Trillions of microorganisms reside in the intestine and maintain gut ho-43P. claraP. clara+Trypsin-488 +TLCKBindTrypsinTrypsindegradationmeostasis. 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, and TH1 cells. We have also identified 11 bacterial strains that induce IFNγ-producing CD8+ T cells in the gut and enhance the therapeutic efficacy of immune checkpoint inhibitors in mouse syngeneic tumor models. 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 trypsin-degrading bacteria from healthy human feces. Although trypsin is indispensable for the host as one of the digestive enzymes, it must be strictly regulated to avoid host injury due to its strong protease activity. Fecal proteome analysis revealed that trypsin is abundant in the colon of germ-free (GF) mice, but markedly reduced in SPF mouse colons, suggesting that commensal intesti-nal bacteria play a role in controlling trypsin levels. Furthermore, high trypsin activity was observed in fecal samples from both humans with inflammatory bowel disease (IBD) and IL-10-deficient mice with colitis, indicating that if trypsin remains proteolytically active in the large intestine, it is associated with disturbance of gut homeostasis. This year, we have successfully identified Para-prevotella clara and Paraprevotella xylaniphila from the microbiome of healthy human donors as potent trypsin-degrading commensals. Mechanistically, mul-tiple lines of evidence suggest that trypsin specifically binds to the surface of Paraprevotella spp. through a mechanism involving type IX secretion system-dependent polysaccharide-binding molecules, and that the binding promotes trypsin autolysis. We also found that intestinal colonization with Paraprevotella spp. and consequent trypsin reduction prevented degradation of secretory IgA. Moreover, Paraprevotella spp. prevented lethal infection by murine hepatitis virus, which is a mouse coronavirus that requires proteolytic cleavage of the spike protein for its entry into host cells. Therefore, a microbiome-based ap-proach targeting excessive proteases may represent a therapeutic strategy for inflammatory and infectious diseases.Figure: Trypsin accumulates on the surface of P. claraP. clara was incubated with Alexa488-labelled trypsin in the presence of the trypsin inhibitor TLCK in vitro. Tryp-sin was found to accumulate on the surface of P. clara within minutes.Recent Major PublicationsTuganbaev T, Mor U, Bashiardes S, Liwinski T, Nobs SP, Leshem A, Dori-Bachash M, Thaiss CA, Pinker EY, Ratiner K, Adlung L, Federici S, Kleimeyer C, Moresi C, Yamada T, Cohen Y, Zhang X, Massalha H, Massasa E, Kuperman Y, Koni PA, Harmelin A, Gao N, Itzkovitz S, Honda K, Shapiro H, Elinav E. Diet Diurnally Regulates Small Intes-tinal Microbiome-Epithelial-Immune Homeostasis and Enteritis. Cell 182, 1441-1459.e21 (2020)Nagayama M, Yano T, Atarashi K, Tanoue T, Sekiya M, Kobayashi Y, Sakamoto H, Miura K, Sunada K, Kawaguchi T, Morita S, Sugita K, Narushima S, Barnich N, Isayama J, Kiridooshi Y, Shiota A, Suda W, Hattori M, Yamamoto H, Honda K*. TH1 cell-inducing Escherichia coli strain identified from the small intestinal mucosa of patients with Crohn’s disease. Gut Microbes 12, 1788898 (2020)Finlay BB, Goldszmid R, Honda K, Trinchieri G, Wargo J, Zitvogel L. Can we harness the microbiota to enhance the efficacy of cancer immunotherapy? Nat Rev Immu-nol 20, 522-528 (2020)Laboratory for Gut HomeostasisTeam Leader: Kenya Honda
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