# Linking a prominent gut microbiome-derived metabolite to host proteostasis

> **NIH NIH F32** · HARVARD MEDICAL SCHOOL · 2024 · $79,756

## Abstract

Project Summary
Bacteria in the human microbiome produce a complex pool of bioactive small molecules that have been
associated with effects on human biology in health and disease, but the mechanisms of action of these molecules
remain largely undefined. This proposal builds on preliminary data that a microbiome-derived small molecule,
the secondary bile acid lithocholic acid (LCA), induces the Unfolded Protein Response (UPR), a signaling
pathway that responds to endoplasmic reticulum (ER) stress. This observation links a microbiome-derived small
molecule to a basic aspect of host cell biology. In this proposal, the applicant seeks to bring this observation to
the mechanistic level using three complementary aims. In Aim 1, the consequences of LCA-mediated UPR
activation will be defined in physiological models of liver homeostasis and injury. In Aim 2, the molecular
mechanism by which LCA induces the UPR will be dissected using a combination of in-depth monitoring of ER
function and chemical and genetic perturbations to probe the roles of putative signaling pathways and receptors.
In Aim 3, the broader scope of UPR induction by bile acids, both individually and in combinations, will be
assessed using high-throughput assays and animal models.
Together, this work will establish the molecular basis of UPR induction by microbiome-derived small molecules.
Dysregulation of the UPR is implicated in metabolic disorders, neurodegenerative disease, and multiple forms
of cancer. Thus, this work may inform the development of biomarkers and therapeutic strategies for such
diseases. More broadly, this work will provide a blueprint to define how small molecules from the microbiome
shape host biology by impacting fundamental cell biological processes.
Harvard Medical School houses world leaders in biomedical research in a collaborative and multidisciplinary
environment and contains cutting-edge facilities for microscopy, genomics, and proteomics that will support the
proposed research. The co-sponsors Dr. Marco Jost and Dr. Wade Harper are experts in studying host-
microbiome interactions and regulation proteostasis, respectively, and provide complementary technical
expertise and mentoring viewpoints. Completion of the proposed research will directly support the applicant’s
training goals, including training in microbiome biology, systematic genetics, and animal models of disease and
growth of skills to support an academic career.

## Key facts

- **NIH application ID:** 10889049
- **Project number:** 5F32GM149112-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Nolan Kenji Kwaisun Maier
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $79,756
- **Award type:** 5
- **Project period:** 2023-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889049

## Citation

> US National Institutes of Health, RePORTER application 10889049, Linking a prominent gut microbiome-derived metabolite to host proteostasis (5F32GM149112-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10889049. Licensed CC0.

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