# Exploring the role and mechanisms of action of UC pouchitis-associated pathobionts (PAP) to gain insights into the etiopathogenesis of Inflammatory Bowel Diseases

> **NIH NIH F31** · UNIVERSITY OF CHICAGO · 2024 · $48,974

## Abstract

PROJECT SUMMARY/ABSTRACT
Inflammatory Bowel Diseases (IBD) are a growing concern in industrialized and newly developing countries as
the environment, lifestyles, and diets change. IBD involves a complex interplay between the host's
environment, diet, genetics, and gut microbiota, each necessary but insufficient to cause disease. However, it
is unclear what initiates these diseases, what the relative contributions of these factors play in the
pathogenesis of IBD, and what makes these diseases chronic. Current therapies are still imprecise, and
preventative disease strategies for high-risk patients are non-existent. Some evidence suggests that changes
in the gut microbiota can influence the risk and trigger IBD. Our lab uses a human model involving ulcerative
colitis(UC) patients who undergo colectomy followed by creating an ileal pouch-anal anastomosis (IPAA). In
theory, IPAA should be curative, but nearly half of these patients develop an inflammatory condition of the ileal
pouch called pouchitis, whereas non-IBD patients undergoing the same procedure rarely develop pouchitis.
These patients were followed and sampled longitudinally, and metagenomic data shows blooms of pathobionts
such as Bacteroides fragilis before and during the development of pouchitis. Upon antibiotic-induced
remission, the relative abundance of B. fragilis decreased, implicating it as a potential trigger and sustainer of
pouchitis. The proposed research strategy tests the hypothesis that pouchitis-associated pathobionts (PAP)
like Bacteroides fragilis cause in IPAA-associated pouchitis. Notably all the B. fragilis strains cultivated from
UC pouchitis patients are non-enterotoxigenic strains that were present even before the IPAA was
performed. Thus, we believe that insight gained through these studies will directly relate to the
etiopathogenesis of human IBD. As a counterpart to the human pouchitis model, we employ germ-free (GF)
and SPF (specific pathogen-free) wild-type (WT) and IL10 knockout (IL10-/-) mice where engraftment of PAP B.
fragilis in the latter is associated with increased incidence and severity of colitis. I will determine whether B.
fragilis promotes colitis directly and/or indirectly by causing perturbations in the membership and function of the
indigenous colonic microbiota. SPF, but not GF, IL10-/- mice are genetically predisposed to developing IBD.
Human PAP B. fragilis strains readily engraft into SPF IL10-/- mouse microbiota, but not that of WT mice, and
promote the development of colitis. Using Bulk-RNA Sequencing analysis and flow cytometry, I will evaluate
how the presence of B. fragilis alters the host's immune responses and gene expression in the GI tract of GF
and SPF IL-10-/- mice. Fecal samples, regional intestinal luminal, and mucosal content will be subjected to 16S
rRNA, metagenomic, and metabolomic analyses to assess if B. fragilis leads to dysbiosis–promoting chronic
colitis in the IL10-/- mouse model. This study provides critical insight ...

## Key facts

- **NIH application ID:** 10873722
- **Project number:** 5F31DK136333-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Joash Lake
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-04-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873722

## Citation

> US National Institutes of Health, RePORTER application 10873722, Exploring the role and mechanisms of action of UC pouchitis-associated pathobionts (PAP) to gain insights into the etiopathogenesis of Inflammatory Bowel Diseases (5F31DK136333-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10873722. Licensed CC0.

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