Cytokine-specific autoantibodies shape the gut microbiome in autoimmune polyendocrine syndrome type 1.

Anders Ø Petersen, Martta Jokinen, Damian R Plichta, Gerhard Liebisch, Wolfram Gronwald, Katja Dettmer, Peter J Oefner, Hera Vlamakis, Daniel C Chung, Annamari Ranki, Ramnik J Xavier

Journal: The Journal of allergy and clinical immunology 2021;148(3):876-888

PMID: 33819509

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Abstract

BACKGROUND

Gastrointestinal dysfunction is a frequent and disabling manifestation of autoimmune polyendocrine syndrome type 1 (APS-1), a rare monogenic multiorgan autoimmune disease caused by the loss of central AIRE-controlled immune tolerance.

OBJECTIVES

This study aimed to understand the role of the gut microbiome in APS-1 symptoms and potentially alleviate common gastrointestinal symptoms by probiotic intervention.

METHODS

This study characterized the fecal microbiomes of 28 patients with APS-1 and searched for associations with gastrointestinal symptoms, circulating anti-cytokine autoantibodies, and tryptophan-related metabolites. Additionally, daily doses of the probiotic Lactobacillus rhamnosus GG were administered for 3 months.

RESULTS

Of 581 metagenomic operational taxonomic units (mOTUs) characterized in total, 14 were significantly associated with patients with APS-1 compared with healthy controls, with 6 mOTUs depleted and 8 enriched in patients with APS-1. Four overabundant mOTUs were significantly associated with severity of constipation. Phylogenetically conserved microbial associations with autoantibodies against cytokines were observed. After the 3-month intervention with the probiotic L rhamnosus GG, a subset of gastrointestinal symptoms were alleviated. L rhamnosus GG abundance was increased postintervention and corresponded with decreased abundances of Alistipes onderdonkii and Collinsella aerofaciens, 2 species positively associated with severity of diarrhea in patients with APS-1.

CONCLUSIONS

The APS-1 microbiome correlates with several APS-1 symptoms, some of which are alleviated after a 3-month L rhamnosus GG intervention. Autoantibodies against cytokines appear to shape the gut microbiome by positively correlating with a taxonomically consistent group of bacteria.

Address: Broad Institute of MIT and Harvard, Cambridge, Mass; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, Mass; Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark.; Department of Dermatology and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Broad Institute of MIT and Harvard, Cambridge, Mass; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, Mass.; Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany.; Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Mass.; Department of Dermatology and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Electronic address: [email protected].; Broad Institute of MIT and Harvard, Cambridge, Mass; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, Mass; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Mass. Electronic address: [email protected].

DOI: 10.1016/j.jaci.2021.03.025

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MeSH Terms: Actinobacteria, Adolescent, Adult, Aged, Autoantibodies, Bacteroidetes, Child, Child, Preschool, Cytokines, Female, Gastrointestinal Microbiome, Humans, Lacticaseibacillus rhamnosus, Male, Middle Aged, Mutation, Polyendocrinopathies, Autoimmune, Probiotics, Transcription Factors, Young Adult, AIRE Protein