Dietary Capsaicin Improves Metabolic Profile Through A Gut Microbiota-dependent Manner

Accumulating evidence suggest that chronic low-grade inflammation?CLGI?is central to the pathogenesis of obesity,which is considered a global public health problem,and linked with several complications including insulin resistance.Systemic CLGI is identified by elevated circulating levels of inflammatory cytokines.It is well-known that systemic CLGI damages pancreatic beta cells,disrupts insulin action and mediates glucose intolerance in obesity.Metabolic endotoxemia has been shown to be the primary contributor to the pathogenesis of CLGI,characterized by the increased plasma bacterial lipopolysaccharide?LPS?levels which are believed to originate from Gram-negative gut microbiome that spill into the systemic circulation as a direct result of gut barrier dysfunction.Diet is the most important factor that determines the gut microbiota composition.High-fat diet-induced obesity-promoting altered microbiome and resultant gut barrier disintegration have been implicated as key factors facilitating metabolic endotoxemia.Altered gut microbiota composition?e.g.increased abundance of LPS-producing bacteria?and/or function?e.g.changes in LPS biosynthesis and short chain fatty acids production?are key factors affecting the gut barrier integrity.Thus many efforts have been made to modify the metabolic endotoxemia through dietary interventions,which could be the promising way to prevent obesity and related diseases.Capsaicin?CAP?is the active and pungent ingredient of chili peppers,which are widely used in the cuisines around the world.Accumulating laboratory studies suggests that CAP has beneficial effects in controlling obesity,cardiovascular disease and cancer,which has lead to an increased focus on its pharmacological properties and clinical application.However,previous studies have yielded inconsistent results when evaluating the above effects in human.In addition,capsaicin has an inhibitory effect to pathogenic bacteria,such as Escherichia coli,and promote the growth of the probiotic bacteria such as Lactobacillus and Bifidobacterium.Until now,only one study showed that CAP intervention enriched the abundances of gut Prevotella,Lactobacillus and Akkermansia in mice using q PCR approach,while the overall impact of CAP on gut microbial ecology is still poorly understood.Based on the above researches,we aim to determine whether the beneficial metabolic effects of dietary CAP are mediated through the gut microbiota remodeling and examine how the molecular mechanisms involved in the interactions between dietary CAP and the gut microbiota influence the systemic low-grade inflammation.This study was first designed to evaluate the impact of dietary CAP on the metabolic and inflammatory profiles and gut microbial ecology of healthy subjects consuming a 6-week controlled diet by 16 S r RNA gene sequencing,and further assess the association between CAP effects and gut enterotypes.Then,the fecal microbiota transplantation experiments were conducted in germ-free mice to demonstrated whether dietary CAP-induced protection against HFD-induced obesity is transferrable.Moreover,microbiota depletion by a cocktail of antibiotics was used to detect whether it is sufficient to block CAP-induced protective phenotype against obesity.The main results and conclusions of this study are as follows:1.Healthy subjects differentially respond to dietary capsaicin correlating with the specific gut enterotypesAlthough gut microbiota in healthy adult is relatively stable,but 10 mg/d of capsaicin intervention for 2 weeks,can increase the relative abundance of the SCFAs producing bacteria,such as Faecalibacteria?P <0.05?,while promoting the plasma levels of gastrointestinal hormones,sucha as ghrelin,GIP and GLP-1?P <0.05?.Here,Bacteroides?E1?and Prevotella?E2?enterotypes were observed in our study.Furthermore,we found that dietary CAP had better improving effects on the plasma ghrelin,GIP and GLP-1 concentrations in E1 subjects although both E1 and E2 subjects responded to the CAP interventions.Furthermore,high CAP interventions significantly increased the concentrations of fecal butyrate only in E1 group,which plays important roles in protecting mucosal barrier function and stimulating the secretions of GI hormones2.The anti-obesity effect of dietary capsaicin is mediated through the improvement of the gut barrier function.A high-fat diet decreased the expression of intestinal tight junction proteins Occludin and ZO-1,increased intestinal permeability,while a higher plasma level of LPS,chronic low-grade inflammation and impaired glucose tolerance were observed.Dietary capsaicin can improve the gut barrier function and decrease intestinal permeability and improve bacterial translocation,metabolic endotoxemia,chronic low-grade inflammation and impaired glucose tolerance in high-fat diet-induced obesity mice.3.Gut microbiota plays an important role in anti-obesity effect of dietary capsaicinDietary intestines of mice capsaicin can significantly increase the relative abundance of the SCFAs producing bacteria,such as Lachnospiraceae and Ruminococcaceae?P < 0.05?.It caused lower levels of Lipopolysaccharide?LPS?-producing family S24₇.Predicted function analysis showed depletion of genes involved in bacterial LPS synthesis in response to CAP.The anti-obesity and microbiota-modulating effects were abolished by antibiotics and transmitted via horizontal feces transfer from CAP-treated mice to HFD-fed mice.These results showed that the gut microbiota is a key regulator in anti-obesity effect of capsaicin.4.The endocannabinoid system also contributes to prevention of HFD-induced gut barrier dysfunctionDietary capsaicin significantly increased the expression of Cannabinoid receptor 1?CB1?in colon.CB1 agonist can prevent beneficial metabolic effects of dietary capsaicin,induced bacteria translocation,metabolic endotoxemia,chronic low-grade inflammation,impaired glucose tolerance and weight gain.These results showed that the CB1 inhibition is partially mediated in the beneficial metabolic effects of CAP.In summary,this is the first study to systematically evaluate the impact of CAP on human gut microbiota linking with the metabolic and inflammation profiles.And our study showed that gut enterotypes may influence the beneficial effects of dietary CAP.High-throughput 16 S r RNA gene sequencing revealed that CAP significantly 28 increased butyragenic bacteria,decreased LPS-producing bacteria?e.g.S24-7 family?and LPS biosynthesis.By using antibiotics and microbiota transplantation,we proved that gut microbiota plays a causal role in dietary CAP–induced protective phenotype against high-fat diet-induced chronic low-grade inflammation and obesity.Moreover,CB1 inhibition was partially involved in the beneficial effect of CAP.Together,these data suggest that gut microbiome is a critical factor for the anti-obesity effects of CAP,providing a new evidence for the personalized nutrition guidance of CAP intervention on health promotion linking with gut microbiota patterns.