# Mechanisms linking gut microbiota metabolomics and epithelial repair in HIV infection

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $50,520

## Abstract

PROJECT SUMMARY
Human immunodeficiency virus (HIV) infection is characterized by depletion in CD4+ T cells and persistent
immune activation as a result of epithelial barrier disruption and systemic translocation of microbial products.
Immune targets of HIV such as CD4+ T cells, macrophages, and dendritic cells have been the main research
focus for many years, but modifications in these cell types have not explained HIV-induced epithelial damage.
For this reason, better understanding of epithelial cell metabolism and interactions with gut microbiota has
been an important aspect of intestinal barrier function in HIV. Studies have shown that treatment with probiotic
microbiota can positively impact mucosal immune responses, support renewal of the gut epithelial barrier, and
suppress inflammation. We utilized injections of probiotic L. plantarum in a ligated ileal loop model in chronic
SIV-infected rhesus macaques to investigate mechanisms of epithelial damage and repair. Through a
metabolomics approach, I found that epithelial cell damage may be linked to malonate accumulation, activating
transcription factor NF-kB and downstream epithelial damage. Treatment with L. plantarum reduced levels of
malonate in the gut and repaired epithelial integrity. We want to investigate the role of malonate metabolism in
the gut to answer mechanistic questions regarding the role of microbiota in modulating gut barriers and the
immune system in HIV and other inflammatory diseases. First, we will test the source of malonate
overproduction in HIV infection using cell culture models and proteomic analysis. Then, we will assess the
molecular mechanisms of NF-kB activation by malonate accumulation and determine if inhibiting this pathway
genetically could prevent phenotypic changes in epithelial integrity. Finally, we will evaluate the ability of L.
plantarum to reduce epithelial damage through malonate reduction. The outcomes from this study will address
the immunometabolomic connection between gut microbiota and host cell function in HIV infection. Identifying
regulatory elements of chronic gut inflammation and damage will be an essential contribution to research in
autoimmune or infectious diseasees targeting the gastrointestinal tract.
Hypothesis 1: Epithelial barrier damage is induced by increased malonate production in response to HIV
infection. Furthermore, we hypothesize that L. plantarum can restore epithelial barrier integrity by reducing
malonate accumulation.
Aim 1: To demonstrate that epithelial cells produce excess malonate in response to HIV infection
Aim 2: To determine if malonate induces NF-kB activation through post-translational malonylation
Aim 3: To investigate the ability of L. plantarum to repair epithelial damage through malonate reduction

## Key facts

- **NIH application ID:** 9957013
- **Project number:** 5F30AI150462-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Katti Robin Crakes
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957013

## Citation

> US National Institutes of Health, RePORTER application 9957013, Mechanisms linking gut microbiota metabolomics and epithelial repair in HIV infection (5F30AI150462-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9957013. Licensed CC0.

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