# Cartilage Microbial Products as Novel Drivers of Knee Osteoarthritis Epigenetic Dysregulation

> **NIH VA I01** · OKLAHOMA CITY VA MEDICAL CENTER · 2024 · —

## Abstract

Project Summary / Abstract
The objective of the proposed research is to better understand how age- and obesity-related gut
microbiome changes are reflected in the knee cartilage microbiome and how these changes may be
associated with knee osteoarthritis (OA) with a particular focus on epigenetics. OA is a leading cause of
disability among Veterans and occurs at roughly 5x the rate of civilians. The incidence of OA rises with
increases in age and obesity, and previously published studies have outlined gut microbiome changes with
both age and obesity. Furthermore, OA in mice related to obesity can be lessened through dietary
interventions that reshape the microbiome, and we have recently described a novel cartilage microbiome in
humans and mice that changes with OA development. Our laboratory has previously examined in detail the
epigenetic changes within cartilage, subchondral bone, and peripheral blood that are associated with OA
development, and we have generated preliminary data that microbial DNA amplified from human OA
cartilage can induce similar epigenetic changes in chondrocytes in vitro. In this project, our first Aim is to
determine whether age- and obesity-related changes in the gut microbiome in human OA patients and
healthy controls are reflected in similar changes in various joint microbiome niches, including cartilage,
subchondral bone, and synovium. To do this, we will obtain paired cecal and cartilage samples from end-
stage OA patients undergoing total knee replacement and matched control cadaveric samples from the
NDRI. We will then profile microbiomes using 16s bacterial gene next-generation sequencing. We will
then generate machine learning models of microbial changes associated with normal aging and obesity and
compare these with OA-aging and OA-obesity. Our second Aim will determine whether age- and/or
obesity-related cartilage microbiome changes impact OA outcomes and the cartilage microbiome
specifically, using fecal microbiome transplantation (FMT) from human OA patients with and without
aging and obesity into germ-free mice, and evaluating OA outcomes following DMM surgery. We will also
examine both systemic and local inflammation associated with differences in microbiome transplants at
prespecified timepoints using CyTOF. Our third Aim will evaluate epigenetic changes both within joint
tissues and inflammatory cells induced by differences in the gut microbiome, using the same transplantation
groups as in Aim 2. The proposed work is important, as we do not have a full understanding of why age
and obesity are associated with increases in OA risk, nor do we understand how the cartilage microbiome
influences OA risk. Our work is quite innovative in its use of paired gut and cartilage microbial samples,
the next-generation techniques used to evaluate the microbiome, and our use of germ-free mouse
microbiome transplantation to evaluate OA outcomes. We will also be the first to apply whole-genome
bisulfite sequencing technique...

## Key facts

- **NIH application ID:** 10809625
- **Project number:** 5I01CX002494-02
- **Recipient organization:** OKLAHOMA CITY VA MEDICAL CENTER
- **Principal Investigator:** Matlock Jeffries
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-10-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809625

## Citation

> US National Institutes of Health, RePORTER application 10809625, Cartilage Microbial Products as Novel Drivers of Knee Osteoarthritis Epigenetic Dysregulation (5I01CX002494-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10809625. Licensed CC0.

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