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

J Allergy Clin Immunol. 2021 Sep;148(3):876-888. doi: 10.1016/j.jaci.2021.03.025. Epub 2021 Apr 2.

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.

Keywords: APECED; APS-1; GABA; Lactobacillus rhamnosus GG; autoantibody; autoimmunity; chemokine; cytokine; microbiome; tryptophan.

Publication types

  • Controlled Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actinobacteria / genetics
  • Actinobacteria / isolation & purification
  • Adolescent
  • Adult
  • Aged
  • Autoantibodies / blood
  • Autoantibodies / immunology*
  • Bacteroidetes / genetics
  • Bacteroidetes / isolation & purification
  • Child
  • Child, Preschool
  • Cytokines / immunology*
  • Female
  • Gastrointestinal Microbiome*
  • Humans
  • Lactobacillus rhamnosus*
  • Male
  • Middle Aged
  • Mutation
  • Polyendocrinopathies, Autoimmune / blood
  • Polyendocrinopathies, Autoimmune / genetics
  • Polyendocrinopathies, Autoimmune / immunology*
  • Polyendocrinopathies, Autoimmune / microbiology*
  • Probiotics / therapeutic use*
  • Transcription Factors / genetics
  • Young Adult

Substances

  • APECED protein
  • Autoantibodies
  • Cytokines
  • Transcription Factors

Supplementary concepts

  • Alistipes onderdonkii
  • Collinsella aerofaciens