A recent study, published in Cellular and Molecular Gastroenterology and Hepatology has revealed a new mechanism that may explain inflammatory bowel disease (IBD). These new findings open up the possibility of patients with mutations in the PTPN2 gene benefitting from personalised treatments.
An autoimmune response
IBD is an umbrella term for Crohn’s disease and ulcerative colitis, autoimmune disorders characterised by chronic inflammation in the gastrointestinal tract. IBD can be debilitating and there is currently no cure. Finding effective, long-term treatments is difficult due to the complex nature of the condition; a variety of different genetic and environmental factors can contribute to the onset of the disease. Furthermore, the makeup of the gut microbiome has been heavily implicated in IBD. This unique combination of factors leads to the disruption of the intestinal epithelium, causing increased intestinal permeability that allows the translocation of microbes and, ultimately, a dysregulated immune response.
The PTPN2 gene is responsible for intestinal barrier maintenance, and mutations in the gene have been previously implicated in IBD onset. In this particular study, the researchers from the University of California Riverside set out to assess the impact of PTPN2 loss of function in mouse models of IBD.
Loss of function
The team knocked out the expression of PTPN2 in their mouse models to assess the impact this would have on the intestinal barrier. They observed that the loss of PTPN2 led to a decrease of cells known as “Paneth” cells. These are found exclusively in the intestinal mucosa and secrete antimicrobial peptides that play a significant role in the regulation of the gut microbiome. A transcriptional analysis confirmed that the expression of these peptides was lowered in PTPN2 knock-out mice. In addition, the Paneth cells that remained in the intestine suffered from structural defects in the endoplasmic reticulum.
The dysregulation of the microbiome creates an opportunity for bacteria to colonise in places they shouldn’t, leading to infection of the intestine and subsequent immune responses. In particular, E. coli is known to invade the intestine in the absence of antimicrobial peptides. This led the researchers to the conclusion that PTPN2 is responsible for the regulation of Paneth cell-derived antimicrobials, loss of which leads to bacterial dysbiosis in the gut.
IBD is a relatively common condition and has huge impacts on the everyday lives of patients. However, the wide range of genetic and environmental factors known to contribute to the disease create difficulties in discovering and distributing effective, long-term treatments. This study pinpoints one specific cause of the condition in mice and provides hope that, should the results be mirrored in humans, a personalised approach could be taken to treat those with PTPN2 loss-of-function mutations. Discussing the results, author Declan McCole stated: “This study develops our focus on improving personalized medicine approaches in IBD by understanding how patients with variants in the PTPN2 gene develop IBD.” He added: “This work sets the foundation for our new research project that will identify pharmacologic agents capable of rescuing Paneth cell function and reducing the contributions of microbes to intestinal inflammation.”