# Engineering microbiomes and their molecular determinants for production of butyrate and secondary bile acids from resistant starch

> **NIH NIH P01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $380,316

## Abstract

PROJECT SUMMARY/ABSTRACT – PROJECT 3
The production of butyrate from gut microbiomes results from interactions between microbes in anaerobic
food webs. Identifying butyrogenic combinations of microbes, environmental conditions and fermentable
fibers will underlie strategies for manipulating the microbiomes in BMT patients to provide therapeutic
concentrations of butyrate. Hypotheses: 1) Maximal production of SCFAs from fermentable fibers
requires the combination of a primary fiber degraders, secondary fermenters and hydrogen-consuming
microbes. 2) The ratio of butyrate to total SCFAs is dependent on the taxonomic membership of
communities, which is selected by the concentrations of H2, bile acids, pH and turnover time of the
environment. Approaches: We will use covariation analysis of microbiomes from a healthy human
cohort to identify butyrogenic combinations of fermentable fibers, physical conditions and microbes. We
will test these predictions by assembling synthetic communities of the identified microbes and measuring
butyrate production in vitro under various conditions, including the removal of hydrogen by
hydrogenotrophic microbes. We will also select co-evolved butyrogenic communities from fecal inocula
using multiple passages through media containing fermentable fiber as the primary carbon and energy
source.
Once transported into an intestinal epithelial cell, butyrate can be oxidized by mitochondria. It and can
also stimulate mitochondrial biogenesis through Peroxisome Proliferator-Activated Receptors (PPARs)
located on the nucleus. Understanding the interaction between a butyrogenic microbiome and epithelial
cells will provide a mechanistic explanation of the temporal dynamics between butyrate production and
host cell respiration. Hypothesis: In vitro and in vivo respiration and mitochondrial biogenesis in colonic
epithelial cells will be stimulated by butyrate. Approaches: Respiration and PPAR activation will be
measured in enteroids exposed to butyrate under varying environmental conditions. For in vivo estimates
of respiration, mice at six weeks of age will be placed on a Western diet supplemented with a fermentable
fiber(s) or accessible starch. GI tissues will be harvested at intervals up to 12 weeks and succinate
dehydrogenase and cytochrome oxidase activities will be measured to quantify the capacity for cellular
respiration. Cell respiration and mucosal O2 concentrations will be tracked in germ-free mice treated 5-
aminosalicylic acid, a PPAR agonist, to distinguish between mitochondrial biosynthesis and butyrate
oxidation. Mice colonized with synthetic communities of microbes to be used to test the impact of
microbiomes of different butyrogenic capacity on respiration.

## Key facts

- **NIH application ID:** 10241907
- **Project number:** 5P01HL149633-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Thomas M Schmidt
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,316
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241907

## Citation

> US National Institutes of Health, RePORTER application 10241907, Engineering microbiomes and their molecular determinants for production of butyrate and secondary bile acids from resistant starch (5P01HL149633-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241907. Licensed CC0.

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