Gut-derived butyrate suppresses ocular surface inflammation

Area of Science:

• Ophthalmology
• Microbiology
• Immunology

Background:

• Dry eye disease is an inflammatory ocular condition linked to gut microbiome alterations.
• The gut microbiome influences ocular surface homeostasis through microbially produced molecules.
• Short-chain fatty acids (SCFAs), like butyrate, are key microbial metabolites with potential systemic effects.

Purpose of the Study:

• To investigate the role of microbially produced SCFAs in mediating the gut-eye axis.
• To determine if the SCFA transporter SLC5A8 is involved in ocular surface responses to SCFAs.
• To evaluate the therapeutic potential of SCFA supplementation for dry eye disease.

Main Methods:

• Expression analysis of SCFA transporter SLC5A8 in murine ocular tissues.
• In vitro studies using corneal epithelial cells and bone marrow-derived dendritic cells (BMDCs) treated with phenylbutyrate (PBA).
• In vivo studies using knockout mice and desiccating stress (DS) models treated with tributyrin, a butyrate prodrug.

Main Results:

• SLC5A8 is expressed in murine conjunctival and corneal epithelium.
• PBA pre-treatment reduced pro-inflammatory TNF expression in corneal cells and BMDCs, an effect dependent on SLC5A8.
• Oral tributyrin treatment reduced ocular surface inflammation in mice undergoing DS, partially requiring SLC5A8.
• Tributyrin treatment downregulated Type I interferon signaling genes in conjunctival tissue.

Conclusions:

• The SCFA transporter SLC5A8 is crucial for mediating the protective effects of SCFAs on the ocular surface.
• Gut-derived SCFAs, delivered orally, can mitigate ocular surface inflammation associated with dry eye.
• These findings support the hypothesis that SCFAs contribute to maintaining ocular surface homeostasis via the gut-eye axis.