title: Proinflammatory cytokine interferon-γ and microbiome-derived metabolites dictate epigenetic switch between forkhead box protein 3 isoforms in coeliac disease.
abstract: Coeliac disease (CD) is an autoimmune enteropathy triggered by gluten and characterized by a strong T helper type 1 (Th1)/Th17 immune response in the small intestine. Regulatory T cells (Treg) are CD4+CD25++forkhead box protein 3 (FoxP3+) cells that regulate the immune response. Conversely to its counterpart, FoxP3 full length (FL), the alternatively spliced isoform FoxP3 Δ2, cannot properly down-regulate the Th17-driven immune response. As the active state of CD has been associated with impairments in Tregcell function, we aimed at determining whether imbalances between FoxP3 isoforms may be associated with the disease. Intestinal biopsies from patients with active CD showed increased expression of FOXP3 Δ2 isoform over FL, while both isoforms were expressed similarly in non-coeliac control subjects (HC). Conversely to what we saw in the intestine, peripheral blood mononuclear cells (PBMC) from HC subjects did not show the same balance between isoforms. We therefore hypothesized that the intestinal microenvironment may play a role in modulating alternative splicing. The proinflammatory intestinal microenvironment of active patients has been reported to be enriched in butyrate-producing bacteria, while high concentrations of lactate have been shown to characterize the preclinical stage of the disease. We show that the combination of interferon (IFN)-γ and butyrate triggers the balance between FoxP3 isoforms in HC subjects, while the same does not occur in CD patients. Furthermore, we report that lactate increases both isoforms in CD patients. Collectively, these findings highlight the importance of the ratio between FoxP3 isoforms in CD and, for the first time, associate the alternative splicing process mechanistically with microbial-derived metabolites.
authors.affiliation: Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.|Graduate Program in Life Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: G
authors.initials: G
authors.lastname: Serena
authors.affiliation: Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Yan
authors.affiliation: Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Camhi
authors.affiliation: Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.affiliation: Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Lima
authors.affiliation: Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.|Celiac Center, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sapone
authors.affiliation: Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Leonard
authors.affiliation: Celiac Center, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Mukherjee
authors.affiliation: Department of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Nath
authors.affiliation: Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Lammers
authors.affiliation: Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.|European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Fasano
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015704:CD4 Antigens / Q000378:metabolism; D002446:Celiac Disease / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D064307:Microbiota / Q000502:physiology*; D008875:Middle Aged; D020033:Protein Isoforms / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism; D055815:Young Adult
chemical_list: D015704:CD4 Antigens; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D020033:Protein Isoforms; D007371:Interferon-gamma
keywords: Treg; autoimmunity; celiac disease; microbiome