High Fat Diet-Induced Gut Microbiota Exacerbates Inflammation and Obesity in Mice via the TLR4 Signaling Pathway

Abstract

Background & AimsWhile it is widely accepted that obesity is associated with low-grade systemic inflammation, the molecular origin of the inflammation remains unknown. Here, we investigated the effect of endotoxin-induced inflammation via TLR4 signaling pathway at both systemic and intestinal levels in response to a high-fat diet.MethodsC57BL/6J and TLR4-deficient C57BL/10ScNJ mice were maintained on a low-fat (10 kcal % fat) diet (LFD) or a high–fat (60 kcal % fat) diet (HFD) for 8 weeks.ResultsHFD induced macrophage infiltration and inflammation in the adipose tissue, as well as an increase in the circulating proinflammatory cytokines. HFD increased both plasma and fecal endotoxin levels and resulted in dysregulation of the gut microbiota by increasing the Firmicutes to Bacteriodetes ratio. HFD induced the growth of Enterobecteriaceae and the production of endotoxin in vitro. Furthermore, HFD induced colonic inflammation, including the increased expression of proinflammatory cytokines, the induction of Toll-like receptor 4 (TLR4), iNOS, COX-2, and the activation of NF-κB in the colon. HFD reduced the expression of tight junction-associated proteins claudin-1 and occludin in the colon. HFD mice demonstrated higher levels of Akt and FOXO3 phosphorylation in the colon compared to the LFD mice. While the body weight of HFD-fed mice was significantly increased in both TLR4-deficient and wild type mice, the epididymal fat weight and plasma endotoxin level of HFD-fed TLR4-deficient mice were 69% and 18% of HFD-fed wild type mice, respectively. Furthermore, HFD did not increase the proinflammatory cytokine levels in TLR4-deficient mice.ConclusionsHFD induces inflammation by increasing endotoxin levels in the intestinal lumen as well as in the plasma by altering the gut microbiota composition and increasing its intestinal permeability through the induction of TLR4, thereby accelerating obesity.

Polygala tenuifolia extract inhibits lipid accumulation in 3T3-L1 adipocytes and high-fat diet–induced obese mouse model and affects hepatic transcriptome and gut microbiota profiles

“…These changes in gut microbiota profiles were similar to the evidence presented in previous reports for treating obesity with prebiotics (oligofructose) and antibiotics (vancomycin or penicillin) [64,65]. Furthermore, PTE treatment caused a reduction in both Lachnospiraceae and Ruminococcaceae populations, which positively correlate with obesity, in subjects fed a HFD [66,67]. In addition, PTE treatment restored the HFD-mediated reduction in the S24-7 population (a Bacteroidetes phylum), an effect also observed when subjects’ physical activity levels are increased [68].…”

Innate immunity in diabetes and diabetic nephropathy

“…Similarly, Tlr4 -/-mice fed a HFD demonstrated reduced intestinal permeability, increased plasma endotoxin and proinflammatory cytokine levels, and increased epididymal fat weight 84 . Interestingly, chronic intake of a HFD leads to severe pulmonary damage and mortality in Tlr2 -/-Tlr4 -/-mice 85 , suggesting that diet and innate immune deficiency have a strong impact on the composition of the gut microbiota, which can lead to life-threatening conditions.…”

Dietary coconut water vinegar for improvement of obesity-associated inflammation in high-fat-diet-treated mice

“…An increasing population ratio of the Blautia genus, in the phylum Firmicutes, to the Bacteroides genus, in the phylum Bacteroidetes, was commonly found in the gut microbiota of obese mice. This pattern of gut microbiota further promoted inflammation via induction of the toll-like receptor-4, iNOS, and NF-κB [38]. In this study, coconut water vinegar treatment significantly increased the population of Bacteroides without affecting the population of the Blautia genus in the HFD obese mice.…”

“…Chronic obesity has been correlated with the development of liver disease owing to prolonged, mild inflammation induced by obesity [36,37]. iNOS is an inflammatory mediator that promotes the production of reactive oxygen species, NO, and endogenous signalling molecules, which contribute towards prolonging mild systemic inflammation in the liver of HFD-fed obese mice [38], which subsequently contributes to the pathogenesis of HFD-induced insulin resistance [39]. Previous studies have shown that vinegar has an anti-inflammatory effect on paracetamol-induced liver damage in mice [19].…”

“…However, the role of Sarcina organisms in obese subjects remains unclear and is worth further evaluation. In addition, the changes in the gut microbiota may indirectly reduce inflammation in obese mice as it controls the population of the pathogenic microbes that produce the endotoxin that induces gut inflammation [38]. Hence, the anti-inflammatory effect of coconut water vinegar may also benefit from alterations in the gut microbes.…”