From gut to blood: barrier dysfunction as a driver of systemic low-grade inflammation in cardiometabolic disease

Abstract

Chronic, low-grade inflammation is increasingly recognized as a fundamental driver of noncommunicable diseases—including obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and neurodegeneration—yet the initiating events remain incompletely understood. Accumulating evidence implicates gut barrier dysfunction and bacterial translocation as pivotal mechanisms linking environmental and metabolic stressors to systemic inflammation. Mechanistically, obesity-associated depletion of typically beneficial taxa (e.g., Faecalibacterium, Roseburia, Akkermansia muciniphila) and enrichment of proinflammatory Enterobacteriaceae reduce expression of tight junction proteins—including, occludin, claudins, and zonula occludens-1 (ZO-1)—and increase the vascular permeability marker, plasmalemma vesicle-associated protein (PV-1). Combined with diminished secretion of host defense peptides (e.g., Reg3γ, lysozyme) and mucus thinning, these changes facilitate LPS-driven activation of Toll-like receptor (TLR)4 and downstream cytokines. We integrate preclinical and clinical data demonstrating how these processes propagate systemic inflammation via the gut-liver and gut-vascular axes, contributing to MASLD, insulin resistance, and vascular dysfunction. Finally, we highlight emerging interventions aimed at restoring barrier integrity—ranging from short-chain fatty acid (SCFA) supplementation and Glucagon-like peptide-2 (GLP-2) receptor agonists to host defense peptide-based therapies—and discuss methodological advances for assessing gut permeability in vivo. Understanding the gut as a dynamic interface between host and environment, and its crucial role in mediating inflammation, will be pivotal for the development of effective interventions targeting the global epidemic of obesity-related disease.

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