The gut microbiota regulates key hepatic functions, notably through the production of bacterial metabolites that are transported via the portal circulation. We evaluated the effects of metabolites produced by the gut microbiota from aromatic amino acids (phenylacetate, benzoate, p ‐cresol, and indole) on liver inflammation induced by bacterial endotoxin. Precision‐cut liver slices prepared from control mice, Kupffer cell (KC)‐depleted mice, and obese mice (ob/ob) were treated with or without LPS and bacterial metabolites. We observed beneficial effects of indole that dose‐dependently reduced the LPS‐induced up‐regulation of proinflammatory mediators at both mRNA and protein levels in precision‐cut liver slices prepared from control or ob/ob mice. KC depletion partly prevented the antiinflammatory effects of indole, notably through a reduction of nucleotide‐binding domain and leucine‐rich repeat containing (NLR) family pyrin domain‐containing 3 (NLRP3) pathway activation. In vivo , the oral administration of indole before an LPS injection reduced the expression of key proteins of the NF‐KB pathway and downstream proinflammatory gene up‐regulation. Indole also prevented LPS‐induced alterations of cholesterol metabolism through a transcriptional regulation associated with increased 4β‐hydroxycholesterol hepatic levels. In summary, indole appears as a bacterial metabolite produced from tryptophan that is able to counteract the detrimental effects of LPS in the liver. Indole could be a new target to develop innovative strategies to decrease hepatic inflammation.—Beaumont, M., Neyrinck, A. M., Olivares, M., Rodriguez, J., de Rocca Serra, A., Roumain, M., Bindels, L. B., Cani, P. D., Evenepoel, P., Muccioli, G. G., Demoulin, J.‐B., Delzenne, N. M. The gut microbiota metabolite indole alleviates liver inflammation in mice. FASEB J. 32, 6681–6693 (2018). www.fasebj.org

Purpose: Inulin-type fructans (ITF) are prebiotic dietary fibre (DF) that may confer beneficial health effects, by interacting with the gut microbiota. We have tested the hypothesis that a dietary intervention promoting inulin intakeversusplacebo influences fecal microbial-derived metabolites and markers related to gut integrity and inflammation in obese patients.Methods: Microbiota (16S rRNA sequencing), long- and short-chain fatty acids (LCFA, SCFA), bile acids, zonulin, and calprotectin were analyzed in fecal samples obtained from obese patients included in a randomized, placebo-controlled trial. Participants received either 16 g/d native inulin (prebioticn = 12)versusmaltodextrin (placebon = 12), coupled to dietary advice to consume inulin-richversusinulin-poor vegetables for 3 months, in addition to dietary caloric restriction.Results: Both placebo and prebiotic interventions lowered energy and protein intake. A substantial increase inBifidobacteriumwas detected after ITF treatment (q = 0.049) supporting our recent data obtained in a larger cohort. Interestingly, fecal calprotectin, a marker of gut inflammation, was reduced upon ITF treatment. Both prebiotic and placebo interventions increased the ratio of tauro-conjugated/free bile acids in feces. Prebiotic treatment did not significantly modify fecal SCFA content but it increased fecal rumenic acid, a conjugated linoleic acid (cis-9,trans-11 CLA) with immunomodulatory properties, that correlated notably to the expansion ofBifidobacterium(p = 0.031;r = 0.052).Conclusions: Our study demonstrates that ITF-prebiotic intake during 3 months decreases a fecal marker of intestinal inflammation in obese patients. Our data point to a potential contribution of microbial lipid-derived metabolites in gastro-intestinal dysfunction related to obesity.ClinicalTrials.gov Identifier: NCT03852069 (February 22, 2019 retrospectively, registered).

Dietary fibers are considered beneficial nutrients for health. Current data suggest that their interaction with the gut microbiota largely contributes to their physiological effects. In this context, chitin-glucan (CG) improves metabolic disorders associated with obesity in mice, but its effect on gut microbiota has never been evaluated in humans. This study explores the effect of a 3-week intervention with CG supplementation in healthy individuals on gut microbiota composition and bacterial metabolites. CG was given to healthy volunteers (n = 15) for three weeks as a supplement (4.5 g/day). Food diary, visual analog and Bristol stool form scales and a “quality of life” survey were analyzed. Among gut microbiota-derived metabolites, bile acids (BA), long- and short-chain fatty acids (LCFA, SCFA) profiling were assessed in stool samples. The gut microbiota (primary outcome) was analyzed by Illumina sequencing. A 3-week supplementation with CG is well tolerated in healthy humans. CG induces specific changes in the gut microbiota composition, with Eubacterium, Dorea and Roseburia genera showing the strongest regulation. In addition, CG increased bacterial metabolites in feces including butyric, iso-valeric, caproic and vaccenic acids. No major changes were observed for the fecal BA profile following CG intervention. In summary, our work reveals new potential bacterial genera and gut microbiota-derived metabolites characterizing the interaction between an insoluble dietary fiber -CG- and the gut microbiota.

Diverse metabolic disorders have been associated with an alteration of N-acylethanolamine (NAE) levels. These bioactive lipids are synthesized mainly by N-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and influence host metabolism. We have previously discovered that NAPE-PLD in the intestine and adipose tissue is connected to the pathophysiology of obesity. However, the physiological function of NAPE-PLD in the liver remains to be deciphered. To study the role of liver NAPE-PLD on metabolism, we generated a new mouse model of inducible Napepld hepatocyte-specific deletion (Napepld^∆Hep mice). In this study, we report that Napepld^∆Hep mice develop a high-fat diet-like phenotype, characterized by an increased fat mass gain, hepatic steatosis and we show that Napepld^∆Hep mice are more sensitive to liver inflammation. We also demonstrate that the role of liver NAPE-PLD goes beyond the mere synthesis of NAEs, since the deletion of NAPE-PLD is associated with a marked modification of various bioactive lipids involved in host homeostasis such as oxysterols and bile acids. Collectively these data suggest that NAPE-PLD in hepatocytes is a key regulator of liver bioactive lipid synthesis and a dysregulation of this enzyme leads to metabolic complications. Therefore, deepening our understanding of the regulation of NAPE-PLD could be crucial to tackle obesity and related comorbidities.

A recent study has reported that the administration during gestation of a highly rancid hoki liver oil, obtained by oxidation through sustained exposure to oxygen gas and incident light for 30 days, causes newborn mortality in rats. This effect was attributed to lipid hydroperoxides formed in the omega-3 long-chain polyunsaturated fatty acid-rich oil, while other chemical changes in the damaged oil were overlooked. In the present study, the oxidation condition employed to damage the hoki liver oil was replicated, and the extreme rancidity was confirmed. A detailed analysis of temporal chemical changes resulting from the sustained oxidative challenge involved measures of eicosapentaenoic acid/docosahexaenoic acid (EPA/DHA) omega-3 oil oxidative quality (peroxide value, para-anisidine value, total oxidation number, acid value, oligomers, antioxidant content, and induction time) as well as changes in fatty acid content, volatiles, isoprostanoids, and oxysterols. The chemical description was extended to refined anchovy oil, which is a more representative ingredient oil used in omega-3 finished products. The present study also analyzed the effects of a different oxidation method involving thermal exposure in the dark in contact with air, which is an oxidation condition that is more relevant to retail products. The two oils had different susceptibility to the oxidation conditions, resulting in distinct chemical oxidation signatures that were determined primarily by antioxidant protection as well as specific methodological aspects of the applied oxidative conditions. Unique isoprostanoids and oxysterols were formed in the over-oxidized fish oils, which are discussed in light of their potential biological activities.

Bile acids exert diverse actions on host metabolism and immunity through bile acid-activated receptors, including Takeda G protein-coupled receptor 5 (TGR5). We have recently evidenced an alteration in bile acids in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. This current study aims to further explore the links emerging between bile acids and cancer cachexia. First, we showed that bile flow is reduced in cachectic mice. Next, comparing mice inoculated with cachexia-inducing and with non-cachexia-inducing C26 colon carcinoma cells, we demonstrated that alterations in the bile acid pathways and profile are directly associated with cachexia. Finally, we performed an interventional study using ursodeoxycholic acid (UDCA), a compound commonly used in hepatobiliary disorders, to induce bile acid secretion and decrease inflammation. We found that UDCA does not improve hepatic inflammation and worsens muscle atrophy in cachectic mice. This exacerbation of the cachectic phenotype upon UDCA was accompanied by a decreased TGR5 activity, suggesting that TGR5 agonists, known to reduce inflammation in several pathological conditions, could potentially counteract cachectic features. This work brings to light major evidence sustaining the emerging links between bile acids and cancer cachexia and reinforces the interest in studying bile acid-activated receptors in this context.