Inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis, which cause chronic inflammation in the intestines. It’s an autoimmune disorder affecting about 3 million US adults with symptoms such as diarrhea, rectal bleeding, fatigue, and stomach cramps. The intestinal epithelium, particularly Paneth cells, play an essential role in IBD as they regulate the gut microbiota with antimicrobial peptides. Disrupting the epithelium during inflammation can exacerbate IBD symptoms.
A recent study led by UC Riverside has provided insights into how Inflammatory Bowel Disease (IBD) can develop. The study examined the gut microbiomes of healthy individuals and those with IBD. The researchers found distinct differences in the gut microbiomes of individuals with IBD compared to healthy individuals.
A recent mouse study led by biomedical scientist and IBD expert Declan F. McCole at the University of California, Riverside, has found that decreased activity of the PTPN2 gene in intestinal epithelial cells reduces the production of Paneth cell antimicrobial peptides.
Published in the journal Cellular and Molecular Gastroenterology and Hepatology, the study establishes a critical link between PTPN2 and Paneth cells, which play an essential role in maintaining normal gut microbe properties. The study also suggests that a specific type of E. coli bacteria, AIEC, may worsen inflammation in IBD patients.
“We know that in IBD, Paneth cells are often unable to produce sufficient antimicrobial peptides or respond appropriately to gut bacteria,” McCole said.
“These functional defects can also be associated with changes in the structure of Paneth cells that reduce their ability to secrete the protective antimicrobial peptides, leading to increases in the populations of bacteria associated with IBD, such as AIEC. These structural changes in the appearance of Paneth cells can also serve as a marker of disease in IBD, especially Crohn’s disease.”
“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,” McCole said.
PTPN2 gene variants are linked to a higher risk of Inflammatory Bowel Disease (IBD). A recent study in mice found that the PTPN2 gene is crucial for maintaining the intestinal epithelial cell (IEC) barrier, communication between IECs and macrophages, and regulating the gut microbiome. The study aimed to determine how the loss of PTPN2 affects the function and subtype of ileal IECs in vivo.
For the study, researchers used mice with different versions of the Ptpn2 gene – wild-type, heterozygous, and knockout – and mice with inducible deletion of Ptpn2 in intestinal epithelial cells (IECs). They utilized imaging techniques, flow cytometry, enteroid culture, and gene and protein analysis of IEC markers to investigate the effects of Ptpn2 loss on the function of IECs.
Ptpn2-KO mice showed reduced expression of Paneth cell-associated antimicrobial peptides and Paneth cell numbers, disrupted endoplasmic reticulum architecture, and increased CHOP protein. However, there was increased expression of Paneth cell-stimulatory cytokines IL-22 and IFN-γ+ in CD4+ T-cells from Ptpn2-KO ileum. These findings were confirmed in epithelium-specific Ptpn2ΔIEC mice, which also showed impaired lysozyme protein levels in Paneth cells compared to control mice.
In conclusion, the study found that Ptpn2 deficiency leads to reduced Paneth cell viability, disrupted endoplasmic reticulum architecture, and compromised production of Paneth cell-specific antimicrobial peptides. These effects may increase susceptibility to intestinal infection and dysbiosis in mice.
The researchers suggest that their findings could lead to new treatments for IBD, such as therapies that target TLR2 to restore balance to the gut microbiome. The study also highlights the importance of maintaining a healthy gut microbiome to prevent the development of IBD and other gut-related disorders.
- Vinicus Canale, Marianne Spalinger et al. PTPN2 is a Critical Regulator of Ileal Paneth Cell Viability and Function in Mice. Cellular and Molecular Gastroenterology and Hepatology. DOI: 10.1016/j.jcmgh.2023.03.009