Intestinal Barrier Dysfunction Exacerbates Neuroinflammation via the TLR4 Pathway in Mice With Heart Failure

Abstract

AimsThe present study aimed to investigate alterations in neuroinflammation after heart failure (HF) and explore the potential mechanisms.MethodsMale wild-type (WT) and Toll-like receptor 4 (TLR4)-knockout (KO) mice were subjected to sham operation or ligation of the left anterior descending coronary artery to induce HF. 8 weeks later, cardiac functions were analyzed by echocardiography, and intestinal barrier functions were examined by measuring tight junction protein expression, intestinal permeability and plasma metabolite levels. Alterations in neuroinflammation in the brain were examined by measuring microglial activation, inflammatory cytokine levels and the proinflammatory signaling pathway. The intestinal barrier protector intestinal alkaline phosphatase (IAP) and intestinal homeostasis inhibitor L-phenylalanine (L-Phe) were used to examine the relationship between intestinal barrier dysfunction and neuroinflammation in mice with HF.ResultsEight weeks later, WT mice with HF displayed obvious increases in intestinal permeability and plasma lipopolysaccharide (LPS) levels, which were accompanied by elevated expression of TLR4 in the brain and enhanced neuroinflammation. Treatment with the intestinal barrier protector IAP significantly attenuated neuroinflammation after HF while effectively increasing plasma LPS levels. TLR4-KO mice showed significant improvements in HF-induced neuroinflammation, which was not markedly affected by intestinal barrier inhibitors or protectors.ConclusionHF could induce intestinal barrier dysfunction and increase gut-to-blood translocation of LPS, which could further promote neuroinflammation through the TLR4 pathway.

Circulating Lipopolysaccharides and Impaired Antioxidant Status in Patients With Atrial Fibrillation. Data From the ATHERO-AF Study

“…Thus, HF is associated with gut barrier dysfunction resulting in an increased LPS translocation into systemic circulation ( 20 ). Also in this case, TLR4 knockout mice had lower inflammation, confirming the role of LPS-TLR4 interaction as an important mechanism contributing to systemic inflammation ( 21 ).…”

Helicobacter pylori and Alzheimer’s Disease-Related Metabolic Dysfunction: Activation of TLR4/Myd88 Inflammation Pathway from p53 Perspective and a Case Study of Low-Dose Radiation Intervention

“…IHC detection indicated occludin and ZO-1, which function to protect intestinal permeability, as decreased in mice transplanted with AD and AD + MD mice feces compared to the Con group (Figure E–G). IHC scores for TLR4 and Myd88, which activate the inflammation-related signaling pathway and are typically associated with metabolic dysfunction, increased in mice transplanted with AD and AD + MD mice feces (Figure H,I). Thus, increased H. pylori colonization is associated with increased AD-induced metabolic dysfunction, potentially aided by increased gut permeability through activation of the TLR4-Myd88 signaling pathway.…”

Role of Intestinal Alkaline Phosphatase in Innate Immunity

“…Intestine-specific transgenic overexpression of IAP in IAP Tg mice improved intestinal barrier function as measured by FITC-dextran levels in plasma as well as reversed the reduction in fecal zonulin in WD-fed mice [ 21 ]. IAP supplementation also attenuated neuroinflammation in a mice model of heart failure (HF) including reducing intestinal barrier permeability, decreasing plasma LPS levels, and increasing protein levels of tight junction proteins in HF mice [ 22 ]. Treatment with L-phenylalanine, an inhibitor of IAP activity, abrogated the protective effects of IAP in HF mice.…”

“…Danielak et al showed that supplementation of IAP in combination with voluntary exercise caused a reduced expression of proinflammatory cytokines TNF-α, IL-1 β, and IL-6 in a colitis mouse model fed with standard diet (SD) or high-fat diet (HFD) [ 27 ]. In another study, oral IAP reduced TNF-α and IL-6 in brains of mice mode of heart failure [ 22 ]. IAP ameliorated colitis in mice and inhibited LPS-induced IL-6 and TNF-α production [ 28 ].…”