Akkermansia muciniphila regulates food allergy in a diet-dependent manner

Alterations in the gut microbiome, including diet-driven changes, are linked to the rising prevalence of food allergy, yet little is known about how speci�c gut bacteria incite breakdown of oral tolerance. Here, we show that depriving specic-pathogen-free mice of dietary �ber leads to an increase of the mucolytic bacterium Akkermansia muciniphila, which is associated with a surge in the colonic type 2 immune cells and IgE-coated commensals, and microbiota-mediated gut mucosal barrier dysfunction. These changes manifest into exacerbated sensitization to food allergens, ovalbumin and peanut. To demonstrate the causal role of A. muciniphila, we employed a tractable synthetic human gut microbiota in gnotobiotic mice. The presence of A. muciniphila within the microbiota, combined with �ber deprivation, resulted in stronger anti-commensal IgE coating and type 2 immune responses, which worsened symptoms of food allergy. Our study supports a mechanistic link between diet and a mucolytic gut microbe in regulating food allergy.

[1]  A. Hirayama,et al.  Dietary fibers boost gut microbiota-produced B vitamin pool and alter host immune landscape , 2024, Microbiome.

[2]  Ryan D. Crawford,et al.  Phenotypic and Genomic Diversification in Complex Carbohydrate-Degrading Human Gut Bacteria , 2022, mSystems.

[3]  M. Ollert,et al.  Intestinal mucus barrier: a missing piece of the puzzle in food allergy. , 2021, Trends in molecular medicine.

[4]  Edoardo Pasolli,et al.  Specific gut microbiome signatures and the associated pro-inflamatory functions are linked to pediatric allergy and acquisition of immune tolerance , 2021, Nature Communications.

[5]  James A. London,et al.  A single sulfatase is required to access colonic mucin by a gut bacterium , 2021, Nature.

[6]  E. Martens,et al.  Constructing a gnotobiotic mouse model with a synthetic human gut microbiome to study host–microbe cross talk , 2021, STAR protocols.

[7]  C. Akdis.  Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions? , 2021, Nature Reviews Immunology.

[8]  J. Raes,et al.  Local immune response to food antigens drives meal-induced abdominal pain , 2021, Nature.

[9]  D. Brenner,et al.  Deprivation of dietary fiber in specific-pathogen-free mice promotes susceptibility to the intestinal mucosal pathogen Citrobacter rodentium , 2021, bioRxiv.

[10]  H. Renz,et al.  Early life microbial exposures and allergy risks: opportunities for prevention , 2020, Nature Reviews Immunology.

[11]  F. Hentges,et al.  Comprehensive mapping of immune tolerance yields a regulatory TNF receptor 2 signature in a murine model of successful Fel d 1‐specific immunotherapy using high‐dose CpG adjuvant , 2020, Allergy.

[12]  T. Yi,et al.  The role of IL-22 in intestinal health and disease , 2020, The Journal of experimental medicine.

[13]  U. Wehkamp,et al.  Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses. , 2019, The Journal of allergy and clinical immunology.

[14]  James R. Brown,et al.  Obesity and disease severity magnify disturbed microbiome-immune interactions in asthma patients , 2019, Nature Communications.

[15]  Francesco Asnicar,et al.  Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2 , 2019, Nature Biotechnology.

[16]  P. Engel,et al.  High dietary fat intake induces a microbiota signature that promotes food allergy. , 2019, The Journal of allergy and clinical immunology.

[17]  D. Plichta,et al.  Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis , 2019, Science.

[18]  A. Krogulska,et al.  Prevalence of allergic diseases in children with inflammatory bowel disease , 2019, Postepy dermatologii i alergologii.

[19]  G. Gerber,et al.  Microbiota Therapy Acts Via a Regulatory T Cell MyD88/RORγt Pathway to Suppress Food Allergy , 2019, Nature Medicine.

[20]  Mark M. Davis,et al.  Allergen-specific CD8+ T cells in peanut-allergic individuals. , 2019, The Journal of allergy and clinical immunology.

[21]  K. Nadeau,et al.  Prevalence and Severity of Food Allergies Among US Adults , 2019, JAMA network open.

[22]  D. Antonopoulos,et al.  Healthy infants harbor intestinal bacteria that protect against food allergy , 2018, Nature Medicine.

[23]  H. Flint,et al.  Mechanistic Insights Into the Cross-Feeding of Ruminococcus gnavus and Ruminococcus bromii on Host and Dietary Carbohydrates , 2018, Front. Microbiol..

[24]  E. Martens,et al.  Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier , 2018, Nature Reviews Microbiology.

[25]  Leland McInnes,et al.  UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction , 2018, ArXiv.

[26]  F. Bäckhed,et al.  Bifidobacteria or Fiber Protects against Diet-Induced Microbiota-Mediated Colonic Mucus Deterioration. , 2018, Cell host & microbe.

[27]  B. Becher,et al.  CyTOF workflow: differential discovery in high-throughput high-dimensional cytometry datasets , 2017, F1000Research.

[28]  T. Urich,et al.  Lifestyle and Horizontal Gene Transfer-Mediated Evolution of Mucispirillum schaedleri, a Core Member of the Murine Gut Microbiota , 2017, mSystems.

[29]  C. Nagler,et al.  The Influence of the Microbiome on Allergic Sensitization to Food , 2017, The Journal of Immunology.

[30]  P. Wilmes,et al.  A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility , 2016, Cell.

[31]  Gunnar C. Hansson,et al.  Immunological aspects of intestinal mucus and mucins , 2016, Nature Reviews Immunology.

[32]  C. Mackay,et al.  Dietary Fiber and Bacterial SCFA Enhance Oral Tolerance and Protect against Food Allergy through Diverse Cellular Pathways. , 2016, Cell reports.

[33]  Justin L Sonnenburg,et al.  Quantitative Imaging of Gut Microbiota Spatial Organization. , 2015, Cell host & microbe.

[34]  Y. Saeys,et al.  FlowSOM: Using self‐organizing maps for visualization and interpretation of cytometry data , 2015, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[35]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[36]  A. Xu,et al.  Serological Investigation of Food Specific Immunoglobulin G Antibodies in Patients with Inflammatory Bowel Diseases , 2014, PloS one.

[37]  D. Antonopoulos,et al.  Commensal bacteria protect against food allergen sensitization , 2014, Proceedings of the National Academy of Sciences.

[38]  R. Newberry,et al.  Microbial Sensing by Goblet Cells Controls Immune Surveillance of Luminal Antigens in the Colon , 2014, Mucosal Immunology.

[39]  Bihui Huang,et al.  Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals , 2013, Science.

[40]  Lucie Geurts,et al.  Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity , 2013, Proceedings of the National Academy of Sciences.

[41]  Susan Holmes,et al.  phyloseq: An R Package for Reproducible Interactive Analysis and Graphics of Microbiome Census Data , 2013, PloS one.

[42]  M. Suárez-Fariñas,et al.  Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. , 2012, The Journal of allergy and clinical immunology.

[43]  Pelin Yilmaz,et al.  The SILVA ribosomal RNA gene database project: improved data processing and web-based tools , 2012, Nucleic Acids Res..

[44]  W. D. de Vos,et al.  Modulation of Mucosal Immune Response, Tolerance, and Proliferation in Mice Colonized by the Mucin-Degrader Akkermansia muciniphila , 2011, Front. Microbio..

[45]  R. Kumar,et al.  The Prevalence, Severity, and Distribution of Childhood Food Allergy in the United States , 2011, Pediatrics.

[46]  Werner Müller,et al.  Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. , 2011, Immunity.

[47]  Gunnar C. Hansson,et al.  The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host–microbial interactions , 2010, Proceedings of the National Academy of Sciences.

[48]  F. Casellas,et al.  Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum , 2006, Gut.

[49]  M. Leach,et al.  IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. , 2001, Immunity.

[50]  C. Hsieh,et al.  T cell genetic background determines default T helper phenotype development in vitro , 1995, The Journal of experimental medicine.

[51]  M. Johansson,et al.  An ex vivo method for studying mucus formation , properties , and thickness in human colonic biopsies and mouse small and large intestinal explants , 2012 .

[52]  Xunrong Luo,et al.  Impairing oral tolerance promotes allergy and anaphylaxis: a new murine food allergy model. , 2009, The Journal of allergy and clinical immunology.