Biotherapeutic metabolite repairs gut damage caused by HIV infection

Researchers at the UC Davis School of Medicine have identified a naturally occurring metabolite that repairs gut damage caused by HIV infection and significantly improves the effectiveness of antiretroviral therapy (ART) in the nonhuman primate model of HIV/AIDS.

The biotherapeutic metabolite, 10-hydroxystearic acid (10-HSA), is produced by the beneficial gut bacterium Lactiplantibacillus plantarum. L. plantarum is a common lactic acid bacterium found in many over-the-counter probiotics and fermented foods. It also occurs naturally in the human gut.

The findings were published in Nature Microbiology.

Current HIV therapies are remarkably effective at controlling viral replication, but they do not fully repair the profound damage HIV causes in the gut. Our findings suggest that restoring the gut's structural and immune health can enhance antiretroviral treatment and opens an entirely new avenue for achieving more durable control of HIV."

Satya Dandekar, senior author of the study and a distinguished professor, Department of Medical Microbiology and Immunology, UC Davis Health

HIV and the late stage of the infection, AIDS, remain major global public health issues. In 2025, an estimated 40.9 million people were living with HIV, and approximately 1.2 million people acquired new HIV infections. In 2025, around 570,000 people died from AIDS-related illnesses worldwide.

HIV damages gut immune system

Gut-associated lymphoid tissue, the body's largest immune tissue and key regulator of the body's immune system, is an early target of HIV. The virus severely damages the immune and epithelial cells in the gut's lining. This damage leads to an inflamed, leaky gut, a weakened defense system and decreased nutrient absorption. The virus also disrupts mitochondrial function (mitochondria are organelles that generate energy within the cells).

Even with strict adherence to ART, many people living with HIV have persistent gut inflammation caused by the virus. Previous research from Dandekar's lab showed L. plantarum could quickly heal the chronically inflamed leaky gut associated with HIV.

For this study, the researchers identified metabolites produced by L. plantarum in the virally inflamed gut environment in the non-human primate model of HIV/AIDS. Among the hundreds of molecules created by L. plantarum, one metabolite, 10-HSA, emerged as the strongest candidate for repairing the gut barrier and reducing inflammation.

Using X-ray crystallography to visualize 10-HSA interactions at the atomic level, researchers demonstrated that 10-HSA directly binds to PPAR-alpha, a nuclear receptor that regulates key biological processes.

This binding promoted histone crotonylation, an epigenetic modification that helps regulate gene activity. The resulting cascade of cellular events reprogrammed gene expression to restore mitochondrial function and energy metabolism while supporting repair of the gut lining.

Researchers also found that 10-HSA increased mitochondrial respiration of gut epithelial cells during HIV inflammatory conditions, boosting energy-generating capacity and reducing harmful reactive oxygen species.

Testing the approach in nonhuman primates

To determine whether the benefits of 10-HSA translate to living organisms, the team conducted two independent studies at the UC Davis National Biomedical Research Institute in non-human primates infected with simian immunodeficiency virus (SIV), a close relative of HIV.

The first study evaluated 10-HSA alone without ART. This led to intestinal repair, improved key markers of gut function, improved mitochondrial health, reduced inflammatory signaling and partially restored the gut microbiota.
The second study evaluated 10-HSA in combination with ART. Significantly, the combined treatment showed faster clearance of viral burden than ART alone. The combination also promoted faster recovery of gut immune cells, reduced immune activation, restored epithelial barrier integrity and restored beneficial gut microbiota and microbial diversity.

"The findings suggest repairing the tissue damage caused by HIV may be as important as suppressing the virus itself with antiretroviral therapy," said Dylan Kramer, first author of the study and recent Ph.D. graduate from the Dandekar Lab. "By rebuilding the gut barrier, restoring mitochondrial function and reducing inflammation, 10-HSA helps create conditions that support stronger immune recovery and more effective antiviral therapy for HIV."

The authors caution that the results are from preclinical models. The studies showed no adverse effects. The research supports testing the safety and effectiveness of 10-HSA in humans.

"Our research shows that host health, microbial health and viral control are deeply interconnected," Dandekar said. She noted that treating the damaged gut ecosystem facilitates recovery of the immune system, leading to regained functions that have been lost during HIV infection. Additionally, treating the damaged gut during HIV infection can improve outcomes beyond what antiviral drugs can achieve alone.

"The restoration of gut barrier integrity and microbial balance through 10-HSA supplementation may represent a promising therapeutic strategy, with implications that extend beyond HIV to other chronic inflammatory diseases of the gastrointestinal tract," Dandekar said.

Source:

Journal reference:

Kramer, D., et al. (2026). Microbiota-derived 10-hydroxystearic acid activates PPARα to restore gut epithelial barrier integrity and enhance anti-retroviral therapy. Nature Microbiology. DOI: 10.1038/s41564-026-02433-0. https://www.nature.com/articles/s41564-026-02433-0