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Intestinal gluconeogenesis (IGN), gastric bypass (GBP) and gut microbiota positively regulate glucose homeostasis and diet-induced dysmetabolism. GBP modulates gut microbiota, whether IGN could shape it has not been investigated. We studied gut microbiota and microbiome in wild type and IGN-deficient mice, undergoing GBP or not, and fed on either a normal chow (NC) or a high-fat/high-sucrose (HFHS) diet. We also studied fecal and urine metabolome in NC-fed mice. IGN and GBP had a different effect on the gut microbiota of mice fed with NC and HFHS diet. IGN inactivation increased abundance of Deltaproteobacteria on NC and of Proteobacteria such as Helicobacter on HFHS diet. GBP increased abundance of Firmicutes and Proteobacteria on NC-fed WT mice and of Firmicutes, Bacteroidetes and Proteobacteria on HFHS-fed WT mice. The combined effect of IGN inactivation and GBP increased abundance of Actinobacteria on NC and the abundance of Enterococcaceae and Enterobacteriaceae on HFHS diet. A reduction was observed in the amounf of short-chain fatty acids in fecal (by GBP) and in both fecal and urine (by IGN inactivation) metabolome. IGN and GBP, separately or combined, shape gut microbiota and microbiome on NC- and HFHS-fed mice, and modify fecal and urine metabolome.

SummaryOver the past decade, the gut microbiota has emerged as an important regulator of nervous system’s health and disease states1. Yet, its contribution to the pathogenesis of chronic somatic pain remains poorly documented. Chronic pain is a heavily debilitating disease affecting more than 1.5 billion people worldwide that can manifest through a long-lasting hypersensitivity to mechanical and/or thermal stimulations2,3. Maladaptive responses of dorsal root ganglia (DRG) neurons and spinal cord (SC) interneurons to tissue injuries and also of non-neuronal cells including DRG macrophages and SC microglia are acknowledged as important drivers of sensory symptoms underlying chronic pain4,3,5–7. Recent evidence shows that signals from gut microbiota are required for the initiation of injury-induced sensory hypersensitivity, via the ability to interact with the immune system8–11. However, whether and how gut microbiota promotes pain chronicity remains unknown. Here, we report that male mice lackingMyosin1a(KO)12raised under single genotype housing conditions (KO-SGH) are predisposed to develop chronic injury-induced mechanical pain. We demonstrate that this predisposition is caused by their dysbiotic gut microbiota, which sustains the immune response in the DRG following neuropathic injury. Parental antibiotic treatment modifies gut microbiota composition and completely rescues the injury-induced chronic pain and associated DRG inflammatory response in male KO-SGH offspring. Together, our data establish a causal relationship between a dysbiotic gut microbiota and the predisposition to injury-induced chronic pain.

ObjectivesClinical studies revealed that early-life adverse events contribute to the development of IBS in adulthood. The aim of our study was to investigate the relationship between prenatal stress (PS), gut microbiota and visceral hypersensitivity with a focus on bacterial lipopeptides containing γ-aminobutyric acid (GABA).DesignWe developed a model of PS in mice and evaluated, in adult offspring, visceral hypersensitivity to colorectal distension (CRD), colon inflammation, barrier function and gut microbiota taxonomy. We quantified the production of lipopeptides containing GABA by mass spectrometry in a specific strain of bacteria decreased in PS, in PS mouse colons, and in faeces of patients with IBS and healthy volunteers (HVs). Finally, we assessed their effect on PS-induced visceral hypersensitivity.ResultsPrenatally stressed mice of both sexes presented visceral hypersensitivity, no overt colon inflammation or barrier dysfunction but a gut microbiota dysbiosis. The dysbiosis was distinguished by a decreased abundance ofLigilactobacillus murinus, in both sexes, inversely correlated with visceral hypersensitivity to CRD in mice. An isolate from this bacterial species produced several lipopeptides containing GABA including C14AsnGABA. Interestingly, intracolonic treatment with C14AsnGABA decreased the visceral sensitivity of PS mice to CRD. The concentration of C16LeuGABA, a lipopeptide which inhibited sensory neurons activation, was decreased in faeces of patients with IBS compared with HVs.ConclusionPS impacts the gut microbiota composition and metabolic function in adulthood. The reduced capacity of the gut microbiota to produce GABA lipopeptides could be one of the mechanisms linking PS and visceral hypersensitivity in adulthood.

International audience; The identification of a functional molecular moiety relating the lipopolysaccharides (LPSs) to their capacity to induce inflammation-mediated metabolic diseases needed to be performed. We previously described a proportional increase in the relative abundance of the 16 SrDNA bacterial gene from the genus Ralstonia, within the microbiota from the adipose tissue stroma vascular fraction of obese patients, suggesting a causal role of the bacteria. Therefore, we first characterized the structures of the lipids A, the inflammatory inducing moieties of LPSs, of three Ralstonia species: Ralstonia eutropha, R. mannitolilytica and R. pickettii, and then compared each, in terms of in vitro inflammatory capacities. R. pickettii lipid A displaying only 5 Fatty Acids (FA) was a weaker inducer of inflammation, compared to the two other species harboring hexa-acylated lipids A, despite the presence of 2 AraN substituents on the phosphate groups. With regard to in vitro pro-inflammatory activities, TNF-alpha and IL-6 inducing capacities were compared on THP-1 cells treated with LPSs isolated from the three Ralstonia. R. pickettii, with low inflammatory capacities, and recently involved in nosocomial outcomes, could explain the low inflammatory level reported in previous studies on diabetic patients and animals. In addition, transmission electron microscopy was performed on the three Ralstonia species. It showed that the R. pickettii under-acylated LPSs, with a higher level of phosphate substitution had the capacity of producing more outer membrane vesicles (OMVs). The latter could facilitate transfer of LPSs to the blood and explain the increased low-grade inflammation observed in obese/diabetic patients. (C) 2019 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.

[Background]: The gut microbiome and iron status are known to play a role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), although their complex interaction remains unclear., [Results]: Here, we applied an integrative systems medicine approach (faecal metagenomics, plasma and urine metabolomics, hepatic transcriptomics) in 2 well-characterised human cohorts of subjects with obesity (discovery n = 49 and validation n = 628) and an independent cohort formed by both individuals with and without obesity (n = 130), combined with in vitro and animal models. Serum ferritin levels, as a markers of liver iron stores, were positively associated with liver fat accumulation in parallel with lower gut microbial gene richness, composition and functionality. Specifically, ferritin had strong negative associations with the Pasteurellaceae, Leuconostocaceae and Micrococcaea families. It also had consistent negative associations with several Veillonella, Bifidobacterium and Lactobacillus species, but positive associations with Bacteroides and Prevotella spp. Notably, the ferritin-associated bacterial families had a strong correlation with iron-related liver genes. In addition, several bacterial functions related to iron metabolism (transport, chelation, heme and siderophore biosynthesis) and NAFLD (fatty acid and glutathione biosynthesis) were also associated with the host serum ferritin levels. This iron-related microbiome signature was linked to a transcriptomic and metabolomic signature associated to the degree of liver fat accumulation through hepatic glucose metabolism. In particular, we found a consistent association among serum ferritin, Pasteurellaceae and Micrococcacea families, bacterial functions involved in histidine transport, the host circulating histidine levels and the liver expression of GYS2 and SEC24B. Serum ferritin was also related to bacterial glycine transporters, the host glycine serum levels and the liver expression of glycine transporters. The transcriptomic findings were replicated in human primary hepatocytes, where iron supplementation also led to triglycerides accumulation and induced the expression of lipid and iron metabolism genes in synergy with palmitic acid. We further explored the direct impact of the microbiome on iron metabolism and liver fact accumulation through transplantation of faecal microbiota into recipient’s mice. In line with the results in humans, transplantation from ‘high ferritin donors’ resulted in alterations in several genes related to iron metabolism and fatty acid accumulation in recipient’s mice., [Conclusions]: Altogether, a significant interplay among the gut microbiome, iron status and liver fat accumulation is revealed, with potential significance for target therapies., This work was supported by EU-FP7 FLORINASH (Health-F2-2009-241913) to R.B., M.F., J.M.F.R., E.H. and J.K.N. Infrastructure support was provided by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC). L.H. was in receipt of an MRC Intermediate Research Fellowship in Data Science (grant number MR/L01632X/1, UK Med-Bio). This work was also partly supported by funding to M.-E.D. (EU METACARDIS under agreement HEALTH-F4-2012-305312, Neuron II under agreement 291840 and the MRC MR/M501797/1) and by grants from the French National Research Agency (ANR-10-LABX-46 [European Genomics Institute for Diabetes]), from the National Center for Precision Diabetic Medicine – PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), by the European Union (FEDER), by the Hauts-de-France Regional Council (Agreement 20001891/NP0025517) and by the European Metropolis of Lille (MEL, Agreement 2019_ESR_11) and by Isite ULNE (R-002-20-TALENT-DUMAS), also jointly funded by ANR (ANR-16-IDEX-0004-ULNE) the Hauts-de-France Regional Council (Agreement 20002045) and by the European Metropolis of Lille (MEL). J.M.-P. is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP18/00009), co-funded by the European Social Fund ‘Investing in your future’. María Arnoriaga Rodríguez is funded by a predoctoral Río Hortega contract (CM19/00190, co-funded by European Social Fund ‘Investing in your future’) from the Instituto de Salud Carlos III, Spain. This work was supported by grants to AM from the Spanish Ministry of Science and Innovation (PID2019-105969GB-I00) and Generalitat Valenciana (project Prometeo/2018/133).

Infections of genotoxic Escherichia coli spread concomitantly with urbanized progression. These bacteria may prompt cell senescence and affect DNA stability, inducing cancer via the production of colibactin, a genotoxin shown capable of affecting host DNA in eukaryotic cells. In this study, we show that the action of colibactin may also be directed against other bacteria of the gut microbiota in which genotoxic E. coli bacteria have been introduced. Indeed, the presence of genotoxic E. coli induced a change in both the structure and function of the gut microbiota. Our data indicate that genotoxic E. coli may use colibactin to compete for gut niche utilization., The genotoxin colibactin produced by resident bacteria of the gut microbiota may have tumorigenic effect by inducing DNA double-strand breaks in host cells. Yet, the effect of colibactin on gut microbiota composition and functions remains unknown. To address this point, we designed an experiment in which pregnant mice were colonized with the following: (i) a commensal Escherichia coli strain, (ii) a commensal E. coli strain plus a genotoxic E. coli strain, (iii) a commensal E. coli strain plus a nongenotoxic E. coli mutant strain unable to produce mature colibactin. Then, we analyzed the gut microbiota in pups at day 15 and day 35 after birth. At day 15, mice that were colonized at birth with the genotoxic strain showed lower levels of Proteobacteria and taxa belonging to the Proteobacteria, a modest effect on overall microbial diversity, and no effect on gut microbiome. At day 35, mice that received the genotoxic strain showed lower Firmicutes and taxa belonging to the Firmicutes, together with a strong effect on overall microbial diversity and higher microbial functions related to DNA repair. Moreover, the genotoxic strain strongly affected gut microbial diversity evolution of pups receiving the genotoxic strain between day 15 and day 35. Our data show that colibactin, beyond targeting the host, may also exert its genotoxic effect on the gut microbiota. IMPORTANCE Infections of genotoxic Escherichia coli spread concomitantly with urbanized progression. These bacteria may prompt cell senescence and affect DNA stability, inducing cancer via the production of colibactin, a genotoxin shown capable of affecting host DNA in eukaryotic cells. In this study, we show that the action of colibactin may also be directed against other bacteria of the gut microbiota in which genotoxic E. coli bacteria have been introduced. Indeed, the presence of genotoxic E. coli induced a change in both the structure and function of the gut microbiota. Our data indicate that genotoxic E. coli may use colibactin to compete for gut niche utilization.

Background: Necrotizing enterocolitis (NEC) is a devastating condition in preterm infants due to multiple factors, including gut microbiota dysbiosis. NEC development is poorly understood, due to the focus on severe NEC (NEC-2/3). Methods: We studied the gut microbiota, microbiome and metabolome of children with suspected NEC (NEC-1). Results: NEC-1 gut microbiota had a higher abundance of the Streptococcus (second 10-days of life) and Staphylococcus (third 10-days of life) species. NEC-1 children showed a microbiome evolution in the third 10-days of life being the most divergent, and were associated with a different metabolomic signature than in healthy children. The NEC-1 microbiome had increased glycosaminoglycan degradation and lysosome activity by the first 10-days of life, and was more sensitive to childbirth, low birth weight and gestational age, than healthy microbiome. NEC-1 fecal metabolome was more divergent by the second month of life. Conclusions: NEC-1 gut microbiota and microbiome modifications appear more distinguishable by the third 10-days of life, compared to healthy children. These data identify a precise window of time (i.e., the third 10-days of life) and provide microbial targets to fight/blunt NEC-1 progression.

figures for JCM submission

Backgrounds & AimsAs the bile acid (BA) pool composition is of major impact on liver pathophysiology, we studied its regulation by the BA receptor TGR5, promoting hepatoprotection against BA overload.MethodsWT, total and hepato-specific TGR5-KO, and TGR5-overexpressing mice were used in: partial and 90% extended hepatectomies (EH) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (1%)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied TGR5 impact on: BA pool composition, liver injury, regeneration and survival. Particular focus was made on gut microbiota (GM) and gallbladder (GB) function analysis. BA pool composition was analyzed in patients undergoing major hepatectomy.ResultsThe TGR5-KO hyperhydrophobic BA pool was not related to BA synthesis alteration, nor to the TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and cohousing experiments. The TGR5-dependent control of GB dilatation was crucial for BA pool composition, as determined by experiments including RO treatment +/− cholecystectomy. The poor TGR5-KO post-EH survival rate, related with exacerbated peribiliary necrosis and BA overload, was improved by shifting the BA pool towards a more hydrophilic composition (CT and UDCA treatments). After either BDL or CA-enriched diet +/− cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic BA pool was correlated with an unfavorable outcome after hepatectomy.ConclusionBA pool composition is crucial for hepatoprotection in mice and humans. We point TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions.Lay summaryThrough multiple in vivo experimental approaches in mice, together with a patients study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function and liver protection. We showed that the bile acid pool composition is crucial for optimal liver repair, not only in mice but also in human patients undergoing major hepatectomy.

Background : Necrotizing enterocolitis (NEC) is a devastating condition of the preterm new-born due to multiple factors, including gut microbiota dysbiosis. Since NEC development is poorly understood due to main focus on late stages 2 and 3, we studied the gut microbiota and metabolome evolution of NEC at a very early onset. Results NEC-1 gut microbiota had a higher abundance of Streptococcus (second decade of life) and Staphylococcus (third decade of life) species. NEC-1 children showed a microbiome evolution in the third decade of life being the most divergent and associated to a different metabolomic signature than in healthy children. NEC-1 microbiome had increased glycosaminoglycan degradation and lysosome activity by the first decade of life and was more sensitive to factors such as childbirth, low birth weight and gestational age, than healthy microbiome. NEC-1 fecal metabolome was more divergent by the second month of life. Conclusions: The modifications of gut microbiota and microbiome during NEC-1 development appear more distinguishable by the third decade of life, when compared to healthy children. These data identify a precise window of time (i.e. third decade of life) and provide microbial targets to fight/blunt the progression of NEC by stage 1.

Necrotizing enterocolitis (NEC) is a devastating condition of the preterm new-born due to multiple factors, including gut microbiota dysbiosis. Since NEC development is poorly understood due to main focus on more severe NEC (NEC-2/3), we studied the gut microbiota and metabolome evolution of of children with suspected NEC (NEC-1). NEC-1 gut microbiota had a higher abundance of Streptococcus (second decade of life) and Staphylococcus (third decade of life) species. NEC-1 children showed a microbiome evolution in the third decade of life being the most divergent and associated to a different metabolomic signature than in healthy children. NEC-1 microbiome had increased glycosaminoglycan degradation and lysosome activity by the first decade of life and was more sensitive to factors such as childbirth, low birth weight and gestational age, than healthy microbiome. NEC-1 fecal metabolome was more divergent by the second month of life. The modifications of gut microbiota and microbiome during NEC-1 development appear more distinguishable by the third decade of life, when compared to healthy children. These data identify a precise window of time (i.e. third decade of life) and provide microbial targets to fight/blunt the progression of NEC-1. Funding Statement: This study was in part supported by the company Longevie SA in the persons of Michel LOSETO and Enzo LOSETO, as a donation to M.S. Longevie SA was not involved in any discussion nor provided any opinion on any part of this manuscript. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study was approved (number of the approval: DC 2016-2804) by Neonatal and Pediatric Intensive Care Unit and Neonatology Department of Purpan Hospital in Toulouse, France. The parents of the children involved in this study gave their approval by written consensus.

International audience; SCOPE: Targeting gut microbiota dysbiosis by prebiotics is effective, though side-effects such as abdominal bloating and flatulence may arise following high prebiotic consumption over weeks. Our aim was therefore to optimize the current protocol for prebiotic use. METHODS AND RESULTS: To examine the prebiotic properties of plant extracts, we conducted two independent studies in ob/ob mice, over two weeks. In the first study, we evaluated Porphyra umbilicalis and Melissa officinalis L. extracts; in the second study, we assessed a high- vs. low-dose of an Emblica officinalis Gaertn extract. These plant extracts affected gut microbiota, caecum metabolome and induced a significant lower plasma triacylglycerols (TG) following the treatment with P. umbilicalis and significant higher plasma free fatty acids (FFA) following treatment with the low-dose of E. officinalis Gaertn. Glucose- and insulin-tolerance were not affected but white adipose tissue and liver gene expression were modified. In the first study, IL-6 hepatic gene expression was significantly (adjusted P = 0.0015) and positively (r = 0.80) correlated with the bacterial order Clostridiales in all mice. CONCLUSION: Our data show that a 2-week treatment with plant extracts affects the dysbiotic gut microbiota and changes both caecum metabolome and markers of lipid metabolism in ob/ob mice.

International audience; It has recently become evident that the periodontium (gingiva, desmodontal ligament, cementum and alveolar bone) and the associated microbiota play a pivotal role in regulating human health and diseases. The oral cavity is the second largest microbiota in the body with around 500 different bacterial species identified today. When disruption of oral cavity and dysbiosis occur, the proportion of strict anaerobic Gram-negative bacteria is then increased. Patients with periodontitis present 27 to 53% more risk to develop diabetes than the control population suggesting that periodontitis is an aggravating factor in the incidence of diabetes. Moreover, dysbiosis of oral microbiota is involved in both periodontal and metabolic disorders (cardiovascular diseases, dyslipidaemia …). The oral diabetic dysbiosis is characterized by a specific bacteria Porphyromonas, which is highly expressed in periodontal diseases and could exacerbate insulin resistance. In this review, we will address the nature of the oral microbiota and how it affects systemic pathologies with a bidirectional interaction. We also propose that using prebiotics like Akkermansia muciniphila may influence oral microbiota as novel therapeutic strategies. The discovery of the implication of oral microbiota for the control of metabolic diseases could be a new way for personalized medicine.

International audience; By combining genetic, metagenomic and metabolic data in humans, a recent study has identified causal relationships between the capacity of gutmicroorganisms to produce short-chain fatty acids, such as butyrate and propionate, and metabolic traits of the host, including insulin response during an oral glucose tolerance test and susceptibility to type 2 diabetes mellitus.

The human microbiota is a modulator of the immune system. Variations in the placental microbiota could be related with pregnancy disorders. We profiled the placental microbiota and microbiome in women with gestational diabetes (GDM) and studied its relation to maternal metabolism and placental expression of anti-inflammatory cytokines. Placental microbiota and microbiome and expression of anti-inflammatory cytokines (IL10, TIMP3, ITGAX, and MRC1MR) were analyzed in placentas from women with GDM and from control women. Fasting insulin, glucose, O’Sullivan glucose, lipids, and blood cell counts were assessed at second and third trimester of pregnancy. Bacteria belonging to the Pseudomonadales order and Acinetobacter genus showed lower relative abundance in women with GDM compared to control (P < 0.05). In GDM, lower abundance of placental Acinetobacter associated with a more adverse metabolic (higher O’Sullivan glucose) and inflammatory phenotype (lower blood eosinophil count and lower placental expression of IL10 and TIMP3) (P < 0.05 to P = 0.001). Calcium signaling pathway was increased in GDM placental microbiome. A distinct microbiota profile and microbiome is present in GDM. Acinetobacter has been recently shown to induce IL-10 in mice. GDM could constitute a state of placental microbiota-driven altered immunologic tolerance, making placental microbiota a new target for therapy in GDM.

Gut microbes are active participants of host metabolism. At birth, child physiology is committed towards healthiness or sickness depending, in part, on maternal condition (i.e. lean vs obesity) and delivery. Finally, changes from breastfeeding to solid food also account to define gut microbiota ecology in adulthood. Nowadays, alterations of gut microbiota, named dysbiosis, are acquired risk factors for multiple diseases, especially type 2 diabetes and obesity. Despite important evidence linking nutrition to dysbiosis to energetic dysmetabolism, molecular mechanisms for causality are still missing. That the status of gut microbiota of mother and child is crucial for future diseases is witnessed by adulthood overweight and obesity observed in children with dysbiosis. In this short review we highlight the importance of early life events related to the microbiota and their impact on future adult disease risk. Therefore, our effort to treat or prevent metabolic diseases should be addressed towards early or previous life steps, when microbial decisions are going to affect our metabolic fate.

International audience; OBJECTIVE: To identify a causal mechanism responsible for the enhancement of insulin resistance and hyperglycaemia following periodontitis in mice fed a fat-enriched diet. DESIGN: We set-up a unique animal model of periodontitis in C57Bl/6 female mice by infecting the periodontal tissue with specific and alive pathogens like Porphyromonas gingivalis (Pg), Fusobacterium nucleatum and Prevotella intermedia. The mice were then fed with a diabetogenic/non-obesogenic fat-enriched diet for up to 3 months. Alveolar bone loss, periodontal microbiota dysbiosis and features of glucose metabolism were quantified. Eventually, adoptive transfer of cervical (regional) and systemic immune cells was performed to demonstrate the causal role of the cervical immune system. RESULTS: Periodontitis induced a periodontal microbiota dysbiosis without mainly affecting gut microbiota. The disease concomitantly impacted on the regional and systemic immune response impairing glucose metabolism. The transfer of cervical lymph-node cells from infected mice to naive recipients guarded against periodontitis-aggravated metabolic disease. A treatment with inactivated Pg prior to the periodontal infection induced specific antibodies against Pg and protected the mouse from periodontitis-induced dysmetabolism. Finally, a 1-month subcutaneous chronic infusion of low rates of lipopolysaccharides from Pg mimicked the impact of periodontitis on immune and metabolic parameters. CONCLUSIONS: We identified that insulin resistance in the high-fat fed mouse is enhanced by pathogen-induced periodontitis. This is caused by an adaptive immune response specifically directed against pathogens and associated with a periodontal dysbiosis

Evidence from animals suggests that gut microbiota affects brain structure and function but evidence in humans is scarce.This study sought to evaluate potential interactions among gut microbiota composition, brain microstructure, and cognitive tests in obese and nonobese subjects.This was a cross-sectional study at a tertiary hospital including 20 consecutive obese and 19 nonobese subjects similar in age and sex.Gut microbiota (16S bacterial gene pyrosequencing), brain microstructure (diffusion tensor imaging of brain white and gray matter and R2* sequences in magnetic resonance imaging) and cognitive tests.Hierarchical clustering revealed a specific gut microbiota-brain map profile for obese individuals who could be discriminated from nonobese subjects (accuracy of 0.81). Strikingly, Shannon index was linked to R2* and fractional anisotropy of the hypothalamus, caudate nucleus, and hippocampus, suggesting sparing of these brain structures with increased bacterial biodiversity. Microbiota profile also clustered with cognitive function. The relative abundance of Actinobacteria phylum was linked not only to magnetic resonance imaging diffusion tensor imaging variables in the thalamus, hypothalamus, and amygdala but also to cognitive test scores related to speed, attention, and cognitive flexibility.In sum, obesity status affects microbiota-brain microstructure and function crosstalk.

In the version of this article originally published, the received date was missing. It should have been listed as 2 January 2018. The error has been corrected in the HTML and PDF versions of this article.

Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies. Metabolic activity of specific human gut microorganisms contributes to liver steatosis in obese women.

International audience; Alterations of both ecology and functions of gut microbiota are conspicuous traits of several inflammatory pathologies, notably metabolic diseases such as obesity and type 2 diabetes. Moreover, the proliferation of enterobacteria, subdominant members of the intestinal microbial ecosystem, has been shown to be favored by Western diet, the strongest inducer of both metabolic diseases and gut microbiota dysbiosis. The inner interdependence between the host and the gut microbiota is based on a plethora of molecular mechanisms by which host and intestinal microbes modify each other. Among these mechanisms are as follows: (i) the well-known metabolic impact of short chain fatty acids, produced by microbial fermentation of complex carbohydrates from plants; (ii) a mutual modulation of miRNAs expression, both on the eukaryotic (host) and prokaryotic (gut microbes) side; (iii) the production by enterobacteria of virulence factors such as the genotoxin colibactin, shown to alter the integrity of host genome and induce a senescence-like phenotype in vitro; (iv) the microbial excretion of outer-membrane vesicles, which, in addition to other functions, may act as a carrier for multiple molecules such as toxins to be delivered to target cells. In this review, I describe the major molecular mechanisms by which gut microbes exert their metabolic impact at a multi-organ level (the gut barrier being in the front line) and support the emerging triad of metabolic diseases, gut microbiota dysbiosis and enterobacteria infections.

Objective Elite athletes are prone to develop oral diseases, which could increase the risk for injuries. The aim of this study was to evaluate the oral health and the composition of oral microbiota of elite rugby players compared to the general population. Methods We set up a case-control study by screening 24 professional rugby players (PRG) and 22 control patients (CG) for dental and gingival examinations and performed a taxonomic analysis and a predicted functional analysis of oral microbiota. Results The Decay, Missing and Filled (DMF) teeth index (5.54 ± 6.18 versus 2.14 ± 3.01; p = 0.01) and the frequency of gingivitis (58,33% versus 13.63%) were significantly increased in PRG compared to CG. PRG were characterized by a dysbiotic oral microbiota (Shannon Index: 3.32 ± 0.62 in PRG versus 3.79 ± 0.68 in CG; p = 0.03) with an increase of Streptococcus (58.43 ± 16.84 versus 42.60 ± 17.45; p = 0.005), the main genus implicated in caries. Predicted metagenomics of oral microbiota in rugby players was suggestive of a cariogenic metagenome favourable to the development of caries. Conclusions Our study shows that the oral health of PRG was poorer than the general population. PRG are characterized by a dysbiotic oral microbiota with an increase of the relative abundance of Streptococcus genus, positively correlated to the weight and negatively correlated to the diversity of oral microbiota. Clinical significance Dental screening should be included in the medical follow-up of professional rugby players as a part of their health management. New strategies such as using probiotics like Lactobacillus could help to control the dysbiosis of oral microbiota.

Pattern recognition receptors link metabolite and bacteria-derived inflammation to insulin resistance during obesity. We demonstrate that NOD2 detection of bacterial cell wall peptidoglycan (PGN) regulates metabolic inflammation and insulin sensitivity. An obesity-promoting high-fat diet (HFD) increased NOD2 in hepatocytes and adipocytes, and NOD2(-/-) mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a HFD. This effect is independent of altered adiposity or NOD2 in hematopoietic-derived immune cells. Instead, increased metabolic inflammation and insulin resistance in NOD2(-/-) mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact PGN-NOD2 sensing system regulated gut mucosal bacterial colonization and a metabolic tissue dysbiosis that is a potential trigger for increased metabolic inflammation and insulin resistance. Gut dysbiosis in HFD-fed NOD2(-/-) mice is an independent and transmissible factor that contributes to metabolic inflammation and insulin resistance when transferred to WT, germ-free mice. These findings warrant scrutiny of bacterial component detection, dysbiosis, and protective immune responses in the links between inflammatory gut and metabolic diseases, including diabetes.

cope : To examine the potential relationship among gene expression markers of adipose tissue browning, gut microbiota and insulin sensitivity in humans. Methods and results : Gut microbiota composition and gene markers of browning were analysed in subcutaneous (SAT) and visceral (VAT) adipose tissue from morbidly obese subjects (n = 34). Plasma acetate was measured through 1H NMR and insulin sensitivity using euglycemic hyperinsulinemic clamp. Subjects with insulin resistance showed an increase in the relative abundance (RA) of the phyla Bacteroidetes and Proteobacteria while RA of Firmicutes was decreased. In all subjects, Firmicutes RA was negatively correlated with HbA1c and fasting triglycerides, whereas Proteobacteria RA was negatively correlated with insulin sensitivity. Firmicutes RA was positively associated with markers of brown adipocytes (PRDM16, UCP1 and DIO2) in SAT, but not in VAT. Multivariate regression analysis indicated that Firmicutes RA contributed significantly to SAT PRDM16, UCP1 and DIO2 mRNA variance after controlling for age, BMI, HbA1c or insulin sensitivity. Interestingly, Firmicutes RA, specifically those bacteria belonging to Ruminococcaceae family, was positively associated with plasma acetate levels, which were also linked to SAT PRDM16 mRNA and insulin sensitivity. Conclusion : Gut microbiota composition is linked to adipose tissue browning and insulin action in morbidly obese subjects, possibly through circulating acetate. This article is protected by copyright. All rights reserved

Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4 months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin–microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla, and many of the metformin-regulated genes in these species encoded metalloproteins or metal transporters. Our findings provide support for the notion that altered gut microbiota mediates some of metformin's antidiabetic effects.

The purpose of this study was to investigate the expression of human adipose tissue protein 53 (p53) in subjects who varied widely in terms of obesity and insulin resistance. We also analyzed different in vivo and in vitro models to try to comprehend the associations found in humans.p53 was analyzed in human adipose and isolated adipocytes, in high fat-fed and GLP-1R KO mice, during in vitro adipogenesis, and in adipocytes after high glucose, rosiglitazone and inflammatory conditions. The effects of surgery-induced weight loss and ex vivo metformin were also evaluated.Omental (OM) p53 gene expression (+27%, P=0.001) and protein (+11%, P=0.04) were increased in obese subjects and high fat diet-induced obese mice (+86%, P=0.018). Although the obesity-associated inflammatory milieu was associated with increased OM p53, this was negatively related to insulin resistance and glycated hemoglobin, and positively with biomarkers for insulin sensitivity. Multiple linear regression analyses revealed that glycated hemoglobin (P0.0001) and body mass index (P=0.048) contributed independently to explain 13.7% (P0.0001) of the OM p53 variance. Accordingly, the improvement of insulin sensitivity with surgery-induced weight loss (+51%, P=0.01) and metformin (+42%, P=0.02) led to increased adipose p53. While the glucose-intolerant GLP-1R KO mice showed decreased mesenteric p53 (-45.4%, P=0.017), high glucose led to decreased p53 in pre-adipocytes (-27%, P0.0001). Inflammatory treatments led to increased p53 (+35%, P0.0001), while Rs downregulated this expression (-40%, P=0.005) in mature adipocytes.Inflammation and insulin resistance exert dual effects on adipose p53, which seems to be the final result of these opposing forces.

Over the last decade, the research community has revealed the role of a new organ: the intestinal microbiota. It is considered as a symbiont that is part of our organism since, at birth, it educates the immune system and contributes to the development of the intestinal vasculature and most probably the nervous system. With the advent of new generation sequencing techniques, a catalogue of genes that belong to this microbiome has been established that lists more than 5 million non-redundant genes called the metagenome. Using germ free mice colonized with the microbiota from different origins, it has been formally demonstrated that the intestinal microbiota causes the onset of metabolic diseases. Further to the role of point mutations in our genome, the microbiota can explain the on-going worldwide pandemic of obesity and diabetes, its dissemination and family inheritance, as well as the diversity of the associated metabolic phenotypes. More recently, the discovery of bacterial DNA within host tissues, such as the liver, the adipose tissue and the blood, which establishes a tissue microbiota, introduces new opportunities to identify targets and predictive biomarkers based on the host to microbiota interaction, as well as to define new strategies for pharmacological, immunomodulatory vaccines and nutritional applications.

La derniere decennie a vu la decouverte d’un nouvel organe, le microbiote intestinal, caracterise par d’immenses et pleiotropes fonctions biologiques. Les milliards de cellules qui le constituent sont en tres etroite harmonie fonctionnelle avec leur hote. Ainsi, plus de 4 millions de genes bacteriens repartis dans plus de 1 500 especes discourent entre eux, avec l’organisme et avec l’environnement pour etablir une ecologie mutualisee. Tout desequilibre nutritionnel revient a modifier cette symbiose et, ainsi, a changer les relations qui existent avec les bacteries elles-memes pour le controle de notre metabolisme energetique. La pandemie actuelle de diabete de type 2 et d’obesite ne peut etre uniquement liee aux variations de notre genome. Ainsi, elle pourrait trouver son origine dans notre metagenome, c’est-a-dire dans des millions de genes bacteriens presents dans notre intestin. Cet organe, dont la genomique plastique se renouvelle au quotidien, nous est transmis par nos parents, mais il est egalement influence par nos habitudes de vie et notre environnement a la naissance. Sa diversite, son caractere evolutif rapide, son influence sur le metabolisme, ainsi que la decouverte d’un microbiote interne tissulaire a l’interieur de l’organisme, ouvrent de nouvelles opportunites therapeutiques pharmacologiques et nutritionnelles, ainsi que la possibilite d’identifier l’etat physiopathologique de chaque individu par des biomarqueurs tres precis composant la fiche signaletique metagenomique. Ainsi, la medecine individualisee trouve, dans le metagenome, l’origine meme de son ambition.

Personalized medicine is becoming day-after-day more urgent taking into account the great diversity characterizing patients affected by a given pathology, especially metabolic diseases. In fact, antidiabetic/obesity treatments have shown a reduced or no effect at all in some patients, representing a major challenge physicians have to face worldwide. Therefore, efforts have to be put to identify individual factors affecting our susceptibility towards a given medication. In that regard, gut microbiota may stand for the missing piece of the metabolic puzzle regulating host response, since its role in the induction of metabolic diseases has now been achieved. In fact, we firstly provided a bacterial explanation for the low-grade chronic inflammation featuring metabolic diseases, by showing the lipopolysaccharide as a trigger and risk factor of such pathologies. However, despite similar lineages of microbes characterize the gut of people, important differences still remain, which may be responsible for opposite effect of treatments such as pre- or probiotics, whose efficacy seems to be governed by the own gut microbiota of subjects. We have recently shown that gut microbiota is associated to the inclination to resist or not high-fat diet-induced type 2 diabetes in mice. In addition, the direct targeting of gut microbes by dietary fibers reversed the observed metabolic phenotype. These results, together with the literature, strongly suggest gut microbiota as a new target for the development of personalized metabolic therapy.

Calgranulin B (S100A9) was recognized as a candidate type 2 diabetes (T2D) gene in the genomic profiling of muscle from a rodent model of T2D and identifying the human orthologs of genes localized in T2D susceptibility regions. Circulating and S100A9 expressions in muscle and adipose tissue, isolated fat cells, and mouse models were evaluated. A common 5'-upstream single-nucleotide polymorphism (SNP; rs3014866) for S100A9 was analyzed, as well as the effects of weight loss and treatments in vitro with recombinant S100A9. S100a9 expression was increased in muscle of diabetic mice (1.6-fold, p = 0.002), and in muscle from subjects with impaired glucose tolerance (∼4-fold, p = 0.028; n = 34). The rs3014866 SNP was associated with circulating S100A9 and the risk of T2D, having TT carriers at 28 % (p = 0.03) lower risk (n = 1,450). Indeed, increased circulating S100A9 (∼4-fold, p = 0.03; n = 206) and subcutaneous (2-fold, p = 0.01) and omental (1.4-fold, p = 0.04) S100A9 gene expressions (n = 83) in TT carriers run in parallel to decreased fasting glucose and glycated hemoglobin. Accordingly, metformin led to increased S100A9 mRNA in ex vivo-treated adipose tissue explants (n = 5/treatment). Otherwise, obese subjects showed a compensatory increase in circulating and S100A9 expressions in adipose (n = 126), as further demonstrated by decreased levels after diet- (-34 %, p = 0.002; n = 20) and surgery-induced (-58 %, p = 0.02; n = 8) weight loss. Lipopolysaccharide led to increased S100A9 in adipose from mice (n = 5/treatment) while recombinant S100A9 downregulated inflammation in adipocytes (n = 3/treatment). Current findings support the strategy of testing differentially expressed genes in mice and human orthologs associated with T2D. The increased S100A9 reported for obesity and insulin resistance may be envisioned as a compensatory mechanism for inflammation.

The early detection of liver fibrosis among patients with nonalcoholic fatty liver disease (NAFLD) is an important clinical need. In view of the suggested role played by bacterial translocation in liver disease and obesity, we sought to investigate the relationship between blood microbiota and liver fibrosis (LF) in European cohorts of patients with severe obesity. We carried out a cross-sectional study of obese patients, well characterized with respect to the severity of the NAFLD, in the cohort FLORINASH. This cohort has been divided into a discovery cohort comprising 50 Spanish patients and then in a validation cohort of 71 Italian patients. Blood bacterial DNA was analyzed both quantitatively by 16S ribosomal DNA (rDNA) quantitative polymerase chain reaction and qualitatively by 16S rDNA targeted metagenomic sequencing and functional metagenome prediction. Spanish plasma bile acid contents were analyzed by liquid chromatography/mass spectrometry. The 16S rDNA concentration was significantly higher in patients of the discovery cohort with LF. By 16S sequencing, we found specific differences in the proportion of several bacterial taxa in both blood and feces that correlate with the presence of LF, thus defining a specific signature of the liver disease. Several secondary/primary bile acid ratios were also decreased with LF in the discovery cohort. We confirmed, in the validation cohort, the correlation between blood 16S rDNA concentration and LF, whereas we did not confirm the specific bacterial taxa signature, despite a similar trend in patients with more-severe fibrosis.Changes in blood microbiota are associated with LF in obese patients. Blood microbiota analysis provides potential biomarkers for the detection of LF in this population. (Hepatology 2016;64:2015-2027).

The identification of molecular factors bridging gut microbiota dysbiosis to alterations of host metabolism still remains a major goal in biomedical research. In fact, on one hand, there is a worldwide consensus about the systemic impact, from brain to liver, from heart to adipose tissue, of gut microbiota dysbiosis. On the other hand, beyond the microbial production of short chain fatty acids and their vast metabolic properties, little is known about the molecular mechanisms linking a change in the activity of gut microbes to a modification of host cell metabolism. In this context, microRNAs (also known as miRs) are promising molecules which could allow explaining how dysbiosis is converted into metabolic outcomes since: 1- miRs are pleiotropic regulators of gene expression, targeting multiple mRNAs at once; 2- miRs expression in specific organs such as the intestine has been demonstrated to be under the control of gut microbiota; 3- alterations in miRs expression have been found in the majority of tissues targeted by gut microbiota dysbiosis during metabolic diseases such as liver, adipose tissue, pancreas, skeletal muscle, intestine, heart and also the brain. In this short review major publications in the growing field of miRs-based metabolic control at a systemic level will be discussed together with a putative link with gut microbiota dysbiosis.

Over the last five years an increasing effort has been made to understand the role of intestinal microbiota in health and disease, resulting in regarding to it as a new organ actively involved in the control of host metabolism, both in humans and mice. Amongst hundreds (up to thousand) germ species inhabiting the intestine, few of them are cultivable. Nevertheless, next-generation sequencing-based molecular technologies have been developed, allowing to overcome this problem and shed light on the way the gut microbiota undergoes dramatic changes during (patho)-physiological modifications of the host. Hence, the study of the overall gut germ genome (metagenome) and transcriptome (microbiome) has been launched. Thus, Genomics and Transcriptomics have begun to be increasingly used, opening the so called "Omics" era, including Proteomics and Metabolomics techniques as well. Taken together, the "Omics" allow the study of gut microbiota impact on whole host metabolism, resulting in the definition of new metabolic profiles (i.e. the presence of metabolites within the blood defines a metabolomic profile), others than those based on nucleic acid analyses only. Once demonstrated the involvement of gut microbiota within metabolic diseases, "Omics" analyses has allowed the identification of the obesity-induced gut microbiota imbalance, characterized by increased Firmicutes to Bacteroidetes ratio (metagenomics) and of the so called "core microbiome", focusing on the gut microbiota at a gene- rather than, solely, at a taxonomic-level. In addition, metabolomics studies revealed, for instance, the implication of gut microbiota to nonalcoholic fatty liver disease in insulin-resistant mice. Additionally, the use of germ-free (axenic) mice has made possible the microflora transfer to investigate the mechanisms through which gut microbes modulate host metabolism, albeit the molecular actors of the host� � � gut-microbiota interplay remain to be fully determined. Here, we report the role of "Omics" in the multiple analyses of gut microbiota-driven metabolic modifications of the host, proposing also to focus on lipopolysaccharides (LPS), the Gram negative proinflammatory molecules we already showed to be the initiators of metabolic diseases.

International audience; The role of the gut microbiota in the induction of metabolic diseases has now been increasingly recognized worldwide. Indeed, a specific gut microbiota has been shown to characterize lean versus obese phenotypes both in humans and mice. We have also recently demonstrated that a precise gut microbiota is associated with the host's responsiveness to a high-fat diet. Therefore, we hypothesized that insulin resistance in humans could also be linked to a specific gut microbiota. To this aim, microbial DNA and RNA were extracted from the appendix contents of insulin-resistant versus insulin-sensitive obese subjects, matched for body mass index and age, and analyzed by DNA- and RNA-DGGE. Microbial DNA analysis showed that the patients fully segregated according to their degree of insulin action. Conversely, microbial RNA investigation showed that some degree of homology still existed between insulin-sensitive and insulin-resistant patients. Quantitative trait analysis, ordinary least squares regression, principal components regression, partial least squares, canonical correlation analysis, and canonical correspondence analysis also showed a net separation of the two phenotypes analyzed. We conclude that a specific gut microbial profile is associated with insulin action in humans.