Slc6a13 deficiency promotes Th17 responses during intestinal bacterial infection

Ren, Wenkai; Liao, Yuexia; Ding, Xueyan; Jiang, Ye; Yan, Jiameng; Xia, Yaoyao; Tan, Bin; Lin, Zhijie; Duan, Jielin; Jia, Xin‐Ming; Yang, Guan; Deng, Jinping; Zhu, Congrui; Hardwidge, Philip R.; Li, Junxia; Zhu, Guoqiang; Yin, Yulong

doi:10.1038/s41385-018-0111-7

Cited by 34 publications

(42 citation statements)

References 40 publications

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“…However, consistent with our results, there is no direct evidence which revealed that GABA supplementation contributed to the growth of weaning piglets in previous studies [19,21]. But previous studies and our results both demonstrated that GABA could modify intestine immunity and metabolism condition [21,22]. In the present study, 40 mg•kg −1 of GABA supplementation decreased the aspartic acid level but increased the histidine level in the serum of normal piglets, while there are no significant changes in serum amino acid contents of ETEC-infected piglets.…”

Section: Discussionsupporting

confidence: 78%

“…Our previous study also revealed that GABA supplementation can modulate the intestinal functions, including intestinal immunity, intestinal amino acid profiles, and gut microbiota in weanling piglets [21]. Furthermore, recent studies reported that GABA could alleviate intestinal pathogenic infection through attenuating epithelial cell apoptosis and promoting host Th17 responses [22,23]. Moreover, a previous study found that intestinal microbiota-derived GABA also could increase intestinal IL-17 expression by activating mechanistic target of rapamycin complex 1-(mTORC1-) ribosomal protein S6 kinase 1 (S6K1) signaling in the context of ETEC or Citrobacter rodentium infection and drug-induced intestinal inflammation [24].…”

Section: Introductionmentioning

confidence: 87%

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Effects of GABA Supplementation on Intestinal SIgA Secretion and Gut Microbiota in the Healthy and ETEC-Infected Weanling Piglets

Zhao

Wang

et al. 2020

Mediators of Inflammation

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Pathogenic enterotoxigenic Escherichia coli (ETEC) has been considered a major cause of diarrhea which is a serious public health problem in humans and animals. This study was aimed at examining the effect of γ-aminobutyric acid (GABA) supplementation on intestinal secretory immunoglobulin A (SIgA) secretion and gut microbiota profile in healthy and ETEC-infected weaning piglets. A total of thirty-seven weaning piglets were randomly distributed into two groups fed with the basal diet or supplemented with 40 mg·kg−1 of GABA for three weeks, and some piglets were infected with ETEC at the last week. According to whether ETEC was inoculated or not, the experiment was divided into two stages (referred as CON1 and CON2 and GABA1 and GABA2). The growth performance, organ indices, amino acid levels, and biochemical parameters of serum, intestinal SIgA concentration, gut microbiota composition, and intestinal metabolites were analyzed at the end of each stage. We found that, in both the normal and ETEC-infected piglets, jejunal SIgA secretion and expression of some cytokines, such as IL-4, IL-13, and IL-17, were increased by GABA supplementation. Meanwhile, we observed that some low-abundance microbes, like Enterococcus and Bacteroidetes, were markedly increased in GABA-supplemented groups. KEGG enrichment analysis revealed that the nitrogen metabolism, sphingolipid signaling pathway, sphingolipid metabolism, and microbial metabolism in diverse environments were enriched in the GABA1 group. Further analysis revealed that alterations in microbial metabolism were closely correlated to changes in the abundances of Enterococcus and Bacteroidetes. In conclusion, GABA supplementation can enhance intestinal mucosal immunity by promoting jejunal SIgA secretion, which might be related with the T-cell-dependent pathway and altered gut microbiota structure and metabolism.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 87%

Effects of GABA Supplementation on Intestinal SIgA Secretion and Gut Microbiota in the Healthy and ETEC-Infected Weanling Piglets

Zhao

Wang

et al. 2020

Mediators of Inflammation

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“…Upon activation, effector T cells generally increase both glucose and glutamine metabolism in order to generate biomass to support T-cell growth and proliferation, whereas memory T cells and regulatory T cells rely more heavily on fatty acid oxidation to fuel immune surveillance and suppressive function [16]. There are additional nuances in the metabolism of T-cell subsets that have also been described in previous studies [17][18][19]. We recently reported that splenic T cells from influenza-infected obese mice have increased oxidative metabolism compared to splenic T cells from influenza-infected lean mice.…”

Section: Introductionmentioning

confidence: 68%

Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity

et al. 2020

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Background Obesity is associated with impaired primary and secondary immune responses to influenza infection, with T cells playing a critical role. T-cell function is highly influenced by the cellular metabolic state; however, it remains unknown how altered systemic metabolism in obesity alters T-cell metabolism and function to influence immune response. Our objective was to identify the altered cellular metabolic state of T cells from obese mice so that we may target T-cell metabolism to improve immune response to infection. Methods Mice were fed normal chow or high-fat diet for 18-19 weeks. Changes in T-cell populations were analyzed in both adipose tissue and spleens using flow cytometry. Splenic T cells were further analyzed for nutrient uptake and extracellular metabolic flux. As changes in T-cell mitochondrial oxidation were observed in obesity, obese mice were treated with metformin for 6 weeks and compared to lean control mice or obese mice undergoing weight loss through diet switch; immunity was measured by survival to influenza infection. Results We found changes in T-cell populations in adipose tissue of high-fat diet-induced obese mice, characterized by decreased proportions of Treg cells and increased proportions of CD8 + T cells. Activated CD4 + T cells from obese mice had increased glucose uptake and oxygen consumption rate (OCR), compared to T cells from lean controls, indicating increased mitochondrial oxidation of glucose. Treatment of isolated CD4 + T cells with metformin was found to inhibit OCR in vitro and alter the expression of several activation markers. Last, treatment of obese mice with metformin, but not weight loss, was able to improve survival to influenza in obesity. Conclusions T cells from obese mice have an altered metabolic profile characterized by increased glucose oxidation, which can be targeted to improve survival against influenza infection.

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“…These results strongly suggest that serine deprivation inhibits IL-1β production in M1 macrophages through mTOR signaling. Previously, we have shown that gamma-aminobutyric acid affects the activation of mTOR signaling in Th17 cells through its receptor in the cell membrane (61,62), while others (e.g., leucine and arginine) modulates the activation of mTOR signaling in the cytoplasm (63, 64). Other amino acids, in particular leucine, have been shown to regulate cell differentiation and function through the mTOR signaling.…”

Section: Discussionmentioning

confidence: 99%

Serine Supports IL-1β Production in Macrophages Through mTOR Signaling

Chen

Xia

et al. 2020

Front. Immunol.

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Intracellular metabolic programs tightly regulate the functions of macrophages, and previous studies have shown that serine mainly shapes the macrophage function via one-carbon metabolism. However, it is unknown whether serine modulates the macrophage function independent of one-carbon metabolism. Here, we find that serine deprivation lowers interleukin (IL)-1β production and inflammasome activation, as well as reprograms the transcriptomic and metabolic profile in M1 macrophages. Intriguingly, supplementation of formate, glycine, dNTPs, and glucose cannot rescue the production of IL-1β from serine-deprived macrophages. Mechanistically, serine deprivation inhibits macrophage IL-1β production through inhibition of mechanistic target of rapamycin (mTOR) signaling. Of note, the macrophages from mice feeding serine-free diet have lower IL-1β production, and these mice also show less inflammation after LPS challenge. Collectively, our data highlight a new regulatory mechanism for serine to modulate the macrophage function.

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Slc6a13 deficiency promotes Th17 responses during intestinal bacterial infection

Cited by 34 publications

References 40 publications

Effects of GABA Supplementation on Intestinal SIgA Secretion and Gut Microbiota in the Healthy and ETEC-Infected Weanling Piglets

Effects of GABA Supplementation on Intestinal SIgA Secretion and Gut Microbiota in the Healthy and ETEC-Infected Weanling Piglets

Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity

Serine Supports IL-1β Production in Macrophages Through mTOR Signaling

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