Defined microbiota transplant restores Th17/RORγt⁺regulatory T cell balance in mice colonized with inflammatory bowel disease microbiotas

Abstract

The building evidence for the contribution of microbiota to human disease has spurred an effort to develop therapies that target the gut microbiota. This is particularly evident in inflammatory bowel diseases (IBDs), where clinical trials of fecal microbiota transplantation have shown some efficacy. To aid the development of novel microbiota-targeted therapies and to better understand the biology underpinning such treatments, we have used gnotobiotic mice to model microbiota manipulations in the context of microbiotas from humans with inflammatory bowel disease. Mice colonized with IBD donor-derived microbiotas exhibit a stereotypical set of phenotypes, characterized by abundant mucosal Th17 cells, a deficit in the tolerogenic RORγt+ regulatory T (Treg) cell subset, and susceptibility to disease in colitis models. Transplanting healthy donor-derived microbiotas into mice colonized with human IBD microbiotas led to induction of RORγt+ Treg cells, which was associated with an increase in the density of the microbiotas following transplant. Microbiota transplant reduced gut Th17 cells in mice colonized with a microbiota from a donor with Crohn’s disease. By culturing strains from this microbiota and screening them in vivo, we identified a specific strain that potently induces Th17 cells. Microbiota transplants reduced the relative abundance of this strain in the gut microbiota, which was correlated with a reduction in Th17 cells and protection from colitis.

Role of Interleukin-17 in Acute Pancreatitis

“…Intestinal Th17 cells can be induced by specific microbes, including Escherichia coli and Bifidobacterium. Escherichia coli was positively correlated with the proportion of RORγt+ and IL-17A + Th17 cells in the colon, while the proportion of IL-17A + Th17 cells in the colon of mice lacking only Escherichia coli was significantly reduced ( 97 ). Bifidobacterium and Lactobacillus inhibited the expression of IL-6 and IL-17 while facilitating the protein synthesis of major tight junction proteins ( 98 ).…”

Poly(ADP‑ribose) polymerase‑1 inhibitor ameliorates dextran sulfate sodium‑induced colitis in mice by regulating the balance of Th17/Treg cells and inhibiting the NF‑κB signaling pathway

“…A study indicated that zinc deficiency activates the IL-23/Th17 axis, aggravating experimental colitis in mice ( 48 ). In addition, in a model of colitis, the transplantation of defined microbial flora has been shown to restore the balance of Th17/Tregs ( 49 ). Moreover, studies have confirmed that both Compound Sophorae Decoction and Rhubarb Peony Decoction exert protective effects against DSS-induced colitis in mice, and the mechanisms are related to the regulation of the Th17/Treg balance ( 50 , 51 ).…”

Gut microbiota and bone metabolism

“…135 Some GM-derived metabolites, such as shortchain fatty acids (SCFAs), can also mediate bone homeostasis through Tregs/Th17 cells. 136 Although evidence for a direct correlation between the GM and bone loss secondary to diseases is sparse, some disorders, such as IBD 137 and diabetes, 138 are associated with Tregs/Th17 cell-mediated inflammation. Moreover, these diseases are often accompanied by alterations in GM composition.…”