Obesity and type 2 diabetes are associated with low-grade inflammation and specific 34 changes in gut microbiota composition [1][2][3][4][5][6][7] . We previously demonstrated that administration 35 of Akkermansia muciniphila prevents the development of obesity and associated 36 complications 8 . However, its mechanisms of action remain unclear, whilst the sensitivity of 37 A. muciniphila to oxygen and the presence of animal-derived compounds in its growth 38 medium currently limit the development of translational approaches for human medicine 9 . 39Here we addressed these issues by showing that A. muciniphila retains its efficacy when Akkermansia muciniphila is one of the most abundant members of the human gut 53 microbiota, representing between 1 and 5% of our intestinal microbes 10,11 to improve glucose intolerance and insulin resistance regardless of the growth medium used and 71 independently of food intake ( Fig. 1a-g). 72 We previously showed that autoclaving A. muciniphila abolished its beneficial effects 8 . (Fig. 1a-c and Supplemental Fig. 1a-c). In both sets of 81 experiments, we found that mice treated with pasteurized A. muciniphila displayed a much lower 82 glucose intolerance and insulin concentration when compared to the HFD group, resulting in a 83 lower insulin resistance (IR) index (Fig. 1d-g and Supplemental Fig. 1d-g). Treatment with 84 pasteurized A. muciniphila also led to greater goblet cell density in the ileum when compared to 85 ND-fed mice (Fig. 1h), suggesting a higher mucus production, while normalizing the mean 86 adipocyte diameter (Fig. 2a-b) and significantly lowering plasma leptin when compared to HFD-87 fed mice (Fig. 2c). These effects were not observed in mice treated with live A. muciniphila. A 88 similar trend could be observed for plasma resistin (Supplemental Fig. 1h), thereby suggesting 89 improved insulin sensitivity, while plasma adiponectin remained unaffected in all conditions 90 (Supplemental Fig. 1i). We found that mice treated with pasteurized A. muciniphila had a higher 91 fecal caloric content when compared to all other groups (Fig. 2d), suggesting a lower energy (Fig. 2e-g). This resulted in a normalization of the HFD-induced shift of 37% with the 104 pasteurized bacterium, and 17% with the live bacterium ( Fig. 2f). 105By comparing the metabolic profiles of the different groups, we found that the shift 106 induced by pasteurized A. muciniphila was mainly associated with trimethylamine (TMA) and TMA to TMAO, a metabolite associated with atherosclerosis 19,20 . While exposure to a HFD led 114 to a two-fold higher Fmo3 expression when compared to ND-fed mice, treatment with 115 pasteurized A. muciniphila reversed this effect (Fig. 2j) Fmo3 expression were not associated with a modification of plasma TMA and TMAO, as all 121 HFD-fed group displayed similar concentrations for both metabolites (Fig. 2k,l) (Fig. 3a), but not cells expressing TLR5, TLR9 or the NOD2 receptor (Fig. 3b-131 d). 132Genomic and proteomic analyses of A. muciniphila identified p...

Metabolic syndrome is characterized by a constellation of comorbidities that predispose individuals to an increased risk of developing cardiovascular pathologies as well as type 2 diabetes mellitus (T2DM)1. The gut microbiota is considered as a new key contributor involved in the onset of obesity-related disorders2. In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated T2DM, or hypertension3–8. As the administration of A.muciniphila has never been investigated in humans, we conducted a randomized double-blind placebo-controlled pilot study in overweight/obese insulin resistant volunteers, 40 were enroled and 32 completed the trial. The primary endpoints were on safety, tolerability and metabolic parameters (i.e., insulin resistance, circulating lipids, visceral adiposity, body mass). The secondary outcomes were the gut barrier function (i.e., plasma lipopolysacharrides (LPS) and gut microbiota composition. In this single-center study, we demonstrated that daily oral supplementation of 1010 bacteria either alive or pasteurized A.muciniphila for 3 months was safe and well tolerated. Compared to the Placebo, pasteurized A.muciniphila improved insulin sensitivity (+28.62±7.02%, P=0.002), reduced insulinemia (-34.08±7.12%, P=0.006) and plasma total cholesterol (-8.68±2.38%, P=0.02). Pasteurized A.muciniphila supplementation slightly decreased body weight (-2.27±0.92kg, P=0.091) as compared to the Placebo group, and fat mass (-1.37±0.82kg, P=0.092) and hip circumference (-2.63±1.14cm, P = 0.091) as compared to baseline. After 3 months of supplementation, A.muciniphila reduced the levels of relevant blood markers of liver dysfunction and inflammation while the overall gut microbiome structure was unaffected. In conclusion, this proof-of-concept study (NCT02637115) shows that the intervention was safe and well-tolerated and that the supplementation with A.muciniphila improves several metabolic paramaters.

The gut microbiota is now considered as one of the key elements contributing to the regulation of host health. Virtually all our body sites are colonised by microbes suggesting different types of crosstalk with our organs. Because of the development of molecular tools and techniques (ie, metagenomic, metabolomic, lipidomic, metatranscriptomic), the complex interactions occurring between the host and the different microorganisms are progressively being deciphered. Nowadays, gut microbiota deviations are linked with many diseases including obesity, type 2 diabetes, hepatic steatosis, intestinal bowel diseases (IBDs) and several types of cancer. Thus, suggesting that various pathways involved in immunity, energy, lipid and glucose metabolism are affected.In this review, specific attention is given to provide a critical evaluation of the current understanding in this field. Numerous molecular mechanisms explaining how gut bacteria might be causally linked with the protection or the onset of diseases are discussed. We examine well-established metabolites (ie, short-chain fatty acids, bile acids, trimethylamine N-oxide) and extend this to more recently identified molecular actors (ie, endocannabinoids, bioactive lipids, phenolic-derived compounds, advanced glycation end products and enterosynes) and their specific receptors such as peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ), aryl hydrocarbon receptor (AhR), and G protein-coupled receptors (ie, GPR41, GPR43, GPR119, Takeda G protein-coupled receptor 5).Altogether, understanding the complexity and the molecular aspects linking gut microbes to health will help to set the basis for novel therapies that are already being developed.

Mutations in mitofusin 2 (MFN2) have been reported in Charcot-Marie-Tooth type 2 (CMT2) families. To study the distribution of mutations in MFN2 we screened 323 families and isolated patients with distinct CMT phenotypes. In 29 probands, we identified 22 distinct MFN2 mutations, and 14 of these mutations have not been reported before. All mutations were located in the cytoplasmic domains of the MFN2 protein. Patients presented with a classical but rather severe CMT phenotype, since 28% of them were wheelchair-dependent. Some had additional features as optic atrophy. Most patients had an early onset and severe disease status, whereas a smaller group experienced a later onset and milder disease course. Electrophysiological data showed in the majority of patients normal to slightly reduced nerve conduction velocities with often severely reduced amplitudes of the compound motor and sensory nerve action potentials. Examination of sural nerve specimens showed loss of large myelinated fibres and degenerative mitochondrial changes. In patients with a documented family history of CMT2 the frequency of MFN2 mutations was 33% indicating that MFN2 mutations are a major cause in this population.

Facts and figures on the gut microbiota The term microbiota refers to all the microorganisms present in the various ecosystems in the human body. Diverse communities of microorganisms are located throughout the human body, including the gut, lungs, vaginal and urinary tracts and skin. The microbiota is composed of several types of microbes: bacteria, archaea, viruses, phages, yeast and fungi 1. Humans have constantly coevolved in the presence of these microorganisms, thereby establishing symbiotic relationships. Several lines of evidence suggest that in addition to bacteria, other types of microbes, such as fungi, protozoa and viruses, also have important interactions with the human in which they reside, referred to as the host in this review 2,3. Nevertheless, interactions between bacteria and human cells have been studied the most and will be the focus of this review. The human body carries approximately 3.9 × 10 13 bacterial cells, with the largest amount residing in the large intestine: 10 11 bacteria cells g-1 of wet stool 4. At the most recent estimation, almost 10 million non-redundant microbial genes have been identified in the human gut 5. This number is 150-fold higher than the number of genes in the human genome 6. Therefore, the metabolic capacity of the gut microbiota greatly exceeds the metabolic capacity of human cells. The theory of energy harvest Pioneering studies linking SCFAs and energy harvest. The complex and dynamic ecosystem of the gut microbiota contributes to the metabolism of various compounds, thereby leading to the production of numerous metabolites. In the early 2000s, pioneering studies from Gordon and colleagues 11 linked the production of specific metabolites, such as short-chain fatty acids (SCFAs), to host energy homeostasis (Table 1). Bäckhed et al. 12 demonstrated the role of the gut microbiota in host energy metabolism and growth by showing that germ-free mice gained less body weight and fat mass than conventionalised mice (that is, those harbouring a gut microbiota). This difference was observed despite increased food intake in germ-free mice. The same group of researchers found that the microbiota of genetic obese mice (ob/ob) harvests more energy than their lean ob/+ counterparts. In addition, this phenotype was transferred in germ-free mice transplanted with the microbiota from the obese donors 11. Initially, the hypothesis was that this shift provided more SCFAs (acetate, propionate, butyrate and lactate) that could be used as metabolic substrates by the host (Fig. 1). In addition, it was suggested that the gut microbiota contributed to energy metabolism through a direct interaction with the digestive tract. Indeed, the germ-free mice exhibit a lower level of caecal SCFAs than