin, thereby mediating bacterial adhesion to epithelial cells. Although robust immune responses are induced to eliminate pathogenic bacteria in the host, they are suppressed against harmless commensal bacteria. The mechanism(s) underlying such a differentiation remains unclear. This study sought to determine the roles of intimate adhesion in the induction of specific immune responses upon C. rodentium infection. To this end, microbiota-depleted mice were infected with the Tir-F strain expressing full-length Tir or mutant strains expressing the C-terminal truncated Tir that is defective in intimin binding and host cell actin polymerization. There were no differences in the colonization kinetics and Abs responses against C. rodentium LPS among the strains, whereas Abs against the virulence factors were only produced on Tir-F infection. Although there were no differences in the virulence factors mRNA expression levels, colonic hyperplasia, and bacterial translocation to the systemic organs irrespective of the strain, adhesion to colonic epithelial cells was reduced in the mutant strain-infected mice. Furthermore, transcriptomic analysis indicated that robust inflammatory and immune responses were only induced in the Tir-F-infected group and were suppressed in the mutant-infected groups. Taken together, these findings suggest that Tir-mediated intimate adhesion induces inflammatory and immune responses, resulting in the induction of virulence factor-specific Abs.
... First, these communities are typically neither defined nor cultured (with exceptions; Wagner et al., 2016;Britton et al., 2019Britton et al., , 2020, limiting the establishment of causality for specific microbes and/or microbial products. Second, while it is clear that microbes derived from humans can modulate particular facets of the murine immune system, host-specificity in such interactions (Atarashi et al., 2015) means that human-derived microbiota may not shape immune responses equivalent to murine-derived microbes (Gaboriau-Routhiau et al., 2009;Chung et al., 2012;Lundberg et al., 2020). Third, human-derived microbiomes are not as well adapted to the murine intestine as mousederived communities. ...
... Fundamental differences between mice and humans mean that key aspects of host-microbiome interactions may not be modeled in a murine system. Indeed, the specificity in molecular aspects of host-microbe interactions (Lecuit et al., 1999;Atarashi et al., 2015) demands systems to study human-derived microbes in the context of human cells. The advent of sophisticated in vitro/ex vivo approaches that use human-derived cells that can themselves be genetically manipulated represent attractive alternatives that can be used in parallel to murine models. ...
Article
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The profound impact of the gut microbiome on host health has led to a revolution in biomedical research, motivating researchers from disparate fields to define the specific molecular mechanisms that mediate host-beneficial effects. The advent of genomic technologies allied to the use of model microbiomes in gnotobiotic mouse models has transformed our understanding of intestinal microbial ecology and the impact of the microbiome on the host. However, despite incredible advances, our understanding of the host-microbiome dialogue that shapes host physiology is still in its infancy. Progress has been limited by challenges associated with developing model systems that are both tractable enough to provide key mechanistic insights while also reflecting the enormous complexity of the gut ecosystem. Simplified model microbiomes have facilitated detailed interrogation of transcriptional and metabolic functions of the microbiome but do not recapitulate the interactions seen in complex communities. Conversely, intact complex communities from mice or humans provide a more physiologically relevant community type, but can limit our ability to uncover high-resolution insights into microbiome function. Moreover, complex microbiomes from lab-derived mice or humans often do not readily imprint human-like phenotypes. Therefore, improved model microbiomes that are highly defined and tractable, but that more accurately recapitulate human microbiome-induced phenotypic variation are required to improve understanding of fundamental processes governing host-microbiome mutualism. This improved understanding will enhance the translational relevance of studies that address how the microbiome promotes host health and influences disease states. Microbial exposures in wild mice, both symbiotic and infectious in nature, have recently been established to more readily recapitulate human-like phenotypes. The development of synthetic model communities from such “wild mice” therefore represents an attractive strategy to overcome the limitations of current approaches. Advances in microbial culturing approaches that allow for the generation of large and diverse libraries of isolates, coupled to ever more affordable large-scale genomic sequencing, mean that we are now ideally positioned to develop such systems. Furthermore, the development of sophisticated in vitro systems is allowing for detailed insights into host-microbiome interactions to be obtained. Here we discuss the need to leverage such approaches and highlight key challenges that remain to be addressed.
... For example, segmented filamentous bacteria (SFB) (6) and Bifidobacterium adolescentis (51) were identified to specifically induce T helper 17 (Th17) cells in the intestine. The Th17-inducing property of SFB was demonstrated to be dependent on their direct association with the gut epithelium (52). SFB stimulate microbial adhesion-triggered endocytosis in epithelial cells and induce SFB-antigenspecific, tissue-resident and homeostatic Th17 cells (53). ...
Article
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The collection of microorganisms living in the mammalian gastrointestinal tract, termed the gut microbiota, has been shown to have profound impacts on host health and increasingly is regarded as a viable therapeutic target. Clinical studies of fecal microbiota transplantation (FMT) have demonstrated potential efficacy of microbiota-based therapies for diseases including Clostridioides difficile infections, inflammatory bowel disease, graft-versus-host disease and cancer. However, the lack of understanding of the active ingredients and potential risks of such therapies pose challenges for clinical application. Meanwhile, efforts are being made to identify effector microbes directly associated with a given phenotype, to establish causality and to devise well-characterized microbial therapeutics for clinical use. Strategies based on defined microbial components will likely enhance the potential of microbiota-targeted therapies.
... The colonization of commensal segmented filamentous bacteria (SFB) was found to induce RORγt + Th17 cells to produce IL-17A, which is mediated by ILC3-derived IL-22 [145], as well as promote the differentiation of Peyer's patch Tfh cells [146]. The differentiation of CD4 + Th17 cells, which have been known to have defensive functions against bacterial pathogens, were also demonstrated to be induced in response to colonization with SFB and certain extracellular pathogens [147]. Intestinal DCs also respond to commensal bacteria, producing IL-6 and Il-23p19, thereby induces the production of IL-17 and IL-22 by Th17 and ILCs, which enhances intestinal barrier integrity [109]. ...
Article
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Despite considerable epidemiological evidence indicating comorbidity between metabolic disorders, such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, and inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, as well as common pathophysiological features shared by these two categories of diseases, the relationship between their pathogenesis at molecular levels are not well described. Intestinal barrier dysfunction is a characteristic pathological feature of IBD, which also plays causal roles in the pathogenesis of chronic inflammatory metabolic disorders. Increased intestinal permeability is associated with a pro-inflammatory response of the intestinal immune system, possibly leading to the development of both diseases. In addition, dysregulated interactions between the gut microbiota and the host immunity have been found to contribute to immune-mediated disorders including the two diseases. In connection with disrupted gut microbial composition, alterations in gut microbiota-derived metabolites have also been shown to be closely related to the pathogeneses of both diseases. Focusing on these prominent pathophysiological features observed in both metabolic disorders and IBD, this review highlights and summarizes the molecular risk factors that may link between the pathogeneses of the two diseases, which is aimed at providing a comprehensive understanding of molecular mechanisms underlying their comorbidity.
... The lamina propria of the small intestine is rich in Th17 cells, and the changes in the local microenvironment are the main factors for Th17 cells activation. In 2015, Koji Atarashiit et al. discovered that the adhesion of microorganisms to intestinal epithelial cells was a crucial condition for inducing the production of Th17 cells [41]. The level of intestinal Th17 cells could be changed by regulating the intestinal ora through diet [42,43]. ...
Preprint
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Background: Perioperative neurocognitive disorders (PND) occur frequently in elderly patients after surgery, but the mechanism of PND is not very clear at present. It is reported that anesthesia/surgery could cause intestinal flora imbalance and induce neurocognitive impairment. However, the effect of intestinal flora on PND is poorly understood. We previously found that peripheral interleukin-17A (IL17A) destroyed the blood-brain barrier (BBB), leading to central inflammation and neurocognitive impairment. The small intestine is the main place where Th17 cells are produced. Therefore, we hypothesized that Th17 cells and IL-17 may be an important bridge for intestinal microbes to cause neuroinflammation. Methods: Exploratory laparotomy was performed to establish PND model under sevoflurane anesthesia. 16S rRNA high-throughput sequencing was used to detect the changes of intestinal flora. To explore the relationship between intestinal flora and PND, compound antibiotics were used to eliminate intestinal flora before anesthesia/surgery, and behavior tests, such as open field, Y maze, and fear conditioning tests were applied to detect the changes of memory ability and which was compared with the rats that did not receive compound antibiotics. The number of Th17 cells and Foxp3 cells was detected by flow cytometry in the Peyer's patches (PP), mesenteric lymph nodes (MLN), blood and brain. Hippocampus IL17, IL17RA, IL6 and IL10 were detected by Western blot. Hippocampus IL17, IL17R and IBA1 (ionized calcium binding adaptor molecule1) were detected by immunofluorescence. Results: Anesthesia/surgery caused intestinal flora imbalance and induced neurocognitive impairment, increased the number of Th17 cells in the PP, MLN, blood and brain, up-regulated the lever of IL17, IL17R and inflammatory factor production in the hippocampus. The administration of compound antibiotics before anesthesia/surgery evidently inhibited this effect, including decreased the number of Th17 cells, down-regulated the lever of IL17, IL17R and inflammatory factor production, and improved the memory function. In addition, we found that IL17R was co-labeled with IBA1 in a large amount in the hippocampus through immunofluorescence double-staining. Conclusion: Our study suggested that intestinal dysbacteriosis-propelled T helper 17 cells activation might play an important role in the pathogenesis of PND.
... Serum levels of IL-17 ( Figure 4B, p < 0.05), and colon tissue expression levels of IL-23 and IL-17 were significantly upregulated ( Figures 4D, E, p < 0.05). The IL-17RA pathway may be activated by gut microbiota (Figure 4F), and is related to most autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis (AS), and inflammatory bowel disease (Atarashi et al., 2015;Kim et al., 2016). IL-23 may induce pathogenic Th17 cells and promote inflammatory disease (Lee et al., 2020). ...
Article
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It is known that the microbiome affects human physiology, emotion, disease, growth, and development. Most humans exhibit reduced appetites under high temperature and high humidity (HTHH) conditions, and HTHH environments favor fungal growth. Therefore, we hypothesized that the colonic mycobiota may affect the host’s appetite under HTHH conditions. Changes in humidity are also associated with autoimmune diseases. In the current study mice were fed in an HTHH environment (32°C ± 2°C, relative humidity 95%) maintained via an artificial climate box for 8 hours per day for 21 days. Food intake, the colonic fungal microbiome, the feces metabolome, and appetite regulators were monitored. Components of the interleukin 17 pathway were also examined. In the experimental groups food intake and body weight were reduced, and the colonic mycobiota and fecal metabolome were substantially altered compared to control groups maintained at 25°C ± 2°C and relative humidity 65%. The appetite-related proteins LEPT and POMC were upregulated in the hypothalamus ( p < 0.05), and NYP gene expression was downregulated ( p < 0.05). The expression levels of PYY and O-linked β-N-acetylglucosamine were altered in colonic tissues ( p < 0.05), and interleukin 17 expression was upregulated in the colon. There was a strong correlation between colonic fungus and sugar metabolism. In fimo some metabolites of cholesterol, tromethamine, and cadaverine were significantly increased. There was significant elevation of the characteristic fungi Solicoccozyma aeria , and associated appetite suppression and interleukin 17 receptor signaling activation in some susceptible hosts, and disturbance of gut bacteria and fungi. The results indicate that the gut mycobiota plays an important role in the hypothalamus endocrine system with respect to appetite regulation via the gut-brain axis, and also plays an indispensable role in the stability of the gut microbiome and immunity. The mechanisms involved in these associations require extensive further studies.
... A subsequent study suggested that intestinal Th17 cells exclusively harbor SFB specific T cell receptor (TCR) responding upon exposure to SFB antigen (24). Notably, besides SFB, distinct pathogens and other human-derived intestinal bacteria with the ability to attach to the epithelium as well as fungi have been demonstrated to induce Th17 cell differentiation (25). ...
Article
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The intestinal microbiota modulates IL-22 production in the intestine, including the induction of IL-22-producing CD4+ T helper cells. Which specific bacteria are responsible for the induction of these cells is less well understood. Here, we demonstrate through the use of novel gnotobiotic knock-in reporter mice that segmented filamentous bacteria (SFB), which are known for their ability to induce Th17 cells, also induce distinct IL-17A negative CD4+ T cell populations in the intestine. A subset of these cells instead produces IL-22 upon restimulation ex vivo and also during enteric infections. Furthermore, they produce a distinct set of cytokines compared to Th17 cells including the differential expression of IL-17F and IFN-γ. Importantly, genetic models demonstrate that these cells, presumably Th22 cells, develop independently of intestinal Th17 cells. Together, our data identifies that besides Th17, SFB also induces CD4+ T cell populations, which serve as immediate source of IL-22 during intestinal inflammation.
... Candidatus arthromitus) and bacteria from Firmicutes or Proteobacteria could trigger the production of Th17 and intestinal local inflammation (Atarashi et al. 2015;Ivanov II et al. 2008). Unexpectedly, our correlation analysis revealed a negative instead of a positive relationship between the dominant microbes in NOD mice and leukomonocytes or their ratio, which suggested that a more specific classification of leukomonocytes should be conducted to discover the authentic association between the dominant microbes and those specific groups of leukomonocytes, especially activated T cells. ...
Article
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Intestinal flora changes were found in patients and animals with type 1 diabetes (T1D). However, few studies have provided any explicit clues of changes in highly disease related commensal microbiota before disease onset and their relationships with disordered peripheral immune cells. We conducted 16S rRNA microbiota analysis of non-obese diabetic (NOD) mice from weaning to diabetes onset to identify highly disease related microbes and performed Spearman correlation analysis between anomalous flora and peripheral immune cells. We found NOD mice had increased exclusive bacteria and decreased community richness or diversity, besides, with the features of decreased abundance of Bacteroidetes and increased abundance of Firmicutes, Proteobacteria or Deferribacteres and remarkable fluctuations of genus relative abundance. Furthermore, kinds of highly T1D related genus and their strong correlations with peripheral immune cells, especially neutrophils, were discovered. Microbial changes in NOD mice differed from that of ICR mice and highly disease associated microbes have strong correlations with the peripheral neutrophil ratio, which provide evidence that neutrophils are possibly involved in the pathogenesis of T1D.
... It has been reported that Th17 cells are induced when there is an increased representation of Proteobacteria, including adherent/invasive E. coli (AIEC), in the gut microflora. Th17 cell hyperactivity is involved in the pathogenesis of IBD [40,41], which may be compounded by an accumulation of regulatory T cells with functional abnormalities, due to a decrease in butyric acid producing bacteria [42]. ...
Article
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Adrenomedullin (AM) is a bioactive peptide with various physiological functions, including vasodilation, angiogenesis, anti-inflammation, organ protection, and tissue repair. AM suppresses inflammatory cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function, mucosal epithelial repair, and immune function in the intestinal bacteria of animal models with intestinal inflammation. We have been promoting translational research to develop novel therapeutic agents for inflammatory bowel disease (IBD) using AM and have started clinical research for IBD patients since 2010. A multicenter clinical trial is currently underway in Japan for patients with refractory ulcerative colitis and Crohn’s disease. Moreover, since current AM administration is limited to continuous intravenous infusion, the development of a subcutaneous formulation using long-acting AM is underway for outpatient treatment.
... ;https://doi.org/10.1101https://doi.org/10. /2021 other Th17-inducing microbes, B. adolescentis possesses the ability to tightly associate with the intestinal epithelium (Atarashi et al., 2015;Tan et al., 2016). Moreover, low-or high-FODMAP diets were shown to ameliorate or exacerbate, respectively, intestinal inflammation and barrier dysfunction in rats (Zhou et al., 2018). ...
Preprint
Changes in microbiome composition have been associated with a wide array of human diseases, turning the human microbiota into an attractive target for therapeutic intervention. Yet clinical translation of these findings requires the establishment of causative connections between specific microbial taxa and their functional impact on host tissues. Here, we colonized gut organ cultures with longitudinal microbiota samples collected from newly-diagnosed and therapy-naive irritable bowel syndrome (IBS) patients under low-FODMAP (fermentable Oligo-, Di-, Mono-saccharides and Polyols) diet. We show that post-diet microbiota regulates intestinal expression of inflammatory and neuro-muscular gene-sets. Specifically, we identify Bifidobacterium adolescentis as a diet-sensitive pathobiont that alters tight junction integrity and disrupts gut barrier functions. Collectively, we present a unique pathway discovery approach for mechanistic dissection and identification of functional diet-host-microbiota modules. Our data support the hypothesis that the gut microbiota mediates the beneficial effects of low-FODMAP diet, and reinforce the potential feasibility of microbiome based-therapies in IBS.
... The probiotic Lactobacillus, either used alone or with other probiotics, could inhibit the intestinal inflammation induced by C. rodentium infection through inducing the production of IL-22 and activating regulatory T cells [9]. Segmented filamentous bacteria (SFB), an anaerobic commensal bacterium tightly adherent to intestinal epithelial cells, enhanced the host resistance to C. rodentium infection by inducing intestinal Th17 cells [10,11]. The abundance of Lachnospiraceae, one of major short-chain fatty acid-producing commensal bacteria, was correlated with less intestinal inflammation induced by C. rodentium infection [12]. ...
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Background Dysregulated gut microbiota is one of major pathogenic factors in the development of colitis. Dock2 acts as a guanine nucleotide exchange factor (GEF) and activates small G protein RAC1. Our previous study showed that, compared to wild type (WT) mice, Dock2 −/− mice were more susceptible to colitis induced by Citrobacter rodentium infection. However, it is not clear whether gut microbiota affects the host susceptibility to enteric bacterial infection in Dock2 −/− mice. Results In this study, we demonstrated that Dock2 regulated the gut microbiota and affected the host susceptibility to C. rodentium infection by co-housing, fecal microbiota transfer and antibiotic treatment methods. Microbiota analysis by 16 S rRNA gene sequencing showed that Dock2 increased the abundance of prevotellaceae-NK3B31-group and Lactobacillus but decreased that of Helicobacter . Conclusions These results suggest that Dock2 regulates the composition of gut microbiota and affects the host susceptibility to C. rodentium infection.
... It could be concluded that presence of microbial colonies is important for proper functioning of immune system. Epithelial adherent bacteria such as segmented filamentous bacteria, Citrobactrodentium and Escherichia coli can promote the differentiation of T H 17 cells (Atarashi et al. 2015;Powell et al. 2017). Segmented filamentous bacteria is found to be critically involved in T H 1 cell differentiation, whereas Bacteroides fragilis and selective clostridial clusters can upregulate the T cells count (Powell et al. 2017). ...
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The neurodegeneration and its related CNS pathologies need an urgent toolbox to minimize the global mental health burden. The neuroimmune system critically regulates the brain maturation and survival of neurons across the nervous system. The chronic manipulated immunological drive can accelerate the neuronal pathology hence promoting the burden of neurodegenerative disorders. The gut is home for trillions of microorganisms having a mutual relationship with the host system. The gut-brain axis is a unique biochemical pathway through which the gut residing microbes connects with the brain cells and regulates various physiological and pathological cascades. The gut microbiota and CNS communicate using a common language that synchronizes the tuning of immune cells. The intestinal gut microbial community has a profound role in the maturation of the immune system as well as the development of the nervous system. We have critically summarised the clinical and preclinical reports from the past a decade emphasising that the significant changes in gut microbiota can enhance the host susceptibility towards neurodegenerative disorders. In this review, we have discussed how the gut microbiota-mediated immune response inclines the host physiology towards neurodegeneration and indicated the gut microbiota as a potential future candidate for the management of neurodegenerative disorders.
... One enigma is whether or not the probiotic bacteria could colonize the intestine by peroral administration, if so for how long they could stay in place after the administration is removed. This would challenge the actions of probiotics when regarded as contact-dependent (47). As aforementioned, the established microbiota in adulthood remains quite stable albeit the fluctuation under drastic changes (10). ...
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Inflammatory bowel disease (IBD) is a recurrent chronic inflammatory condition of the intestine without any efficient therapeutic regimens. Gut microbiota, which plays an instrumental role in the development and maturation of the immune system, has been implicated in the pathogenesis of IBD. Emerging evidence has established that early-life events particularly maternal influences and antibiotic treatment are strongly correlated with the health or susceptibility to disease of an individual in later life. Thus, it is proposed that there is a critical period in infancy, during which the environmental exposures bestow a long-term pathophysiological imprint. This notion sheds new light on the development of novel approaches for the treatment, i.e., early interventions, more precisely, the prevention of many uncurable chronic inflammatory diseases like IBD. In this review, we have integrated current evidence to describe the feasibility of the “able-to-be-regulated microbiota,” summarized the underlying mechanisms of the “microbiota-driven immune system education,” explored the optimal intervention time window, and discussed the potential of designing early-probiotic treatment as a new prevention strategy for IBD.
... Recently it has been confirmed that colonization by the gut microbiota shapes the marked B cell pool and individualized immunoglobulin repertoires, indicating the great importance of the gut microbiome to the immune system [36]. Another representative example is segmented filamentous bacteria, which can induce the differentiation of Th17 cells through the adherence to intestinal epithelial cells [37]. The gut microbiome is remodeled by changes in diet patterns and the application of antibiotics by forces of modernization. ...
Article
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Uveitis is a leading cause of sight-threatening disease worldwide and is characterized by inflammation of the uvea, retina, and optic nerve. Among the forms of uveitis, immune-mediated uveitis represents the majority of cases in developed countries, while infectious uveitis is more common in developing countries. A Western lifestyle is thought to be one of the factors contributing to the difference and is responsible for the increasing incidence of immune-mediated uveitis. A vast range of studies have reported the importance of lifestyle factors, including smoking, gut microbiome, diet, and physical activity on immune-mediated uveitis patients and animal models of uveitis; however, there is a lack of an expert-led consensus initiative for the management of immune-mediated uveitis patients in the area of lifestyle. Herein, we summarize the advancements in the role of lifestyle factors in immune-mediated uveitis based on clinical and experimental evidence and make suggestions for patients to ameliorate inflammation and improve the prognosis, including quitting smoking, engaging in regular physical activity, consuming a personalized anti-inflammatory diet, and optimizing the gut microbiome.
... The recently described bacterial family Christensenellaceae is one of the five taxa considered a signature of healthy gut and its relative abundance in the normal gut is associated with human longevity, and inversely correlated with body mass index and metabolic syndrome (rev. in Waters and Ley, 2019). Firmicutes bacterium ASF500 are among the bacterial strains able to cause robust induction of T helper 17 cells (Atarashi et al., 2015), critical in protecting mucosal surfaces against microbial pathogens, in concert with other immune cells (Omenetti and Pizarro, 2015), and in protecting the integrity of intestinal barrier to bacteria (Stockinger and Omenetti, 2017). ...
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The microbiome co-evolved with their mammalian host over thousands of years. This commensal relationship serves a pivotal role in various metabolic, physiological, and immunological processes. Recently we discovered impaired adrenal catecholamine stress responses in germ-free mice suggesting developmental modification of the reflex arc or absence of an ongoing microbiome signal. To determine whether maturational arrest or an absent bacteria-derived metabolite was the cause, we tested whether depleting gut microbiome in young adult animals could also alter the peripheral stress responses to insulin-induced hypoglycemia. Groups of C57Bl6 male mice were given regular water (control) or a cocktail of non-absorbable broad-spectrum antibiotics (Abx) in the drinking water for two weeks before injection with insulin or saline. Abx mice displayed a profound decrease in microbial diversity and abundance of Bacteroidetes and Firmicutes, plus a markedly enlarged caecum and no detectable by-products of bacterial fermentation (sp. short chain fatty acids, SCFA). Tonic and stress-induced epinephrine levels were attenuated. Recolonization (Abx + R) restored bacterial diversity, but not the sympathoadrenal system responsiveness or caecal acetate, propionate and butyrate levels. In contrast, corticosterone (HPA) and glucagon (parasympathetic) resting values and responses to hypoglycemia remained similar across all conditions. Oral supplementation with SCFA improved epinephrine responses to hypoglycaemia. Whole genome shotgun sequence profiling of fecal samples from control, Abx and Abx + R cohorts identified nine microbes (SCFA producers) absent from both Abx and Abx + R groups. These results implicate gut microbiome depletion plus its attendant reduction in SCFA signalling in adversely affecting the release of epinephrine in response to hypoglycemia. We speculate that regardless of postnatal age, amutable microbiome messaging system exists throughout life. Unravelling these mechanisms could lead to new therapeutic possibilities through controlled manipulation of the gut microbiota and its ability to alter systemic neurotransmitter responsiveness.
... Increased Proteobacteria has been previously associated with dysbiosis [42,43], and enterocolic inflammation possibly through local induction of intestinal Th17 cell responses [44]. Helicobacter pylori, a prominent Proteobacterium, has been found to utilize multiple mechanisms to incite local inflammation while simultaneously evading its own destruction via interleukin-33, which decreases interferon-γ production [45][46][47]. ...
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Background Though the gut microbiome has been associated with efficacy of immunotherapy (ICI) in certain cancers, similar findings have not been identified for microbiomes from other body sites and their correlation to treatment response and immune related adverse events (irAEs) in lung cancer (LC) patients receiving ICIs. Methods We designed a prospective cohort study conducted from 2018 to 2020 at a single-center academic institution to assess for correlations between the microbiome in various body sites with treatment response and development of irAEs in LC patients treated with ICIs. Patients must have had measurable disease, ECOG 0–2, and good organ function to be included. Data was collected for analysis from January 2019 to October 2020. Patients with histopathologically confirmed, advanced/metastatic LC planned to undergo immunotherapy-based treatment were enrolled between September 2018 and June 2019. Nasal, buccal and gut microbiome samples were obtained prior to initiation of immunotherapy +/− chemotherapy, at development of adverse events (irAEs), and at improvement of irAEs to grade 1 or less. Results Thirty-seven patients were enrolled, and 34 patients were evaluable for this report. 32 healthy controls (HC) from the same geographic region were included to compare baseline gut microbiota. Compared to HC, LC gut microbiota exhibited significantly lower α-diversity. The gut microbiome of patients who did not suffer irAEs were found to have relative enrichment of Bifidobacterium (p = 0.001) and Desulfovibrio (p = 0.0002). Responders to combined chemoimmunotherapy exhibited increased Clostridiales (p = 0.018) but reduced Rikenellaceae (p = 0.016). In responders to chemoimmunotherapy we also observed enrichment of Finegoldia in nasal microbiome, and increased Megasphaera but reduced Actinobacillus in buccal samples. Longitudinal samples exhibited a trend of α-diversity and certain microbial changes during the development and resolution of irAEs. Conclusions This pilot study identifies significant differences in the gut microbiome between HC and LC patients, and their correlation to treatment response and irAEs in LC. In addition, it suggests potential predictive utility in nasal and buccal microbiomes, warranting further validation with a larger cohort and mechanistic dissection using preclinical models. Trial registration ClinicalTrials.gov, NCT03688347. Retrospectively registered 09/28/2018.
... However, a possible explanation might be the specific life style and anatomical localization of various members of the microbiota. Adhesion of segmented filamentous bacteria to epithelial cells is critical for its ability to trigger Th17 cell responses (Atarashi et al., 2015). Similarly, A. muciniphila and H. hepaticus engage in intimate interactions with the host. ...
Article
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Key aspects of intestinal T cells, including their antigen specificity and their selection by the microbiota and other intestinal antigens, as well as the contribution of individual T cell clones to regulatory and effector functions, remain unresolved. Here we tracked adoptively transferred T cell populations to specify the interrelation of T cell receptor repertoire and the gut antigenic environment. We show that dominant TCRα clonotypes were shared between interferon-γ- and interleukin-17-producing but not regulatory Foxp3⁺ T cells. Identical TCRα clonotypes accumulated in the colon of different individuals, whereas antibiotics or defined colonization correlated with the expansion of distinct expanded T cell clonotypes. Our results demonstrate key aspects of intestinal CD4⁺ T cell activation and suggest that few microbial species exert a dominant effect on the intestinal T cell repertoire during colitis. We speculate that dominant proinflammatory T cell clones might provide a therapeutic target in human inflammatory bowel disease.
... The microbiome plays an essential role in regulating immune responses [12,13], and numerous mechanisms have been identified through which the microbiome affects immune cell functions, both locally and systemically. For example, microbiome-produced metabolites such as short-chain fatty acids (SCFAs) directly affect myeloid cells [14], while the attachment of segmented filamentous bacteria to the intestinal epithelium improves the function of T helper 17 cells [13,15]. Moreover, while the microbiome has been proposed to influence the efficacy of vaccines, only a few studies have investigated this [16,17]. ...
Article
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Background The bacillus Calmette-Guérin (BCG) vaccine protects against tuberculosis and heterologous infections but elicits high inter-individual variation in specific and nonspecific, or trained, immune responses. While the gut microbiome is increasingly recognized as an important modulator of vaccine responses and immunity in general, its potential role in BCG-induced protection is largely unknown. Results Stool and blood were collected from 321 healthy adults before BCG vaccination, followed by blood sampling after 2 weeks and 3 months. Metagenomics based on de novo genome assembly reveals 43 immunomodulatory taxa. The nonspecific, trained immune response is detected by altered production of cytokines IL-6, IL-1β, and TNF-α upon ex vivo blood restimulation with Staphylococcus aureus and negatively correlates with abundance of Roseburia . The specific response, measured by IFN-γ production upon Mycobacterium tuberculosis stimulation, is associated positively with Ruminococcus and Eggerthella lenta . The identified immunomodulatory taxa also have the strongest effects on circulating metabolites, with Roseburia affecting phenylalanine metabolism. This is corroborated by abundances of relevant enzymes, suggesting alternate phenylalanine metabolism modules are activated in a Roseburia species-dependent manner. Conclusions Variability in cytokine production after BCG vaccination is associated with the abundance of microbial genomes, which in turn affect or produce metabolites in circulation. Roseburia is found to alter both trained immune responses and phenylalanine metabolism, revealing microbes and microbial products that may alter BCG-induced immunity. Together, our findings contribute to the understanding of specific and trained immune responses after BCG vaccination.
... The signals to achieve Th17 differentiation are in part generated by the SFB-bound epithelial cells and involve intestinal macrophages and intestinal dendritic cells [57,58]. Binding of SFB to the host epithelial cells via the holdfast structure leads to a rearrangement of the actin cytoskeleton, induction of SAA, and production of reactive oxygen species (ROS), which aids in mediating Th17 cell differentiation [53,59]. In addition, binding of SFB induces expression of inducible NOS2 involved in ROS generation and elevated expression of RegIIIγ, representing a secreted, directly bactericidal C-type lectin that specifically targets Gram-positive bacteria [53,60]. ...
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Lipocalin 2 (LCN2) mediates key roles in innate immune responses. It has affinity for many lipophilic ligands and binds various siderophores, thereby limiting bacterial growth by iron sequestration. Furthermore, LCN2 protects against obesity and metabolic syndrome by interfering with the composition of gut microbiota. Consequently, complete or hepatocyte-specific ablation of the Lcn2 gene is associated with higher susceptibility to bacterial infections. In the present study, we comparatively profiled microbiota in fecal samples of wild type and Lcn2 null mice and show, in contrast to previous reports, that the quantity of DNA in feces of Lcn2 null mice is significantly lower than that in wild type mice (p < 0.001). By using the hypervariable V4 region of the 16S rDNA gene and Next-Generation Sequencing methods, we found a statistically significant change in 16 taxonomic units in Lcn2-/- mice, including eight gender-specific deviations. In particular, members of Clostridium, Escherichia, Helicobacter, Lactococcus, Prevotellaceae_UCG-001 and Staphylococcus appeared to expand in the intestinal tract of knockout mice. Interestingly, the proportion of Escherichia (200-fold) and Staphylococcus (10-fold) as well as the abundance of intestinal bacteria encoding the LCN2-sensitive siderphore enterobactin (entA) was significantly increased in male Lcn2 null mice (743-fold, p < 0.001). This was accompanied by significant higher immune cell infiltration in the ileum as demonstrated by increased immunoreactivity against the pan-leukocyte protein CD45, the lymphocyte transcription factor MUM-1/IRF4, and the macrophage antigen CD68/Macrosialin. In addition, we found a higher expression of mucosal mast cell proteases indicating a higher number of those innate immune cells. Finally, the ileum of Lcn2 null mice displayed a high abundance of segmented filamentous bacteria, which are intimately associated with the mucosal cell layer, provoking epithelial antimicrobial responses and affecting T-helper cell polarization.
... In animals harboring B. fragilis not expressing PSA, H. hepaticus induces colitic disease and pro-inflammatory cytokine production in the colon [29]. In addition to B. fragilis, other gut-resident bacteria such as Clostridiales have been demonstrated to trigger regulatory T cells, or signaling pathways such as the activation of the colitogenic Th1 and Th17 responses by AIEC, segmented filamentous bacteria, and Citrobacter rodentium [30][31][32]. Consequently, the use of live biotherapeutic products that either add to anti-inflammatory mechanisms or counteract these pro-inflammatory mechanisms might be a strategy to restore homeostasis and immune tolerance in the gut. ...
Article
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The intestinal microbiota is a complex community that consists of an ecosystem with a dynamic interplay between bacteria, fungi, archaea, and viruses. Recent advances in model systems have revealed that the gut microbiome is critical for maintaining homeostasis through metabolic digestive function, immune regulation, and intestinal barrier integrity. Taxonomic shifts in the intestinal microbiota are strongly correlated with a multitude of human diseases, including inflammatory bowel disease (IBD). However, many of these studies have been descriptive, and thus the understanding of the cause and effect relationship often remains unclear. Using non-human experimental model systems such as gnotobiotic mice, probiotic mono-colonization, or prebiotic supplementation, researchers have defined numerous species-level functions of the intestinal microbiota that have produced therapeutic candidates for IBD. Despite these advances, the molecular mechanisms responsible for the function of much of the microbiota and the interplay with host cellular processes remain areas of tremendous research potential. In particular, future research will need to unlock the functional molecular units of the microbiota in order to utilize this untapped resource of bioactive molecules for therapy. This review will highlight the advances and remaining challenges of microbiota-based functional studies and therapeutic discovery, specifically in IBD. One of the limiting factors for reviewing this topic is the nascent development of this area with information on some drug candidates still under early commercial development. We will also highlight the current and evolving strategies, including in the biotech industry, used for the discovery of microbiota-derived bioactive molecules in health and disease.
... b-defensin 2 (Uehara et al. 2007), which prospectively affect the microbiota composition. In a mouse model, the Bacteroidetes phylum member Prevotella reduced the secretion of TLR2-regulated proinflammatory cytokines, and severe airway neutrophilia was related to Haemophilus influenzae (Larsen et al. 2015), which might be linked to the quantity of acyl side chains on their corresponding lipopolysaccharide (LPS) (Coats (Kao et al. 2004), which in turn are stimulated by diverse microbial species (Atarashi et al. 2015). In addition, as evidence shows, some organogenesis may also require microbiome-induced signalling through IL-17 or regulatory T (Treg) cells (Rangel-Moreno et al. 2011;Scharschmidt et al. 2015). ...
Article
With the discovery of the lung microbiota, its study in both pulmonary health and disease has become a vibrant area of emerging research interest. Thus far, most studies have described the lung microbiota composition in lung disease quite well, and some of these studies indicated alterations in lung microbial communities related to the onset and development of lung disease and vice versa. However, the underlying mechanisms, particularly the cellular and molecular links, are still largely unknown. In this review, we highlight the current progress in the complex cellular and molecular mechanisms by which the lung microbiome interacts with immune homeostasis and pulmonary disease pathogenesis to advance our understanding of the elaborate function of the lung microbiota in lung disease. We hope that this work can attract more attention to this still-young yet very promising field to facilitate the identification of new therapeutic targets and provide more innovative therapies. Additional accurate standard-based methodologies and technological breakthroughs are critical to propel the field forward to ultimately achieve the goal of maintaining respiratory health.
... Th1 responses in GF mice can be restored via host colonization with a wide range of microbes, including the wellstudied pathogen Listeria monocytogenes, which enhances Th1 development through macrophage production of the T cell-stimulating factor, interleukin 12 (IL-12) (Hsieh et al. 1993). Intracellular bacteria like L. monocytogenes explicitly stimulate Th1 responses in the gut (Atarashi et al. 2015). In addition, GF mice have a decreased number of T helper type 17 (Th17) cells. ...
Chapter
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Since Joshua Lederberg defined the gut microbiome and its collective genetic material present in the gastrointestinal tract (GIT), the gut microbiome attracted the attention of researchers worldwide. The human gut microbiota is divided into many phyla in which the gut microbiota is comprised primarily of four main phyla that include Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. Recent studies focused on the microbe-host interactions which included their effects on the metabolism and immunity. In addition, the gut microbiome plays an important role in the absorption of nutrients and minerals; the biosynthesis of enzymes, vitamins, and amino acids; and the production of short-chain fatty acids (SCFAs). In this chapter, we shed the light on different groups of gut microbiomes and their effects on human health and diseases.
... 15 In addition to widely recognized pathogenesis, C. albicans has been recently hypothesized to have potential health benefits for the human host. This includes C. albicans-mediated inhibition of Escherichia coli migration from the rectum to the bladder, protecting from UTIs, 16 and a role of C. albicans in the development of the mucosal immune response in the human gut. 9 ...
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Objective This series of articles, titled The Vaginal Microbiome (VMB), written on behalf of the International Society for the Study of Vulvovaginal Disease, aims to summarize the recent findings and understanding of the vaginal bacterial microbiota, mainly regarding areas relevant to clinicians specializing in vulvovaginal disorders. Materials and Methods A search of PubMed database was performed, using the search terms “vaginal microbiome” with “Candida,” “vaginitis,” “urinary microbiome,” “recurrent urinary tract infections,” “sexually transmitted infections,” “human immunodeficiency virus,” “human papillomavirus,” “nonspecific vaginitis,” “vulvodynia,” and “vulvovaginal symptoms.” Full article texts were reviewed. Reference lists were screened for additional articles. The third article in this series describes VMB in various urogenital disorders. Results Variable patterns of the VMB are found in patients with vulvovaginal candidiasis, challenging the idea of a protective role of lactobacilli. Highly similar strains of health-associated commensal bacteria are shared in both the bladder and vagina of the same individual and may provide protection against urinary tract infections. Dysbiotic VMB increases the risk of urinary tract infection. Loss of vaginal lactic acid–producing bacteria combined with elevated pH, increase the risk for sexually transmitted infections, although the exact protective mechanisms of the VMB against sexually transmitted infections are still unknown. Conclusions The VMB may constitute a biological barrier to pathogenic microorganisms. When the predominance of lactobacilli community is disrupted, there is an increased risk for the acquisition of various vaginal pathogents. Longitudinal studies are needed to describe the association between the host, bacterial, and fungal components of the VMB.
Article
Besides tumor cell–intrinsic oncogenic pathways, host and environmental factors have a major impact on cancer immunosurveillance and the efficacy of immunotherapeutics. Several modalities of anticancer treatments including immunogenic chemotherapies and immune checkpoint inhibitors lose their efficacy in patients treated with broad-spectrum antibiotics, pointing to a key role for the gut microbiota. The complex interactions between intestinal microbes, gut immunity and anti-tumor responses constitute an emerging field of investigation. In this work, we revise key primary literature, with an emphasis on recent mechanistic insights, unraveling the interplay between the immunosurveillance of colon cancers and ileal factors including the local microbiota, tissue architecture and immune system.
Article
Cytidine triphosphate:phosphocholine cytidylyltransferase-α (CTα) is the rate limiting enzyme in the pathway for de novo phosphatidylcholine (PC) synthesis. When CTα is deleted from intestinal epithelial cells of adult mice (CTαIKO mice) fed a high-fat diet they present with weight loss, lipid malabsorption, and high postprandial GLP-1 levels. The current study aimed to characterize the changes that occur in the small intestines of CTαIKO mice using transcriptomics and to determine whether acute weight loss in CTαIKO mice could be rescued. We found that impaired de novo PC synthesis in the gut is linked to lower abundance of transcripts related to lipid metabolism and higher abundance of transcripts related to ER stress, cell death, and inflammation. Induction of the host defence response in CTαIKO mice was also associated with loss of goblet cells. Additionally, we found that impaired fatty acid uptake occurs in isolated intestinal sacs from CTαIKO mice. However, acute body weight loss and enhanced postprandial secretion of GLP-1 occurs in CTαIKO mice independent of dietary fat content. Antibiotic treatment prevented acute weight loss and normalized jejunum TG concentrations after refeeding but did not alter enhanced postprandial GLP-1 secretion, induction of an ER stress and host defence response, or loss of goblet cells in CTαIKO mice. Dietary PC supplementation partially prevented loss of goblet cells but was unable to normalize jejunal TG or plasma GLP-1 concentrations after refeeding in CTαIKO mice. Together these data show that there is a specific requirement from de novo PC synthesis in maintaining small intestinal homeostasis.
Chapter
Accumulating evidence suggests that microbiota are involved in the physiology and pathology and have implications in health and disease. The role of microbiota in various physiological processes, including the immune system and brain function, is well established. A great deal of studies has suggested the role of gut microbes in the brain’s physiology and pathology. The maturation and development of the human central nervous system (CNS) are regulated by both intrinsic and extrinsic factors, including microbiota. Studies mostly from germ-free animals or animals treated with broad-spectrum antibiotics show that specific microbiota can impact CNS physiology and neurochemical processes. The germ-free mice show neurological deficiencies in learning, memory, recognition, and emotional behaviors. Levels of the essential neurotransmitters such as serotonin, N-methyl-d-aspartate, and brain-derived neurotrophic factor are different from those in commonly grown mice. In humans, evidence for interplay between gastrointestinal pathology and neuropsychiatric conditions was presented in anxiety, depression, and autism. The gut microbiota was involved in the development and homeostasis of CNS in various pathways. In this chapter the roles of microbiota and development and function of the nervous system, gut–brain interactions, neurodegeneration, and potential approaches for treating CNS disorders will be discussed.
Article
The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors. Disrupted gut permeability (leaky gut syndrome) can represent a predisposing or aggravating condition in obesity and the metabolically associated liver steatosis (nonalcoholic fatty liver disease, NAFLD). In what follows, we describe the morphological-functional features of the intestinal barrier, the role of major modifiers of the intestinal barrier, and discuss the recent evidence pointing to the key role of intestinal permeability in obesity/NAFLD.
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Large-scale studies of human gut microbiomes have revealed broad differences in composition across geographically distinct populations. Yet, studies examining impacts of microbiome composition on various health outcomes typically focus on single populations, posing the question of whether compositional differences between populations translate into differences in susceptibility. Using germ-free mice humanized with microbiome samples from 30 donors representing three countries, we observe robust differences in susceptibility to Citrobacter rodentium, a model for enteropathogenic Escherichia coli infections, according to geographic origin. We do not see similar responses to Listeria monocytogenes infections. We further find that cohousing the most susceptible and most resistant mice confers protection from C. rodentium infection. This work underscores the importance of increasing global participation in microbiome studies related to health outcomes. Diverse cohorts are needed to identify both population-specific responses to specific microbiome interventions and to achieve broader-reaching biological conclusions that generalize across populations.
Thesis
In 1863, Rudolf Virchow proposed that tumors arise from sites of chronic inflammation. This concept was largely ignored throughout the majority of the next century as the genetic basis of cancer was explored. However, it has become well appreciated that inflammation and cancer are intimately linked. For example, chronic inflammation of the intestine in the form of Inflammatory Bowel Disease (IBD) predisposes to the development of colon cancer. Although the vast majority of colon tumors do not arise from sites of chronic inflammation, sporadic colon tumors elicit an inflammatory response that is essential for tumor growth, progression, and evasion of anti-tumor immunity. Hypoxia is a well-characterized feature of nearly all solid tumors and promotes stabilization of the hypoxia inducible transcription factors (HIF-1α and HIF-2α) with known roles in modulating tumor-associated inflammation. We have previously reported that intestinal epithelial HIF-2α is an important driver of the acute inflammatory response in colitis. The present work describes a novel axis by which intestinal epithelial HIF-2α serves as a critical link between inflammation and cancer of the colon. Mechanistically, our work shows a crucial role for intestinal epithelial HIF-2α in regulation of the immune microenvironment of colon tumors through recruitment of intra-tumoral neutrophils. Neutrophils are granulocytic myeloid cells of the innate immune system that are the first responders to sites of infection to limit microbes. Neutrophils are highly infiltrated in nearly all solid tumors including colon cancer. We showed that neutrophil influx was due to direct HIF-2α-dependent regulation of the potent neutrophil chemokine CXCL1. These data identify a novel role for HIF-2α in modulation of the tumor immune microenvironment of inflammation-driven colon tumors and suggest therapeutic potential. Our data suggested an important role for neutrophils in the maintenance of colon tumors. However, the importance of neutrophils in the initiation of colon tumorigenesis is largely unknown. Using mice with constitutive genetic depletion of neutrophils, the present work demonstrates an essential role for neutrophils in restricting colon tumor growth and progression in both inflammation-driven and sporadic colon tumor models. Neutrophil depletion correlated with robust expansion of colon-tumor associated microbiota and tumor-associated B-cells, both of which had important roles in neutrophil-deficient colon tumorigenesis. Together, our data suggest divergent roles for neutrophils in the initiation and maintenance of colon tumors. The work presented in this thesis also shows an important role for the transcription factor, myc-associated zinc finger (MAZ) in colitis and colon cancer. MAZ is an inflammation induced transcription factor that has a previously identified role as a HIF-2α transcriptional cofactor. We show that MAZ is highly active in human colitis and colon cancer. The present work delineates a critical function for MAZ in the inflammatory progression of colitis and colon cancer through regulation of oncogenic STAT3 signaling. Collectively, these studies shed new light onto the inflammatory progression of colon cancer and propose potential therapeutic targets.
Article
The alveolar bone is a unique osseous tissue due to the presence of the teeth and the proximity of commensal oral microbes. Commensal microbe effects on alveolar bone homeostasis have been attributed to the oral microbiota, yet the impact of commensal gut microbes is unknown. Study purpose was to elucidate whether commensal gut microbes regulate osteoimmune mechanisms and skeletal homeostasis in alveolar bone. Male C57BL/6T germfree (GF) littermate mice were maintained as GF or monoassociated with segmented filamentous bacteria (SFB), a commensal gut bacterium. SFB has been shown to elicit broad immune response effects, including the induction of TH17/IL17A immunity, which impacts the development and homeostasis of host tissues. SFB colonized the gut, but not oral cavity, and increased IL17A levels in the ileum and serum. SFB had catabolic effects on alveolar bone and non-oral skeletal sites, which was attributed to enhanced osteoclastogenesis. The alveolar bone marrow of SFB vs. GF mice had increased dendritic cells, activated helper T-cells, TH1 cells, TH17 cells, and upregulated Tnf. Primary osteoblast cultures from SFB and GF mice were stimulated with vehicle-control, IL17A, or TNF to elucidate osteoblast-derived signaling factors contributing to the pro-osteoclastic phenotype in SFB mice. Treatment of RAW264.7 osteoclastic cells with supernatants from vehicle-stimulated SFB vs. GF osteoblasts recapitulated the osteoclast phenotype found in vivo. Supernatants from TNF-stimulated osteoblasts normalized RAW264.7 osteoclast endpoints across SFB and GF cultures, which was dependent on the induction of CXCL1 and CCL2. This report reveals that commensal gut microbes have the capacity to regulate osteoimmune processes in alveolar bone. Outcomes from this investigation challenge the current paradigm that alveolar bone health and homeostasis is strictly regulated by oral microbes.
Article
Colorectal cancer (CRC) is the third most frequently diagnosed cancer in both males and females in the Unites States. Colonoscopy is considered a safe method for screening this disorder; however, it can be challenging for patients. As research on microbiota, especially anaerobic microbiota, has expanded substantially, new links have been determined between anaerobic bacteria and CRC progression. These associations can be useful in screening CRC in the near future. This review discusses current research investigating the presence of anaerobic bacteria, including Bacteroides fragilis, Peptostreptococcus anaerobius, Clostridium septicum, Porphyromonas gingivalis, Fusobacterium nucleatum, and Parvimonas micra in CRC and presents an overview about their mechanisms of action. We also discuss the current anaerobic probiotics used for the treatment and prevention of CRC.
Article
Preventive vaccination is currently the most affordable and economical way to reduce morbidity and mortality from many infections, improve quality and human life expectancy with an almost ideal balance of benefits and risks among all medical procedures. The article deals with the reasons for variability of the immune response caused by vaccines, between individuals and between populations, which is of fundamental importance for human health. The authors have presented data indicating a key role of the gut microbiota in the control of the immune response to vaccination. Particular attention is paid to the microbial diversity in different loci of the body. The role of microorganisms in the proper functioning of the body and the formation of a number of pathological conditions is described. Most modern vaccines are live-attenuated, killed / inactivated or subunit (recombinant) vaccines, and they are designed for the parenteral route of administration. Most of these vaccines elicit a weak immune response, especially in the mucous membranes, due to the route of administration and are associated with weak cell-mediated immunity. Therefore, mechanisms that can enhance virus-specific vaccine immunity in infants and children are required, such as the use of more potent or selective immunity-enhancing adjuvants. Some probiotic strains may be considered as promising vaccine adjuvants. This article evaluates the recent clinical studies of probiotics used to enhance vaccine-specific immunity in adults and infants. The present-day knowledge on the role of the probiotic strain Lactobacillus rhamnosus GG with the aim of activating immunity after vaccination are presented.
Article
In this study, cyclophosphamide (Cy) was used to treat mice to establish an immunosuppressant model in mice, and the regulatory effects of polysaccharides from Fuzhuan brick tea (FBTPSs) including crude FBTPSs (CFBTPSs) and the purified fraction (FBTPSs-3) on the immune function and gut microbiota of mice were investigated. The results showed that CFBTPSs and FBTPSs-3 restored the levels of body weight, feed intake, immune organ index, cytokine and immunoglobulin A in mice. The Cy-induced injury of gut including intestinal morphology and expression of tight junction proteins were also restored. Furthermore, CFBTPSs and FBTPSs-3 could significantly modulate gut microbiota by increasing the relative abundance of Muribaculaceae and reduceing the relative abundances of Lachnospiraceae, Helicobacteraceae, Clostridaceae, Desulfovibrionaceae and Deferribacteraceae. Moreover, the gut microbiota derived short-chain fatty acids might play an important role in improvement of immune function by FBTPSs. Our results showed that FBTPSs could regulate the immune function of mice, which provided evidences for the development of FBTPSs as potentially functional foods to improve human health.
Chapter
Gut microbiota play an important role in host health and disease pathogenesis. The gastrointestinal tract, which is heavily colonized by microbes, has essential functions, and dysbiosis can lead to intestinal inflammation and disease. Probiotics and prebiotics are microbiota management tools for improving host health. Probiotic microorganisms act in a variety of means, while prebiotics are substrates that are selectively utilized by host microorganisms and confer health benefits. The use of some probiotics and prebiotics is justified by robust assessments of efficacy, but not all products have been validated; the goal is evidence-based use by healthcare professionals.
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El cuerpo humano está expuesto continuamente a microorganismos tanto fijos como transitorios, así como sus metabolitos tóxicos, lo cual puede conducir a la aparición y progresión del cáncer en sitios distantes al hábitat particular de cada microbio. Diversos estudios científicos han hecho posible entender la relación estrecha que existe entre microbioma y cáncer, ya que los componentes del primero, al tener la capacidad de migrar a diferentes zonas del cuerpo, pueden contribuir al desarrollo de diversas enfermedades crónicas. Los estudios de metagenómica sugieren que la disbiosis, en la microbiota comensal, está asociada con trastornos inflamatorios y varios tipos de cáncer, los cuales pueden ocurrir por sus efectos sobre el metabolismo, la proliferación celular y la inmunidad. La microbiota puede producir el cáncer cuando existen condiciones predisponentes, como en la etapa inicial de la progresión tumoral (iniciación), inestabilidad genética, susceptibilidad a la respuesta inmune del huésped, a la progresión y la respuesta a la terapia. La relación más estrecha, entre el microbioma y el cáncer, es a través de la desregulación del sistema inmune. En este trabajo revisamos las actuales evidencias sobre la asociación entre la microbiota y algunos tipos de cáncer como el cáncer gástrico, colorrectal, próstata, ovario, oral, pulmón y mama.
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Endometriosis is a disease that has a strong relationship with complex immune disorders and may be associated with gut microbiota through the altered immune system. To date, there are few papers that examine the relationship between endometriosis and gut microbiota which related to estrogen and helper T cells.
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The FUT2 loss-of-function mutations are highly prevalent and are associated with inflammatory bowel disease (IBD). To investigate the impact of FUT2 loss-of-function mutation on the gut microbiota in patients with IBD, 81 endoscopically confirmed IBD patients were genotyped and divided into 3 groups: homozygous for functional FUT2 genes (SeSe), with one copy of non-functional FUT2 gene (Sese), or homozygous for non-functional FUT2 genes (sese). Escherichia, which attaches to fucosylated glycoconjugates, was the only abundant genus exhibiting decreased abundance in sese patients. Compared with SeSe or Sese patients, sese patients exhibited higher abundance in CD8⁺ inducing Alistipe and Phascolarctobacterium and Th17 inducing Erysipelotrichaceae UCG-003. Counter-intuitively, butyrate-producing bacteria were more abundant in sese patients. Consistently, metabolomics analysis found higher levels of butyrate in sese patients. Our data support the hypothesis that FUT2 loss-of-function mutation participates in the IBD pathogenesis by decreasing binding sites for adherent bacteria and thus altering the gut microbiota. Decreased abundances of adherent bacteria may allow the overgrowth of bacteria that induce inflammatory T cells, leading to intestinal inflammation. As FUT2 loss-of-function mutations are highly prevalent, the identification of T cell inducing bacteria in sese patients could be valuable for the development of personalized microbial intervention for IBD.
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The ability of the innate and adaptive immune systems to communicate with each other is central to protective immune responses and maintenance of host health. Myeloid cells of the innate immune system are able to sense microbial ligands, perturbations in cellular homeostasis, and virulence factors, thereby allowing them to relay distinct pathogen-specific information to naïve T cells in the form of pathogen-derived peptides and a unique cytokine milieu. Once primed, effector T helper cells produce lineage-defining cytokines to help combat the original pathogen, and a subset of these cells persist as memory or effector-memory populations. These memory T cells then play a dual role in host protection by not only responding rapidly to reinfection, but by also directly instructing myeloid cells to express licensing cytokines. This means there is a bi-directional flow of information first from the innate to the adaptive immune system, and then from the adaptive back to innate immune system. Here, we focus on how signals, first from pathogens and then from primed effector and memory T cells, are integrated by myeloid cells and its consequences for protective immunity or systemic inflammation.
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The composition of the intestinal microbiota is associated with both the development of tumors and the efficacy of anti-tumor immunity. Here, we examined the impact of microbiota-specific T cells in anti-colorectal cancer (CRC) immunity. Introduction of Helicobacter hepaticus (Hhep) in a mouse model of CRC did not alter the microbial landscape but increased tumor infiltration by cytotoxic lymphocytes and inhibited tumor growth. Anti-tumor immunity was independent of CD8⁺ T cells but dependent upon CD4⁺ T cells, B cells, and natural killer (NK) cells. Hhep colonization induced Hhep-specific T follicular helper (Tfh) cells, increased the number of colon Tfh cells, and supported the maturation of Hhep+ tumor-adjacent tertiary lymphoid structures. Tfh cells were necessary for Hhep-mediated tumor control and immune infiltration, and adoptive transfer of Hhep-specific CD4⁺ T cells to Tfh cell-deficient Bcl6fl/flCd4Cre mice restored anti-tumor immunity. Thus, introduction of immunogenic intestinal bacteria can promote Tfh-associated anti-tumor immunity in the colon, suggesting therapeutic approaches for the treatment of CRC.
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Bacterial activation of T helper 17 (Th17) cells exacerbates mouse models of autoimmunity, but how human-associated bacteria impact Th17-driven disease remains elusive. We show that human gut Actinobacterium Eggerthella lenta induces intestinal Th17 activation by lifting inhibition of the Th17 transcription factor Rorγt through cell- and antigen-independent mechanisms. E. lenta is enriched in inflammatory bowel disease (IBD) patients and worsens colitis in a Rorc-dependent manner in mice. Th17 activation varies across E. lenta strains, which is attributable to the cardiac glycoside reductase 2 (Cgr2) enzyme. Cgr2 is sufficient to induce interleukin (IL)-17a, a major Th17 cytokine. cgr2+ E. lenta deplete putative steroidal glycosides in pure culture; related compounds are negatively associated with human IBD severity. Finally, leveraging the sensitivity of Cgr2 to dietary arginine, we prevented E. lenta-induced intestinal inflammation in mice. Together, these results support a role for human gut bacterial metabolism in driving Th17-dependent autoimmunity.
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The extreme diversity of the human immune system, forged and maintained throughout evolutionary history, provides a potent defense against opportunistic pathogens. At the same time, this immune variation is the substrate upon which a plethora of immune-associated diseases develop. Genetic analysis suggests that thousands of individually weak loci together drive up to half of the observed immune variation. Intense selection maintains this genetic diversity, even selecting for the introgressed Neanderthal or Denisovan alleles that have reintroduced variation lost during the out-of-Africa migration. Variations in age, sex, diet, environmental exposure, and microbiome each potentially explain the residual variation, with proof-of-concept studies demonstrating both plausible mechanisms and correlative associations. The confounding interaction of many of these variables currently makes it difficult to assign definitive contributions. Here, we review the current state of play in the field, identify the key unknowns in the causality of immune variation, and identify the multidisciplinary pathways toward an improved understanding.
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Interactions between the microbiota and mammalian host are essential for defense against infection, but the microbial-derived cues that mediate this relationship remain unclear. Here, we find that intestinal epithelial cell (IEC)-associated commensal bacteria, segmented filamentous bacteria (SFB), promote early protection against the pathogen Citrobacter rodentium, independent of CD4⁺ T cells. SFB induced histone modifications in IECs at sites enriched for retinoic acid receptor motifs, suggesting that SFB may enhance defense through retinoic acid (RA). Consistent with this, inhibiting RA signaling suppressed SFB-induced protection. Intestinal RA levels were elevated in SFB mice, despite the inhibition of mammalian RA production, indicating that SFB directly modulate RA. Interestingly, RA was produced by intestinal bacteria, and the loss of bacterial-intrinsic aldehyde dehydrogenase activity decreased the RA levels and increased infection. These data reveal RA as an unexpected microbiota-derived metabolite that primes innate defense and suggests that pre- and probiotic approaches to elevate RA could prevent or combat infections.
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In this issue of Cell Host & Microbe, Alexander et al. show that the enzyme cardiac glycoside reductase 2 (cgr2), which is produced by Eggerthella lenta, metabolizes RORγT inhibitors, resulting in an increased Th17 response and more severe inflammation in colitis models. The effect of cgr2 can be neutralized by a diet rich in arginine.
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Microbiota regulate intestinal physiology by modifying host gene expression along the length of the intestine but the underlying regulatory mechanisms remain unresolved. Transcriptional specificity occurs through interactions between transcription factors (TFs) and cis-regulatory regions (CRRs) characterized by nucleosome-depleted accessible chromatin. We profiled transcriptome and accessible chromatin landscapes in intestinal epithelial cells (IECs) from mice reared in the presence or absence of microbiota. We show that regional differences in gene transcription along the intestinal tract were accompanied by major alterations in chromatin accessibility. Surprisingly, we discovered that microbiota modify host gene transcription in IECs without significantly impacting the accessible chromatin landscape. Instead, microbiota regulation of host gene transcription might be achieved by differential expression of specific TFs and enrichment of their binding sites in nucleosome depleted CRRs near target genes. Our results suggest that the chromatin landscape in IECs is pre-programmed by the host in a region-specific manner to permit responses to microbiota through binding of open CRRs by specific TFs.
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T-helper-17 (TH17) cells have critical roles in mucosal defence and in autoimmune disease pathogenesis. They are most abundant in the small intestine lamina propria, where their presence requires colonization of mice with microbiota. Segmented filamentous bacteria (SFB) are sufficient to induce TH17 cells and to promote TH17-dependent autoimmune disease in animal models. However, the specificity of TH17 cells, the mechanism of their induction by distinct bacteria, and the means by which they foster tissue-specific inflammation remain unknown. Here we show that the T-cell antigen receptor (TCR) repertoire of intestinal TH17 cells in SFB-colonized mice has minimal overlap with that of other intestinal CD4(+) T cells and that most TH17 cells, but not other T cells, recognize antigens encoded by SFB. T cells with antigen receptors specific for SFB-encoded peptides differentiated into RORγt-expressing TH17 cells, even if SFB-colonized mice also harboured a strong TH1 cell inducer, Listeria monocytogenes, in their intestine. The match of T-cell effector function with antigen specificity is thus determined by the type of bacteria that produce the antigen. These findings have significant implications for understanding how commensal microbiota contribute to organ-specific autoimmunity and for developing novel mucosal vaccines.
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The intestinal microbiota and tissue resident myeloid cells promote immune responses that maintain intestinal homeostasis in the host. However, the cellular cues that translate microbial signals into intestinal homeostasis remain unclear. Here, we show that deficient granulocyte macrophage colony-stimulating factor (GM-CSF) production altered mononuclear phagocyte (MNP) effector functions and led to reduced regulatory T cell (Tregs) numbers and impaired oral tolerance. We observed that RORγt(+) innate lymphoid cells (ILC) are the primary source of GM-CSF in the gut and that ILC-driven GM-CSF production was dependent on the ability of macrophages to sense microbial signals and produce interleukin (IL)-1β. Our findings reveal that commensal microbes promote a crosstalk between innate myeloid and lymphoid cells that leads to immune homeostasis in the intestine.
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Innate lymphoid cells (ILCs) are a family of developmentally related cells that are involved in immunity and in tissue development and remodelling. Recent research has identified several distinct members of this family. Confusingly, many different names have been used to characterize these newly identified ILC subsets. Here, we propose that ILCs should be categorized into three groups based on the cytokines that they can produce and the transcription factors that regulate their development and function.
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The laboratory mouse is the most widely used mammalian model organism in biomedical research. The 2.6 × 10(9) bases of the mouse genome possess a high degree of conservation with the human genome, so a thorough annotation of the mouse genome will be of significant value to understanding the function of the human genome. So far, most of the functional sequences in the mouse genome have yet to be found, and the cis-regulatory sequences in particular are still poorly annotated. Comparative genomics has been a powerful tool for the discovery of these sequences, but on its own it cannot resolve their temporal and spatial functions. Recently, ChIP-Seq has been developed to identify cis-regulatory elements in the genomes of several organisms including humans, Drosophila melanogaster and Caenorhabditis elegans. Here we apply the same experimental approach to a diverse set of 19 tissues and cell types in the mouse to produce a map of nearly 300,000 murine cis-regulatory sequences. The annotated sequences add up to 11% of the mouse genome, and include more than 70% of conserved non-coding sequences. We define tissue-specific enhancers and identify potential transcription factors regulating gene expression in each tissue or cell type. Finally, we show that much of the mouse genome is organized into domains of coordinately regulated enhancers and promoters. Our results provide a resource for the annotation of functional elements in the mammalian genome and for the study of mechanisms regulating tissue-specific gene expression.
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Gut microbial induction of host immune maturation exemplifies host-microbe mutualism. We colonized germ-free (GF) mice with mouse microbiota (MMb) or human microbiota (HMb) to determine whether small intestinal immune maturation depends on a coevolved host-specific microbiota. Gut bacterial numbers and phylum abundance were similar in MMb and HMb mice, but bacterial species differed, especially the Firmicutes. HMb mouse intestines had low levels of CD4(+) and CD8(+) T cells, few proliferating T cells, few dendritic cells, and low antimicrobial peptide expression--all characteristics of GF mice. Rat microbiota also failed to fully expand intestinal T cell numbers in mice. Colonizing GF or HMb mice with mouse-segmented filamentous bacteria (SFB) partially restored T cell numbers, suggesting that SFB and other MMb organisms are required for full immune maturation in mice. Importantly, MMb conferred better protection against Salmonella infection than HMb. A host-specific microbiota appears to be critical for a healthy immune system.
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The virulence mechanisms that allow pathogens to colonize the intestine remain unclear. Here, we show that germ-free animals are unable to eradicate Citrobacter rodentium, a model for human infections with attaching and effacing bacteria. Early in infection, virulence genes were expressed and required for pathogen growth in conventionally raised mice but not germ-free mice. Virulence gene expression was down-regulated during the late phase of infection, which led to relocation of the pathogen to the intestinal lumen where it was outcompeted by commensals. The ability of commensals to outcompete C. rodentium was determined, at least in part, by the capacity of the pathogen and commensals to grow on structurally similar carbohydrates. Thus, pathogen colonization is controlled by bacterial virulence and through competition with metabolically related commensals.
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Segmented filamentous bacteria (SFB) are host-specific intestinal symbionts that comprise a distinct clade within the Clostridiaceae, designated Candidatus Arthromitus. SFB display a unique life cycle within the host, involving differentiation into multiple cell types. The latter include filaments that attach intimately to intestinal epithelial cells, and from which "holdfasts" and spores develop. SFB induce a multifaceted immune response, leading to host protection from intestinal pathogens. Cultivation resistance has hindered characterization of these enigmatic bacteria. In the present study, we isolated five SFB filaments from a mouse using a microfluidic device equipped with laser tweezers, generated genome sequences from each, and compared these sequences with each other, as well as to recently published SFB genome sequences. Based on the resulting analyses, SFB appear to be dependent on the host for a variety of essential nutrients. SFB have a relatively high abundance of predicted proteins devoted to cell cycle control and to envelope biogenesis, and have a group of SFB-specific autolysins and a dynamin-like protein. Among the five filament genomes, an average of 8.6% of predicted proteins were novel, including a family of secreted SFB-specific proteins. Four ADP-ribosyltransferase (ADPRT) sequence types, and a myosin-cross-reactive antigen (MCRA) protein were discovered; we hypothesize that they are involved in modulation of host responses. The presence of polymorphisms among mouse SFB genomes suggests the evolution of distinct SFB lineages. Overall, our results reveal several aspects of SFB adaptation to the mammalian intestinal tract.
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T(H)17 cells are a lineage of CD4(+) T cells that are critical for host defense and autoimmunity by expressing the cytokines IL-17A, IL-17F, and IL-22. A feature of T(H)17 cells at steady state is their ubiquitous presence in the lamina propria of the small intestine. The induction of these steady-state intestinal T(H)17 (sT(H)17) cells is dependent on the presence of the microbiota. However, the signaling pathway linking the microbiota to the development of intestinal sT(H)17 cells remains unclear. In this study, we show that IL-1β, but not IL-6, is induced by the presence of the microbiota in intestinal macrophages and is required for the induction of sT(H)17 cells. In the absence of IL-1β-IL-1R or MyD88 signaling, there is a selective reduction in the frequency of intestinal sT(H)17 cells and impaired production of IL-17 and IL-22. Myeloid differentiation factor 88-deficient (MyD88(-/-)) and germ-free (GF) mice, but not IL-1R(-/-) mice, exhibit impairment in IL-1β induction. Microbiota-induced IL-1β acts directly on IL-1R-expressing T cells to drive the generation of sT(H)17 cells. Furthermore, administration of IL-1β into GF mice induces the development of retinoic acid receptor-related orphan receptor γt-expressing sT(H)17 cells in the small intestine, but not in the spleen. Thus, commensal-induced IL-1β production is a critical step for sT(H)17 differentiation in the intestine, which may have therapeutic implications for T(H)17-mediated pathologies.
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The mammalian intestine is home to ~100 trillion bacteria that perform important metabolic functions for their hosts. The proximity of vast numbers of bacteria to host intestinal tissues raises the question of how symbiotic host-bacterial relationships are maintained without eliciting potentially harmful immune responses. Here, we show that RegIIIγ, a secreted antibacterial lectin, is essential for maintaining a ~50-micrometer zone that physically separates the microbiota from the small intestinal epithelial surface. Loss of host-bacterial segregation in RegIIIγ(-/-) mice was coupled to increased bacterial colonization of the intestinal epithelial surface and enhanced activation of intestinal adaptive immune responses by the microbiota. Together, our findings reveal that RegIIIγ is a fundamental immune mechanism that promotes host-bacterial mutualism by regulating the spatial relationships between microbiota and host.
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Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.
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To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.
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Adaptive immune responses rely on differentiation of CD4 T helper cells into subsets with distinct effector functions best suited for host defence against the invading pathogen. Interleukin (IL)-17-producing T helper cells (T(H)17) are a recently identified subset, separate from the T helper type 1 (T(H)1) and T helper type 2 (T(H)2) subsets. Synergy between the cytokines transforming growth factor-beta and IL-6 in vitro induces development of T(H)17 cells in mouse and human systems, whereas IL-23 supports expansion of these cells. However, it is not known which conditions in vivo would induce this combination of cytokines. Furthermore, it is enigmatic that a combination of pro-inflammatory and anti-inflammatory cytokines would be required to generate an effector T(H)17 response. Here we show that the relevant physiological stimulus triggering this combination of cytokines is the recognition and phagocytosis of infected apoptotic cells by dendritic cells. Phagocytosis of infected apoptotic cells uniquely triggers the combination of IL-6 and transforming growth factor-beta through recognition of pathogen-associated molecular patterns and phosphatidylserine exposed on apoptotic cells, respectively. Conversely, phagocytosis of apoptotic cells in the absence of microbial signals induces differentiation of the closely related regulatory T cells, which are important for controlling autoimmunity. Blocking apoptosis during infection of the mouse intestinal epithelium with the rodent pathogen Citrobacter rodentium, which models human infections with the attaching and effacing enteropathogenic and enterohaemorrhagic Escherichia coli, impairs the characteristic T(H)17 response in the lamina propria. Our results demonstrate that infected apoptotic cells are a critical component of the innate immune signals instructing T(H)17 differentiation, and point to pathogens particularly adept at triggering apoptosis that might preferentially induce T(H)17-mediated immunity. Because T(H)17 cells have been correlated with autoimmune diseases, investigation of the pathways of innate recognition of infected apoptotic cells might lead to improved understanding of the causative defects in autoimmunity.
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The requirements for in vivo steady state differentiation of IL-17-producing T-helper (Th17) cells, which are potent inflammation effectors, remain obscure. We report that Th17 cell differentiation in the lamina propria (LP) of the small intestine requires specific commensal microbiota and is inhibited by treating mice with selective antibiotics. Mice from different sources had marked differences in their Th17 cell numbers and animals lacking Th17 cells acquired them after introduction of bacteria from Th17 cell-sufficient mice. Differentiation of Th17 cells correlated with the presence of cytophaga-flavobacter-bacteroidetes (CFB) bacteria in the intestine and was independent of toll-like receptor, IL-21 or IL-23 signaling, but required appropriate TGF-beta activation. Absence of Th17 cell-inducing bacteria was accompanied by increase in Foxp3+ regulatory T cells (Treg) in the LP. Our results suggest that composition of intestinal microbiota regulates the Th17:Treg balance in the LP and may thus influence intestinal immunity, tolerance, and susceptibility to inflammatory bowel diseases.
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We normally live in symbiosis with ∼10¹³ bacteria present in the colon. Among the several mechanisms maintaining the bacteria/host balance, there is limited understanding of the structure, function, and properties of intestinal mucus. We now demonstrate that the mouse colonic mucus consists of two layers extending 150 μm above the epithelial cells. Proteomics revealed that both of these layers have similar protein composition, with the large gel-forming mucin Muc2 as the major structural component. The inner layer is densely packed, firmly attached to the epithelium, and devoid of bacteria. In contrast, the outer layer is movable, has an expanded volume due to proteolytic cleavages of the Muc2 mucin, and is colonized by bacteria. Muc2−/− mice have bacteria in direct contact with the epithelial cells and far down in the crypts, explaining the inflammation and cancer development observed in these animals. These findings show that the Muc2 mucin can build a mucus barrier that separates bacteria from the colon epithelia and suggest that defects in this mucus can cause colon inflammation. • commensal bacteria • proteomics • ulcerative colitis • large intestine • colon cancer
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Interleukin (IL)-17-producing CD4(+) T lymphocytes (T(H)17 cells) constitute a subset of T-helper cells involved in host defence and several immune disorders. An intriguing feature of T(H)17 cells is their selective and constitutive presence in the intestinal lamina propria. Here we show that adenosine 5'-triphosphate (ATP) that can be derived from commensal bacteria activates a unique subset of lamina propria cells, CD70(high)CD11c(low) cells, leading to the differentiation of T(H)17 cells. Germ-free mice exhibit much lower concentrations of luminal ATP, accompanied by fewer lamina propria T(H)17 cells, compared to specific-pathogen-free mice. Systemic or rectal administration of ATP into these germ-free mice results in a marked increase in the number of lamina propria T(H)17 cells. A CD70(high)CD11c(low) subset of the lamina propria cells expresses T(H)17-prone molecules, such as IL-6, IL-23p19 and transforming-growth-factor-beta-activating integrin-alphaV and -beta8, in response to ATP stimulation, and preferentially induces T(H)17 differentiation of co-cultured naive CD4(+) T cells. The critical role of ATP is further underscored by the observation that administration of ATP exacerbates a T-cell-mediated colitis model with enhanced T(H)17 differentiation. These observations highlight the importance of commensal bacteria and ATP for T(H)17 differentiation in health and disease, and offer an explanation of why T(H)17 cells specifically present in the intestinal lamina propria.
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Selective attachment of indigenous, apathogenic, segmented filamentous bacteria to follicle-associated epithelia of terminal ileal Peyer's patches involves both the specialized M cells and normal enterocytes. A striking, highly localized cytoplasmic accumulation of polymerized actin, which resembles that associated with adherence of enteropathogenic Escherichia coli to cultured epithelial cells, occurs at attachment sites of segmented filamentous bacteria. The epithelial response to the attachment of microorganisms may thus involve mechanisms which are the same for diverse microorganisms.
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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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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 ⁺ , CD45RB low 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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RORγt(+) Th17 cells are important for mucosal defenses but also contribute to autoimmune disease. They accumulate in the intestine in response to microbiota and produce IL-17 cytokines. Segmented filamentous bacteria (SFB) are Th17-inducing commensals that potentiate autoimmunity in mice. RORγt(+) T cells were induced in mesenteric lymph nodes early after SFB colonization and distributed across different segments of the gastrointestinal tract. However, robust IL-17A production was restricted to the ileum, where SFB makes direct contact with the epithelium and induces serum amyloid A proteins 1 and 2 (SAA1/2), which promote local IL-17A expression in RORγt(+) T cells. We identified an SFB-dependent role of type 3 innate lymphoid cells (ILC3), which secreted IL-22 that induced epithelial SAA production in a Stat3-dependent manner. This highlights the critical role of tissue microenvironment in activating effector functions of committed Th17 cells, which may have important implications for how these cells contribute to inflammatory disease.
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We constructed isogenic Shiga (-like) toxin (Stx-1 and/or Stx-2) gene-deletion mutants of enterohemorrhagic Escherichia coli (EHEC) GPU96MM (O157:H7). A vector with temperature-sensitive replication origin was used for the construction. The parts of stx-1 and stx-2 on the GPU96MM genome were replaced with kanamycin and chloramphenicol resistance genes, respectively. The mutants deficient in stx-1, stx-2, and both of them were named GPU993, GPU994, and GPU995, respectively. Each mutation was confirmed by the polymerase chain reaction, enzyme-linked immunosorbent assay using antibodies to B subunits of Stx-1 and Stx-2, and the cytotoxic activity of the bacterial culture supernatants toward HeLa cells was detected for GPU96MM and the mutants except for GPU995. These results indicate that GPU993 and GPU994 lack productivity for the respective toxins and GPU995, for both of them.
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Specific members of the intestinal microbiota dramatically affect inflammatory bowel disease (IBD) in mice. In humans, however, identifying bacteria that preferentially affect disease susceptibility and severity remains a major challenge. Here, we used flow-cytometry-based bacterial cell sorting and 16S sequencing to characterize taxa-specific coating of the intestinal microbiota with immunoglobulin A (IgA-SEQ) and show that high IgA coating uniquely identifies colitogenic intestinal bacteria in a mouse model of microbiota-driven colitis. We then used IgA-SEQ and extensive anaerobic culturing of fecal bacteria from IBD patients to create personalized disease-associated gut microbiota culture collections with predefined levels of IgA coating. Using these collections, we found that intestinal bacteria selected on the basis of high coating with IgA conferred dramatic susceptibility to colitis in germ-free mice. Thus, our studies suggest that IgA coating identifies inflammatory commensals that preferentially drive intestinal disease. Targeted elimination of such bacteria may reduce, reverse, or even prevent disease development.
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How commensal microbiota contributes to immune cell homeostasis at barrier surfaces is poorly understood. Lamina propria (LP) T helper 17 (Th17) cells participate in mucosal protection and are induced by commensal segmented filamentous bacteria (SFB). Here we show that MHCII-dependent antigen presentation of SFB antigens by intestinal dendritic cells (DCs) is crucial for Th17 cell induction. Expression of MHCII on CD11c(+) cells was necessary and sufficient for SFB-induced Th17 cell differentiation. Most SFB-induced Th17 cells recognized SFB in an MHCII-dependent manner. SFB primed and induced Th17 cells locally in the LP and Th17 cell induction occurred normally in mice lacking secondary lymphoid organs. The importance of other innate cells was unveiled by the finding that RORγt(+) innate lymphoid cells (ILCs) strongly inhibited SFB-independent Th17 cell differentiation in an MHCII-dependent manner. Our results outline the complex role of DCs and ILCs in the regulation of intestinal Th17 cell homeostasis.
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Rho GTPases are historically known to be central regulators of actin cytoskeleton reorganisation. This affects many processes including cell migration. In addition, members of the Rac subfamily are known to be involved in reactive oxygen species (ROS) production through regulation of NADPH oxidase (Nox) activity. This review focuses on relationships between Nox regulated ROS, Rho GTPases, and cytoskeletal reorganization, in the context of cell migration. It has become clear that ROS participate in the regulation of certain Rho GTPase family members thus mediating cytoskeletal reorganisation. The role of the actin cytoskeleton in providing a scaffold for components of the Nox complex needs to be examined in the light of these new advances. During cell migration Rho GTPases, ROS, and cytoskeletal organisation appear to function as a complex regulatory network. However, more work is needed to fully elucidate the interactions between these factors and their potential in vivo importance. Ultrastructural analysis, i.e. electron microscopy, particularly immunogold labelling, will enable direct visualisation of subcellular compartments. This in conjunction with analysis of tissues lacking specific Rho GTPases and Nox components will facilitate a detailed examination of the interactions of these structures with the actin cytoskeleton. In combination with analysis of ROS production, including its subcellular location, this data will contribute significantly to our understanding of this intricate network under physiological conditions. Based on this, in vivo and in vitro studies can then be combined in order to elucidate the signalling pathways involved and their targets.
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Manipulation of the gut microbiota holds great promise for the treatment of inflammatory and allergic diseases. Although numerous probiotic microorganisms have been identified, there remains a compelling need to discover organisms that elicit more robust therapeutic responses, are compatible with the host, and can affect a specific arm of the host immune system in a well-controlled, physiological manner. Here we use a rational approach to isolate CD4(+)FOXP3(+) regulatory T (Treg)-cell-inducing bacterial strains from the human indigenous microbiota. Starting with a healthy human faecal sample, a sequence of selection steps was applied to obtain mice colonized with human microbiota enriched in Treg-cell-inducing species. From these mice, we isolated and selected 17 strains of bacteria on the basis of their high potency in enhancing Treg cell abundance and inducing important anti-inflammatory molecules-including interleukin-10 (IL-) and inducible T-cell co-stimulator (ICOS)-in Treg cells upon inoculation into germ-free mice. Genome sequencing revealed that the 17 strains fall within clusters IV, XIVa and XVIII of Clostridia, which lack prominent toxins and virulence factors. The 17 strains act as a community to provide bacterial antigens and a TGF-β-rich environment to help expansion and differentiation of Treg cells. Oral administration of the combination of 17 strains to adult mice attenuated disease in models of colitis and allergic diarrhoea. Use of the isolated strains may allow for tailored therapeutic manipulation of human immune disorders.
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The recent discovery of a new CD4(+) T cell subset, Th17, has transformed our understanding of the pathogenetic basis of an increasing number of chronic immune-mediated diseases. Particularly in tissues that interface with the microbial environment-such as the intestinal and respiratory tracts and the skin-where most of the Th17 cells in the body reside, dysregulated immunity to self (or the extended self, the diverse microbiota that normally colonize these tissues) can result in chronic inflammatory disease. In this review, we focus on recent advances in the biology of the Th17 pathway and on genome-wide association studies that implicate this immune pathway in human disease involving these tissues. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 8 is January 24, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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Segmented filamentous bacteria (SFB) are noncultivable commensals inhabiting the gut of various vertebrate species and have been shown to induce Th17 cells in mice. We present the complete genome sequences of both rat and mouse SFB isolated from SFB-monocolonized hosts. The rat and mouse SFB genomes each harbor a single circular chromosome of 1.52 and 1.59 Mb encoding 1346 and 1420 protein-coding genes, respectively. The overall nucleotide identity between the two genomes is 86%, and the substitution rate was estimated to be similar to that of the free-living E. coli. SFB genomes encode typical genes for anaerobic fermentation and spore and flagella formation, but lack most of the amino acid biosynthesis enzymes, reminiscent of pathogenic Clostridia, exhibiting large dependency on the host. However, SFB lack most of the clostridial virulence-related genes. Comparative analysis with clostridial genomes suggested possible mechanisms for host responses and specific adaptations in the intestine.
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Commensal microbes can have a substantial impact on autoimmune disorders, but the underlying molecular and cellular mechanisms remain largely unexplored. We report that autoimmune arthritis was strongly attenuated in the K/BxN mouse model under germ-free (GF) conditions, accompanied by reductions in serum autoantibody titers, splenic autoantibody-secreting cells, germinal centers, and the splenic T helper 17 (Th17) cell population. Neutralization of interleukin-17 prevented arthritis development in specific-pathogen-free K/BxN mice resulting from a direct effect of this cytokine on B cells to inhibit germinal center formation. The systemic deficiencies of the GF animals reflected a loss of Th17 cells from the small intestinal lamina propria. Introduction of a single gut-residing species, segmented filamentous bacteria, into GF animals reinstated the lamina propria Th17 cell compartment and production of autoantibodies, and arthritis rapidly ensued. Thus, a single commensal microbe, via its ability to promote a specific Th cell subset, can drive an autoimmune disease.
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Candida albicans causes mucosal and disseminated candidiasis, which represent serious problems for the rapidly expanding immunocompromised population. Until recently, Th1-mediated immunity was thought to confer the primary protection, particularly for oral candidiasis. However, emerging data indicate that the newly-defined Th17 compartment appears to play the predominant role in mucosal candidiasis.