# Linking diet, gut microbiota and autoimmune disease: Bacteria induced phytoestrogen metabolites impact immune function in Experimental Autoimmune Encephalitis

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2021 · $381,250

## Abstract

Although the link between the immune system and the gut microbiome is being increasingly appreciated, the
mechanistic links between the microbiome and inflammatory autoimmune diseases such as multiple sclerosis
(MS) are unclear. Thus, there is a critical need to define mechanisms by which gut bacteria maintain immune
homeostasis and thereby affect neuroinflammation. We have recently reported that MS patients have altered
gut microbiota compared to healthy controls, with a reduced abundance of certain human gut bacteria
(Parabacteroides, Adlercreutzia, and Prevotella) with the ability to metabolize phytoestrogen. Gut bacteria
metabolize phytoestrogen into equol which has structural similarity with estrogen, and can regulate immune
responses through estrogen receptors and AMP-activated protein kinase (AMPK). Our preliminary data
showing significantly milder EAE in mice on a phytoestrogen (Isoflavones) containing diet compared to those
on a phytoestrogen free diet suggest a critical role of phytoestrogen in modulation of EAE. Additionally,
Prevotella histicola, a member of the Prevotella genus, can suppress disease in experimental autoimmune
encephalomyelitis (EAE), a preclinical murine model of MS. However, the importance of phyoestrogen
metabolism in P. histicola–mediated disease suppression is unknown. The central hypothesis of the proposed
studies is that the human gut commensal P. histicola mediate its disease-protective effect through metabolism
of phytoestrogen and subsequent activation of immunoregulatory cells. We will test our central hypothesis
using animal model, genetically modified mice, and a cell culture approach in the following two specific aims. In
first aim, we will utilize P. histicola as a representative phytoestrogen-metabolizing gut commensal bacteria to
determine whether metabolism of phytoestrogen is required for ability of P. histicola to suppress disease and
induce Tregs and/or CD103+ Tolerogenic dendritic cells (DCs). We will determine the importance of AMPK
signaling in the phytoestrogen induced activation of Tregs and/or tolerogenic DCs. In second aim, we will
determine whether the phytoestrogen plus bacteria mediate the induction of immunoregulatory cells via
estrogen receptor (ER)-dependent pathways in intestinal epithelial cells and/or immune cells. Our study is fit
for the “High Priority Immunology Grant (R01) mechanism because we are proposing to determine the
mechanisms underlying the microbial impact on systemic immunity which can be harnessed in designing
potential mono as well as combination therapies because drugs with diverse non-overlapping mechanisms
might provide maximal benefit to MS patients. We will determine whether phytoestrogen-metabolizing bacteria
maintain a disease-free state by tilting the Tregs to Th1/Th17 balance towards Tregs through its interaction
with estrogen receptors and the AMPK pathway. We expect the outcome of our study will have a positive
impact on development of gut microbial-flor...

## Key facts

- **NIH application ID:** 10092915
- **Project number:** 5R01AI137075-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Ashutosh Kumar Mangalam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2018-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092915

## Citation

> US National Institutes of Health, RePORTER application 10092915, Linking diet, gut microbiota and autoimmune disease: Bacteria induced phytoestrogen metabolites impact immune function in Experimental Autoimmune Encephalitis (5R01AI137075-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10092915. Licensed CC0.

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