# Androgen deprivation promotes diabetic wound healing in mice through modulation of wound microbiome and immune response

## TL;DR

Reducing androgen levels in diabetic mice improved wound healing by changing the wound's bacteria and reducing inflammation.

## Contribution

This study reveals a novel mechanism linking androgen levels, wound microbiome, and immune response in diabetic wound healing.

## Key findings

- Androgen deprivation accelerated wound closure and improved tissue repair in diabetic mice.
- Castration reduced inflammation and increased M2 macrophage polarization in wound areas.
- Microbial diversity increased, with beneficial bacteria like Escherichia-Shigella linked to faster healing.

## Abstract

Delayed wound healing is a major complication of diabetes, often associated with chronic inflammation and microbial dysbiosis. Although androgens are known to impair wound repair, their role in diabetic wound healing, particularly in regulating the local wound microbiome and associated immune response, remains poorly understood. In this study, we investigated whether androgen deprivation via surgical castration could enhance diabetic wound healing by modulating local microbial communities and inflammation.

A full-thickness wound model was established in db/db mice. Surgical castration was used to achieve androgen deprivation. Wound closure and histology were assessed longitudinally. Blood glucose and body weight were monitored. The local immune microenvironment was profiled, focusing on pro-inflammatory factors and macrophage polarization. 16S rRNA sequencing characterized α-diversity and community composition over time. Functional prediction analyses inferred microbial metabolic potential, and machine-learning models evaluated taxa associated with healing dynamics.

Androgen deprivation significantly accelerated wound closure and improved histological outcomes without altering blood glucose or body weight. The wound microenvironment showed reduced pro-inflammatory factors and enhanced M2 macrophage polarization. 16S rRNA sequencing revealed increased microbial α-diversity and durable shifts in community composition, most prominently during early healing. Escherichia-Shigella, Rhodococcus, and Ochrobactrum were enriched, while Staphylococcus abundance decreased. Functional prediction indicated elevated microbial metabolic activity after castration. Machine-learning analysis identified Escherichia-Shigella as a key genus associated with accelerated healing.

Low androgen levels were associated with improved diabetic wound repair, potentially by attenuating local inflammation and fostering a more diverse, metabolically active microbiota. These data support a mechanistic link among androgens, wound inflammation, and the microbiome, and suggest host-directed therapeutic strategies for chronic diabetic wounds.