The Experts below are selected from a list of 2172 Experts worldwide ranked by ideXlab platform
Clara Belzer - One of the best experts on this subject based on the ideXlab platform.
-
The interaction of Akkermansia muciniphila with host-derived substances, bacteria and diets
Applied Microbiology and Biotechnology, 2021Co-Authors: Tatsuro Hagi, Clara BelzerAbstract:Trillions of microbes inhabit the human gut and build extremely complex communities. Gut microbes contribute to host metabolisms for better or worse and are widely studied and associated with health and disease. Akkermansia muciniphila is a gut microbiota member, which uses mucin as both carbon and nitrogen sources. Many studies on A . muciniphila have been conducted since this unique bacterium was first described in 2004. A . muciniphila can play an important role in our health because of its beneficial effects, such as improving type II diabetes and obesity and anti-inflammation. A . muciniphila establishes its position as a next-generation probiotic. Besides the effect of A . muciniphila on host health, a technique for boosting has been investigated. In this review, we show what factors can modulate the abundance of A . muciniphila focusing on the interaction with host-derived substances, other bacteria and diets. This review also refers to the possibility of the interaction between medicine and A . muciniphila ; this will open up future treatment strategies that can increase A . muciniphila abundance in the gut. Key points • Host-derived substances such as bile, microRNA and melatonin as well as mucin have beneficial effects on A. muciniphila. • Gut and probiotic bacteria and diet ingredients such as carbohydrates and phytochemicals could boost the abundance of A. muciniphila. • Several medicines could affect the growth of A. muciniphila.
-
The effect of bile acids on the growth and global gene expression profiles in Akkermansia muciniphila
Applied Microbiology and Biotechnology, 2020Co-Authors: Tatsuro Hagi, Sharon Y. Geerlings, Bart Nijsse, Clara BelzerAbstract:Akkermansia muciniphila is a prominent member of the gut microbiota and the organism gets exposed to bile acids within this niche. Several gut bacteria have bile response genes to metabolize bile acids or an ability to change their membrane structure to prevent membrane damage from bile acids. To understand the response to bile acids and how A . muciniphila can persist in the gut, we studied the effect of bile acids and individual bile salts on growth. In addition, the change in gene expression under ox-bile condition was studied. The growth of A . muciniphila was inhibited by ox-bile and the bile salts mixture. Individual bile salts have differential effects on the growth. Although most bile salts inhibited the growth of A . muciniphila , an increased growth was observed under culture conditions with sodium deoxycholate. Zaragozic acid A, which is a squalene synthase inhibitor leading to changes in the membrane structure, increased the susceptibility of A . muciniphila to bile acids. Transcriptome analysis showed that gene clusters associated with an ABC transporter and RND transporter were upregulated in the presence of ox-bile. In contrast, a gene cluster containing a potassium transporter was downregulated. Membrane transporter inhibitors also decreased the tolerance to bile acids of A . muciniphila . Our results indicated that membrane transporters and the squalene-associated membrane structure could be major bile response systems required for bile tolerance in A. muciniphila . Key points • The growth of Akkermansia muciniphila was inhibited by most bile salts. • Sodium deoxycholate increased the growth of A. muciniphila. • The genes encoding transporters and hopanoid synthesis were upregulated by ox-bile. • The inhibitors of transporters and hopanoid synthesis reduced ox-bile tolerance.
-
Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in nod mice
Gut, 2018Co-Authors: Clara Belzer, Janneke P Ouwerkerk, Hubert Plovier, Arno Hanninen, Raine Toivonen, Sakari Poysti, Rohini Emani, Patrice D CaniAbstract:Objective Intestinal microbiota is implicated in the pathogenesis of autoimmune type 1 diabetes in humans and in non-obese diabetic (NOD) mice, but evidence on its causality and on the role of individual microbiota members is limited. We investigated if different diabetes incidence in two NOD colonies was due to microbiota differences and aimed to identify individual microbiota members with potential significance. Design We profiled intestinal microbiota between two NOD mouse colonies showing high or low diabetes incidence by 16S ribosomal RNA gene sequencing and colonised the high-incidence colony with the microbiota of the low-incidence colony. Based on unaltered incidence, we identified a few taxa which were not effectively transferred and thereafter, transferred experimentally one of these to test its potential significance. Results Although the high-incidence colony adopted most microbial taxa present in the low-incidence colony, diabetes incidence remained unaltered. Among the few taxa which were not transferred, Akkermansia muciniphila was identified. As A. muciniphila abundancy is inversely correlated to the risk of developing type 1 diabetes-related autoantibodies, we transferred A. muciniphila experimentally to the high-incidence colony. A. muciniphila transfer promoted mucus production and increased expression of antimicrobial peptide Reg3γ , outcompeted Ruminococcus torques from the microbiota, lowered serum endotoxin levels and islet toll-like receptor expression, promoted regulatory immunity and delayed diabetes development. Conclusion Transfer of the whole microbiota may not reduce diabetes incidence despite a major change in gut microbiota, but single symbionts such as A. muciniphila with beneficial metabolic and immune signalling effects may reduce diabetes incidence when administered as a probiotic.
-
Akkermansia muciniphila in the human gastrointestinal tract when where and how
Microorganisms, 2018Co-Authors: Sharon Y. Geerlings, Ioannis Kostopoulos, Clara BelzerAbstract:Akkermansia muciniphila is a mucin-degrading bacterium of the phylum Verrucomicrobia. Its abundance in the human intestinal tract is inversely correlated to several disease states. A. muciniphila resides in the mucus layer of the large intestine, where it is involved in maintaining intestinal integrity. We explore the presence of Akkermansia-like spp. based on its 16S rRNA sequence and metagenomic signatures in the human body so as to understand its colonization pattern in time and space. A. muciniphila signatures were detected in colonic samples as early as a few weeks after birth and likely could be maintained throughout life. The sites where Akkermansia-like sequences (including Verrucomicrobia phylum and/or Akkermansia spp. sequences found in the literature) were detected apart from the colon included human milk, the oral cavity, the pancreas, the biliary system, the small intestine, and the appendix. The function of Akkermansia-like spp. in these sites may differ from that in the mucosal layer of the colon. A. muciniphila present in the appendix or in human milk could play a role in the re-colonization of the colon or breast-fed infants, respectively. In conclusion, even though A. muciniphila is most abundantly present in the colon, the presence of Akkermansia-like spp. along the digestive tract indicates that this bacterium might have more functions than those currently known.
-
model driven design of a minimal medium for Akkermansia muciniphila confirms mucus adaptation
Microbial Biotechnology, 2018Co-Authors: Steven Aalvink, Maria Suarezdiez, Peter J. Schaap, Clara BelzerAbstract:: The abundance of the human intestinal symbiont Akkermansia muciniphila has found to be inversely correlated with several diseases, including metabolic syndrome and obesity. A. muciniphila is known to use mucin as sole carbon and nitrogen source. To study the physiology and the potential for therapeutic applications of this bacterium, we designed a defined minimal medium. The composition of the medium was based on the genome-scale metabolic model of A. muciniphila and the composition of mucin. Our results indicate that A. muciniphila does not code for GlmS, the enzyme that mediates the conversion of fructose-6-phosphate (Fru6P) to glucosamine-6-phosphate (GlcN6P), which is essential in peptidoglycan formation. The only annotated enzyme that could mediate this conversion is Amuc-NagB on locus Amuc_1822. We found that Amuc-NagB was unable to form GlcN6P from Fru6P at physiological conditions, while it efficiently catalyzed the reverse reaction. To overcome this inability, N-acetylglucosamine needs to be present in the medium for A. muciniphila growth. With these findings, the genome-scale metabolic model was updated and used to accurately predict growth of A. muciniphila on synthetic media. The finding that A. muciniphila has a necessity for GlcNAc, which is present in mucin further prompts the adaptation to its mucosal niche.
Patrice D Cani - One of the best experts on this subject based on the ideXlab platform.
-
toxicological safety evaluation of pasteurized Akkermansia muciniphila
Journal of Applied Toxicology, 2020Co-Authors: Céline Druart, Hubert Plovier, Alizee Brient, Kirt R. Phipps, Patrice D CaniAbstract:Gut microorganisms are vital for many aspects of human health, and the commensal bacterium Akkermansia muciniphila has repeatedly been identified as a key component of intestinal microbiota. Reductions in A. muciniphila abundance are associated with increased prevalence of metabolic disorders such as obesity and type 2 diabetes. It was recently discovered that administration of A. muciniphila has beneficial effects and that these are not diminished, but rather enhanced after pasteurization. Pasteurized A. muciniphila is proposed for use as a food ingredient, and was therefore subjected to a nonclinical safety assessment, comprising genotoxicity assays (bacterial reverse mutation and in vitro mammalian cell micronucleus tests) and a 90-day toxicity study. For the latter, Han Wistar rats were administered with the vehicle or pasteurized A. muciniphila at doses of 75, 375 or 1500 mg/kg body weight/day (equivalent to 4.8 × 109 , 2.4 × 1010 , or 9.6 × 1010 A. muciniphila cells/kg body weight/day) by oral gavage for 90 consecutive days. The study assessed potential effects on clinical observations (including detailed arena observations and a modified Irwin test), body weight, food and water consumption, clinical pathology, organ weights, and macroscopic and microscopic pathology. The results of both in vitro genotoxicity studies were negative. No test item-related adverse effects were observed in the 90-day study; therefore, 1500 mg/kg body weight/day (the highest dose tested, equivalent to 9.6 × 1010 A. muciniphila cells/kg body weight/day) was established as the no-observed-adverse-effect-level. These results support that pasteurized A. muciniphila is safe for use as a food ingredient.
-
pasteurized Akkermansia muciniphila increases whole body energy expenditure and fecal energy excretion in diet induced obese mice
Gut microbes, 2020Co-Authors: Clara Depommier, Amandine Everard, Nathalie M Delzenne, Patrice D CaniAbstract:Accumulating evidence points to Akkermansia muciniphila as a novel candidate to prevent or treat obesity-related metabolic disorders. We recently observed, in mice and in humans, that pasteurizatio...
-
Akkermansia muciniphila reduces porphyromonas gingivalis induced inflammation and periodontal bone destruction
Journal of Clinical Periodontology, 2020Co-Authors: George Rubin, Zev Kizelnik, Nasreen S Haque, Olivier Huck, Hannah Mulhall, Radha Iyer, John D Perpich, Patrice D Cani, Salomon AmarAbstract:Aim: Akkermansia muciniphila is a beneficial gut commensal, whose anti-inflammatory properties have recently been demonstrated. This study aimed to evaluate the effect of A. muciniphila on Porphyromonas gingivalis elicited inflammation. Material and Methods: In lean and obese mice, A. muciniphila was administered in P. gingivalis-induced calvarial abscess and in experimental periodontitis model (EIP). Bone destruction and inflammation were evaluated by histomorphometric analysis. In vitro, A. muciniphila was co-cultured with P. gingivalis, growth and virulence factor expression was evaluated. Bone marrow macrophages (BMMϕ) and gingival epithelial cells (TIGK) were exposed to both bacterial strains, and the expression of inflammatory mediators, as well as tight junction markers, was analysed. Results: In a model of calvarial infection, A. muciniphila decreased inflammatory cell infiltration and bone destruction. In EIP, treatment with A. muciniphila resulted in a decreased alveolar bone loss. In vitro, the addition of A. muciniphila to P. gingivalis-infected BMMϕ increased anti-inflammatory IL-10 and decreased IL-12. Additionally, A. muciniphila exposure increases the expression of junctional integrity markers such as integrin-β1, E-cadherin and ZO-1 in TIGK cells. A. muciniphila co-culture with P. gingivalis reduced gingipains mRNA expression. Discussion: This study demonstrated the protective effects of A. muciniphila administration and may open consideration to its use as an adjunctive therapeutic agent to periodontal treatment.
-
pasteurized Akkermansia muciniphila protects from fat mass gain but not from bone loss
American Journal of Physiology-endocrinology and Metabolism, 2020Co-Authors: Lina Lawenius, Julia M Scheffler, Ulrika Islander, Hubert Plovier, Petra Henning, Hannah Colldén, Karin Gustafsson, Patrice D Cani, Claes OhlssonAbstract:Probiotic bacteria can protect from ovariectomy (ovx)-induced bone loss in mice. Akkermansia muciniphila is considered to have probiotic potential due to its beneficial effect on obesity and insuli...
-
Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in nod mice
Gut, 2018Co-Authors: Clara Belzer, Janneke P Ouwerkerk, Hubert Plovier, Arno Hanninen, Raine Toivonen, Sakari Poysti, Rohini Emani, Patrice D CaniAbstract:Objective Intestinal microbiota is implicated in the pathogenesis of autoimmune type 1 diabetes in humans and in non-obese diabetic (NOD) mice, but evidence on its causality and on the role of individual microbiota members is limited. We investigated if different diabetes incidence in two NOD colonies was due to microbiota differences and aimed to identify individual microbiota members with potential significance. Design We profiled intestinal microbiota between two NOD mouse colonies showing high or low diabetes incidence by 16S ribosomal RNA gene sequencing and colonised the high-incidence colony with the microbiota of the low-incidence colony. Based on unaltered incidence, we identified a few taxa which were not effectively transferred and thereafter, transferred experimentally one of these to test its potential significance. Results Although the high-incidence colony adopted most microbial taxa present in the low-incidence colony, diabetes incidence remained unaltered. Among the few taxa which were not transferred, Akkermansia muciniphila was identified. As A. muciniphila abundancy is inversely correlated to the risk of developing type 1 diabetes-related autoantibodies, we transferred A. muciniphila experimentally to the high-incidence colony. A. muciniphila transfer promoted mucus production and increased expression of antimicrobial peptide Reg3γ , outcompeted Ruminococcus torques from the microbiota, lowered serum endotoxin levels and islet toll-like receptor expression, promoted regulatory immunity and delayed diabetes development. Conclusion Transfer of the whole microbiota may not reduce diabetes incidence despite a major change in gut microbiota, but single symbionts such as A. muciniphila with beneficial metabolic and immune signalling effects may reduce diabetes incidence when administered as a probiotic.
Chaithanya Chelakkot - One of the best experts on this subject based on the ideXlab platform.
-
Akkermansia muciniphila derived extracellular vesicles influence gut permeability through the regulation of tight junctions
Experimental and Molecular Medicine, 2018Co-Authors: Chaithanya Chelakkot, Jaewang Ghim, Yonghoon Kwon, Jinseong Jeon, Hyun Taek Park, Youngwoo Choi, Haesim ParkAbstract:The gut microbiota has an important role in the gut barrier, inflammation and metabolic functions. Studies have identified a close association between the intestinal barrier and metabolic diseases, including obesity and type 2 diabetes (T2D). Recently, Akkermansia muciniphila has been reported as a beneficial bacterium that reduces gut barrier disruption and insulin resistance. Here we evaluated the role of A. muciniphila-derived extracellular vesicles (AmEVs) in the regulation of gut permeability. We found that there are more AmEVs in the fecal samples of healthy controls compared with those of patients with T2D. In addition, AmEV administration enhanced tight junction function, reduced body weight gain and improved glucose tolerance in high-fat diet (HFD)-induced diabetic mice. To test the direct effect of AmEVs on human epithelial cells, cultured Caco-2 cells were treated with these vesicles. AmEVs decreased the gut permeability of lipopolysaccharide-treated Caco-2 cells, whereas Escherichia coli-derived EVs had no significant effect. Interestingly, the expression of occludin was increased by AmEV treatment. Overall, these results imply that AmEVs may act as a functional moiety for controlling gut permeability and that the regulation of intestinal barrier integrity can improve metabolic functions in HFD-fed mice. Secretions from a particular gut bacterium improve metabolic function and glucose tolerance in mice with type II diabetes. Gut bacteria are crucial to maintaining the intestinal barrier, which separates gut contents from the rest of the body and protects from external pathogens. Following a study demonstrating that levels of the gut bacterium Akkermansia muciniphila are reduced in obese people, Sung Ho Ryu at Pohang University of Science and Technology and Yoon-Keun Kim at MD Healthcare Inc, South Korea, and co-workers, investigated the role of A.muciniphila in type II diabetes. They found that lipid structures termed extracellular vesicles (EVs) secreted by A.muciniphila were more prolific in the faeces of healthy patients than those with type II diabetes. Administration of these bacterial EVs to diabetic mice enhanced gut barrier wall integrity, reduced weight gain and improved glucose tolerance.
-
Akkermansia muciniphila derived extracellular vesicles influence gut permeability through the regulation of tight junctions
Experimental and Molecular Medicine, 2018Co-Authors: Chaithanya Chelakkot, Jaewang Ghim, Yonghoon Kwon, Jinseong Jeon, Hyun Taek Park, Youngwoo Choi, Daekyum Kim, Minseon Kim, Young Koo Jee, Yong Song GhoAbstract:The gut microbiota has an important role in the gut barrier, inflammation and metabolic functions. Studies have identified a close association between the intestinal barrier and metabolic diseases, including obesity and type 2 diabetes (T2D). Recently, Akkermansia muciniphila has been reported as a beneficial bacterium that reduces gut barrier disruption and insulin resistance. Here we evaluated the role of A. muciniphila-derived extracellular vesicles (AmEVs) in the regulation of gut permeability. We found that there are more AmEVs in the fecal samples of healthy controls compared with those of patients with T2D. In addition, AmEV administration enhanced tight junction function, reduced body weight gain and improved glucose tolerance in high-fat diet (HFD)-induced diabetic mice. To test the direct effect of AmEVs on human epithelial cells, cultured Caco-2 cells were treated with these vesicles. AmEVs decreased the gut permeability of lipopolysaccharide-treated Caco-2 cells, whereas Escherichia coli-derived EVs had no significant effect. Interestingly, the expression of occludin was increased by AmEV treatment. Overall, these results imply that AmEVs may act as a functional moiety for controlling gut permeability and that the regulation of intestinal barrier integrity can improve metabolic functions in HFD-fed mice.
Josef Voglmeir - One of the best experts on this subject based on the ideXlab platform.
-
Cloning, purification and biochemical characterisation of a GH35 beta-1,3/beta-1,6-galactosidase from the mucin-degrading gut bacterium Akkermansia muciniphila
Glycoconjugate Journal, 2018Co-Authors: Bi-shan Guo, Lucy Crouch, Zhi-peng Cai, David N Bolam, Feng Zheng, Meng Wang, Li Liu, Josef VoglmeirAbstract:A putative GH35 β-galactosidase gene from the mucin-degrading bacterium Akkermansia muciniphila was successfully cloned and further investigated. The recombinant enzyme with the molecular mass of 74 kDa was purified to homogeneity and biochemically characterised. The optimum temperature of the enzyme was 42 °C, and the optimum pH was determined to be pH 3.5. The addition of sodium dodecyl sulphate (SDS) reduced the enzyme’s activity significantly. The addition of Mg2+-ions decreased the activity of the β-galactosidase, whereas other metal ions or EDTA showed no inhibitory effect. The enzyme catalysed the hydrolysis of β1,3- and β1,6- linked galactose residues from various substrates, whereas only negligible amounts of β1,4-galactose were hydrolysed. The present study describes the first functional characterisation of a β-galactosidase from this human gut symbiont.
-
cloning purification and biochemical characterization of two β n acetylhexosaminidases from the mucin degrading gut bacterium Akkermansia muciniphila
Carbohydrate Research, 2018Co-Authors: Meng Wang, Huan Chen, Xiaoyang Zhang, Xiaochun Hu, Josef VoglmeirAbstract:Abstract Two genes encoding the β- N -acetylhexosaminidases Am2301 and Am2446 were cloned successfully from the mucin-degrading bacterium Akkermansia muciniphila. The recombinant enzymes with molecular masses of 61 kDa and 78 kDa were isolated and biochemically characterised. The optimum temperature of both enzymes was 37 °C, and the optimum pH was determined to be pH 5.0 for Am2301 and pH 6.5 for Am2446. The addition of sodium dodecyl sulphate (SDS) reduced the enzymes' activity significantly. Cu 2+ -ions decreased the activity of Am2301 by 70%, while the activity of Am2446 was significantly reduced by Fe 3+ -ions. PugNAc strongly inhibited both enzymes already in the sub-micromolar concentration range. The enzymes catalysed the hydrolysis of β1,4-linked N -acetylgalactosamine and β1,6-linked N -acetylglucosamine from glycan standards, as well as β1,2-linked N-acetylglucosamine units from the non-reducing end of N -glycans. The present study describes the first functional characterisation of β- N -acetylhexosaminidases from this human gut symbiont.
-
biochemical characterisation of the neuraminidase pool of the human gut symbiont Akkermansia muciniphila
Carbohydrate Research, 2015Co-Authors: Kun Huang, Mao M Wang, Anna Kulinich, Hong Y, Juana Elizabeth Reyes Martinez, Xu C Duan, Huan Chen, Sabine L Flitsch, Josef VoglmeirAbstract:Abstract Since the isolation and identification of Akkermansia muciniphila one decade ago, much attention has been drawn to this gut bacterium due to its role in obesity and type 2 diabetes. This report describes the discovery and biochemical characterisation of all four putative neuraminidases annotated in the A. muciniphila genome. Recombinantly expressed candidate genes, which were designated Am0705, Am0707, Am1757 and Am2085, were shown to cover complementary pH ranges between 4.0 and 9.5. Temperature optima of the enzymes lay between 37 and 42 °C. All four enzymes were strongly inhibited by Cu 2+ and Zn 2+ , and loss of activity after the addition of EDTA suggests that all neuraminidases, with the exception of Am0707, require divalent metal ions for their catalytic function. Chemoenzymatically synthesised α2,3- and α2,6-linked indoyl-sialosides were utilised to determine the regioselectivity and substrate promiscuity of the neuraminidases towards C5-modifications of sialic acids with N -acetyl-, N -glycolyl-, N -propionyl-, or hydroxyl-groups. The combination of simple purification procedures and good activities of some of the characterised neuraminidases makes them potentially interesting as tools in bioanalytical or industrial applications.
Noora Ottman - One of the best experts on this subject based on the ideXlab platform.
-
genome scale model and omics analysis of metabolic capacities of Akkermansia muciniphila reveal a preferential mucin degrading lifestyle
Applied and Environmental Microbiology, 2017Co-Authors: Noora Ottman, Mark Davids, Maria Suarezdiez, Vitor Martins Dos A P Santos, Peter J. Schaap, Hauke Smidt, Sjef Boeren, Clara BelzerAbstract:The composition and activity of the microbiota in the human gastrointestinal tract is primarily shaped by nutrients derived either from food or the host. Bacteria colonizing the mucus layer have evolved to use mucin as a carbon and energy source. One of the members of the mucosa-associated microbiota is Akkermansia muciniphila , which is capable of producing an extensive repertoire of mucin-degrading enzymes. To further study substrate utilization abilities of A. muciniphila , we constructed a genome-scale metabolic model to test amino acid auxotrophy, vitamin biosynthesis, and sugar degrading capacities. The model-supported predictions were validated by in vitro experiments, which showed A. muciniphila to be able to utilize the mucin-derived monosaccharides fucose, galactose, and N-acetylglucosamine. Growth was also observed on N-acetylgalactosamine even though the metabolic model did not predict this. The uptake of these sugars, as well as the non-mucin sugar glucose, was enhanced in the presence of mucin, indicating that additional mucin-derived components are needed for optimal growth. Transcriptome analysis by RNA-Seq comparing the gene expression of A. muciniphila grown on mucin or glucose confirmed the activity of the genes involved in mucin degradation, and revealed most of these to be upregulated in the presence of mucin. The transcriptional response was confirmed by a proteome analysis, altogether revealing a hierarchy in the use of sugars, reflecting the adaptation of A. muciniphila to the mucosal environment. In conclusion, these findings provide molecular insights into the lifestyle of A. muciniphila and further confirm its role as a mucin specialist in the gut. IMPORTANCE Akkermansia muciniphila is among the most abundant mucosal bacteria in humans and in a wide range of other animals. Recently, A. muciniphila has attracted considerable attention because of its capacity to protect against diet-induced obesity in mouse models. However, the physiology of A. muciniphila has not been studied in detail. Hence, we constructed a genome scale model and describe its validation by transcriptomic and proteomic approaches on bacterial cells grown on mucus and glucose, a non-mucus sugar. The results provide detailed molecular insight into the mucus-degrading lifestyle of A. muciniphila , and further confirm the role of this mucin specialist in producing propionate and acetate under conditions of the intestinal tract.
-
pili like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function
PLOS ONE, 2017Co-Authors: Noora Ottman, Justus Reunanen, Marjolein Meijerink, Taija E Pietila, Veera Kainulainen, Judith Klievink, Laura Huuskonen, Steven AalvinkAbstract:Gut barrier function is key in maintaining a balanced response between the host and its microbiome. The microbiota can modulate changes in gut barrier as well as metabolic and inflammatory responses. This highly complex system involves numerous microbiota-derived factors. The gut symbiont Akkermansia muciniphila is positively correlated with a lean phenotype, reduced body weight gain, amelioration of metabolic responses and restoration of gut barrier function by modulation of mucus layer thickness. However, the molecular mechanisms behind its metabolic and immunological regulatory properties are unexplored. Herein, we identify a highly abundant outer membrane pili-like protein of A. muciniphila MucT that is directly involved in immune regulation and enhancement of trans-epithelial resistance. The purified Amuc_1100 protein and enrichments containing all its associated proteins induced production of specific cytokines through activation of Toll-like receptor (TLR) 2 and TLR4. This mainly leads to high levels of IL-10 similar to those induced by the other beneficial immune suppressive microorganisms such as Faecalibacterium prausnitzii A2-165 and Lactobacillus plantarum WCFS1. Together these results indicate that outer membrane protein composition and particularly the newly identified highly abundant pili-like protein Amuc_1100 of A. muciniphila are involved in host immunological homeostasis at the gut mucosa, and improvement of gut barrier function.
-
a purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice
Nature Medicine, 2017Co-Authors: Hubert Plovier, Noora Ottman, Lucie Geurts, Clara Depommier, Julien Chilloux, Thibaut Duparc, Amandine Everard, Céline Druart, Laeticia LichtensteinAbstract:Akkermansia muciniphila, a member of the gut microbiome, has been shown to improve metabolism in mice. Here it is reported that its pasteurization further improves this effect, and that one of its membrane proteins by itself has a similar benefit.
-
a purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice
Nature Medicine, 2017Co-Authors: Hubert Plovier, Noora Ottman, Lucie Geurts, Clara Depommier, Julien Chilloux, Amandine Everard, Céline Druart, Matthias Van Hul, Thibaut DuparcAbstract:Akkermansia muciniphila, a member of the gut microbiome, has been shown to improve metabolism in mice. Here it is reported that its pasteurization further improves this effect, and that one of its membrane proteins by itself has a similar benefit. Obesity and type 2 diabetes are associated with low-grade inflammation and specific changes in gut microbiota composition1,2,3,4,5,6,7. We previously demonstrated that administration of Akkermansia muciniphila to mice prevents the development of obesity and associated complications8. However, the underlying mechanisms of this protective effect remain unclear. Moreover, the sensitivity of A. muciniphila to oxygen and the presence of animal-derived compounds in its growth medium currently limit the development of translational approaches for human medicine9. We have addressed these issues here by showing that A. muciniphila retains its efficacy when grown on a synthetic medium compatible with human administration. Unexpectedly, we discovered that pasteurization of A. muciniphila enhanced its capacity to reduce fat mass development, insulin resistance and dyslipidemia in mice. These improvements were notably associated with a modulation of the host urinary metabolomics profile and intestinal energy absorption. We demonstrated that Amuc_1100, a specific protein isolated from the outer membrane of A. muciniphila, interacts with Toll-like receptor 2, is stable at temperatures used for pasteurization, improves the gut barrier and partly recapitulates the beneficial effects of the bacterium. Finally, we showed that administration of live or pasteurized A. muciniphila grown on the synthetic medium is safe in humans. These findings provide support for the use of different preparations of A. muciniphila as therapeutic options to target human obesity and associated disorders.
-
Akkermansia muciniphila adheres to enterocytes and strengthens the integrity of the epithelial cell layer
Applied and Environmental Microbiology, 2015Co-Authors: Justus Reunanen, Noora Ottman, Clara Belzer, Veera Kainulainen, Laura Huuskonen, Heikki Huhtinen, Reetta SatokariAbstract:Akkermansia muciniphila is a Gram-negative mucin-degrading bacterium that resides in the gastrointestinal tracts of humans and animals. A. muciniphila has been linked with intestinal health and improved metabolic status in obese and type 2 diabetic subjects. Specifically, A. muciniphila has been shown to reduce high-fat-diet-induced endotoxemia, which develops as a result of an impaired gut barrier. Despite the accumulating evidence of the health-promoting effects of A. muciniphila, the mechanisms of interaction of the bacterium with the host have received little attention. In this study, we used several in vitro models to investigate the adhesion of A. muciniphila to the intestinal epithelium and its interaction with the host mucosa. We found that A. muciniphila adheres strongly to the Caco-2 and HT-29 human colonic cell lines but not to human colonic mucus. In addition, A. muciniphila showed binding to the extracellular matrix protein laminin but not to collagen I or IV, fibronectin, or fetuin. Importantly, A. muciniphila improved enterocyte monolayer integrity, as shown by a significant increase in the transepithelial electrical resistance (TER) of cocultures of Caco-2 cells with the bacterium. Further, A. muciniphila induced interleukin 8 (IL-8) production by enterocytes at cell concentrations 100-fold higher than those for Escherichia coli, suggesting a very low level of proinflammatory activity in the epithelium. In conclusion, our results demonstrate that A. muciniphila adheres to the intestinal epithelium and strengthens enterocyte monolayer integrity in vitro, suggesting an ability to fortify an impaired gut barrier. These results support earlier associative in vivo studies and provide insights into the interaction of A. muciniphila with the host.