# Communicating Intestinal Inflammation to the Brain in Alzheimer's Disease

> **NIH NIH RF1** · UNIVERSITY OF NORTH DAKOTA · 2020 · $1,420,768

## Abstract

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.

## Key facts

- **NIH application ID:** 10071058
- **Project number:** 1RF1AG069378-01
- **Recipient organization:** UNIVERSITY OF NORTH DAKOTA
- **Principal Investigator:** Colin K Combs
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,420,768
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071058

## Citation

> US National Institutes of Health, RePORTER application 10071058, Communicating Intestinal Inflammation to the Brain in Alzheimer's Disease (1RF1AG069378-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10071058. Licensed CC0.

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