Mode of action of Akkermansia muciniphila in the intestinal dialogue: role of extracellular proteins, metabolites and cell envelope components

Abstract

Akkermansia muciniphila is a promising next-generation beneficial microbe due to its natural presence in the mucus layer of the gut, its symbiotic ability to degrade mucus, and its capacity to improve the intestinal barrier function. A. muciniphila is able to counteract weight gain and immuno-metabolic disturbances in several animal models. Many of these disorders, including obesity and auto-immune diseases, have been associated with decreased gut barrier function and consequent increased inflammation. Since A. muciniphila was found to normalize these changes and strengthen the gut barrier function, it is hypothesized that other beneficial effects of A. muciniphila might be caused by this restoration. In search for A. muciniphila’s mode of action in enhancing the gut barrier function and promoting health, we reasoned that secreted components or cell envelope components of A. muciniphila are interesting candidates as they can potentially reach and interact with the epithelial barrier. In this review, we focus on the potential mechanisms through which A. muciniphila can exert its beneficial effects on the host by the production of extracellular and secreted proteins, metabolites and cell envelope components. These products have been studied in isolation for their structure, signaling capacity, and in some cases, also for their effects in preclinical models. This includes the protein known as Amuc_1100, which we here rename as pilus-associated signaling (PAS) protein , the P9 protein encoded by Amuc_1631, the short-chain fatty acids acetate and propionate, and cell envelope components, such as phosphatidylethanolamine and peptidoglycan.

Keywords

Akkermansia muciniphila / Amuc_1100 / pilus-associated signaling protein / P9 / extracellular and secreted proteins / metabolites / cell envelope components

References

[1] Karcher N,Punčochář M.Genomic diversity and ecology of human-associated Akkermansia species in the gut microbiome revealed by extensive metagenomic assembly.Genome Biol2021;22:209 PMCID:PMC8278651

[2] Geerlings SY,Koehorst JJ.Genomic convergence between Akkermansia muciniphila in different mammalian hosts.BMC Microbiol2021;21:298 PMCID:PMC8555344

[3] Cani PD,Derrien M,de Vos WM.Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms.Nat Rev Gastroenterol Hepatol2022;19:625-37

[4] Cani PD.Next-generation beneficial microbes: the case of Akkermansia muciniphila.Front Microbiol2017;8:1765 PMCID:PMC5614963

[5] Dao MC,Aron-Wisnewsky J.MICRO-Obes ConsortiumAkkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology.Gut2016;65:426-36

[6] Dehghanbanadaki H,Keshavarz Azizi Raftar S.Global scientific output trend for Akkermansia muciniphila research: a bibliometric and scientometric analysis.BMC Med Inform Decis Mak2020;20:291 PMCID:PMC7654583

[7] Fassatoui M,Díaz-Rizzolo DA.Gut microbiota imbalances in Tunisian participants with type 1 and type 2 diabetes mellitus.Biosci Rep2019;39:BSR20182348 PMCID:PMC6579978

[8] Rajilić-Stojanović M,Guarner F.Phylogenetic analysis of dysbiosis in ulcerative colitis during remission.Inflamm Bowel Dis2013;19:481-8

[9] Png CW,Gilshenan KS.Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria.Am J Gastroenterol2010;105:2420-8

[10] Everard A,Geurts L.Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity.Proc Natl Acad Sci USA2013;110:9066-71 PMCID:PMC3670398

[11] Zhang T,Wu X.Alterations of Akkermansia muciniphila in the inflammatory bowel disease patients with washed microbiota transplantation.Appl Microbiol Biotechnol2020;104:10203-15

[12] Pittayanon R,Leontiadis GI.Differences in gut microbiota in patients with vs without inflammatory bowel diseases: a systematic review.Gastroenterology2020;158:930-946.e1

[13] Demirci M,Uysal HK.Reduced Akkermansia muciniphila and Faecalibacterium prausnitzii levels in the gut microbiota of children with allergic asthma.Allergol Immunopathol (Madr)2019;47:365-71

[14] Plovier H,Druart C.A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice.Nat Med2017;23:107-13

[15] Hänninen A,Pöysti S.Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice.Gut2018;67:1445-53

[16] Zhai R,Zhang L,Zhao L.Strain-specific anti-inflammatory properties of two Akkermansia muciniphila strains on chronic colitis in mice.Front Cell Infect Microbiol2019;9:239 PMCID:PMC6624636

[17] Han Y,Wang B.Role of Akkermansia muciniphila in the development of nonalcoholic fatty liver disease: current knowledge and perspectives.Front Med2022;16:667-85

[18] Acharya KD,Ward DV.Differential effects of Akkermansia-enriched fecal microbiota transplant on energy balance in female mice on high-fat diet.Front Endocrinol (Lausanne)2022;13:1010806 PMCID:PMC9647077

[19] Li N,Sun C.Change of intestinal microbiota in cerebral ischemic stroke patients.BMC Microbiol2019;19:191 PMCID:PMC6700817

[20] Nishiwaki H,Ishida T.Meta-analysis of gut dysbiosis in parkinson’s disease.Mov Disord2020;35:1626-35

[21] Consortium. Electronic address: [e-mail], iMSMS Consortium. Gut microbiome of multiple sclerosis patients and paired household healthy controls reveal associations with disease risk and course.Cell2022;185:3467-3486.e16

[22] Liu S,Moreira T.Oral administration of miR-30d from feces of MS patients suppresses MS-like symptoms in mice by expanding Akkermansia muciniphila.2019;26:779-94.e8 PMCID:PMC6948921

[23] Gotkine M,Elinav E.Amyotrophic lateral sclerosis and intestinal microbiota-toward establishing cause and effect.Gut Microbes2020;11:1833-41 PMCID:PMC7524331

[24] Nath N,Paintlia MK,Hoda MN.Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis.J Immunol2009;182:8005-14 PMCID:PMC2965405

[25] Rotermund C,Fitzgerald JC.The therapeutic potential of metformin in neurodegenerative diseases.Front Endocrinol (Lausanne)2018;9:400 PMCID:PMC6060268

[26] de la Cuesta-Zuluaga J,Corrales-Agudelo V.Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut.Diabetes Care2017;40:54-62

[27] Routy B,Daillère R,Wargo JA.The gut microbiota influences anticancer immunosurveillance and general health.Nat Rev Clin Oncol2018;15:382-96

[28] Jin Y,Xia L.The diversity of gut microbiome is associated with favorable responses to anti-programmed death 1 immunotherapy in Chinese patients with NSCLC.J Thorac Oncol2019;14:1378-89

[29] Zheng Y,Tu X.Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma.J Immunother Cancer2019;7:193 PMCID:PMC6651993

[30] Derosa L,Thomas AM.Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer.Nat Med2022;28:315-24 PMCID:PMC9330544

[31] Lee KA,Bolte LA.Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma.Nat Med2022;28:535-44 PMCID:PMC8938272

[32] Shi L,Chen G.Combining IL-2-based immunotherapy with commensal probiotics produces enhanced antitumor immune response and tumor clearance.J Immunother Cancer2020;8:e000973 PMCID:PMC7542661

[33] Daisley BA,Abdur-Rashid K.Abiraterone acetate preferentially enriches for the gut commensal Akkermansia muciniphila in castrate-resistant prostate cancer patients.Nat Commun2020;11:4822 PMCID:PMC7515896

[34] Terrisse S,Ueda K.Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer.J Immunother Cancer2022;10:e004191 PMCID:PMC8928383

[35] Martel J,Ko YF,Young JD.Gut barrier disruption and chronic disease.Trends Endocrinol Metab2022;33:247-65

[36] Akdis CA.Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions?.Nat Rev Immunol2021;21:739-51

[37] Derrien M,Plugge CM.Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium.Int J Syst Evol Microbiol2004;54:1469-76

[38] Ottman N,Suarez-Diez M.Genome-scale model and omics analysis of metabolic capacities of Akkermansia muciniphila reveal a preferential mucin-degrading lifestyle.Appl Environ Microbiol2017;83 PMCID:PMC5583483

[39] van Passel MW,Zoetendal EG.The genome of Akkermansia muciniphila, a dedicated intestinal mucin degrader, and its use in exploring intestinal metagenomes.PLoS One2011;6:e16876 PMCID:PMC3048395

[40] Li Z,Wang Y.Global trends in Akkermansia muciniphila research: a bibliometric visualization.Front Microbiol2022;13:1037708 PMCID:PMC9685322

[41] Depommier C,Druart C.Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study.Nat Med2019;25:1096-103 PMCID:PMC6699990

[42] Turck D,Castenmiller J.EFSA Panel on NutritionNovel Foods and Food Allergens (NDA)Safety of pasteurised Akkermansia muciniphila as a novel food pursuant to Regulation (EU) 2015/2283.EFSA J2021;19:e06780 PMCID:PMC8409316

[43] Raftar S,Yadegar A.The protective effects of live and pasteurized Akkermansia muciniphila and its extracellular vesicles against HFD/CCl4-induced liver injury.Microbiol Spectr2021;9:e00484-21 PMCID:PMC8557882

[44] Chelakkot C,Kim DK.Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions.Exp Mol Med2018;50:e450 PMCID:PMC5903829

[45] Ashrafian F,Behrouzi A.Akkermansia muciniphila-derived extracellular vesicles as a mucosal delivery vector for amelioration of obesity in mice.Front Microbiol2019;10:2155 PMCID:PMC6779730

[46] Ashrafian F,Lari A.Extracellular vesicles and pasteurized cells derived from Akkermansia muciniphila protect against high-fat induced obesity in mice.Microb Cell Fact2021;20:219 PMCID:PMC8645101

[47] Kang CS,Choi EJ.Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis.PLoS One2013;8:e76520 PMCID:PMC3811976

[48] Ottman N,Meijerink M.Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function.PLoS One2017;12:e0173004 PMCID:PMC5332112

[49] Ligthart K,de Vos WM.Bridging bacteria and the gut: functional aspects of type IV pili.Trends Microbiol2020;28:340-8

[50] Rooijers K,Juste C.An iterative workflow for mining the human intestinal metaproteome.BMC Genomics2011;12:6 PMCID:PMC3023752

[51] Wang J,Wang R.The variable oligomeric state of Amuc_1100 from Akkermansia muciniphila.J Struct Biol2020;212:107593

[52] Mou L,Chen Y.Crystal structure of monomeric Amuc_1100 from Akkermansia muciniphila.Acta Crystallogr F Struct Biol Commun2020;76:168-74 PMCID:PMC7137384

[53] de Vos WM, Tytgat HLP, Swarts DC. AMUC-1100 polypeptide variants for effecting immune signalling and/or affecting intestinal barrier function and/or modulating metabolic status. Available from: https://research.wur.nl/en/publications/amuc-1100-polypeptide-variants-for-effecting-immune-signalling-an [Last accessed on 7 Mar 2023]

[54] Liu Y,Tang L.TLR4 regulates RORγt⁺ regulatory T-cell responses and susceptibility to colon inflammation through interaction with Akkermansia muciniphila.Microbiome2022;10:98 PMCID:PMC9235089

[55] Dong X,Liu X,Zhang X.[Prokaryotic expression of Amuc_1100 protein and its effects on high-fat diet rats combined streptozotocin injection].Wei Sheng Yan Jiu2020;49:785-822

[56] Deng SS,Liu X,Zhang XL.[Protective Effects of Akkermansia muciniphila and Amuc_1100 Protein on Rats on High-Fat Diet Combined with Streptozotocin Injection].Sichuan Da Xue Xue Bao Yi Xue Ban2022;53:83-91

[57] Zhang FL,Zhang Z.Surface-Displayed Amuc_1100 From Akkermansia muciniphila on Lactococcus lactis ZHY1 improves hepatic steatosis and intestinal health in high-fat-fed zebrafish.Front Nutr2021;8:726108 PMCID:PMC8548614

[58] Naiel MAE,Ghazanfar S,Abdelnour SA.The risk assessment of high-fat diet in farmed fish and its mitigation approaches: A review.J Anim Physiol Anim Nutr (Berl)2022;

[59] Wang L,Feng Y.A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8⁺ T cells in mice.Gut2020;69:1988-97 PMCID:PMC7569398

[60] Lavelle A.Gut microbiota-derived metabolites as key actors in inflammatory bowel disease.Nat Rev Gastroenterol Hepatol2020;17:223-37

[61] Agus A,Sokol H.Gut microbiota regulation of tryptophan metabolism in health and disease.Cell Host Microbe2018;23:716-24

[62] Gu Z,Shen Y.Akkermansia muciniphila and its outer protein Amuc_1100 regulates tryptophan metabolism in colitis.Food Funct2021;12:10184-95

[63] Laursen MF,von Burg N.Bifidobacterium species associated with breastfeeding produce aromatic lactic acids in the infant gut.Nat Microbiol2021;6:1367-82 PMCID:PMC8556157

[64] Cervantes-Barragan L,Tianero MD.Lactobacillus reuteri induces gut intraepithelial CD4⁺CD8αα⁺ T cells.Science2017;357:806-10 PMCID:PMC5687812

[65] Zelante T,Cunha C.Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22.Immunity2013;39:372-85

[66] Stasi C,Milani S.The relationship between the serotonin metabolism, gut-microbiota and the gut-brain axis.Curr Drug Metab2019;20:646-55

[67] Latorre E,Grasa L.Intestinal serotonin transporter inhibition by toll-like receptor 2 activation. A feedback modulation.PLoS One2016;11:e0169303 PMCID:PMC5199115

[68] Wang J,Wang R,Tang Z.The outer membrane protein Amuc_1100 of Akkermansia muciniphila promotes intestinal 5-HT biosynthesis and extracellular availability through TLR2 signalling.Food Funct2021;12:3597-610

[69] Cheng R,Wang J,Zhang M.The outer membrane protein Amuc_1100 of Akkermansia muciniphila alleviates the depression-like behavior of depressed mice induced by chronic stress.Biochem Biophys Res Commun2021;566:170-6

[70] Sun Y,Cheng R,Zhang M.Outer membrane protein Amuc_1100 of Akkermansia muciniphila alleviates antibiotic-induced anxiety and depression-like behavior in mice.Physiol Behav2023;258:114023

[71] Cheng R,Sun Y,Zhang M.The modified outer membrane protein Amuc_1100 of Akkermansia muciniphila improves chronic stress-induced anxiety and depression-like behavior in mice.Food Funct2022;13:10748-58

[72] Chen S,Zhang G.Akkermansia muciniphila and its outer membrane protein Amuc_1100 prophylactically attenuate 5-fluorouracil-induced intestinal mucositis.Biochem Biophys Res Commun2022;614:34-40

[73] Lam RS,Lenzo JC.Macrophage depletion abates Porphyromonas gingivalis-induced alveolar bone resorption in mice.J Immunol2014;193:2349-62

[74] Coretti L,Florio E.Subgingival dysbiosis in smoker and non-smoker patients with chronic periodontitis.Mol Med Rep2017;15:2007-14 PMCID:PMC5364964

[75] Huck O,Rubin G.Akkermansia muciniphila reduces Porphyromonas gingivalis-induced inflammation and periodontal bone destruction.J Clin Periodontol2020;47:202-12

[76] Mulhall H,Deragon M,Huck O.Akkermansia muciniphila and Its Pili-Like Protein Amuc_1100 modulate macrophage polarization in experimental periodontitis.Infect Immun2020;89 PMCID:PMC7927938

[77] Krzyszczyk P,Palmer A.The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes.Front Physiol2018;9:419 PMCID:PMC5938667

[78] Yoon HS,Yun MS.Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice.Nat Microbiol2021;6:563-73

[79] Krieger JP,Sanchez-Watts G.Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats.Am J Physiol Regul Integr Comp Physiol2018;315:R708-20 PMCID:PMC6230883

[80] Ellingsgaard H,Schuler B.Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells.Nat Med2011;17:1481-9 PMCID:PMC4286294

[81] Yoon HS,Yun MS.Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice.Nat Microbiol2021;6:563-73

[82] Gwang-pyo G,Jung-hwan J,Tae-wook N. Patent WO2020076136A2: Akkermansia muciniphila strain and use thereof. 2020. Available from: https://patents.google.com/patent/WO2020076136A2/en?oq=WO2020076136A2 [Last accessed on 13 Mar 2023]

[83] Petersen TN,von Heijne G.SignalP 4.0: discriminating signal peptides from transmembrane regions.Nat Methods2011;8:785-6

[84] Cani PD.A newly identified protein from Akkermansia muciniphila stimulates GLP-1 secretion.Cell Metab2021;33:1073-5

[85] Kim BC,Kim JH.In: Haneul Patent & Law Firm, editor. South Korea: Korean Intellectual Property Office; 2020.Patent 10-2020-0129059: Peptides for the prevention or treatment of inflammatory bowel disease [Korean].

[86] Qian K,Wang J,Wang Y.A β-N-acetylhexosaminidase Amuc_2109 from Akkermansia muciniphila protects against dextran sulfate sodium-induced colitis in mice by enhancing intestinal barrier and modulating gut microbiota.Food Funct2022;13:2216-27

[87] Meng X,Wu H,Fang X.Akkermansia muciniphila aspartic protease Amuc_1434* inhibits human colorectal cancer LS174T Cell viability via TRAIL-mediated apoptosis pathway.Int J Mol Sci2020;21:3385 PMCID:PMC7246985

[88] Jiang Y,Zheng C.Acetyltransferase from Akkermansia muciniphila blunts colorectal tumourigenesis by reprogramming tumour microenvironment.Gut2023:gutjnl-2022

[89] Koh A,Kovatcheva-Datchary P.From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites.Cell2016;165:1332-45

[90] Blaak EE,Theis S.Short chain fatty acids in human gut and metabolic health.Benef Microbes2020;11:411-55

[91] Zarrinpar A,Yooseph S.Diet and feeding pattern affect the diurnal dynamics of the gut microbiome.Cell Metab2014;20:1006-17 PMCID:PMC4255146

[92] Xie J,Zhang X.The Akkermansia muciniphila metabolite harmaline protects the host from systemic viral infection through the bile acid-TGR5-NF-κB axis. In. Cell Metabolism; Preprint. Review Complete.

[93] Xie J,Zhang X.Microbial metabolite harmaline protects against virus-induced systemic inflammation.Nat Microbiol2023;8:10-1

[94] Khan FA,Iqbal Z.Recent pharmacological developments in β-carboline alkaloid “harmaline”.Eur J Pharmacol2013;721:391-4

[95] Brito-da-Costa AM,Gomes NGM,Madureira-Carvalho Á.Toxicokinetics and toxicodynamics of ayahuasca alkaloids N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine: clinical and forensic impact.Pharmaceuticals (Basel)2020;13:334 PMCID:PMC7690791

[96] Bag P,Mukherjee H.A dihydro-pyrido-indole potently inhibits HSV-1 infection by interfering the viral immediate early transcriptional events.Antiviral Res2014;105:126-34

[97] Martin-Gallausiaux C,Lashermes A.Akkermansia muciniphila upregulates genes involved in maintaining the intestinal barrier function via ADP-heptose-dependent activation of the ALPK1/TIFA pathway.Gut Microbes2022;14:2110639 PMCID:PMC9427033

[98] Garcia-Vello P,Gray J.Peptidoglycan from Akkermansia muciniphila MucT: chemical structure and immunostimulatory properties of muropeptides.Glycobiology2022;32:712-9

[99] Bae M,Liu X.Akkermansia muciniphila phospholipid induces homeostatic immune responses.Nature2022;608:168-73 PMCID:PMC9328018

[100] Vollmer W,de Pedro MA.Peptidoglycan structure and architecture.FEMS Microbiol Rev2008;32:149-67

[101] Boneca IG,Cabanes D.A critical role for peptidoglycan N-deacetylation in Listeria evasion from the host innate immune system.Proc Natl Acad Sci USA2007;104:997-1002 PMCID:PMC1766339

[102] Griffin ME,Becker JL.Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy.Science2021;373:1040-6 PMCID:PMC9503018

[103] Zhang Q,Overmyer KA.Genetic mapping of microbial and host traits reveals production of immunomodulatory lipids by Akkermansia muciniphila in the murine gut.Nat Microbiol2023;8:424-40 PMCID:PMC9981464

[104] López-Lara IM,Geiger O.Membrane lipids in plant-associated bacteria: their biosyntheses and possible functions.Mol Plant Microbe Interact2003;16:567-79

[105] Lee JS,Lim JW.An integrative multiomics approach to characterize anti-adipogenic and anti-lipogenic effects of Akkermansia muciniphila in adipocytes.Biotechnol J2022;17:e2100397

[106] Roshanravan N,Tutunchi H.A comprehensive systematic review of the effectiveness of Akkermansia muciniphila, a member of the gut microbiome, for the management of obesity and associated metabolic disorders.Arch Physiol Biochem2021;:1-11

[107] Abuqwider JN,Altamimi M.Akkermansia muciniphila, a new generation of beneficial microbiota in modulating obesity: a systematic review.Microorganisms2021;9:1098 PMCID:PMC8161007

[108] Bian X,Yang L.Administration of Akkermansia muciniphila ameliorates dextran sulfate sodium-induced ulcerative colitis in mice.Front Microbiol2019;10:2259 PMCID:PMC6779789