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The transcription factor c-MAF is required for the generation of Helicobacter -specific regulatory T cells that selectively restrain pro-inflammatory T H 17 cells; the absence of c-MAF in mouse regulatory T cells results in pathobiont-dependent inflammatory bowel disease. Tolerance mechanism against a gut commensal pathobiont Some common commensal gut bacteria that can cause spontaneous colitis—chronic inflammation in the colon—in susceptible individuals are well tolerated in others, but the reason for this difference is unclear. In this paper, the authors show that, in mice, the transcription factor c-MAF is required for the generation of Helicobacter -specific regulatory T (T reg ) cells, which selectively retrain Helicobacter -specific pro-inflammatory T helper 17 (T H 17) cells. In the absence of c-MAF or the c-MAF-induced cytokine IL-10, the bacterial-specific T reg –T H 17 balance becomes impaired, and the animals develop pathobiont-dependent inflammatory bowel disease. The authors suggest that engineering non-pathogenic T reg -cell-inducing microbes that express pathobiont antigens could be a therapeutic approach to re-establishing homeostatic conditions in patients with inflammatory bowel disease, reducing the effects of the disease. Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases 1 , 2 , 3 , 4 . There is accumulating evidence that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease, often also colonize healthy individuals. These microorganisms, including the Helicobacter species, can induce pathogenic T cells and are collectively referred to as pathobionts 4 , 5 , 6 . However, how such T cells are constrained in healthy individuals is not yet understood. Here we report that host tolerance to a potentially pathogenic bacterium, Helicobacter hepaticus , is mediated by the induction of RORγt + FOXP3 + regulatory T (iT reg ) cells that selectively restrain pro-inflammatory T helper 17 (T H 17) cells and whose function is dependent on the transcription factor c-MAF. Whereas colonization of wild-type mice by H. hepaticus promoted differentiation of RORγt-expressing microorganism-specific iT reg cells in the large intestine, in disease-susceptible IL-10-deficient mice, there was instead expansion of colitogenic T H 17 cells. Inactivation of c-MAF in the T reg cell compartment impaired differentiation and function, including IL-10 production, of bacteria-specific iT reg cells, and resulted in the accumulation of H. hepaticus -specific inflammatory T H 17 cells and spontaneous colitis. By contrast, RORγt inactivation in T reg cells had only a minor effect on the bacteria-specific T reg and T H 17 cell balance, and did not result in inflammation. Our results suggest that pathobiont-dependent inflammatory bowel disease is driven by microbiota-reactive T cells that have escaped this c-MAF-dependent mechanism of iT reg –T H 17 homeostasis.

Host-pathogen interaction influences many non-infectious diseases, including metabolic diseases. Helicobacter hepaticus ( H. hepaticus ) has been found in some metabolic dysfunction-associated steatotic liver disease (MASLD) patients, however, the causal link and underlying mechanisms remain unclear. Here we report that H. hepaticus infection or overexpression of CdtB of H. hepaticus induces lipid deposition in hepatocytes, both in vivo and in vitro. Furthermore, we identify that CdtB translocates to mitochondria with the help of Hsp90, interacts with ATP5A1, reduces mitochondrial respiratory complex V activity, damages mitochondria, and disrupts lipid metabolism. Mechanistically, CdtB-induced lipogenesis depends on the CdtB-mitochondrial ROS-mTORC1-SREBP1 axis and CdtB-mediated NONO expression to enhance nuclear localization of SREBP1 that promote the de novo fatty acid synthesis in the hepatocytes. Neutralization of CdtB significantly alleviates hepatic lipidosis in mice upon H. hepaticus infection. Furthermore, the nucleic acid of H. hepaticus has been detected in the liver tissues of some patients with MASLD, which suggests a certain correlation between liver infection with H. hepaticus and the occurrence and progression of MASLD. Our findings highlight the critical role of CdtB in the pathogenesis of H. hepaticus infection-induced hepatic lipidosis and its potential as a therapeutic target. Here, the authors show that hepatic lipid accumulation induced by Helicobacter hepaticus involves mitochondrial dysfunction and disrupted lipid metabolism via CdtB-ROS-mTORC1-SREBP1 and NONO, highlighting CdtB as a key mediator and potential therapeutic target.

Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells and also inhibits in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin-10-producing CD4 + T cells. These results show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles. A gut issue: Bacterial symbiosis shapes a healthy immune response (Nature Cover 29 May 2008) Microbiologists are beginning to understand how and why mammals are colonized by multitudes of symbiotic bacteria. But what differentiates 'good' from benign or harmful bacteria remains largely unknown. The intestinal microbe Bacteroides fragilis was shown in 2005 to have profound effect on the mammalian immune system, an effect ascribed to a single molecule, capsular polysaccharide A (PSA). Now B. fragilis PSA is shown to protect animals against both bacterial and chemical colitis in a process involving interleukin-10-producing T cells. This suggests that B. fragilis helps maintain human health by suppressing the intestinal inflammatory response, and that symbiosis factors may provide a route to new therapies. In the cover graphic (by Tom DiCesere, Sarkis Mazmanian & Dennis Kasper), In the cover graphic, PSA (yellow) surrounds B. fragilis (green) in the intestine and is taken up by a dendritic cell and processed within the endosomal pathway to a reduced molecular size. The depolymerized PSA is presented by the major histocompatibility complex class II molecule to the CD4 + T cell (green, white, yellow), which becomes activated. Work in this field is being promoted by several major efforts to characterize the human microbiota and determine its role in health and disease, including the Human Microbiome Project. In News Features, Asher Mullard examines the various approaches, and Apoorva Mandavilli reports on a rare opportunity to watch the gut being colonized from scratch after intestinal transplants. Bacteroides fragilis is a member of the human intestinal microbiota. It is reported that a single molecule produced by this bacterium, polysaccharide A, can suppress the intestinal inflammatory response and thus protect from experimental colitis.

Pioneering work in the 1990s first linked a novel microaerobic bacterium, Helicobacter hepaticus, with chronic active hepatitis and inflammatory bowel disease in several murine models. Targeted H. hepaticus infection experiments subsequently demonstrated its ability to induce colitis, colorectal cancer, and extraintestinal diseases in a number of mouse strains with defects in immune function and/or regulation. H. hepaticus is now widely utilized as a model system to dissect how intestinal microbiota interact with the host to produce both inflammatory and tolerogenic responses. This model has been used to make important advances in understanding factors that regulate both acquired and innate immune response within the intestine. Further, it has been an effective tool to help define the function of regulatory T cells, including their ability to directly inhibit the innate inflammatory response to gut microbiota. The complete genomic sequence of H. hepaticus has advanced the identification of several virulence factors and aided in the elucidation of H. hepaticus pathogenesis. Delineating targets of H. hepaticus virulence factors could facilitate novel approaches to treating microbially induced lower bowel inflammatory diseases.

The mouse pathobiont Helicobacter hepaticus can induce typhlocolitis in interleukin-10-deficient mice, and H. hepaticus infection of immunodeficient mice is widely used as a model to study the role of pathogens and commensal bacteria in the pathogenesis of inflammatory bowel disease. C57BL/6J Il10(-/-) mice kept under specific pathogen-free conditions in two different facilities (MHH and MIT), displayed strong differences with respect to their susceptibilities to H. hepaticus-induced intestinal pathology. Mice at MIT developed robust typhlocolitis after infection with H. hepaticus, while mice at MHH developed no significant pathology after infection with the same H. hepaticus strain. We hypothesized that the intestinal microbiota might be responsible for these differences and therefore performed high resolution analysis of the intestinal microbiota composition in uninfected mice from the two facilities by deep sequencing of partial 16S rRNA amplicons. The microbiota composition differed markedly between mice from both facilities. Significant differences were also detected between two groups of MHH mice born in different years. Of the 119 operational taxonomic units (OTUs) that occurred in at least half the cecum or colon samples of at least one mouse group, 24 were only found in MIT mice, and another 13 OTUs could only be found in MHH samples. While most of the MHH-specific OTUs could only be identified to class or family level, the MIT-specific set contained OTUs identified to genus or species level, including the opportunistic pathogen, Bilophila wadsworthia. The susceptibility to H. hepaticus-induced colitis differed considerably between Il10(-/-) mice originating from the two institutions. This was associated with significant differences in microbiota composition, highlighting the importance of characterizing the intestinal microbiome when studying murine models of IBD.

Summary Multiple pathogenic Gram‐negative bacteria produce the cytolethal distending toxin (CDT) with activity of DNase I; CDT can induce DNA double‐strand breaks (DSBs), G2/M cell cycle arrest, and apoptosis in cultured mammalian cells. However, the link of CDT to in vivo tumorigenesis is not fully understood. In this study, 129/SvEv Rag2−/− mice were gavaged with wild‐type Helicobacter hepatics 3B1(Hh) and its isogenic cdtB mutant HhcdtBm7, followed by infection for 10 and 20 weeks (WPI). HhCDT deficiency did not affect cecal colonization levels of HhcdtBm7, but attenuated severity of cecal pathology in HhcdtBm7‐infected mice. Of importance, preneoplasic dysplasia was progressed to cancer from 10 to 20 WPI in the Hh‐infected mice but not in the HhcdtBm7‐infected mice. In addition, the loss of HhCDT significantly dampened transcriptional upregulation of cecal Tnfα and Il‐6, but elevated Il‐10 mRNA levels when compared to Hh at 10 WPI. Furthermore, the presence of HhCDT increased numbers of lower bowel intestinal γH2AX‐positive epithelial cells (a marker of DSBs) at both 10 and 20 WPI and augmented phospho‐Stat3 foci+ intestinal crypts (activation of Stat3) at 20 WPI. Our findings suggest that CDT promoted Hh carcinogenesis by enhancing DSBs and activation of the Tnfα/Il‐6‐Stat3 signaling pathway.

The prevalence of gastric Helicobacter pylori (Hp) infection is ~50% of the world population. However, how Hp infection influences inflammatory bowel disease in humans is not fully defined. In this study, we examined whether co-infection with Hp influenced Helicobacter hepaticus (Hh)–induced intestinal pathology in Rag2−/− mice. Rag2−/− mice of both sexes were infected with Hh, of which a subgroup was followed by infection with Hp two weeks later. Co-infected males, but not females, had significantly higher total colitis index scores in the colon at both 10 and 21 weeks post-Hh infection (WPI) and developed more severe dysplasia at 21 WPI compared with mono-Hh males. There were no significant differences in colonization levels of gastric Hp and colonic Hh between sexes or time-points. In addition, mRNA levels of colonic Il-1β, Ifnγ, Tnfα, Il-17A, Il-17F, Il-18, and Il-23, which play important roles in the development and function of proinflammatory innate lymphoid cell groups 1 and 3, were significantly up-regulated in the dually infected males compared with mono-Hh males at 21 WPI. These data suggest that concomitant Hp infection enhances the inflammatory responses in the colon of-Hh-infected Rag2−/− males, which results in more severe colitis and dysplasia.

Innate intestinal inflammatory responses Interleukin 23 (IL-23) has been implicated in the pathogenesis of autoimmune and chronic inflammatory disorders. New work in a mouse model has identified a previously unrecognized population of innate lymphoid cells that respond to IL-23 by inducing inflammation through the production of IL-17 and interferon-γ. Further work will be needed to establish whether this newly discovered IL-23-driven pathway contributes to chronic inflammatory diseases such as irritable bowel disease. The cytokine interleukin (IL)-23 has inflammatory effects on innate immune cells and can drive colitis, but the cellular and molecular pathways involved are poorly characterized. Here it is shown that bacterial-driven innate colitis involves a previously unknown population of IL-23-responsive innate leukocytes that produce IL-17 and interferon-γ. These cells may represent a target in inflammatory bowel disease. The key role of interleukin (IL)-23 in the pathogenesis of autoimmune and chronic inflammatory disorders is supported by the identification of IL-23 receptor (IL-23R) susceptibility alleles associated with inflammatory bowel disease, psoriasis and ankylosing spondylitis. IL-23-driven inflammation has primarily been linked to the actions of T-helper type 17 (T H 17) cells 1 . Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells 2 and can drive T-cell-independent colitis. However, the downstream cellular and molecular pathways involved in this innate intestinal inflammatory response are poorly characterized. Here we show that bacteria-driven innate colitis is associated with an increased production of IL-17 and interferon-γ in the colon. Stimulation of colonic leukocytes with IL-23 induced the production of IL-17 and interferon-γ exclusively by innate lymphoid cells expressing Thy1, stem cell antigen 1 (SCA-1), retinoic-acid-related orphan receptor (ROR)-γt and IL-23R, and these cells markedly accumulated in the inflamed colon. IL-23-responsive innate intestinal cells are also a feature of T-cell-dependent models of colitis. The transcription factor ROR-γt, which controls IL-23R expression, has a functional role, because Rag -/- Rorc -/- mice failed to develop innate colitis. Last, depletion of Thy1 + innate lymphoid cells completely abrogated acute and chronic innate colitis. These results identify a previously unrecognized IL-23-responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in inflammatory bowel disease.

Summary The enterohepatic Epsilonproteobacterium Helicobacter hepaticus persistently colonizes the intestine of mice and causes chronic inflammatory symptoms in susceptible mouse strains. The bacterial factors causing intestinal inflammation are poorly characterized. A large genomic pathogenicity island, HHGI1, which encodes components of a type VI secretion system (T6SS), was previously shown to contribute to the colitogenic potential of H. hepaticus. We have now characterized the T6SS components Hcp, VgrG1, VgrG2 and VgrG3, encoded on HHGI1, including the potential impact of the T6SS on intestinal inflammation in a mouse T‐cell transfer model. The H. hepaticus T6SS components were expressed during the infection and secreted in a T6SS‐dependent manner, when the bacteria were cultured either in the presence or in the absence of mouse intestinal epithelial cells. Mutants deficient in VgrG1 displayed a significantly lower colitogenic potential in T‐cell‐transferred C57BL/6 Rag2−/− mice, despite an unaltered ability to colonize mice persistently. Intestinal microbiota analyses demonstrated only minor changes in mice infected with wild‐typeH. hepaticus as compared with mice infected with VgrG1‐deficient isogenic bacteria. In addition, competitive assays between both wild‐type and T6SS‐deficient H. hepaticus, and between wild‐type H. hepaticus and Campylobacter jejuni or Enterobacteriaceae species did not show an effect of the T6SS on interbacterial competitiveness. Therefore, we suggest that microbiota alterations did not play a major role in the changes of pro‐inflammatory potential mediated by the T6SS. Cellular innate pro‐inflammatory responses were increased by the secreted T6SS proteins VgrG1 and VgrG2. We therefore concluded that the type VI secretion component VgrG1 can modulate and specifically exacerbate the innate pro‐inflammatory effect of the chronic H. hepaticus infection.

Patients with inflammatory bowel disease (IBD) are at increase risk for bone loss and fractures. Therefore, in the present study, we examined the effect of experimental IBD on bone health.MethodsWe used a murine model of colitis, Helicobacter hepaticus–infected interleukin-10–deficient animals. Molecular and histological properties of bone and intestine were examined to identify the immunopathological consequences of colitis in male and female mice.ResultsAt 6 weeks postinfection, we observed significant trabecular bone loss in male mice but surprisingly not in female mice. This was true for both distal femur and vertebral locations. In addition, H. hepaticus infection suppressed osteoblast markers only in male mice. Consistent with effects on bone health, male mice with H. hepaticus infection had more severe colitis as determined by histology and elevated levels of inflammatory cytokines in the colon. Although H. hepaticus levels in the stool appeared similar in male and female mice 1 week after infection, by 6 weeks, H. hepaticus levels were greater in male mice, indicating that H. hepaticus survival and virulence within the gastrointestinal tract could be gender dependent.ConclusionIn summary, H. hepaticus–induced colitis severity and associated bone loss is gender regulated, possibly as a result of gender-specific effects on H. hepaticus colonization in the mouse gastrointestinal tract and the consequent immunopathological responses.