# Host and microbial basis of human ulcerative colitis and pouchitis:  Identification, role, mechanisms, and resource development of host susceptibility and pathobiont factors

> **NIH NIH RC2** · UNIVERSITY OF CHICAGO · 2021 · $2,040,862

## Abstract

PROJECT SUMMARY/ABSTRACT
Inflammatory bowel diseases (IBD) result from the convergence of host, environmental, and microbial factors,
each necessary, but not sufficient to cause disease. Yet, significant gaps in knowledge remain – among them,
what underlies disease susceptibility and precipitates the onset of IBD. The need to better understand the
causes that lead to these diseases remains a challenge. Post disease onset, numerous confounders and
complications make it problematic to unravel the myriad of contributing factors. Not surprisingly, most human
subject studies fail to go beyond description and association. Inability to sort out cause-effect relationship on a
temporal basis further hinders efforts to improve clinical management and outcomes and to develop effective
strategies for risk stratification and disease prevention. To address this issue, we propose a multi-disciplinary
team approach that will use the lens of a unique clinical model to gain transformative insights that will help
move the needle in IBD. The model involves a subset of patients with medically-refractory ulcerative colitis
(UC) who have undergone total proctocolectomy with ileal pouch anal anastomosis (UC-IPAA) and who can be
followed before and after disease development and serve as their own controls. Half of these patients will
develop an inflammatory condition of their ileal pouch within two years (pouchitis). In an initial exploratory study
of these patients, two discoveries were made which led to the following hypotheses: [1] IBD patients exhibit
an anomalous transcriptional response to microbiota-derived signals that renders them susceptible to
the development of pouchitis, but is not sufficient to cause disease. [2] Specific mucosal pathobionts
that emerge through selection or acquisition of virulence factors trigger pouchitis on the patient's
background of genetic susceptibility. With regard to the latter, differences in specific Bacteroides fragilis
capsular polysaccharide (CPS) biosynthetic gene clusters among luminal and mucosal strains may transform a
commensal microbe to a pathobiont. Three aims are proposed: (1) to investigate the stimuli, role, and
functional impact of specific host genes of the anomalous UC pouch transcriptome that may promote disease
susceptibility, by employing single-cell approaches to define cell-type and -specific contributions and
mechanisms; (2) to identify and isolate microbes involved in promoting pouchitis including CPS variants and
determine the their functional impact on host epithelia and immune cells and role and contribution to initiation
of disease, (3) to develop a research resource for the broader community to advance discovery-based or
hypothesis-generating science. The study will be conducted by a multi-disciplinary team of experts with a
proven and successful record of collaboration and synergy. The proposal links basic, translational, and clinical
scientific research by focusing on molecular and genetic mechanism...

## Key facts

- **NIH application ID:** 10167708
- **Project number:** 5RC2DK122394-03
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** EUGENE B CHANG
- **Activity code:** RC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,040,862
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167708

## Citation

> US National Institutes of Health, RePORTER application 10167708, Host and microbial basis of human ulcerative colitis and pouchitis:  Identification, role, mechanisms, and resource development of host susceptibility and pathobiont factors (5RC2DK122394-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10167708. Licensed CC0.

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