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 1

Presence of the 619W variant promotes chronic colitis.

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Presence of the 619W variant promotes chronic colitis. Chronic colitis w...
Chronic colitis was induced in PTPN22–/– and 619W mice as well as in their respective WT littermates via administration of 4 cycles of DSS (1.5% DSS in the drinking water for 7 days, followed by 10 days recovery, each cycle). (A–D) Weight development (A), representative pictures from colonoscopy (original magnification, ×10) and MEICS (B), quantification of colitis severity (C), and representative pictures from H&E-stained colon sections (original magnification, ×20) at day 85 (D) reveal that 619W mice show enhanced colitis from the second DSS cycle onward. Depicted are mean values and SEM (A–C). Data are representative of 1 of 2 independent experiments with n = 3–6 per experimental group, each experiment. (B–D) Each dot represents 1 mouse. Graph in A shows weight development from the same individuals as in B–D. *P < 0.05, **P < 0.01, Kruskal-Wallis test.