Abstract
Purpose :
Hallmarks of choroidal neovascularization are neovascularisation, inflammation including “activation” of microglia and neurodegeneration in the retina. Short-chain fatty acids (SCFA), the primary metabolites produced by beneficial bacteria when fermenting dietary fibre in the gastrointestinal tract, are speculated to have a crucial role in the microbiota-gut-brain (retina) crosstalk. SCFAs are believed to influence the gut-brain axis through endocrine, vagal and immune pathways, and SCFAs have been shown to cross the blood brain barrier through monocarboxylate transporters. It’s been shown that SCFA can influence microglia cell morphology and function, and hence affect neuroinflammation.
Methods :
Therefore we here tested the effect of SCFA on inflammation, microglia state, neovascularisation and degeneration in the laser-induced mouse model of retinal choroidal neovascularization (CNV) by providing male and female C57Bl6/J mice with SCFA in the drinking water starting at 7 days before the lesion. In order to evaluate the impact of the treatment, several pathogenic parameters, such as leakage and scar size, and microglia distribution, were studied.
Results :
In males, the treatment ameriolated the course of the leakage and lesion size, being most remarkable on day 14 after CNV (pL). Lesion triggered increase in microglia at 7d pL is inhibited by SCFA treatment in males only, both in the inner and outer plexiform layer of the retina. The scar volume and GFAP expression, on the other hand was smaller only in SCFA treated females at 14d pL compared to untreated females. RNA sequencing showed a strong effect of SCFA treatment e.g. on Nr4 and Cyr61 predominantly in the male retina on 7 and 14 pL revealing a sex-dependent regulation of the laser induced inflammation and healing pathways in male and female retina. In vitro, we identified O-Linked β-N-acetylglucosamine (O-GlcNAc), a post-translation modification
and nutrient sensor, is targeted by SCFA treatment in microglia cells.
Conclusions :
Since many genes including Nr4 and Cyr61 are down stream of O-GlcNAc activation, we propose that SCFA is promoting its beneficial effects on microglia cells via the O-GlnNAc pathway.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.