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

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.