Background A20 haploinsufficiency (HA20) is an autoinflammatory disease driven by pathogenic variants in TNFAIP3, which plays a crucial role in regulating immune responses. The clinical manifestations of HA20 resemble those of inflammatory bowel disease (IBD), with prominent gastrointestinal (GI) involvement. Given the well-established association between gut microbiota alterations and IBD, this study aimed to describe the GI involvement of HA20 patients and to investigate their fecal microbiota using shotgun sequencing and metabolomics.Methods This study included 16 HA20 patients and 22 healthy age and sex-matched controls. GI clinical phenotype, liver imaging, and liver and GI tissue histology were assessed. Shotgun metagenomic sequencing was performed on fecal DNA. Fecal metabolomic profiling of bile acids, short-chain fatty acids (SCFAs), and tryptophan metabolites was performed.Results Liver imaging revealed chronic liver disease in 3/5 patients, showing as liver dysmorphia and portal hypertension. Histological analysis showed lymphoplasmocytic infiltrate of the GI tract and the liver. The fecal microbiota of HA20 patients was characterized by marked alterations, including a reduction in microbial diversity and an increase in the pro-inflammatory bacterium Ruminococcus gnavus. Microbial bile acid deconjugation and desulfation were impaired. Additionally, tryptophan metabolism was altered, with a shift towards the kynurenine pathway.Conclusion Our results show that HA20 is associated with gut microbiota alterations and significant disruptions in metabolic pathways, particularly involving bile acids. These alterations could contribute to the chronic inflammation observed in HA20. These findings highlight the role of the gut-liver axis and of mucosal barrier dysfunction in HA20.

With age, low-grade inflammation tends to increase a process known as inflammaging, which is associated with the development of age-related diseases. Concurrently, the gut microbiota undergoes age-related changes in humans. In centenarians and supercentenarians, certain bacteria from the Christensenellaceae family have been found to increase with age and are associated with healthy aging. This study aimed to investigate the potential beneficial effects of Christensenella minuta DSM 22607, a well-characterized strain from this family, on the aging process. Fourteen-month-old male C57BL/6J mice (n = 40) were assigned to four groups receiving either C. minuta DSM 22607 (5 × 109 CFU/mL) or vehicle, combined with ad libitum or calorie-restricted feeding, for 5 months. Intestinal permeability, inflammatory markers, gut microbiota composition, bile acid profiles, and metabolic parameters were assessed via fluorescein isothiocyanate (FITC)-Dextran, soluble CD14, multiplex assay, immune cell staining, short-chain fatty acids determination and 16sDNA sequencing. Data were analyzed using two-way ANOVA with Tukey’s post-hoc test or Mann-Whitney test, with significance set at p < 0.05. Young (6-month-old) and old (19-month-old) mice were compared to validate age-related phenotypes. The effects of DSM 22607 were then evaluated, using food restriction as a positive control. DSM 22607 was found to influence the intestinal barrier by modulating goblet cell populations. Moreover, administration exerted anti-inflammatory effects by reducing pro-inflammatory markers (IL-1β, IL-6) and modulating T lymphocyte, macrophage, and NK cell populations. In addition, DSM 22607 counteracted the effects of food restriction by restoring short-chain fatty acid levels and improving metabolic parameters and bile acid composition. These findings suggest that C. minuta DSM 22607 may represent a promising microbiota-based therapeutic strategy to support healthy aging.

Hibernation is an adaptive strategy that enables certain mammals to survive prolonged periods of starvation and physical inactivity, while maintaining muscle mass. Although some bile acids (BA) have been shown to regulate proteostasis in cell models, their possible role during hibernation has not yet been examined in detail. In the present study, we comprehensively compared serum and feces BA profiles in brown bears (Ursus arctos) during hibernation and the active season and examined bear muscle expression levels of main actors in the BA-mediated signaling pathways and bear microbiota composition. Total serum BA concentration was significantly reduced in hibernating bears; however, the ratio of concentrations of secondary BA to primary BA was higher during hibernation. This indicates that BA metabolism remains active during hibernation, the mechanisms of which we were able to link to both hepatic pathways (transcriptomics) and bear microbiota. Nevertheless, we noted a drastic increase in taurolithocholic acid (TLCA) levels in hibernating bears. Analysis of BA signaling pathways in bear muscle enabled us to show that the BA/TGR5 axis appears to be maintained, presumably to help maintain mitochondrial biogenesis and preserve muscle cell differentiation capacity. This study investigates and suggests potential new mechanisms for the preservation of skeletal muscle during hibernation, which builds the foundation for the development of future treatments for muscle atrophy in humans.

Patients with Clostridioides difficile infection have high colonic levels of primary bile acids, which are potent germinators of Clostridioides difficile. Several studies have suggested that re-establishing a normal bile acid composition is a key factor in fecal microbiota transplantation (FMT) for recurrent C. difficile infection, yet former studies supporting this lacked controls. In a subgroup from a randomized controlled trial, we compared the bile acid composition in patients with recurrent C. difficile infection treated with either FMT, a bacterial mixture, or vancomycin. The fecal bile acid content was analyzed several times before and after treatments. Furthermore, we used 16S rDNA gene sequencing to analyze the presence of some bacterial species involved in bile acid metabolism. Stool donors served as healthy controls. We observed a higher proportion of primary bile acids in patients with recurrent C. difficile infection than in donors, yet a donor-like dominance of secondary bile acids was observed after successful treatment in all groups. The shift seemed to occur earliest in the FMT group, followed by the vancomycin group, and the latest in the bacterial mixture group. In approximately half of the participants, the rise in secondary bile acids was timely associated with the detection of bile acid-transforming bacteria that were absent before treatment. Our findings indicate that FMT re-establishes the bile acid composition faster than vancomycin, reducing the time of susceptibility to recurrences of C. difficile infection. Hence, bacterial mixtures developed as an alternative to donor stool for treating recurrent C. difficile infection might benefit from including bile acid-metabolizing bacteria.

Background and Aims:Microscopic colitis (MC) and bile acid diarrhea (BAD) are common causes of chronic watery diarrhea. Retrospective studies suggest that BAD coexists in a subset of patients with MC, but the interplay and therapeutic implications remain unclear. We aimed to determine the prevalence of BAD in patients with an MC flare using biochemical markers, to assess the effects of budesonide on BAD biomarkers, and to correlate with clinical outcomes. Methods:In this prospective multicenter study conducted at 3 Danish secondary care outpatient clinics, 49 patients with an MC flare were treated with budesonide for 6 weeks. 7α-hydroxy-4-cholesten-3-one (C4) levels ≥46 ng/mL defined BAD. C4 allows timely testing but has 47% sensitivity. Fecal bile acids (BAs) and fibroblast growth factor 19, stool habits, and quality of life were evaluated. Results:BAD was diagnosed in 6 (12%; 95% confidence interval, 5%-25%) of 49 patients (C4 range 47-92 ng/mL). Three patients had a gray zone C4 between 33 and 46 ng/mL. Patients with BAD had lower fibroblast growth factor 19 and high levels of primary and total BA in spot stool samples. Budesonide significantly reduced diarrhea and improved health-related quality of life in all patients. In patients with BAD, budesonide normalized stool BA, but C4 levels remained elevated. Conclusion:These data demonstrate that some patients with MC flare have BAD. In patients with MC and BAD, budesonide reduced diarrhea symptoms and normalized stool BA levels but did not improve an underlying dysregulation of BA homeostasis. Clinicians may consider testing for BAD in patients with recurrent MC. Trials on therapies targeting BAD in MC patients are warranted.

Objectives: Although the mechanism of action of the antidiabetic drug metformin is still a matter of discussions, increasing evidence points to a pivotal role of the gut. Aiming to clarify whether metformin-induced changes in the intestinal tract directly contribute to metabolic improvement, we evaluated the effects of escalating doses (from 50 to 200 mg/kg/day) of metformin orally administered for 4 weeks in mice made glucose intolerant by ten weeks of high fat high sucrose diet. Methods: Several intestinal parameters were studied, including caecal microbiota composition and bile acids profile, ileal FXR signaling, abundance of GLP1-producing cells and goblet cells and blood metabolome. Results: Metformin restored glucose tolerance, fasting insulinemia and HOMA-IR index in a dose-dependent manner. Only a subset of gut-related effects, including mucus production and GLP-1 expression, exhibited a parallel dose–response relationship, suggesting a possible contribution to the observed metabolic improvements. In contrast, other changes, including ileal Fxr-Fgf15 inhibition and hepatic ceramide reduction did not scale with dose, suggesting they are not the main drivers of metformin dose-dependent effects on glycemic control. We also pointed out marked differential sensitivity of gut bacteria to metformin supporting complex interactions of the drug with the microbial ecosystem. Conclusion: Finally, metformin enhanced the proliferation of intestinal epithelium, resulting in increased length of ileal villi. Altogether, this study offers new insights into the metformin mechanism of action and revealed potential novel microbial biomarkers and targets for enhancing its therapeutic efficacy.

Antibiotics notoriously perturb the gut microbiota. We treated healthy volunteers either with cefotaxime or ceftriaxone for 3 days, and collected in each subject 12 faecal samples up to day 90. Using untargeted and targeted phenotypic and genotypic approaches, we studied the changes in the bacterial, phage and fungal components of the microbiota as well as the metabolome and the β-lactamase activity of the stools. This allowed assessing their degrees of perturbation and resilience. While only two subjects had detectable concentrations of antibiotics in their faeces, suggesting important antibiotic degradation in the gut, the intravenous treatment perturbed very significantly the bacterial and phage microbiota, as well as the composition of the metabolome. In contrast, treatment impact was relatively low on the fungal microbiota. At the end of the surveillance period, we found evidence of resilience across the gut system since most components returned to a state like the initial one, even if the structure of the bacterial microbiota changed and the dynamics of the different components over time were rarely correlated. The observed richness of the antibiotic resistance genes repertoire was significantly reduced up to day 30, while a significant increase in the relative abundance of β-lactamase encoding genes was observed up to day 10, consistent with a concomitant increase in the β-lactamase activity of the microbiota. The level of β-lactamase activity at baseline was positively associated with the resilience of the metabolome content of the stools. In healthy adults, antibiotics perturb many components of the microbiota, which return close to the baseline state within 30 days. These data suggest an important role of endogenous β-lactamase-producing anaerobes in protecting the functions of the microbiota by de-activating the antibiotics reaching the colon.

Metabolic syndrome (MetS) is a cluster of several human conditions including abdominal obesity, hypertension, dyslipidemia, and hyperglycemia, all of which are risk factors of type 2 diabetes, cardiovascular disease, and metabolic dysfunction-associated steatotic liver disease (MASLD). Dietary pattern is a well-recognized MetS risk factor, but additional changes related to the modern Western life-style may also contribute to MetS. Here we hypothesize that the disappearance of amoebas in the gut plays a role in the emergence of MetS in association with dietary changes. Four groups of C57B/6J mice fed with a high-fat diet (HFD) or a normal diet (ND) were colonized or not with Entamoeba muris, a commensal amoeba. Seventy days after inoculation, cecal microbiota, and bile acid compositions were analyzed by high-throughput sequencing of 16S rDNA and mass spectrometry, respectively. Cytokine concentrations were measured in the gut, liver, and mesenteric fat looking for low-grade inflammation. The impact of HFD on liver metabolic dysfunction was explored by Oil Red O staining, triglycerides, cholesterol concentrations, and the expression of genes involved in beta-oxidation and lipogenesis. Colonization with E. muris had a beneficial impact, with a reduction in dysbiosis, lower levels of fecal secondary bile acids, and an improvement in hepatic steatosis, arguing for a protective role of commensal amoebas in MetS and more specifically HFD-associated MASLD.

L’haploinsuffisance A20 (HA20) est une maladie monogénique associée à une perte de fonction du gène TNFAIP3. Elle entraîne une diminution de la fonction de la protéine A20, qui est un régulateur négatif de NF-kB. Les patients présentent une fièvre périodique et 46 % d’entre eux présentent des atteintes digestives. La diarrhée est l’un des symptômes les plus invalidants. Dix pour cent des patients présentent une atteinte hépatique, allant de la cholestase asymptomatique à la cirrhose cryptogénique. Le microbiote intestinal forme une relation symbiotique avec l’hôte et façonne ses réponses métaboliques et immunitaires. Les effets du microbiote intestinal dépendent de sa composition et de sa capacité à métaboliser les métabolites dérivés de l’intestin. Ainsi, le déséquilibre entre les communautés bactériennes de l’intestin (dysbiose) peut entraîner des changements dans les profils métaboliques. Les métabolites dérivés de l’intestin comprennent les acides biliaires, les acides gras à chaîne courte (AGCC), et les métabolites dérivés du tryptophane alimentaire. Les acides biliaires peuvent provoquer des lésions coliques lorsque leur métabolisme est altéré. À l’inverse, les AGCC possèdent des effets anti-inflammatoires après leur absorption colique. Enfin, Le tryptophane alimentaire est précurseur de la voie inflammatoire des kynurénines, activée elle-même par les cytokines pro-inflammatoires. Ainsi, une dysbiose et des perturbation des métabolites dérivés du microbiote intestinal pourraient favoriser le phénotype inflammatoire et digestif des patients avec HA20. Objectif : étudier la composition du microbiote intestinal et le profil des acides biliaires, des AGCC et des métabolites dérivés du tryptophane dans une cohorte de patients français avec HA20. Les selles de 17 patients français atteints de HA20 et de 22 sujets sains ont été recueillies. Le microbiote intestinal a été analysé par séquençage 16s. Les acides biliaires, les AGCC et les métabolites du tryptophane fécaux ont été analysés par chromatographie liquide haute performance couplée à la spectrométrie de masse. Les résultats ont été stratifiés en fonction de la consistance des selles définie par l’échelle de Bristol (BSS). Un avis favorable a été obtenu du comité d’éthique de Sorbonne université pour cette recherche. Onze patients étaient des femmes (65 %) et l’âge médian était de 33 ans [12–57]. Cinq patients présentaient des troubles digestifs le jour du prélèvement de selles (douleurs abdominales et diarrhée). Il n’y avait pas de différence de diversité du microbiote entre les groupes. Cependant, les patients HA20 présentaient une composition du microbiome intestinal significativement différente de celle des sujets sains dans l’analyse en composantes principales (p = 0,026). De plus, les patients HA20 présentaient un déficit de déconjugaison et de transformation des acides biliaires en acides biliaires secondaires par les bactéries du microbiote intestinal (p = 0,01, respectivement). Les patients atteints de HA20 présentaient également des niveaux d’acides gras fécaux significativement plus élevés que les sujets sains, suggérant un déficit d’absorption (p = 0,025). Les profils d’acides biliaires et de SCFA étaient significativement plus altérés chez les patients avec un BSS plus élevé (p = 0,016 et p < 0,006, respectivement). Les patients avec HA20 présentaient une augmentation des métabolites de la voie des kynurénines (p = 0,02). Les patients atteints de HA20 présentent une dysbiose spécifique par rapport aux sujets sains, ainsi que des modifications des profils de métabolites dérivés du microbiote intestinal. L’augmentation des acides biliaires toxiques dans l’intestin et l’engagement du tryptophane dans la voie des kynurénines pourraient être impliquée dans les symptômes digestifs de la maladie de HA20. De plus, le déficit d’absorption des AGCC anti-inflammatoires pourrait participer à l’état pro-inflammatoire des patients avec HA20. Ces changements sont plus importants chez les patients souffrant de diarrhée, suggérant une relation causale entre le dysmétabolisme intestinal et les troubles digestifs de le HA20. Les patients avec HA20 présentent une signature fécale pro-inflammatoire associant des perturbations du microbiote intestinal des métabolites qui en dérivent. Des traitements par probiotiques pourraient améliorer les symptômes et l’état inflammatoire des patients avec HA20.

Abstract Background Intestinal dysbiosis is a key feature in the pathogenesis of inflammatory bowel diseases (IBD). Bacterial quorum sensing mediated by acyl-homoserine lactones (AHL) might play a role in the dialogue between the gut microbiota and the host. The main objective of our study was to investigate the presence and expression of AHL synthase and receptor genes in the human gut ecosystem during IBD. Methods To confirm the presence of AHL in the gut, mass spectrometric detection was performed on stool samples from IBD patients and non-IBD subjects. Then, by an in silico approach, we exploited the open access database: Inflammatory Bowel Disease Multi’omics Database, an American cohort with bacterial metagenomes and metatranscriptomes data of stool samples from non-IBD and IBD subjects. To characterise gut dysbiosis, the most discriminating bacterial species between non-IBD and IBD patients were identified by multivariate analysis and allowed us to define two groups (dysbiosis/non-dysbiosis). The search for AHL synthase (luxI) and receptor (luxR) known homolog genes, was performed using Basic Local Alignment Search Tool (BLAST) from previously assembled gene files (presence/absence) as well as raw data sequencing files (relative abundance and expression). Results Mass spectrometry confirmed a higher concentration of AHL molecules in healthy subjects than in relapsing IBD. Regarding in silico analysis, 103 subjects were selected including 50 with Crohn’s disease (CD), 27 with ulcerative colitis (UC), and 26 non-IBD subjects. No luxI-like synthase genes were retrieved by BLAST searches. However, several homologs of receptor genes were identified: sdiA gene from Escherichia coli (7/103 patients) and luxR-like homologs from Bacteroides fragilis and Bacteroides dorei present in all patients. According to disease, only one luxR-like gene from Bacteroides dorei was under-expressed in IBD patients (p = 0.02) compared to non-IBD, especially in CD (p = 0.02) (Figure 1). In dysbiosis situation, one luxR receptor gene from Bacteroides fragilis appeared to be over-expressed (p = 0.04) compared to non-dysbiotic patients (Figure 2). Conclusion Through this computational approach, AHL-synthesising bacteria have not been found. However, the expression of quorum sensing receptor genes appears to be modulated by IBD-associated gut dysbiosis. The role of LuxR receptors, especially in Bacteroides species, should be investigated to understand its impact on gut microbiota (Figure 3). Targeting LuxR receptors of bacterial quorum sensing might represent a new approach to modulate the gut microbiota in IBD.

Summary Background Bile acid diarrhoea is often missed because gold standard nuclear medicine tauroselcholic [75‐Se] acid (SeHCAT) testing has limited availability. Empirical treatment effect has unknown diagnostic performance, whereas plasma 7α‐hydroxy‐4‐cholesten‐3‐one (C4) is inexpensive but lacks sensitivity. Aims To determine diagnostic characteristics of empirical treatment and explore improvements in diagnostics with potential better availability than SeHCAT. Methods This diagnostic accuracy study was part of a randomised, placebo‐controlled trial of colesevelam. Consecutive patients with chronic diarrhoea attending SeHCAT had blood and stool sampled. Key thresholds were C4 > 46 ng/mL and SeHCAT retention ≤10%. A questionnaire recorded patient‐reported empirical treatment effect. We analysed receiver operating characteristics and explored machine learning applied logistic regression and decision tree modelling with internal validation. Results Ninety‐six (38%) of 251 patients had SeHCAT retention ≤10%. The effect of empirical treatment assessed with test results for bile acid studies blinded had 63% (95% confidence interval 44%–79%) sensitivity and 65% (47%–80%) specificity; C4 > 46 ng/mL had 47% (37%–57%) and 92% (87%–96%), respectively. A decision tree combining C4 ≥ 31 ng/mL with ≥1.1 daily watery stools (Bristol type 6 and 7) had 70% (51%–85%) sensitivity and 95% (83%–99%) specificity. The logistic regression model, including C4, the sum of measured stool bile acids and daily watery stools, had 77% (58%–90%) sensitivity and 93% (80%–98%) specificity. Conclusions Diagnosis of bile acid diarrhoea using empirical treatment was inadequate. Exploration suggested considerable improvements in the sensitivity of C4‐based testing, offering potential widely available diagnostics. Further validation is warranted. ClinicalTrials.gov : NCT03876717.

Ceramides (Cer) have been shown as lipotoxic inducers, which disturb numerous cell-signaling pathways, leading to metabolic disorders such as type 2 diabetes. In this study, we aimed to determine the role of de novo hepatic ceramide synthesis in energy and liver homeostasis in mice. We generated mice lacking serine palmitoyltransferase 2 (Sptlc2), the rate limiting enzyme of ceramide de novo synthesis, in liver under albumin promoter. Liver function, glucose homeostasis, bile acid (BA) metabolism and hepatic sphingolipids content were assessed using metabolic tests and LC-MS. Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic Cer, associated with a 10-fold increase in neutral sphingomyelinase 2 (nSMase2) expression, and a decreased sphingomyelin content in the liver. Sptlc2ΔLiv mice were protected against obesity induced by high fat diet and displayed a defect in lipid absorption. In addition, an important increase in tauro-muricholic acid was associated with a downregulation of the nuclear BA receptor FXR target genes. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production, while the latter effect was dampened in presence of nSMase2 inhibitor. Finally, Sptlc2 disruption promoted apoptosis, inflammation and progressive development of hepatic fibrosis, worsening with age. Our data suggest a compensatory mechanism to regulate hepatic ceramides content from sphingomyelin hydrolysis, with deleterious impact on liver homeostasis. In addition, our results show the involvement of hepatic sphingolipid modulation in BA metabolism and hepatic glucose production in an insulin-independent manner, which highlight the still under-researched role of ceramides in many metabolic functions.

Background Bile acid diarrhoea is a common but overlooked cause of chronic watery diarrhoea. Plasma 7 alpha-hydroxy-4-cholesten-3-one (C4) is an alternative to the gold standard tauroselcholic [75Se] acid (SeHCAT) test. Low-certainty evidence supports sequestrant treatment, including colesevelam. We aimed to determine the efficacy and safety of colesevelam in bile acid diarrhoea.Methods In this randomised, double-blind, placebo-controlled, investigator-initiated phase 4 trial of the sequestrant colesevelam in bile acid diarrhoea (SINBAD), we enrolled consecutive patients aged 18-79 years without inflammatory bowel disease attending SeHCAT testing for suspected bile acid diarrhoea at four Danish secondary care centres. Participants were randomly allocated 1:1 to receive 12 days of treatment with colesevelam (overencapsulated tablets of 625 mg) or placebo, with the starting dose of two capsules twice daily and titrated to effect during the first 5 days of treatment. A pharmacist independent of the clinical investigators generated a randomisation list on the web page randomization.com using block randomisation (randomisation was not stratified). C4 and SeHCAT diagnostic results were blinded during treatment. We treated all patients with diarrhoea, with a daily mean of 3 center dot 0 or more bowel movements or 1 center dot 0 or more watery bowel movements (Bristol stool scale type 6 and 7). Remission was defined as the absence of both these criteria during treatment days 6-12. The primary outcome was the intention-to-treat remission rate in bile acid diarrhoea diagnosed by C4 concentration greater than 46 ng/mL. A secondary outcome was the intention-to-treat remission rate in bile acid diarrhoea diagnosed by SeHCAT retention of 10% or less. This trial is registered with ClinicalTrials.gov, NCT03876717.Findings Between Oct 25, 2018, and July 1, 2021, 168 patients were randomly assigned to receive colesevelam (n=84) or placebo (n=84). 41 patients had C4 concentration greater than 46 ng/mL (22 assigned to the colesevelam group and 19 to the placebo group). For the C4-defined primary outcome, 14 (64%) of 22 participants receiving colesevelam versus three (16%) of 19 participants receiving placebo achieved remission (adjusted odds ratio 9 center dot 1, 95% CI 1 center dot 9-62 center dot 8; p=0 center dot 011). For the SeHCAT-defined secondary outcome, 75 of the 168 participants had retention of less than 10% (37 assigned to the colesevelam group and 38 assigned to the placebo group); 22 (59%) of 37 participants receiving colesevelam achieved remission versus five (13%) of 38 participants receiving placebo (adjusted odds ratio 11 center dot 1, 95% CI 3 center dot 4-45 center dot 6; p=0 center dot 00020). There were no serious adverse events. Common adverse events were transient. For patients receiving colesevelam within the primary outcome population, five had abdominal pain, nine had bloating, and four had nausea. For patients receiving placebo, four had abdominal pain, four had bloating, and one had nausea. No participants with bile acid diarrhoea withdrew due to adverse events.Interpretation Colesevelam was superior to placebo at inducing remission of bile acid diarrhoea diagnosed with C4 concentration greater than 46 ng/mL. Secondary outcome data suggest similar efficacy treating SeHCAT-defined bile acid diarrhoea. Colesevelam was safe during the treatment.Funding Fabrikant Vilhelm Pedersen og hustrus mindelegat; recommended by the Novo Nordisk Foundation.Copyright (c) 2023 Published by Elsevier Ltd. All rights reserved.

Synthetic emulsifiers promote metabolic syndrome and considerably alter gut microbiota. Data is lacking regarding natural emulsifiers like plant lecithins, a polar lipid-rich source of 18:3n-3 PUFA (ALA). For 13 weeks, male Swiss mice were fed ALA-replete semi-synthetic high-fat diet (HFD) including lecithin from rapeseed (RL) or soy, vs 2 HFD-controls devoid of lecithin (ALA-replete; low-ALA), vs Chow. Lecithins did not enhance HFDinduced adiposity nor increased inflammation, did not alter gut barrier markers and caecal bile acids, and contributed to n-3 PUFA status. Lecithins improved gut microbiota diversity. RL (10% in fat) even restored alpha-diversity similar to Chow, increased Lachnospiraceae NK4A136, Lactobacillus and Ruminococcaceae UCG-014 groups, and decreased Blautia genus bacteria. The abundance of most beneficial lecithin-enhanced bacteria was positively correlated to the amount of faecal polar lipid-bound ALA. These findings show that lecithins can beneficially affect the gut microbiota in association with changes in lipid residues in the distal gut.

Abstract Background Antibiotics notoriously perturb the gut microbiota. We used untargeted and targeted phenotypic and genotypic approaches to study faecal samples collected up to 90 days following a 3-day course of intravenous β-lactam antibiotics in 22 healthy volunteers. We studied the changes in the bacterial, phage and fungal components of the microbiota as well as the metabolome and the β-lactamase activity of the stools. This allowed assessing their degrees of perturbation and resilience. Results While only two subjects had detectable concentrations of antibiotics in their faeces, suggesting important antibiotic degradation in the gut, the intravenous treatment perturbed very significantly the bacterial and phage microbiota, as well as the composition of the metabolome. In contrast, treatment impact was relatively low on the fungal microbiota. At the end of the surveillance period, we found evidence of resilience across the gut system since most components returned to a state like the initial one, even if the taxonomic composition of the bacterial microbiota changed and the dynamics of the different components over time were rarely correlated. The richness of the resistome was significantly reduced up to day 30, while a significant increase in the relative abundance of β-lactamase encoding genes was observed up to day 10, consistent with a concomitant increase in the β-lactamase activity of the microbiota. The level of β-lactamase activity at baseline was positively associated with the resilience of the metabolome content of the stools. Conclusions In healthy adults, antibiotics perturb all the components of the microbiota, which mostly return to its baseline state within 30 days. These data suggest an important role of endogenous β-lactamases producing anaerobes in protecting the functions of the microbiota by de-activating the antibiotics reaching the colon.

Intestinal dysbiosis is a key feature in the pathogenesis of inflammatory bowel disease (IBD). Acyl-homoserine lactones (AHL) are bacterial quorum-sensing metabolites that may play a role in the changes in host cells-gut microbiota interaction observed during IBD. The objective of our study was to investigate the presence and expression of AHL synthases and receptor genes in the human gut ecosystem during IBD. We used an in silico approach, applied to the Inflammatory Bowel Disease Multi’omics Database comprising bacterial metagenomic and metatranscriptomic data from stools of patients with Crohn’s disease (CD) (n = 50), ulcerative colitis (UC) (n = 27) and non-IBD controls (n = 26). No known putative AHL synthase gene was identified; however, several putative luxR receptors were observed. Regarding the expression of these receptor genes, the luxR gene from Bacteroides dorei was under-expressed in IBD patients (p = 0.02) compared to non-IBD patients, especially in CD patients (p = 0.02). In the dysbiosis situation, one luxR receptor gene from Bacteroides fragilis appeared to be over-expressed (p = 0.04) compared to that of non-dysbiotic patients. Targeting LuxR receptors of bacterial quorum sensing might represent a new approach to modulate the gut microbiota in IBD.

Justification: Bile acids (BA) are the end products of cholesterol catabolism and may act as signalling molecules and metabolic regulators of energy homeostasis. Disorders in BA metabolism can lead to liver and cardiovascular diseases. In a 4-week double-blind RCT (VALOBAB-C), we demonstrated that the daily consumption of a cream cheese enriched with 3 or 5g of milk polar lipids (PL) improved lipid metabolism by reducing hypercholesterolemia in overweight postmenopausal women. Objective: We aimed to determine the effect of milk PL on circulating BA in the fasting and postprandial state. Methods: In the VALOBAB-C trial, postprandial metabolic explorations (0-480min) were performed before and after the intervention, including a standardized high fat-high sucrose breakfast at fasting and a standardized lunch containing the test cream cheese at 240 min. Fasting and postprandial serum bile acid composition was analysed by HPLC-MS/MS. Results: The milk PL intervention slightly increased total fasting BA concentrations (ΔAfter-Before) (PPL=0.03), with no significant effect on BA species profile (% of total BA). Total BA concentration was not impacted during the postprandial period, but the primary/secondary BA ratio was significantly decreased in both milk PL groups versus control. Milk PL decreased the relative abundance of primary BA (PPL=0.02), increased Tauro-conjugated BA (Pgroup=0.02) and highly decreased Glyco-conjugated BA. Proportions of several species were also decreased during the postprandial period, among which GLCA (glycolithocholic acid). The latter is derived from lithocholic acid, whose accumulation is toxic. Such results provide new insights in the knowledge of BA metabolism, and a potential link with the cholesterol-lowering effects of milk PL deserves to be investigated. Significance of the research to the AOCS membership: H&N, EAT and PL division members can be interested by this research regarding lipid ingredients of functional interest and their impact on relevant biomarkers involved in lipid metabolism.