Inflammatory bowel disease (IBD) and Salmonella infection (salmonellosis) are characterized by disruption of the intestinal barrier and severe gut inflammation. A multitude of cell signaling pathways regulate the gut immunological responses. Protein ADP-ribosylation and the enzymes catalyzing this modification, that is, poly(ADP-ribose) polymerases (PARPs), have gained attention in the past few years for their potential roles in the regulation of immunological responses. Yet, the mechanistic basis and more importantly the physiological relevance have largely remained elusive.

This study focuses on PARP14 in gut inflammation. PARP14 expression and function were examined using colon biopsies of IBD vs control patients and tissue material from two mouse models, that is, from the oral dextran sulfate sodium (DSS) exposure colitis model and the oral Salmonella Typhimurium infection model. PARP14 was predominantly expressed by the epithelial cells (with granular cytosolic staining) in human IBD and control patient colons. Analysis of bulk tissue transcriptomic data revealed higher PARP14 expression in the colon of IBD patients as compared to control patients. In mice, upon DSS-treatment and Salmonella infection, majority of the cells expressing PARP14 were epithelial cells, along with some mucosal macrophages. Analysis of Salmonella infection single-cell RNA-Seq data of the small intestine epithelium revealed pronounced PARP14 expression in the enterocytes and Tuft cells. Based on the qPCR analysis, PARP14 expression was higher in the colon of DSS-treated mice as compared to controls. Body-wide genetic PARP14 deficiency was associated with exacerbated colitis in both mouse models. Most importantly, the colon histopathology analysis revealed more severe epithelial barrier damage – including extensive epithelial erosion, Goblet cell loss, and increased immune cell infiltration – in the PARP14-deficient mice. PacBio sequencing (microbiota analysis), flow cytometry (leukocyte population analysis) and RNA-Seq (transcriptomic analysis) were used to study features that potentially associate with the pronounced pathologies of PARP14-deficient mice. While no significant microbiota and leukocyte population differences were detected between wt and PARP14-deficient mice, the transcriptomic analysis indicated a critical regulatory role for PARP14. Bulk RNA sequencing of colon samples showed dysregulated expression of inflammation- and infection-response genes in PARP14- deficient mice both prior and after DSS exposure, while Salmonella infected knockouts lacked key gene expression signatures related to cell adhesion, cell proliferation, and cytoskeletal organization.

In conclusion, this study uncovered a previously unknown role of PARP14 in gut inflammation. PARP14 appears to play a protective role in the gut by maintaining epithelial integrity and modulating mucosal inflammation, possibly as a transcriptional regulator. Biomarker potential of PARP14 in gut disorders merits further investigation.