Intestinal microbiome proposed as potential therapeutic target for AMD

Associations between the gut microbiome and disease is a hot topic in medical research. Sebastian Wolf, MD, PhD, described accumulating evidence pointing to a role of the gut microbiome in the development of age-related macular degeneration (nvAMD).

“We have shown that the gut microbiome is altered in patients with nvAMD compared to healthy controls, and our research supports the idea that the gut microbiome may constitute a link between nutrition, the complement system, and the development of AMD,” said Dr. Wolf, professor of ophthalmology and director and chairman, University Eye Hospital Bern, Bern, Switzerland.

“Perhaps in the future, the composition of the gut microbiome will be a target for the treatment or prevention of AMD,” Dr. Wolf said.

Dr. Wolf explained that people have up to 100 trillion bacteria residing in the gastrointestinal tract. These microorganisms, which represent more than 10,000 different species, play a major role in the digestion of food and thereby influence the global metabolism of the host. Composition of the gut microbiome has been shown to influence the immune and complement system, and to be associated with the development of neurodegenerative and metabolic diseases.

Knowing that nutrition and genetics play a role in the development of AMD, Dr. Wolf and colleagues undertook a series of animal and human studies to investigate if those associations might be mediated by the gut microbiome.

Research done in a mouse model showed that the gut microbiome was significantly altered in animals that were deficient in complement 3 (C3). In another preclinical study, mice fed a high-fat diet were found to have an altered gut microbiome and increased choroidal neovascularization compared controls.

“Relative to control mice, the mice in the high-fat diet group had an increased abundance of the phylum Firmicutes, which includes various gram-positive bacteria, while the control mice had more anaerobic Bacteroides spp in their guts,” Dr. Wolf reported.

Next, a pilot study was performed in humans that evaluated whether the compositional and functional diversity of the intestinal microbiome was associated with nvAMD. It enrolled 12 patients with nvAMD and 11 age-matched controls without AMD and used next-generation sequencing to characterize levels of different microbiome species and metagenomic features.

The study found significant differences between the patients with nvAMD and controls.

“Consistent with our animal experiment, we found more Bacteroides spp in the control group and more Firmicutes in the patients with nvAMD,” Dr. Wolf said.

Specifically, the genera Anaerotruncus, Oscillibacter, Ruminococcus torques, and Eubacterium ventroiosum were relatively enriched in the patients with nvAMD compared with the controls.

Looking at the functional diversity of the microbiome showed that bacteria related to fatty acid digestion were present in higher levels in the controls compared with the nvAMD patients. Patients with nvAMD, however, had greater levels of bacteria affecting glutamate and arginine biosynthesis pathways.

The findings give a basis for suggesting that the gut microbiome links nutrition with AMD risk.

“We have shown that the gut microbiome affects bioavailability of long-chain polyunsaturated fatty acids and it is known that increased levels of arginine are associated with progressive chorioretinal atrophy,” Dr. Wolf explained.

Next, a larger study was undertaken to validate the findings of the pilot trial. The follow-up study included 57 patients with nvAMD and 58 controls. This study analyzed the gut microbiome and included sequencing of single nucleotide polymorphisms in complement genes.

Comparisons between the two groups showed not unexpectedly that there were differences in the complement system genes that have been associated with AMD. Otherwise, the patients and controls were similar in their demographic characteristics and smoking history, Dr. Wolf said.

Analyses of the gut microbiome reproduced the findings from the pilot clinical trial and of the study of mice fed a high-fat diet. The healthy controls had significantly more Oscillobacter spp compared with the nvAMD patients and the nvAMD patients had significantly more Firmicutes spp.

Based on the collective findings of their research, Dr. Wolf and colleagues speculate that the composition of the gut microbiome, influences the risk of developing AMD through its effects on nutrient levels.

They have also expanded their research to look for associations between the gut flora and other retinal diseases.