# The Inflammasome in the Regulation of Intestinal Glucose Homeostasis, Microbiota and Inflammation

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $467,648

## Abstract

ABSTRACT
Human inflammatory bowel diseases (IBD), comprised of ulcerative colitis and Crohn’s disease, constitute a
major health problem in developed countries. While precise etiology is not clearly defined, genetic
predisposition, altered gut microbiota, and Western diet are risk factors for IBD. However, how these factors
are coordinated in inducing and triggering IBD is poorly understood. We recently demonstrated that mice
deficient in the inflammasome are susceptible to experimental colitis, which is associated with altered gut
microbiota. The inflammasome is a multiprotein complex involved in the cleavage of caspase-1, which in turn
activates proinflammatory cytokines IL-1b and IL-18. Our preliminary study demonstrated that the
administration of IL-18 in inflammasome-deficient mice during colitis reduces colitis susceptibility which is
associated with a reduction of pathogenic bacteria, suggesting that the inflammasome/IL-18 signaling axis
plays a critical role in maintaining healthy microbial community and intestinal homeostasis. Notably, IL-18-
deficient and other inflammasome defective mice are prone to develop obesity and exhibit defective glucose
metabolism. Consistently, we observed an elevated level of glucose and reduced expression of a glucose
transporter gene in inflammasome-deficient mouse guts. Notably, glucose is the primary energy source for
many pathogenic bacteria. We, therefore, hypothesize that the inflammasome maintains intestinal glucose
homeostasis via regulation of selective glucose transporters in intestinal epithelial cells, and inflammasome
dysfunction leads to glucose accumulation in the gut triggering colitis via modulation of gut microbiota. These
hypotheses will be tested through addressing two specific aims: Aim 1: to determine the role of dietary glucose
in colitis pathogenesis, and Aim 2: to elucidate the role of the inflammasome in glucose homeostasis in the gut.
Overall, this study will establish a role for dietary simple sugar glucose in colitis pathogenesis, and reveal a
novel immune mechanism for maintaining glucose homeostasis in the gut. The data obtained from this study
will guide diet recommendations for IBD patients and lead to developing novel IBD treatments targeting the
inflammasome or its downstream signaling pathways involved in glucose transport.

## Key facts

- **NIH application ID:** 10848322
- **Project number:** 5R01DK125352-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Hasan Zaki
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $467,648
- **Award type:** 5
- **Project period:** 2021-03-09 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848322

## Citation

> US National Institutes of Health, RePORTER application 10848322, The Inflammasome in the Regulation of Intestinal Glucose Homeostasis, Microbiota and Inflammation (5R01DK125352-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10848322. Licensed CC0.

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