Microbe-produced molecules (xenometabolites) found in foods or produced by gut microbiota are increasingly implicated in microbe-microbe and microbe-host communication. Xenolipids, in particular, are a class of metabolites for which the full catalog remains to be elaborated in mammalian systems. We and others have observed that cis-3,4-methylene-heptanoylcarnitine is a lipid derivative that is one of the most abundant medium-chain acylcarnitines in human blood, hypothesized to be a product of incomplete β-oxidation of one or more "odd-chain" long-chain cyclopropane fatty acids (CpFAs). We deduced two possible candidates, cis-11,12-methylene-pentadecanoic acid (cis-11,12-MPD) and cis-13,14-methylene-heptadecanoic acid (cis-13,14-MHD). Authentic standards were synthesized: cis-11-pentadecenoic acid and cis-13-heptadecenoic acid were generated (using Jones reagent) from cis-11-pentadecene-1-ol and cis-13-heptadecene-1-ol, respectively, and these were converted to CpFAs via a reaction involving diiodomethane. Using these standards in mass spectrometry analyses, we determined the presence/absence of cis-11,12-MPD and cis-13,14-MHD in archived piglet biospecimens. Both CpFAs were detected in rectal contents of sow and soy-fed piglets. Archived mass spectra were analyzed post hoc from a second independent study that used tissue-specific catheterization to monitor net metabolite flux in growing pigs. This confirmed the presence of both CpFAs in plasma and revealed a significant net uptake of the odd-chain CpFAs across the splanchnic tissue bed and liver. The results confirm that the novel xenolipids cis-11,12-MPD and cis-13,14-MHD can be components of the mammalian lipidome and are viable candidate precursors of cis-3,4-methylene-heptanoylcarnitine produced from partial β-oxidation in liver or other tissues.

Combination therapies targeting multiple organs and metabolic pathways are promising therapeutic options to combat obesity progression and/or its comorbidities. The alterations in the composition of the gut microbiota initially observed in obesity have been extended recently to functional alterations. Bacterial functions involve metabolites synthesis that may contribute to both the gut microbiota and the host physiology. Among them are B vitamins, whose metabolism at the systemic, tissue or microbial level are dysfunctional in obesity. We previously reported that the combination of oral supplementation of a prebiotic (fructo-oligosaccharides, FOS) and vitamin B7/B8 (biotin) impedes fat mass accumulation and hyperglycemia in mice with established obesity. This was associated with an attenuation of dysbiosis with improved microbial vitamin metabolism. We now extend this study by characterizing whole-body energy metabolism along with adipose tissue transcriptome and histology in this mouse model. We observed that FOS resulted in increased caloric excretion in parallel with down-regulation of genes and proteins involved in jejunal lipid transport. The combined treatments also strongly inhibited the accumulation of subcutaneous fat mass, with a reduced adipocyte size and expression of lipid metabolism genes. Down-regulation of inflammatory and fibrotic genes and proteins was also observed in both visceral and brown adipose tissues and liver by combined FOS and biotin supplementation. In conclusion, oral administration of a prebiotic and biotin has a beneficial impact on the metabolism of key organs involved in the pathophysiology of obesity, which could have promising translational applications.

L’obésité est associée à des altérations importantes de la composition et des fonctions du microbiote intestinal (MI). Le MI produit des métabolites, comme les vitamines, qui peuvent influencer la santé métabolique par des interactions inter-organes complexes. Notre étude des données métagénomiques du MI de 1545 patients de la cohorte européenne MetaCardis, a montré une altération du métabolisme bactérien de la vitamine B7 (biotine) ainsi qu’une déficience en biotine accrue chez l’hôte, dans les stades les plus avancés d’obésité. La biotine est impliquée dans de nombreuses fonctions, comme le métabolisme des lipides suggérant qu’une perturbation du métabolisme de cette vitamine participerait aux altérations métaboliques de l’hôte. Nous avons d’abord démontré l’implication du MI dans les niveaux circulants de biotine par l’étude de modèles murins de modulation du MI : absence (souris axénique) ou déplétion (par antibiotiques) du MI, transfert de MI d’humain à souris. Nous avons étudié le métabolisme de la biotine dans un modèle murin d’obésité installée, mimant l’obésité sévère chez l’Homme. Pour cela, la supplémentation en biotine concomitante à la modulation du MI par prébiotique a permis de limiter l’altération du phénotype pondéral et glycémique des animaux. L’analyse du transcriptome du tissu adipeux a permis de montrer l’implication des traitements dans des voies clés du métabolisme. Enfin, nous avons observé une amélioration de la diversité et du métabolisme de la biotine dans le MI. L’ensemble de ces résultats suggèrent l’importance de la prise en compte du statut vitaminique au niveau de l’hôte et du MI dans l’obésité sévère.

ObjectivesGut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome’s functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation.DesignWe performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice.ResultsSevere obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration.ConclusionStrategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity.Trial registration numberNCT02059538.

L’obésité sévère est associée à une altération tissulaire majeure et une inflammation chronique dite de bas-grade ainsi qu’à des modifications de la composition et fonctionnalité du microbiote intestinal (MI). L’influence du MI sur le profil métabolique de l’hôte est étudiée, notamment au travers de nombreux métabolites produits par le MI et participant à la communication inter-organes. Les vitamines, en particulier, celles du groupe B, font partie de ces métabolites mais elles ont été négligées dans ce contexte. Parmi elles, la vitamine B7/biotine est impliquée dans de nombreuses fonctions physiologiques dont le métabolisme des lipides et des glucides. La supplémentation en biotine participerait à l’amélioration du métabolisme du glucose dans le diabète de type 2. Toutefois, peu de données existent à ce jour sur l’implication de cette vitamine dans les maladies métaboliques. Notre étude s’intéresse à la question de sa disponibilité et de son statut à la fois dans le microbiote et chez l’hôte en situation d’obésité sévère. Afin de répondre à ces interrogations, nous avons utilisé les données métagénomiques de la cohorte européenne MetaCardis, regroupant près de 2000 patients souffrant de diverses pathologies métaboliques et examiné différents modèles murins complémentaires (changements nutritionnels, chirurgie bariatrique, supplémentations et transfert de microbiote). L’analyse de données métagénomiques de patients avec des degrés d’obésité croissants a permis de mettre en évidence une altération du taux circulant et du métabolisme bactérien de production et transport de la biotine dans l’obésité sévère. Nous avons confirmé cette altération lors de l’induction de l’obésité par un régime riche en lipides chez la souris. La contribution du métabolisme bactérien aux niveaux circulants en biotine a été démontrée chez des souris dénuées de MI (Germ-free), traitées par antibiotiques, ou par transfert de MI (d’humain à souris). Enfin, le métabolisme de la biotine a été exploré dans différents modèles de prise en charge de l’obésité. La chirurgie bariatrique, connue pour induire des améliorations métaboliques et inflammatoires ainsi que des modifications du MI, est associée à une augmentation du potentiel bactérien de production et du taux circulant de biotine à la fois chez l’Homme et la souris. Enfin, la supplémentation concomitante en prébiotique et en biotine dans un modèle murin d’obésité installée (induite par régime gras) a induit une limitation de la prise de masse grasse et de la détérioration du métabolisme glucidique. Ce traitement combiné a permis d’améliorer la diversité du MI ainsi que le métabolisme bactérien de la biotine. Ces résultats originaux suggèrent pour la première fois l’importance de la biotine, et plus généralement des vitamines B, dans l’obésité sévère et ouvrent des perspectives d’investigation clinique de supplémentation en prébiotique et biotine pour la prise en charge de l’obésité.

Roux-en-Y gastric bypass (RYGB) is efficient at inducing drastic albeit variable weight loss and type-2 diabetes (T2D) improvements in patients with severe obesity and T2D. We hypothesized a causal implication of the gut microbiota (GM) in these metabolic benefits, as RYGB is known to deeply impact its composition. In a cohort of 100 patients with baseline T2D who underwent RYGB and were followed for 5-years, we used a hierarchical clustering approach to stratify subjects based on the severity of their T2D (Severe vs Mild) throughout the follow-up. We identified via nanopore-based GM sequencing that the more severe cases of unresolved T2D were associated with a major increase of the class Bacteroidia, including 12 species comprising Phocaeicola dorei, Bacteroides fragilis, and Bacteroides caecimuris. A key observation is that patients who underwent major metabolic improvements do not harbor this enrichment in Bacteroidia, as those who presented mild cases of T2D at all times. In a separate group of 36 patients with similar baseline clinical characteristics and preoperative GM sequencing, we showed that this increase in Bacteroidia was already present at baseline in the most severe cases of T2D. To explore the causal relationship linking this enrichment in Bacteroidia and metabolic alterations, we selected 13 patients across T2D severity clusters at 5-years and performed fecal matter transplants in mice. Our results show that 14 weeks after the transplantations, mice colonized with the GM of Severe donors have impaired glucose tolerance and insulin sensitivity as compared to Mild-recipients, all in the absence of any difference in body weight and composition. GM sequencing of the recipient animals revealed that the hallmark T2D-severity associated bacterial features were transferred and were associated with the animals’ metabolic alterations. Therefore, our results further establish the GM as a key contributor to long-term glucose metabolism improvements (or lack thereof) after RYGB.

Our data highlighted 1) the sweet taste transduction pathway in EECs plays pivotal role for glucose homeostasis at least at gene expression level; 2) metabolic disorders led to altered gene expression of sweet taste signaling pathway in intestine contributing to impaired GLP-1 secretion; and 3) after surgical intestinal modifications, increased expression of α-gustducin contributed to metabolic improvement.

Severe obesity is associated with major tissue alterations and systemic low-grade inflammation as well as with modifications of gut microbiota composition and functionality. Yet, there is increasing evidence revealing that the gut microbiota could influence metabolic health via the production of many microbiota-derived metabolites which contribute to complex interorgan dialogs. Vitamins and more specifically B vitamins have been neglected in this context. Amongst them, Vitamin B7/biotin plays an important role in many physiological functions including carbohydrate and lipid metabolism. Although, biotin supplementation is suggested to improve glucose metabolism in type 2 diabetes (T2D), this vitamin has not been widely studied in metabolic disorders including subjects with severe obesity. We, here, investigated both the bacterial and host metabolism of biotin, using large scale data from the European cohort Metacardis and different murine models. Examining metagenomic data of gut microbiota from human with worsening stages of obesity and diet-induced obesity in mice revealed deficiency in biotin microbial production and transport. This altered gut microbial metabolism was associated with metabolic and inflammatory deterioration in the human host. In the same subjects with severe obesity, we found suboptimal circulating levels of biotin and altered expression of biotin-associated genes in adipose tissue. Then, we demonstrated the contribution of the gut microbiota to the host circulating biotin by a series of experiments performed in Germ-free animals, antibiotic-treated mice and after gut microbiota transfer (from human to mice). Furthermore, we studied gut microbiota biotin metabolism in the context of obesity management. First, bariatric surgery, which is known to improve metabolism and inflammation and to induce changes in gut microbiota composition, was associated with increased bacterial biotin producers together with improved systemic biotin in mice and humans. Second, the concomitant management of biotin status and dysbiosis in the context of installed obesity in mice was explored. The oral supplementation of mice with installed obesity with both biotin and a prebiotic fructoligosaccharide (FOS) led to limited weight gain and glycemic deterioration compared to animals with no supplementation. The mice supplemented by FOS and biotin also improved their bacterial biotin metabolism better than the other groups. Altogether, these results suggest the importance of biotin, and more generally B vitamins, in severe obesity and pave the way for future clinical investigation of biotin and prebiotic administration in humans to prevent obesity from transitioning to a more severe metabolic state.

There are numerous factors involved in obesity progression and maintenance including systemic low-grade inflammation, adipose tissue dysfunction, or gut microbiota dysbiosis. Recently, a growing interest has arisen for vitamins' role in obesity and related disorders, both at the host and gut bacterial level. Indeed, vitamins are provided mostly by food, but some, from the B and K groups in particular, can be synthesized by the gut bacterial ecosystem and absorbed in the colon. Knowing that vitamin deficiency can alter many important cellular functions and lead to serious health issues, it is important to carefully monitor the vitamin status of patients with obesity and potentially already existing comorbidities as well as to examine the dysbiotic gut microbiota and thus potentially altered bacterial metabolism of vitamins. In this review, we examined both murine and human studies, to assess the prevalence of sub-optimal levels of several vitamins in obesity and metabolic alterations. This review also examines the relationship between vitamins and the gut microbiota in terms of vitamin production and the modulation of the gut bacterial ecosystem in conditions of vitamin shortage or supplementation. Furthermore, some strategies to improve vitamin status of patients with severe obesity are proposed within this review.

Dermanyssus infestation is a rural parasitic problem occurs occasionally in urban areas in people with close contact to pigeons. It can be diagnosed through clinical cutaneous symptoms in exposed body parts, nocturnal itching, and presence of mites in infested locations and can be treated by antiacaricide, environmental, and symptomatic treatments.

The intestinal microbiota and its functions are intricately interwoven with host physiology. Colonizing rodents with donor microbiota provides insights into host-microbiota interactions characterization and the understanding of disease physiopathology. However, a better assessment of inoculation methods and recipient mouse models is needed. Here, we compare the engraftment at short and long term of genetically obese mice microbiota in germ-free (GF) mice and juvenile and adult specific pathogen free (SPF) mice. We also tested the effects of initial microbiota depletion before microbiota transfer. In the present work, donor microbiota engraftment was better in juvenile SPF mice than in adult SPF mice. In juvenile mice, initial microbiota depletion using laxatives or antibiotics improved donor microbiota engraftment 9 weeks but not 3 weeks after microbiota transfer. Microbiota-depleted juvenile mice performed better than GF mice 3 weeks after the microbiota transfer. However, 9 weeks after transfer, colonized GF mice microbiota had the lowest Unifrac distance to the donor microbiota. Colonized GF mice were also characterized by a chronic alteration in intestinal absorptive function. With these collective results, we show that the use of juvenile mice subjected to initial microbiota depletion constitutes a valid alternative to GF mice in microbiota transfer studies.

Purpose of ReviewIn this review, we summarize what is currently described in terms of gut microbiota (GM) dysbiosis modification post-bariatric surgery (BS) and their link with BS-induced clinical improvement. We also discuss how the major inter-individual variability in terms of GM changes could impact the clinical improvements seen in patients.Recent FindingsThe persisting increase in severe obesity prevalence has led to the subsequent burst in BS number. Indeed, it is to date the best treatment option to induce major and sustainable weight loss and metabolic improvement in these patients. During obesity, the gut microbiota displays distinctive features such as low microbial gene richness and compositional and functional alterations (termed dysbiosis) which have been associated with low-grade inflammation, increased body weight and fat mass, as well as type-2 diabetes. Interestingly, GM changes post-BS is currently being proposed as one the many mechanism explaining BS beneficial clinical outcomes.SummaryBS enables partial rescue of GM dysbiosis observed during obesity. Some of the GM characteristics modified post-BS (composition in terms of bacteria and functions) are linked to BS beneficial outcomes such as weight loss or metabolic improvements. Nevertheless, the changes in GM post-BS display major variability from one patient to the other. As such, further large sample size studies associated with GM transfer studies in animals are still needed to completely decipher the role of GM in the clinical improvements observed post-surgery.

Contexte : outre une perte de poids massive et durable, le bypass Roux-en-Y (RYGB) permet d’induire une remission du diabete de type 2 (DT2) chez 60% des patients, bien qu’une proportion variable d’entre eux rechute a plus long terme. Des scores predisant le potentiel de remission existent, mais ne sont pas assez precis a plus long terme (>2 ans). L’objectif de cette etude a ete de developper un score de prediction de la remission du DT2 (DR) a 5 ans post-operatoire. Objectifs : nous avons inclus 175 patients DT2 et ayant eu un RYGB il y a au moins 5 ans. En utilisant une methode de machine-learning, nous avons developpe le 5y-Ad-DiaRem en integrant des donnees de l’historique medical, biocliniques et relatives au traitement du DT2. La selection des variables est basee sur les odds-ratios et les differences significatives entre les groupes. Le score a ete valide au sein de trois cohortes Europeennes de RYGB. Resultats : par rapport aux patients en DR a 5 ans, les patients qui ont rechute avaient un DT2 plus severe en basal, ont perdu moins de poids au cours de la 1ere annee, et en ont regagne plus ensuite. Notre score, le 5y-Ad-DiaRem, inclut des parametres pre-operatoires (duree du DT2, nombre de traitements anti-DT2, HbA1C) et a 1 an (glycemie, nombre de traitements anti-DT2, statut de remission et perte de poids a 1 an). Le 5y-Ad-DiaRem predit precisement (aire sous la courbe ROC (AUROC) 90%, precision 85%) la remission a 5 ans, et ce mieux que le DiaRem et l’Ad-DiaRem (AUROC 81 et 84%, precision 79 et 78%, respectivement), ce qui a permis de reclassifier 13 des 39 patients mal classifies par le DiaRem. La robustesse du 5y-Ad-DiaRem a ete confirmee dans 3 cohortes independantes. Conclusions : le 5y-Ad-DiaRem predit precisement la DR a 5 ans, et semble utile pour identifier les patients a risque de rechute. Son utilisation pourrait permettre d’individualiser leur suivi apres la 1ere annee afin d’eviter cette rechute, en limitant par exemple la reprise de poids.

Obesity is a chronic low-grade inflammatory disease (both at the systemic and adipose tissue level) that continues to rise worldwide. It is associated with an abundance of comorbidities, including type 2 diabetes (T2D). Bariatric surgery, which induces modifications of the intestinal tract, is to date the most successful treatment for obesity. Its use has dramatically increased in number as it enables both weight reduction and metabolic improvements, with 60% of patients even achieving diabetes remission. Several mechanisms are actually demonstrated to be involved in those clinical improvements. Importantly, both obesity and T2D share many phenotypic characteristics, including increased systemic and adipose tissue inflammation, as well as gut microbiota dysbiosis. These characteristics are deeply modulated after bariatric surgery. This review will address the host metabolic changes observed after bariatric surgery, focusing on the induced gut architectural changes, as well as on the modifications of the inflammatory tone and the gut microbiota.

OBJECTIVE:Roux-en-Y gastric bypass (RYGB) induces type 2 diabetes remission (DR) in 60% of patients at 1 year, yet long-term relapse occurs in half of these patients. Scoring methods to predict DR outcomes 1 year after surgery that include only baseline parameters cannot accurately predict 5-year DR (5y-DR). We aimed to develop a new score to better predict 5y-DR.RESEARCH DESIGN AND METHODS:We retrospectively included 175 RYGB patients with type 2 diabetes with 5-year follow-up. Using machine learning algorithms, we developed a scoring method, 5-year Advanced-Diabetes Remission (5y-Ad-DiaRem), predicting longer-term DR postsurgery by integrating medical history, bioclinical data, and antidiabetic treatments. The scoring method was based on odds ratios and variables significantly different between groups. This score was further validated in three independent RYGB cohorts from three European countries.RESULTS:Compared with 5y-DR patients, patients who had relapsed after 5 years exhibited more severe type 2 diabetes at baseline, lost significantly less weight during the 1st year after RYGB, and regained more weight afterward. The 5y-Ad-DiaRem includes baseline (diabetes duration, number of antidiabetic treatments, and HbA1c) and 1-year follow-up parameters (glycemia, number of antidiabetic treatments, remission status, 1st-year weight loss). The 5y-Ad-DiaRem was accurate (area under the receiver operating characteristic curve [AUROC], 90%; accuracy, 85%) at predicting 5y-DR, performed better than the Diabetes Remission score (DiaRem) and the Advanced-DiaRem (AUROC, 81% and 84%; accuracy, 79% and 78%, respectively), and correctly reclassified 13 of 39 patients misclassified with the DiaRem. The 5y-Ad-DiaRem robustness was confirmed in the independent cohorts.CONCLUSIONS:The 5y-Ad-DiaRem accurately predicts 5y-DR and appears relevant to identify patients at risk for relapse. Using this score could help personalize patient care after the 1st year post-RYGB to maximize weight loss, limit weight regains, and prevent relapse.