Protein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent manner
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
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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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 9

Transfer of stool after the first DSS cycle recapitulates the phenotype in chronic colitis.

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Transfer of stool after the first DSS cycle recapitulates the phenotype ...
Cecum content was collected from WT, PTPN22–/–, and 619W mice that were treated with DSS for 7 days and allowed to recover for 10 additional days (= day 18 DSS). Cecum content was then transferred into WT, PTPN22–/–, or 619W mice that had been treated with an antibiotic cocktail for 1 week to deplete the microbiota. (A) Schematic overview of the experimental setup. (B–D) Weight development, representative pictures (original magnification, ×10) from H&E-stained terminal colon sections, and scoring of histological damage of 619W mice that received cecum content of treatment-naive 619W mice, WT mice upon colitis induction, or 619W mice after colitis induction (B); PTPN22–/– mice that received cecum content of treatment-naive PTPN22–/– mice, WT mice upon colitis induction, or PTPN22–/– mice after colitis induction (C); and WT mice that received cecum content of treatment-naive WT mice or WT, 619W, or PTPN22–/– mice after colitis induction (D). Depicted are mean values and SEM; n = 5 for each experimental group. Data are representative of 1 of 2 independent experiments. Abx, antibiotic treatment. *P < 0.05, **P < 0.01, Kruskal-Wallis test.