Intestinal Microbiota-Derived GABA Mediates Interleukin-17 Expression during Enterotoxigenic Escherichia coli Infection

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.

Melatonin reprogramming of gut microbiota improves lipid dysmetabolism in high‐fat diet‐fed mice

“…Paired‐end sequencing was performed on the Illumina MiSeq platform, and a phylogenic tree and OTU table were obtained from the Mothur Bayesian classifier. Sequencing libraries were generated and analyzed according to our previous study . Principal coordinate analysis (PCoA) was performed to get principal coordinates and visualize from complex, multidimensional data.…”

Melatonin signaling in T cells: Functions and applications

“…Through MT1/hematopoietic‐specific G protein signaling, melatonin modulates the phosphorylation of STAT3, which seems to depend on IL‐6 because an antibody against IL‐6 significantly abolishes melatonin‐mediated activation of STAT3. Thus, melatonin may influence the differentiation of Th17 through STAT3 which is also an important transcription factor involved in the differentiation of Th17 cells . A mechanistic target of rapamycin (mTOR) signaling also plays a critical role in differentiation of Th17 cells and the pathogenesis of various inflammatory diseases .…”

Slc6a13 deficiency promotes Th17 responses during intestinal bacterial infection

“…13 RT-PCR Real-time PCR was performed according to our previous study. 6 Primers ( Supplementary Table 1) were selected according to previous references. β-Actin was used as an internal control to normalize target gene transcript levels.…”

“…Immunoblotting was performed according to our previous study. 6,14 Signal intensity was digitally quantified and normalized to actin or GAPDH protein abundance.…”

“…[3][4][5] However, GABA promotes intestinal Th17 cell differentiation and interleukin-17 (IL-17) expression during enterotoxigenic Escherichia coli (ETEC) infection in piglets and mice. 6 Thus, the effect of the GABAergic system in the immune system needs further investigations.…”