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      Serum metabolite profiling yields insights into health promoting effect of A. muciniphila in human volunteers with a metabolic syndrome

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          ABSTRACT

          Reduction of A. muciniphila relative abundance in the gut microbiota is a widely accepted signature associated with obesity-related metabolic disorders. Using untargeted metabolomics profiling of fasting plasma, our study aimed at identifying metabolic signatures associated with beneficial properties of alive and pasteurized A. muciniphila when administrated to a cohort of insulin-resistant individuals with metabolic syndrome. Our data highlighted either shared or specific alterations in the metabolome according to the form of A. muciniphila administered with respect to a control group. Common responses encompassed modulation of amino acid metabolism, characterized by reduced levels of arginine and alanine, alongside several intermediates of tyrosine, phenylalanine, tryptophan, and glutathione metabolism. The global increase in levels of acylcarnitines together with specific modulation of acetoacetate also suggested induction of ketogenesis through enhanced β-oxidation. Moreover, our data pinpointed some metabolites of interest considering their emergence as substantial compounds pertaining to health and diseases in the more recent literature.

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          Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity.

          Obesity and type 2 diabetes are characterized by altered gut microbiota, inflammation, and gut barrier disruption. Microbial composition and the mechanisms of interaction with the host that affect gut barrier function during obesity and type 2 diabetes have not been elucidated. We recently isolated Akkermansia muciniphila, which is a mucin-degrading bacterium that resides in the mucus layer. The presence of this bacterium inversely correlates with body weight in rodents and humans. However, the precise physiological roles played by this bacterium during obesity and metabolic disorders are unknown. This study demonstrated that the abundance of A. muciniphila decreased in obese and type 2 diabetic mice. We also observed that prebiotic feeding normalized A. muciniphila abundance, which correlated with an improved metabolic profile. In addition, we demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. A. muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion. Finally, we demonstrated that all these effects required viable A. muciniphila because treatment with heat-killed cells did not improve the metabolic profile or the mucus layer thickness. In summary, this study provides substantial insight into the intricate mechanisms of bacterial (i.e., A. muciniphila) regulation of the cross-talk between the host and gut microbiota. These results also provide a rationale for the development of a treatment that uses this human mucus colonizer for the prevention or treatment of obesity and its associated metabolic disorders.
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            Host-gut microbiota metabolic interactions.

            The composition and activity of the gut microbiota codevelop with the host from birth and is subject to a complex interplay that depends on the host genome, nutrition, and life-style. The gut microbiota is involved in the regulation of multiple host metabolic pathways, giving rise to interactive host-microbiota metabolic, signaling, and immune-inflammatory axes that physiologically connect the gut, liver, muscle, and brain. A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to manipulate the gut microbiota to combat disease and improve health.
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              Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study

              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 disorders 2 . In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated T2DM, or hypertension 3–8 . 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.
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                Author and article information

                Journal
                Gut Microbes
                Gut Microbes
                Gut Microbes
                Taylor & Francis
                1949-0976
                1949-0984
                23 November 2021
                2021
                23 November 2021
                : 13
                : 1
                : 1994270
                Affiliations
                [a ]Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and BIOtechnology (Welbio), UCLouvain, Université Catholique De Louvain; , Brussels, Belgium
                [b ]Pôle Edin, Institut De Recherches Expérimentales Et Cliniques, UCLouvain, Université Catholique De Louvain; , Brussels, Belgium
                [c ]Division of Endocrinology and Nutrition, Cliniques Universitaires St-Luc; , Brussels, Belgium
                [d ]Laboratory of Microbiology, Wageningen University; , Wageningen, The Netherland
                [e ]Human Microbiome Research Program, Faculty of Medicine, University of Helsinki; , Helsinki, Finland
                Author notes
                CONTACT Patrice D. Cani Patrice.cani@ 123456uclouvain.be UCLouvain, Université Catholique De Louvain, Ldri, Metabolism and Nutrition Research Group; , Av. E. Mounier, 73 Box B1.73.11, B-1200 Brussels, Belgium
                Author information
                https://orcid.org/0000-0003-2115-6082
                https://orcid.org/0000-0002-0273-3166
                https://orcid.org/0000-0003-2040-2448
                Article
                1994270
                10.1080/19490976.2021.1994270
                8632301
                34812127
                f014d0ea-164e-4b18-9571-01a1e49c3cdd
                © 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Figures: 5, Tables: 1, References: 89, Pages: 19
                Categories
                Research Article
                Research Paper

                Microbiology & Virology
                a. muciniphila,human,obesity,metabolic syndrome,prediabetes,metabolomic,amino-acids,ketone bodies,acylcarnitines

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