Project Summary The brain communicates with the gastrointestinal tract via the well-established gut-brain axis. Due to an increase in the permeability of blood brain barrier and intestinal epithelial barrier during aging, the brain likely becomes more susceptible to inflammation initiated in the gut. Both chronic inflammatory bowel disease (IBD including ulcerative colitis and Crohn's disease) and Alzheimer's disorder (AD) increase in prevalence among the elderly. However, the role of this intestinal inflammation on AD progression remains unclear. We observed a significant increase in intestinal inflammation and dysfunction during disease in a mouse model of AD. Based upon this data we hypothesize that AD includes intestinal dysfunction as a largely unrecognized component of disease. Moreover, we expect that chronic conditions such as IBD may potentiate progression of AD through inflammatory changes propagated from the intestines to the brain. We will elaborate the link between the intestines and the brain in AD using a transgenic mouse model of AD, AppNL-G-F mice. Our hypothesis will be tested by completing three aims. Aim one will use clinically available intestine-selective T cell inhibitory antibodies to attenuate basal AD intestinal inflammation and colitis-induced exacerbation in AppNL-G-F mice and confirm that intestinal dysfunction contributes to memory deficits in these mice. Aim two will assess the efficacy of the gut-selective inhibitory antibody therapy to decrease brain Aβ levels, gliosis, synaptic loss, and cytokine levels. The final aim will cross the AppNL-G-F mice to Ltatm1Dch mice that carry a null mutation in lymphotoxin α resulting in absence of Peyer's patches and lymph nodes. This genetic approach will provide additional confirmation that intestinal inflammatory changes in the AppNL-G-F mice are required for the memory dysfunction and brain related changes. Completion of the study will verify a critical role of gut inflammation in disease progression and validate a clinically available therapeutic option, anti-α4β7 antibodies, as treatments targeting the gut-brain axis. This suggests that select immunomodulatory agents can be repositioned to combat the inflammatory component of AD without the need for crossing the blood brain barrier.