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Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study.

ABSTRACT: 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 mellitus1. The gut microbiota is 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 type 2 diabetes mellitus or hypertension3-8. Since 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 enrolled and 32 completed the trial. The primary end points were safety, tolerability and metabolic parameters (that is, insulin resistance, circulating lipids, visceral adiposity and body mass). Secondary outcomes were gut barrier function (that is, plasma lipopolysaccharides) and gut microbiota composition. In this single-center study, we demonstrated that daily oral supplementation of 1010 A. muciniphila bacteria either live or pasteurized for three months was safe and well tolerated. Compared to placebo, pasteurized A. muciniphila improved insulin sensitivity (+28.62?±?7.02%, P?=?0.002), and 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?±?0.92?kg, P?=?0.091) compared to the placebo group, and fat mass (-1.37?±?0.82?kg, P?=?0.092) and hip circumference (-2.63?±?1.14?cm, P?=?0.091) compared to baseline. After three months of supplementation, A. muciniphila reduced the levels of the relevant blood markers for liver dysfunction and inflammation while the overall gut microbiome structure was unaffected. In conclusion, this proof-of-concept study (clinical trial no. NCT02637115 ) shows that the intervention was safe and well tolerated and that supplementation with A. muciniphila improves several metabolic parameters.

SUBMITTER: Depommier C

PROVIDER: S-EPMC6699990 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study.

Depommier Clara C Everard Amandine A Druart Céline C Plovier Hubert H Van Hul Matthias M Vieira-Silva Sara S Falony Gwen G Raes Jeroen J Maiter Dominique D Delzenne Nathalie M NM de Barsy Marie M Loumaye Audrey A Hermans Michel P MP Thissen Jean-Paul JP de Vos Willem M WM Cani Patrice D PD

Nature medicine 20190701 7

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<sup>1</sup>. The gut microbiota is a new key contributor involved in the onset of obesity-related disorders<sup>2</sup>. In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated type 2 diabetes mellitus or hyperte ...[more]

PMID: 31263284

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Project description:The mucophilic anaerobic bacterium Akkermansia muciniphila is a prominent member of the gastrointestinal (GI) microbiota and the only known species of the Verrucomicrobia phylum in the mammalian gut. A high prevalence of A. muciniphila in adult humans is associated with leanness and a lower risk for the development of obesity and diabetes. Four distinct A. muciniphila phylogenetic groups have been described, but little is known about their relative abundance in humans or how they impact human metabolic health. In this study, we isolated and characterized 71 new A. muciniphila strains from a cohort of children and adolescents undergoing treatment for obesity. Based on genomic and phenotypic analysis of these strains, we found several phylogroup-specific phenotypes that may impact the colonization of the GI tract or modulate host functions, such as oxygen tolerance, adherence to epithelial cells, iron and sulfur metabolism, and bacterial aggregation. In antibiotic-treated mice, phylogroups AmIV and AmII outcompeted AmI strains. In children and adolescents, AmI strains were most prominent, but we observed high variance in A. muciniphila abundance and single phylogroup dominance, with phylogroup switching occurring in a small subset of patients. Overall, these results highlight that the ecological principles determining which A. muciniphila phylogroup predominates in humans are complex and that A. muciniphila strain genetic and phenotypic diversity may represent an important variable that should be taken into account when making inferences as to this microbe's impact on its host's health.IMPORTANCE The abundance of Akkermansia muciniphila in the gastrointestinal (GI) tract is linked to multiple positive health outcomes. There are four known A. muciniphila phylogroups, yet the prevalence of these phylogroups and how they vary in their ability to influence human health is largely unknown. In this study, we performed a genomic and phenotypic analysis of 71 A. muciniphila strains and identified phylogroup-specific traits such as oxygen tolerance, adherence, and sulfur acquisition that likely influence colonization of the GI tract and differentially impact metabolic and immunological health. In humans, we observed that single Akkermansia phylogroups predominate at a given time but that the phylotype can switch in an individual. This collection of strains provides the foundation for the functional characterization of A. muciniphila phylogroup-specific effects on the multitude of host outcomes associated with Akkermansia colonization, including protection from obesity, diabetes, colitis, and neurological diseases, as well as enhanced responses to cancer immunotherapies.

Project description:BACKGROUND:Akkermansia muciniphila (AM) is a gram-negative, mucin-degrading bacteria inhabiting the gastrointestinal tract associated with host phenotypes and disease states. OBJECTIVE:Explore characteristics of overweight and obese female early-stage (0 to II) breast cancer patients with low AM relative abundance (LAM) vs high (HAM) enrolled in a presurgical weight-loss trial. DESIGN:Secondary analysis of pooled participants in a randomized controlled trial (NCT02224807). PARTICIPANTS/SETTING:During the period from 2014 to 2017, 32 female patients with breast cancer were randomized to weight-loss or attention-control arms from time of diagnosis-to-lumpectomy (mean=30±9 days). INTERVENTION:All were instructed to correct nutrient deficiencies via food sources and on upper-body exercises. The weight-loss group received additional guidance to promote 0.5 to 1 kg/wk weight-loss via energy restriction and aerobic exercise. MAIN OUTCOME MEASURES:At baseline and follow-up, sera, fecal samples, two-24 hour dietary recalls and dual x-ray absorptiometry were obtained. Bacterial DNA was isolated from feces and polymerase chain reaction (16S) amplified. Inflammatory cytokines were measured in sera. STATISTICAL ANALYSES PERFORMED:Differences between LAM and HAM participants were analyzed using t tests and nonparametric tests. Spearman correlations explored relationships between continuous variables. RESULTS:Participants were aged 61±9 years with body mass index 34.8±6. Mean AM relative abundance was 0.02% (0.007% to 0.06%) and 1.59% (0.59% to 13.57%) for LAM and HAM participants, respectively. At baseline, women with HAM vs LAM had lower fat mass (38.9±11.2 kg vs 46.4±9.0 kg; P=0.044). Alpha diversity (ie, species richness) was higher in women with HAM (360.8±84.8 vs 282.4±69.6; P=0.008) at baseline, but attenuated after weight-loss (P=0.058). At baseline, interleukin-6 level was associated with species richness (?=-0.471, P=0.008) and fat mass (?=0.529, P=0.002), but not AM. Change in total dietary fiber was positively associated with AM in LAM (?=0.626, P=0.002), but not HAM (?=0.436, P=0.180) participants. CONCLUSIONS:Among women with early-stage breast cancer, body composition is associated with AM, microbiota diversity, and interleukin-6 level. AM may mediate the effects of dietary fiber in improving microbiota composition.

Project description:ObjectiveTo examine the prospective associations between exposure to perfluoroalkyl substances (PFASs) and longitudinal measurements of glucose metabolism in high-risk overweight and obese Hispanic children.MethodsForty overweight and obese Hispanic children (8-14 years) from urban Los Angeles underwent clinical measures and 2-hour oral glucose tolerance tests (OGTT) at baseline and a follow-up visit (range: 1-3 years after enrollment). Baseline plasma perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS), and the plasma metabolome were measured by liquid-chromatography with high-resolution mass spectrometry. Multiple linear regression models were used to assess the association between baseline PFASs and changes in glucose homeostasis over follow-up. A metabolome-wide association study coupled with pathway enrichment analysis was performed to evaluate metabolic dysregulation associated with plasma PFASs concentrations. We performed a structural integrated analysis aiming to characterize the joint impact of all factors and to identify latent clusters of children with alterations in glucose homeostasis, based on their exposure and metabolomics profile.ResultsEach ln (ng/ml) increase in PFOA and PFHxS concentrations was associated with a 30.6 mg/dL (95% CI: 8.8-52.4) and 10.2 mg/dL (95% CI: 2.7-17.7) increase in 2-hour glucose levels, respectively. A ln (ng/ml) increase in PFHxS concentrations was also associated with 17.8 mg/dL increase in the glucose area under the curve (95% CI: 1.5-34.1). Pathway enrichment analysis showed significant alterations of lipids (e.g., glycosphingolipids, linoleic acid, and de novo lipogenesis), and amino acids (e.g., aspartate and asparagine, tyrosine, arginine and proline) in association to PFASs exposure. The integrated analysis identified a cluster of children with increased 2-h glucose levels over follow up, characterized by increased PFAS levels and altered metabolite patterns.ConclusionsThis proof-of-concept analysis shows that higher PFAS exposure was associated with dysregulation of several lipid and amino acid pathways and longitudinal alterations in glucose homeostasis in Hispanic youth. Larger studies are needed to confirm these findings and fully elucidate the underlying biological mechanisms.

Dataset Information

Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study.

Publications

Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study.

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