Yoshinori Umesaki

Bio: Yoshinori Umesaki is an academic researcher from Honda. The author has contributed to research in topics: Immune system & Intestinal mucosa. The author has an hindex of 33, co-authored 45 publications receiving 14862 citations.

Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species

Abstract: CD4+ T regulatory cells (Tregs), which express the Foxp3 transcription factor, play a critical role in the maintenance of immune homeostasis. Here, we show that in mice, Tregs were most abundant in the colonic mucosa. The spore-forming component of indigenous intestinal microbiota, particularly clusters IV and XIVa of the genus Clostridium, promoted Treg cell accumulation. Colonization of mice by a defined mix of Clostridium strains provided an environment rich in transforming growth factor–β and affected Foxp3+ Treg number and function in the colon. Oral inoculation of Clostridium during the early life of conventionally reared mice resulted in resistance to colitis and systemic immunoglobulin E responses in adult mice, suggesting a new therapeutic approach to autoimmunity and allergy.

Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis

Abstract: Although the effects of commensal bacteria on intestinal immune development seem to be profound, it remains speculative whether the gut microbiota influences extraintestinal biological functions. Multiple sclerosis (MS) is a devastating autoimmune disease leading to progressive deterioration of neurological function. Although the cause of MS is unknown, microorganisms seem to be important for the onset and/or progression of disease. However, it is unclear how microbial colonization, either symbiotic or infectious, affects autoimmunity. Herein, we investigate a role for the microbiota during the induction of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice maintained under germ-free conditions develop significantly attenuated EAE compared with conventionally colonized mice. Germ-free animals, induced for EAE, produce lower levels of the proinflammatory cytokines IFN-γ and IL-17A in both the intestine and spinal cord but display a reciprocal increase in CD4+CD25+Foxp3+ regulatory T cells (Tregs). Mechanistically, we show that gut dendritic cells from germ-free animals are reduced in the ability to stimulate proinflammatory T cell responses. Intestinal colonization with segmented filamentous bacteria (SFB) is known to promote IL-17 production in the gut; here, we show that SFBs also induced IL-17A–producing CD4+ T cells (Th17) in the CNS. Remarkably, germ-free animals harboring SFBs alone developed EAE, showing that gut bacteria can affect neurologic inflammation. These findings reveal that the intestinal microbiota profoundly impacts the balance between pro- and antiinflammatory immune responses during EAE and suggest that modulation of gut bacteria may provide therapeutic targets for extraintestinal inflammatory diseases such as MS.

ATP drives lamina propria T H 17 cell differentiation

Abstract: 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.

The gut microbiota shapes intestinal immune responses during health and disease

Abstract: Immunological dysregulation is the cause of many non-infectious human diseases such as autoimmunity, allergy and cancer. The gastrointestinal tract is the primary site of interaction between the host immune system and microorganisms, both symbiotic and pathogenic. In this Review we discuss findings indicating that developmental aspects of the adaptive immune system are influenced by bacterial colonization of the gut. We also highlight the molecular pathways that mediate host–symbiont interactions that regulate proper immune function. Finally, we present recent evidence to support that disturbances in the bacterial microbiota result in dysregulation of adaptive immune cells, and this may underlie disorders such as inflammatory bowel disease. This raises the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms.

Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases

Abstract: The two primary human inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are idiopathic relapsing disorders characterized by chronic inflammation of the intestinal tract. Although several lines of reasoning suggest that gastrointestinal (GI) microbes influence inflammatory bowel disease (IBD) pathogenesis, the types of microbes involved have not been adequately described. Here we report the results of a culture-independent rRNA sequence analysis of GI tissue samples obtained from CD and UC patients, as well as non-IBD controls. Specimens were obtained through surgery from a variety of intestinal sites and included both pathologically normal and abnormal states. Our results provide comprehensive molecular-based analysis of the microbiota of the human small intestine. Comparison of clone libraries reveals statistically significant differences between the microbiotas of CD and UC patients and those of non-IBD controls. Significantly, our results indicate that a subset of CD and UC samples contained abnormal GI microbiotas, characterized by depletion of commensal bacteria, notably members of the phyla Firmicutes and Bacteroidetes. Patient stratification by GI microbiota provides further evidence that CD represents a spectrum of disease states and suggests that treatment of some forms of IBD may be facilitated by redress of the detected microbiological imbalances.

The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis

Abstract: Regulatory T cells (T regs ) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate T reg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic T regs . We determined that short-chain fatty acids, gut microbiota–derived bacterial fermentation products, regulate the size and function of the colonic T reg pool and protect against colitis in a Ffar2 -dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.

Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells

Abstract: Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.