Short-chain fatty acids and intestinal macrophage immunometabolism in metabolic syndrome: mechanisms and implications for chronic low-grade inflammation
- 1Heilongjiang University of Chinese Medicine
Abstract
Chronic low-grade inflammation (CLGI) is a major feature of metabolic syndrome (MetS), and the intestinal mucosa is an important site where microbial metabolites interact with host immunity. Intestinal lamina propria macrophages (LpMs) maintain mucosal tolerance, barrier homeostasis, and antimicrobial defense, and their phenotype and metabolism are altered in obesity and related metabolic disturbances. Short-chain fatty acids (SCFAs), generated mainly by microbial fermentation of dietary fiber, influence macrophage function through intracellular metabolism, G protein-coupled receptor signaling, and histone deacetylase inhibition. Butyrate is the best-characterized SCFA in this context and regulates glycolysis, mTOR-associated metabolism, antimicrobial responses, and HDAC-dependent inflammatory programs. Acetate and propionate also affect inflammasome activity, cytokine production, receptor signaling, and cellular metabolism. These mechanisms connect microbial metabolism with intestinal inflammation, epithelial barrier function, and systemic metabolic homeostasis. In obesity and insulin resistance, colonic macrophage recruitment and metabolic remodeling are closely associated with disease progression, whereas macrophage-related effects in metabolic dysfunction-associated steatotic liver disease and hypertension involve broader gut–liver, vascular, and renal pathways. Human studies of dietary fiber, microbiota-directed interventions, and SCFA delivery show variable cardiometabolic effects, with outcomes influenced by formulation, route, and baseline metabolic state. Given that most current mechanisms are derived from extraintestinal macrophages and in situ evidence from the human gut remains scarce, this narrative review summarizes the homeostatic biology of intestinal macrophages, the pathways through which SCFAs regulate their immunometabolism, the context-dependent relevance of this axis across MetS components, and the barriers to clinical translation.
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BibTeX
@article{ma2026shortchain,
title = {{Short-chain fatty acids and intestinal macrophage immunometabolism in metabolic syndrome: mechanisms and implications for chronic low-grade inflammation}},
author = {Jiaxin Ma and Chen Li and Hongjun Lou},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.2000672},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.2000672/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Short-chain fatty acids and intestinal macrophage immunometabolism in metabolic syndrome: mechanisms and implications for chronic low-grade inflammation
AU - Jiaxin Ma
AU - Chen Li
AU - Hongjun Lou
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.2000672
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.2000672/full
AB - Chronic low-grade inflammation (CLGI) is a major feature of metabolic syndrome (MetS), and the intestinal mucosa is an important site where microbial metabolites interact with host immunity. Intestinal lamina propria macrophages (LpMs) maintain mucosal tolerance, barrier homeostasis, and antimicrobial defense, and their phenotype and metabolism are altered in obesity and related metabolic disturbances. Short-chain fatty acids (SCFAs), generated mainly by microbial fermentation of dietary fiber, influence macrophage function through intracellular metabolism, G protein-coupled receptor signaling, and histone deacetylase inhibition. Butyrate is the best-characterized SCFA in this context and regulates glycolysis, mTOR-associated metabolism, antimicrobial responses, and HDAC-dependent inflammatory programs. Acetate and propionate also affect inflammasome activity, cytokine production, receptor signaling, and cellular metabolism. These mechanisms connect microbial metabolism with intestinal inflammation, epithelial barrier function, and systemic metabolic homeostasis. In obesity and insulin resistance, colonic macrophage recruitment and metabolic remodeling are closely associated with disease progression, whereas macrophage-related effects in metabolic dysfunction-associated steatotic liver disease and hypertension involve broader gut–liver, vascular, and renal pathways. Human studies of dietary fiber, microbiota-directed interventions, and SCFA delivery show variable cardiometabolic effects, with outcomes influenced by formulation, route, and baseline metabolic state. Given that most current mechanisms are derived from extraintestinal macrophages and in situ evidence from the human gut remains scarce, this narrative review summarizes the homeostatic biology of intestinal macrophages, the pathways through which SCFAs regulate their immunometabolism, the context-dependent relevance of this axis across MetS components, and the barriers to clinical translation.
SN - 1664-3224
ER -