Gut Microbiota Mediates the Protective Effects of Dietary Capsaicin against Chronic Low-Grade Inflammation and Associated Obesity Induced by High-Fat Diet

Abstract

Metabolic endotoxemia originating from dysbiotic gut microbiota has been identified as a primary mediator for triggering the chronic low-grade inflammation (CLGI) responsible for the development of obesity. Capsaicin (CAP) is the major pungent bioactivator in chili peppers and has potent anti-obesity functions, yet the mechanisms linking this effect to gut microbiota remain obscure. Here we show that mice fed a high-fat diet (HFD) supplemented with CAP exhibit lower levels of metabolic endotoxemia and CLGI associated with lower body weight gain. High-resolution responses of the microbiota were examined by 16S rRNA sequencing, short-chain fatty acid (SCFA) measurements, and phylogenetic reconstruction of unobserved states (PICRUSt) analysis. The results showed, among others, that dietary CAP induced increased levels of butyrate-producing Ruminococcaceae and Lachnospiraceae, while it caused lower levels of members of the lipopolysaccharide (LPS)-producing family S24_7. Predicted function analysis (PICRUSt) showed depletion of genes involved in bacterial LPS synthesis in response to CAP. We further identified that inhibition of cannabinoid receptor type 1 (CB1) by CAP also contributes to prevention of HFD-induced gut barrier dysfunction. Importantly, fecal microbiota transplantation experiments conducted in germfree mice demonstrated that dietary CAP-induced protection against HFD-induced obesity is transferrable. Moreover, microbiota depletion by a cocktail of antibiotics was sufficient to block the CAP-induced protective phenotype against obesity, further suggesting the role of microbiota in this context. Together, our findings uncover an interaction between dietary CAP and gut microbiota as a novel mechanism for the anti-obesity effect of CAP acting through prevention of microbial dysbiosis, gut barrier dysfunction, and chronic low-grade inflammation.

SIRT3 Deficiency Promotes High‐Fat Diet‐Induced Nonalcoholic Fatty Liver Disease in Correlation with Impaired Intestinal Permeability through Gut Microbial Dysbiosis

“…The blood samples were collected after 4 h and then centrifuged at 6,000 × rpm for 10 min at 4 °C. The serum was diluted with the same volume of PBS and analyzed for FITC‐dextran with a SpectraMax M2 microplate reader (Molecular Devices, USA) which with an excitation wavelength at 485 nm and an emission wavelength at 535 nm as previously described . Standard curves were used for calculating the samples FITC‐dextran concentration through a serial dilution of FITC‐dextran in PBS (0 ≈ 12.5 µg mL −1 ).…”

“…Liver homogenates were obtained by a tissue homogenizer (IKA, Germany). According to the manufacturer's protocol, Limulus amebocyte lysate reagents were added to plasma and liver homogenates . All of the samples were tested in duplicate, and optical density values were measured using a SpectraMax M2 microplate reader (Molecular Devices, USA) at a wavelength of 545 nm.…”

“…Moreover, lipopolysaccharide (LPS) could be produced by the gut microbiota and through a dysfunctional intestinal barrier, this LPS can reach the systemic circulation and thus the liver, resulting in liver inflammation and damage . Short‐chain fatty acids (SCFA), including butyrate, propionate, and acetate, derived from the bacterial degradation of complex polysaccharides in the intestine, are key factors affecting the gut barrier integrity . It was reported that sodium butyrate (NaB) attenuates high‐fat diet (HFD)‐induced steatohepatitis in mice by improving gut microbiota and intestinal barrier .…”

“…The hepatic ECS is activated in numerous liver diseases, such as NAFLD, and is linked to potential pathologies through modulation of intestinal permeability via the expression of cannabinoid receptors, such as CB1 . The administration of a CB1 agonist enhanced LPS‐induced decreases in the expression of mRNA for gut tight junction proteins, such as zonula occludens‐1 (ZO‐1) and occludin, which are associated with gut permeability . Interestingly, treatment with a CB1 antagonist was accompanied by a decrease in intestinal permeability in humans .…”

Microbiota in obesity: interactions with enteroendocrine, immune and central nervous systems

“…HFD‐induced obesity in mice is accompanied by an increase in bacteria of the family Lachnospiraceae . In contrast, Kang and colleagues showed that the anti‐obesity effects of capsaicin could be partially mediated through an increased abundance of Lachnospiraceae in HFD‐fed mice. Moreover, Menni and colleagues found a lower long‐term weight gain associated with this family in humans.…”