Gut microbiota–derived short‐chain fatty acids regulate group 3 innate lymphoid cells in HCC

Abstract

Background and Aims: Type 3 innate lymphoid cells (ILC3s) are essential for host defense against infection and tissue homeostasis. However, their role in the development of HCC has not been adequately confirmed. In this study, we investigated the immunomodulatory role of short-chain fatty acids (SCFAs) derived from intestinal microbiota in ILC3 regulation.Approach and Results: We report that Lactobacillus reuteri was markedly reduced in the gut microbiota of mice with HCC, accompanied by decreased SCFA levels, especially acetate. Additionally, transplantation of fecal bacteria from wild-type mice or L. reuteri could promote an anticancer effect, elevate acetate levels, and reduce IL-17A secretion in mice with HCC.Mechanistically, acetate reduced the production of IL-17A in hepatic ILC3s by inhibiting histone deacetylase activity, increasing the acetylation of SRY

The crosstalk between the gut microbiota and tumor immunity: Implications for cancer progression and treatment outcomes

“…IL-17A was reported to induce tumor angiogenesis ( 87 , 88 ). Consistently, HCC mice displayed a robust increase in IL-17A expression in hepatic type 3 innate lymphoid cells (ILC3s) ( 58 ). Moreover, tumor-infiltrating ILC3s were a poor prognosis factor in HCC patients.…”

“…It is not surprising that the gut microbiota regulates the development of liver cancer. The relative abundance of Lactobacillus reuteri was decreased in hepatocellular carcinoma (HCC)-bearing mice compared with control mice ( 58 ). HCC mice displayed a substantial reduction in the serum concentration of microbial metabolites including acetate and valerate.…”

Amelioratory Effect of Resistant Starch on Non-alcoholic Fatty Liver Disease via the Gut-Liver Axis

“…Moreover, it has been found that the SCFAs pentanoate can reduce IL-17A production in CD4 + T cells by inhibiting histone deacetylase activity ( 55 ). Similarly, probiotics that synthesize SCFA, particularly acetate, are involved in reducing IL-17A in hepatic type 3 innate lymphoid cells (ILC3s) ( 56 ). It was also found that dietary intake of RS and decreased colonic IL-17A stimulate intestinal immune and endocrine responses that may alter liver health ( 48 ).…”

Drinking vinegar, a potential adjuvant for immunotherapy of HCC?

“…[7] Hu et al found that a pronounced reduction of L. reuteri was observed in carcinogen-induced primary HCC-bearing mice, whereas intestinal transplantation of L. reuteri exhibited significant antitumor immune response to curb HCC progression. [5] L. reuteri used a variety of monosaccharides and disaccharides to produce sodium acetate in a 6-phosphogluconate/ phosphoketolase pathway-dependent manner. [8] Hu et al suggested that intestinal L. reuteri-inhibited HCC progression was due to its metabolite sodium acetate, thus determining the mechanism in details.…”

“…Hu et al found that, after transplantation with gut microbiota from healthy mice or Lactobacillus reuteri (L. reuteri) to the carcinogen-induced primary HCC-bearing mice, the proportion of IL-17A + ILC3s in the liver was evidently decreased, leading to the reduced IL-17A production and suppressed HCC development, thus suggesting the tumor-promotive roles of hepatic ILC3s. [5] IL-17A is known to induce the secretion of chemokine (C-X-C motif) ligand 5 (CXCL5) by HCC cells and then recruit the infiltration of bone marrow-derived suppressor cells (MDSCs) through CXCL5/cysteine-X-cysteine receptor 2 axis, thus promoting MDSC activation, exacerbating tumor immunosuppression, and favoring HCC development. [4] Moreover, the findings by Hu et al also reveal that IL-17A-producing ILC3s can promote HSC activation and fibrosis progression.…”