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 non-communicable 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 ZO-1 – and increase the vascular permeability marker, PV-1. Combined with diminished secretion of host defense peptides (e.g., Reg3γ, lysozyme) and mucus thinning, these changes facilitate LPS-driven activation of TLR4 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 SCFA supplementation and 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.