Studying the Role of PTEN in The Gut and Investigating the Gut-Brain Inflammatory Interaction

Phosphatase and tensin homolog (Pten) deficiency causes tumorigenesis because Pten opposes PI3k-Akt signaling. However, correlation between Pten deficiency and colon cancer remains unclear due to contradicting studies. The first project examines this correlation by generating intestinal epithelial cell (IEC) – specific Pten knockout (KO) mice. However, IEC-Pten deficiency alone did not induce tumorigenesis in mice but maintained the tumor-driving potential. The expression of tumor-promoting and tumor-suppressing genes was decreased and increased, respectively, in the intestine of PtenΔIEC/ΔIEC mice compared to controls. The abundance of Akkermansia muciniphila, capable of inducing chronic intestinal inflammation, was reduced in PtenΔIEC/ΔIEC mice. These findings suggest that altered tumor-associated gene expression and changed gut microbiota shape a tumor-preventive microenvironment in PtenΔIEC/ΔIEC mice. It was recently suggested that PTEN regulates TLR5-induced immune and inflammatory responses in IECs, suggesting an immunomodulatory function of PTEN in the gut. However, this alternative function of PTEN has not been evaluated in an in vivo context of protection against enteropathogenic bacteria. In the second project, PtenΔIEC/ΔIEC mice were subjected to the streptomycin-pre-treated mouse model of Salmonella infection. The bacterial infection in PtenΔIEC/ΔIEC mice increased the mortality, induced gastrointestinal inflammation, up-regulated pro-inflammatory cytokines, and increased bacterial loads in extraintestinal tissues. This suggests that IEC-restricted Pten deficiency renders the host greatly susceptible to Salmonella infection and supports an immune-regulatory role of PTEN in the gut. Lastly, in the third project, chronic gut inflammation is associated with neurodegenerative diseases. However, the direct evidence for and the underlying mechanism of the gut-brain interaction remain obscure. An interleukin-10 (IL-10) KO mouse was fed piroxicam-mixed chow, where it found that the brain and gut had increased levels of IL-1β and IL-6 cytokines. These findings suggest an inflammatory link in the piroxicam-fed IL-10 KO mice. Pten is an important factor in maintaining gut homeostasis, which is important for neural function.