Short-chain fatty acids induce effector T helper cells and cause inflammatory responses in the renal system.

Abstract Short-chain fatty acids (SCFAs) are major products of gut microbial fermentation and profoundly affect host health and disease. SCFAs generate IL-10+ regulatory T cells, which may promote immune tolerance. SCFAs can also induce Th1 and Th17 cells during active immune responses and, therefore, have the potential to induce inflammatory responses. However, the potential function of SCFAs in induction of tissue inflammation has not been documented to date. We investigated, in depth, the impact of elevated SCFA levels on T cells and tissue inflammation in mice. Orally administered SCFAs induced effector (Th1 and Th17) and regulatory T cells in ureter and kidney tissues, and induced T-cell mediated ureteritis leading to kidney hydronephrosis (hereafter called C2RD). Kidney hydronephrosis in C2RD was caused by ureteral obstruction, which was, in turn, induced by SCFA-induced inflammation in the ureteropelvic junction (UPJ) and proximal ureter. Oral administration of all major SCFAs, such as acetate, propionate, and butyrate, induced the disease. We found that C2RD development is dependent on mTOR activation, T cell-derived inflammatory cytokines such as IFNg and IL-17, and gut microbiota. In a manner similar to many types of chronic renal diseases in humans, young or male animals were more susceptible than old or female animals respectively. However, SCFA receptor (GPR41 or GPR43) deficiency did not affect C2RD development. Our study provide evidence for the first time that SCFAs can cause dysregulated T cell responses and tissue inflammation in a specific organ in the body. We believe that our results have significant ramifications in therapeutic applications of SCFAs.