Nozu Tsukasa, Okumura Toshikatsu
Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Center for Medical Education, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
J Neurogastroenterol Motil. 2022 Apr 30;28(2):173-184. doi: 10.5056/jnm21002.
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)-Toll-like 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.
肠易激综合征（IBS）表现为慢性腹痛伴排便习惯改变。大多数患者会出现内脏高敏感性，这可能是由于肠道屏障受损和肠道微生物群改变所致。我们之前证明，在动物IBS模型中，结肠高通透性与内脏高敏感性有关，其通过促肾上腺皮质激素释放因子（CRF）-Toll样受体4（TLR4）-促炎细胞因子信号传导介导。CRF通过TLR4损害肠道屏障。肠道渗漏会导致细菌易位，从而引起生态失调，并增加脂多糖（LPS）。LPS激活TLR4会增加促炎细胞因子的产生，促炎细胞因子会激活内脏感觉神经元，从而诱发内脏高敏感性。LPS还会激活CRF受体，进一步增加肠道通透性。代谢综合征（MS）是一组心血管危险因素，包括胰岛素抵抗、肥胖、血脂异常和高血压，最近有几位研究人员提出，肠道屏障受损和伴有低度全身炎症的生态失调可能与MS有关。此外，TLR4-促炎细胞因子有助于胰岛素抵抗和肥胖的发展。因此，预计IBS和MS之间存在病理生理共性。本综述参考肠道屏障和微生物群讨论了IBS和MS的潜在机制，并探讨了这些疾病之间存在病理生理联系的可能性，重点关注CRF、TLR4和促炎细胞因子信号传导。我们还综述了支持这一可能性的流行病学数据，并讨论了用于MS治疗的药物在IBS治疗中的潜在应用。这一观点可能为探索这些疾病的新治疗方法铺平道路。
