# DECONSTRUCTING INFLAMMATION AND ALTERED MICROBIOTA IN METABOLIC SYNDROME

> **NIH NIH R01** · GEORGIA STATE UNIVERSITY · 2021 · $508,940

## Abstract

Abstract
Humanity is facing an epidemic of interrelated obesity-associated disorders collectively referred to as metabolic
syndrome (Met Syn). Central features of Met Syn include insulin-resistance, hyperlipidemia, hepatic steatosis
and hypertension, all of which can progress to highly morbid and costly diseases such as diabetes,
cardiovascular disease, and liver failure. Met Syn is associated with systemic chronic low-grade inflammation
(LGI). LGI is not merely a marker of Met Syn but, rather, LGI interferes with a panoply of metabolic signaling
pathways, including insulin and leptin signaling, such that chronic LGI promotes Met Syn. Thus, better
understanding of the underlying causes of LGI is germane to managing the Met Syn epidemic. Proposed
causes of LGI include the notion that obesity itself leads to lipid overload, resulting in endoplasmic reticulum
stress that induces the pro-inflammatory gene expression that defines LGI. However, the grant this application
seeks to renew has shown that LGI, and subsequently Met Syn, can also originate from poor management of
gut microbiota, which is, in fact, required for many aspects of Met Syn. While our hypothesis that alterations in
microbiota promote LGI/Met Syn originated from study of mice with a genetically engineered innate immune
deficiency, namely lack of the flagellin receptor toll-like receptor 5 (TLR5) it has since proven applicable to
understanding how diet, particularly industrialization of the food supply, might be altering the microbiota-host
relationship in a manner that promotes LGI and, subsequently, Met Syn. Indeed, we’ve found that a central
feature of Met Syn in both mice and humans, is infiltration of bacteria into the normally near-sterile inner mucus
layer. Such microbiota encroachment can activate pro-inflammatory signaling in the intestine and/or result in
translocation of bacteria, and their products, into liver and adipose tissue thus driving LGI in these organs. In
contrast, obese humans lacking microbiota encroachment also lacked Met Syn . Moreover, in mice, ablation of
microbiota via antibiotics, germfree status, or maintaining gnotobiotic mice with the pathobiont-free
microbiome, results in a seemingly analogous state of “healthy obesity” in response to a western-style diet
(WSD). Together, these results underscore our central hypothesis that microbiota encroachment is a pivotal
event in driving LGI and, subsequently Met Syn. This hypothesis holds that preventing or reversing microbiota
encroachment will ameliorate Met Syn. Hence, we will propose to identify encroaching bacteria (Aim 1) and
define how they drive LGI and impact metabolism (Aim 2). Furthermore, we will develop means to train the
immune system to reduce microbiota encroachment and ameliorate Met Syn (Aim 3).

## Key facts

- **NIH application ID:** 10151289
- **Project number:** 2R01DK099071-08A1
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** Andrew T Gewirtz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $508,940
- **Award type:** 2
- **Project period:** 2013-08-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151289

## Citation

> US National Institutes of Health, RePORTER application 10151289, DECONSTRUCTING INFLAMMATION AND ALTERED MICROBIOTA IN METABOLIC SYNDROME (2R01DK099071-08A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10151289. Licensed CC0.

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