Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis

Sun, Mingming; Wu, Wei; Chen, Liang; Yang, Wenjing; Huang, Xiangsheng; Ma, Cong; Chen, Feidi; Xiao, Yi; Zhao, Ye; Ma, Chunyan; Yao, Suxia; Carpio, Victor H.; Dann, Sara M.; Zhao, Qihong; Liu, Zhanju; Cong, Yingzi

doi:10.1038/s41467-018-05901-2

Cited by 418 publications

(322 citation statements)

References 51 publications

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“…163 Intestine-derived SCFAs also support Treg cell generation in non-lymphoid tissues. [164][165][166] Dietary LCFAs alter the composition of the gut microbiome. 167 Further, LCFAs enhance Th1 and Th17 cell differentiation whereas SCFAs promote Treg cell formation, 168 demonstrating unique phenotypes driven by different fatty acids.…”

Section: Lipid and Cholesterol Synthesismentioning

confidence: 99%

Signaling networks in immunometabolism

Saravia¹,

Raynor²,

Chapman³

et al. 2020

Cell Res

154

136

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Adaptive immunity is essential for pathogen and tumor eradication, but may also trigger uncontrolled or pathological inflammation. T cell receptor, co-stimulatory and cytokine signals coordinately dictate specific signaling networks that trigger the activation and functional programming of T cells. In addition, cellular metabolism promotes T cell responses and is dynamically regulated through the interplay of serine/threonine kinases, immunological cues and nutrient signaling networks. In this review, we summarize the upstream regulators and signaling effectors of key serine/threonine kinase-mediated signaling networks, including PI3K-AGC kinases, mTOR and LKB1-AMPK pathways that regulate metabolism, especially in T cells. We also provide our perspectives about the pending questions and clinical applicability of immunometabolic signaling. Understanding the regulators and effectors of immunometabolic signaling networks may uncover therapeutic targets to modulate metabolic programming and T cell responses in human disease.

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Section: Lipid and Cholesterol Synthesismentioning

confidence: 99%

Signaling networks in immunometabolism

Saravia¹,

Raynor²,

Chapman³

et al. 2020

Cell Res

154

136

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“…Short chain fatty acids (SCFA) produced by gut commensal microbes induce functional colonic Tregs and protect against T cell-dependent experimental colitis (24,32). Depending on the cytokine environment and immunological context, butyrate, acetate, and propionate, the most available SCFA in the gut, can also support IL-10 expression in Th1 and Th17 effector cells, thereby inhibiting colitis caused by pathogenic T cells (33,34). We show herein that SCFA induce RORγt expression in in vitro differentiated Tregs in a c-Maf-dependent and independent manner.…”

Section: Discussionmentioning

confidence: 99%

Multiple Environmental Signaling Pathways Control the Differentiation of RORγt-Expressing Regulatory T Cells

et al. 2020

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RORγt-expressing Tregs form a specialized subset of intestinal CD4 + Foxp3 + cells which is essential to maintain gut homeostasis and tolerance to commensal microbiota. Recently, c-Maf emerged as a critical factor in the regulation of RORγt expression in Tregs. However, aside from c-Maf signaling, the signaling pathways involved in the differentiation of RORγt + Tregs and their possible interplay with c-Maf in this process are largely unknown. We show that RORγt + Treg development is controled by positive as well as negative signals. Along with c-Maf signaling, signals derived from a complex microbiota, as well as IL-6/STAT3-and TGF-β-derived signals act in favor of RORγt + Treg development. Ectopic expression of c-Maf did not rescue RORγt expression in STAT3-deficient Tregs, indicating the presence of additional effectors downstream of STAT3. Moreover, we show that an inflammatory IFN-γ/STAT1 signaling pathway acts as a negative regulator of RORγt + Treg differentiation in a c-Maf independent fashion. These data thus argue for a complex integrative signaling network that finely tunes RORγt expression in Tregs. The finding that type 1 inflammation impedes RORγt + Treg development even in the presence of an active IL-6/STAT3 pathway further suggests a dominant negative effect of STAT1 over STAT3 in this process.

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“…Mechanistically, SCFAs favor the expression of B lymphocyteinduced maturation protein 1 (Blimp-1) in Th1 cells by activating STAT3 and mTOR pathways, thereby accelerating IL-10 generation by Th1 cells and alleviating colitis in mice. 64 Moreover, butyrate-induced IL-10 production is also modulated by Blimp-1 during Th1 cell differentiation. 65 Butyrate signals through GPR41 and GPR43 to accelerate the metabolism of antigen-activated CD8 + T cells, thereby enhancing their memory potential.…”

Section: Microbial Metabolite-mediated Modulation Of Host Immunity Anmentioning

confidence: 99%

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

Zhang

Tang

Chen

et al. 2019

Sig Transduct Target Ther

184

151

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The trillions of microorganisms in the gut microbiome have attracted much attention recently owing to their sophisticated and widespread impacts on numerous aspects of host pathophysiology. Remarkable progress in large-scale sequencing and mass spectrometry has increased our understanding of the influence of the microbiome and/or its metabolites on the onset and progression of extraintestinal cancers and the efficacy of cancer immunotherapy. Given the plasticity in microbial composition and function, microbial-based therapeutic interventions, including dietary modulation, prebiotics, and probiotics, as well as fecal microbial transplantation, potentially permit the development of novel strategies for cancer therapy to improve clinical outcomes. Herein, we summarize the latest evidence on the involvement of the gut microbiome in host immunity and metabolism, the effects of the microbiome on extraintestinal cancers and the immune response, and strategies to modulate the gut microbiome, and we discuss ongoing studies and future areas of research that deserve focused research efforts.

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Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis

Cited by 418 publications

References 51 publications

Signaling networks in immunometabolism

Signaling networks in immunometabolism

Multiple Environmental Signaling Pathways Control the Differentiation of RORγt-Expressing Regulatory T Cells

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

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