Trillions of microorganisms reside in the intestine and maintain gut ho-46meostasis. Our laboratory has been focusing on identifying commensal bacteria that induce specific branches of immune cells in the intestine. We have succeeded in isolating bacterial consortia that stimulate targeted immune responses, including induction of CD4+Foxp3+ regulatory T (Treg) cells, TH17 cells, TH1 cells, and CD8 T cells. The 17 Treg cell-inducing consortium is now under evaluation in a Phase 2 study for therapy in patients with ulcerative coli-tis. The 11 CD8 cell-inducing consortium is now under evaluation in Phase 1/2 studies in the US in combination with anti-PD1 mAb for therapy in patients with checkpoint inhibitor refractory melanoma, gastric cancer and colorectal cancer.In addition to immune-modulatory bacteria, we identified and isolated bile acid-metabolizing bacteria from centenarians’ feces. Centenarians display de-creased susceptibility to ageing-associated illness, chronic inflammation and infectious disease. We found that centenarians have a distinct gut microbiome enriched in microbes capable of generating unique secondary bile acids (BAs), including iso-, 3-oxo-, allo-, 3-oxoallo-, and isoallo-lithocholic acid (LCA). Among these BAs, the biosynthetic pathway for isoalloLCA had not been de-scribed previously. By screening 68 bacterial isolates from a centenarians’ fecal microbiota, we identified Odoribacteraceae strains as effective producers of isoalloLCA, both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3βHSDH) were re-sponsible for isoalloLCA production. IsoalloLCA exerted potent antimicrobial effects against gram-positive, but not gram-negative, multidrug-resistant patho-gens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that specific bile acid metabolism may be involved in reducing the risk of pathobiont infection, thereby potentially contributing to the maintenance of intestinal homeostasis.Figure: Bactericidal effect of isoalloLCA on Enterococcus faeciumScanning electron micrographs of drug-resistant bacte-ria grown in medium without (left) or with (right) the secondary bile acid isoalloLCA. The bacteria grown with isoalloLCA exhibit changes to their shapes.Recent Major PublicationsSato Y, Atarashi K, Plichta DR, Arai Y, Sasajima S, Kearney SM, Suda W, Takeshita K, Sasaki T, Okamoto S, Skelly AN, Okamura Y, Vlamakis H, Li Y, Tanoue T, Takei H, Nittono H, Narushima S, Irie J, Itoh H, Moriya K, Sugiura Y, Sue-matsu M, Moritoki N, Shibata S, Littman DR, Fischbach MA, Uwamino Y, Inoue T, Honda A, Hattori M, Murai T, Xavier RJ, Hirose N, Honda K. Novel bile acid biosynthetic pathways are enriched in the microbiome of centenar-ians. Nature 599, 458-464 (2021)Li Y, Honda K. Toward the development of defined mi-crobial therapeutics. Int Immunol 33, 761-766 (2021)Ito Y, Sasaki T, Li Y, Tanoue T, Sugiura Y, Skelly AN, Suda W, Kawashima Y, Okahashi N, Watanabe E, Horikawa H, Shiohama A, Kurokawa R, Kawakami E, Iseki H, Kawasaki H, Iwakura Y, Shiota A, Yu L, Hisatsune J, Koseki H, Sugai M, Arita M, Ohara O, Matsui T, Suematsu M, Hattori M, Atarashi K, Amagai M, Honda K. Staphylococcus cohnii is a potentially biotherapeutic skin commensal alleviating skin inflammation. Cell Rep 35, 109052 (2021)Invited presentationsHonda K. “Mining the gut microbiota and identifying ef-fector microbes to combat pathogen infection” Seminar series at Genentech (USA/Online) September 2021Honda K. “Microbiota and regulation of intestinal im-munity” Principles of Mucosal Immunology Course (USA/Online) July 2021Honda K. “Identification of unique bile acid-metaboliz-ing bacteria from the microbiome of centenarians” The international centenarian consortium (ICC) conference (Japan/Online) June 2021Honda K. “Mining the human gut microbiota to identify its beneficial components” Seminar series at Center for Immunity and Infection Lausanne, University of Laus-anne (Switzerland/Online) June 2021Honda K. “Identification of Gut Bacterial Strains Involved in the Regulation of Host Physiological Functions” Keystone symposia on Harnessing the Microbiome for Disease Prevention and Therapy (USA/Online) January 2021Laboratory for Gut HomeostasisTeam Leader: Kenya Honda
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