Protein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent manner
Marianne R. Spalinger, … , Gerhard Rogler, Michael Scharl
Marianne R. Spalinger, … , Gerhard Rogler, Michael Scharl
Published May 20, 2019
Citation Information: J Clin Invest. 2019;129(6):2527-2541. https://doi.org/10.1172/JCI123263.
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Research Article Gastroenterology

Protein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent manner

Abstract

The gut microbiota is crucial for our health, and well-balanced interactions between the host’s immune system and the microbiota are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). A variant in protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with reduced risk of developing IBD, but promotes the onset of autoimmune disorders. While the role of PTPN22 in modulating molecular pathways involved in IBD pathogenesis is well studied, its impact on shaping the intestinal microbiota has not been addressed in depth. Here, we demonstrate that mice carrying the PTPN22 variant (619W mice) were protected from acute dextran sulfate sodium (DSS) colitis, but suffered from pronounced inflammation upon chronic DSS treatment. The basal microbiota composition was distinct between genotypes, and DSS-induced dysbiosis was milder in 619W mice than in WT littermates. Transfer of microbiota from 619W mice after the first DSS cycle into treatment-naive 619W mice promoted colitis, indicating that changes in microbial composition enhanced chronic colitis in those animals. This indicates that presence of the PTPN22 variant affects intestinal inflammation by modulating the host’s response to the intestinal microbiota.

Authors

Marianne R. Spalinger, Thomas S.B. Schmidt, Marlene Schwarzfischer, Larissa Hering, Kirstin Atrott, Silvia Lang, Claudia Gottier, Annelies Geirnaert, Christophe Lacroix, Xuezhi Dai, David J. Rawlings, Andrew C. Chan, Christian von Mering, Gerhard Rogler, Michael Scharl

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Figure 3

Cohousing transfers the phenotype from 619W and PTPN22–/– mice to WT littermates.

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Cohousing transfers the phenotype from 619W and PTPN22–/– mice to WT lit...
(A–C) Chronic colitis was induced in WT mice that were cohoused since birth with 619W or PTPN22–/– mice as indicated (A); PTPN22–/– mice that were cohoused since birth and throughout the experiment with WT mice, or mice that were housed only with PTPN22–/– mice after weaning and throughout the experiment (B); or 619W mice that were cohoused since birth and throughout the experiment with WT mice, or mice that were housed only with 619W mice after weaning and throughout the experiment (C). (D) Representative pictures (original magnification, ×10) and scoring of histologic colitis severity in H&E-stained sections of the terminal colon from mice in A–C. Data are representative of 1 of 2 independent experiments. Weight curves show mean ± SEM for each group; n = 3 for H2O group and n = 5 for all other groups. The other graphs show values and SEM, and each dot represents 1 individual mouse. –/–, PTPN22–/–. *P < 0.05, **P < 0.01, Kruskal-Wallis test.