J Neurogastroenterol Motil.  2022 Apr;28(2):173-184. 10.5056/jnm21002.

Pathophysiological Commonality Between Irritable Bowel Syndrome and Metabolic Syndrome: Role of Corticotropin-releasing Factor–Toll-like Receptor 4–Proinflammatory Cytokine Signaling

• Nozu T
• Okumura T

• KMID: 2528032
• DOI: http://doi.org/10.5056/jnm21002

Abstract

Irritable bowel syndrome (IBS) displays chronic abdominal pain with altered defecation. Most of the patients develop visceral hypersensitivity possibly resulting from impaired gut barrier and altered gut microbiota. We previously demonstrated that colonic hyperpermeability with visceral hypersensitivity in animal IBS models, which is mediated via corticotropin-releasing factor (CRF)–Tolllike receptor 4 (TLR4)–proinflammatory cytokine signaling. CRF impairs gut barrier via TLR4. Leaky gut induces bacterial translocation resulting in dysbiosis, and increases lipopolysaccharide (LPS). Activation of TLR4 by LPS increases the production of proinflammatory cytokines, which activate visceral sensory neurons to induce visceral hypersensitivity. LPS also activates CRF receptors to further increase gut permeability. Metabolic syndrome (MS) is a cluster of cardiovascular risk factors, including insulin resistance, obesity, dyslipidemia, and hypertension, and recently several researchers suggested the possibility that impaired gut barrier and dysbiosis with low-grade systemic inflammation are involved in MS. Moreover, TLR4–proinflammatory cytokine contributes to the development of insulin resistance and obesity. Thus, the existence of pathophysiological commonality between IBS and MS is expected. This review discusses the potential mechanisms of IBS and MS with reference to gut barrier and microbiota, and explores the possibility of existence of a pathophysiological link between these diseases with a focus on CRF, TLR4, and proinflammatory cytokine signaling. We also review epidemiological data supporting this possibility, and discuss the potential of therapeutic application of the drugs used for MS to IBS treatment. This notion may pave the way for exploring novel therapeutic approaches for these disorders.

Keyword

Gut barrier; Irritable bowel syndrome; Metabolic syndrome; Microbiota; Toll-like receptor 4