Microbial metabolites, short‐chain fatty acids, restrain tissue bacterial load, chronic inflammation, and associated cancer in the colon of mice

Abstract

The intestinal immune system is regulated by microbes and their metabolites. The roles of gut microbial metabolites in regulating intestinal inflammation and tumorigenesis are incompletely understood. We systematically studied the roles of short-chain fatty acids (SCFAs) and their receptors (GPR43 or GPR41) in regulating tissue bacterial load, acute versus chronic inflammatory responses, and intestinal cancer development. SCFA receptor-, particularly GPR43-, deficient mice were defective in mounting appropriate acute immune responses to promote barrier immunity, and developed uncontrolled chronic inflammatory responses following epithelial damage. Further, intestinal carcinogenesis was increased in GPR43-deficient mice. Dietary fiber and SCFA administration suppressed intestinal inflammation and cancer in both GPR43-dependent and independent manners. The beneficial effect of GPR43 was not mediated by altered microbiota but by host tissue cells and hematopoietic cells to a lesser degree. We found that inability to suppress commensal bacterial invasion into the colonic tissue is associated with the increased chronic Th17-driven inflammation and carcinogenesis in the intestine of GPR43-deficient mice. In sum, our results reveal the beneficial function of the SCFA-GPR43 axis in suppressing bacterial invasion and associated chronic inflammation and carcinogenesis in the colon.

Modulatory effect of Lactobacillus acidophilus KLDS 1.0738 on intestinal short‐chain fatty acids metabolism and GPR41/43 expression in β‐lactoglobulin–sensitized mice

“…30 Kim et al reported that GPR43-deficient mice had exacerbated inflammation along with increased frequencies of Th17 cells in animal models of colitis. 31 Similarly, the present study found that administration of butyrate or L. acidophilus both enhanced the expression of GPR41 and GPR43 in the colon and lung in β-Lg allergic mice, along with decreasing IL-4, IL-6, and IL-17 and increasing IFN-γ and TGF-β levels. Importantly, F I G U R E 7 Effect of Lactobacillus acidophilus KLDS 1.0738 on G-protein-coupled receptor 41 (GPR41) and GPR43 mRNA in (a) colon and (b) spleen tissue of β-Lg-sensitized mice.…”

“…Chang et al suggested that the GPR41/43 activated by SCFAs had an important function in the differentiation and/or activation of T lymphocytes . Kim et al reported that GPR43‐deficient mice had exacerbated inflammation along with increased frequencies of Th17 cells in animal models of colitis . Similarly, the present study found that administration of butyrate or L. acidophilus both enhanced the expression of GPR41 and GPR43 in the colon and lung in β‐Lg allergic mice, along with decreasing IL‐4, IL‐6, and IL‐17 and increasing IFN‐γ and TGF‐β levels.…”

The microbiota and immune‐mediated diseases: Opportunities for therapeutic intervention

“…The receptors for SCFA, GPR43, or GPR41 are expressed on epithelial cells, macrophages, and dendritic cells (DCs). Mice deficient in GPR43 were unable to suppress commensal bacterial invasion into colonic tissue and develop chronic Th17‐driven inflammation and intestinal carcinogenesis [32]. Butyrate a SCFA produced by commensal bacteria has anti‐inflammatory properties, stimulating DCs to induce tolerogenic responses in naïve T cells.…”

Association of Bacteroides acidifaciens relative abundance with high-fibre diet-associated radiosensitisation

“…Dietary fibre manipulation can very rapidly alter the human gut microbiome, with changes in faecal short chain fatty acid (SCFA) levels seen only one day after the diet reaches the distal gut (6). Dietary fibre can also mediate systemic immune effects (7), as can the microbiota-derived SCFAs (8,9). Furthermore, dietary fibre structures align with phenotypes of specific microbes that differ in their metabolic pathways (10).…”

“…Furthermore, dietary fibre structures align with phenotypes of specific microbes that differ in their metabolic pathways (10). SCFAs are known to confer anti-cancer effects (5,8,9). Other metabolites, including small intermediate and end byproducts of endogenous metabolic pathways, products of microbe-host co-metabolism and exogenous signals arising from diet, drugs and other environmental stimuli might also be important (11).…”