Abstract
Intestinal microbiota has critical importance in pathogenesis of intestinal infection; however, the role of intestinal microbiota in intestinal immunity during enterotoxigenic Escherichia coli (ETEC) infection is poorly understood. The present study tested the hypothesis that the intestinal microbiota is associated with intestinal interleukin-17 (IL-17) expression in response to ETEC infection. Here, we found ETEC infection induced expression of intestinal IL-17 and dysbiosis of intestinal microbiota, increasing abundance of γ-aminobutyric acid (GABA)-producing Lactococcus lactis subsp. lactis. Antibiotics treatment in mice lowered the expression of intestinal IL-17 during ETEC infection, while GABA or L. lactis subsp. lactis administration restored the expression of intestinal IL-17. L. lactis subsp. lactis administration also promoted expression of intestinal IL-17 in germ-free mice during ETEC infection. GABA enhanced intestinal IL-17 expression in the context of ETEC infection through activating mechanistic target of rapamycin complex 1 (mTORC1)-ribosomal protein S6 kinase 1 (S6K1) signaling. GABA–mTORC1 signaling also affected intestinal IL-17 expression in response to Citrobacter rodentium infection and in drug-induced model of intestinal inflammation. These findings highlight the importance of intestinal GABA signaling in intestinal IL-17 expression during intestinal infection and indicate the potential of intestinal microbiota-GABA signaling in IL-17-associated intestinal diseases.
Highlights
The intestinal microbiota has critical importance in intestinal infections by increasing colonization resistance and promoting pathogen clearance after infection [1, 2]
Enterotoxigenic Escherichia coli (ETEC) infection enhanced the abundance of RAR-related orphan receptor gamma t (RORγt) in the cytoplasm and nuclei of mouse jejunum (Figure 1D) and ileum (Figure 1E)
The mechanistic target of rapamycin complex 1 (mTORC1) pathway was activated in piglets infected with ETEC, based on the higher abundance of phosphorylated mTORC1 and its downstream target ribosomal protein S6 kinase (S6K) (Figure 2A)
Summary
The intestinal microbiota has critical importance in intestinal infections by increasing colonization resistance and promoting pathogen clearance after infection [1, 2]. Clostridium difficile infection, which is the leading health care-associated illness, usually follows the disruption of the indigenous gut microbiota after antibiotic treatment, leading to the loss of colonization resistance against C. difficile [2,3,4]. Interleukin (IL)-17 promotes local chemokine production to recruit monocytes and neutrophils to sites of inflammation and is important in mediating protection against pathogens, especially against extracellular pathogens [7]. IL-17 combats the microbes attacking epithelial layers and has critical functions in protecting against bacterial infection at mucosal sites [8]. IL-17 is thought to play major roles in the development and pathogenesis of various autoimmune diseases, including rheumatoid arthritis, psoriasis vulgaris, multiple sclerosis, and inflammatory bowel disease [9, 10]
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