A recent study in Ophthalmology Science linked the diversity of bacteria in the gastrointestinal tract to genetic alleles that predispose individuals to age-related macular degeneration (AMD).
Give me some background first.
As a leading cause of blindness globally, little is known about AMD’s pathophysiology.
- Previously: Studies have investigated inflammatory processes, genetic variations, aberrations in lipid synthesis, and environmental factors.
More recently: The gut microbiome has been studied as a possible contributor to the development of immune–mediated conditions elsewhere in the body—such as the eye.
- What we know: Bacteria in the gastrointestinal tract play an important role in digesting carotenoids, pigments obtained through diet from plant sources that protect against photooxidative damage in the retina.
Now, talk about the study.
Researchers at the Casey Eye Institute in Oregon set out to investigate whether:
- Gut microbe profile is pathogenic in AMD development
- Gut microbiome variations can be used to classify AMD
- Genetic risk and Age-Related Eye Disease Studies (AREDS) supplementation (an eye vitamin for patients with moderate to advanced AMD) affect AMD via the gut flora
Factors of interest included: Gut microbial composition, diversity, IgA binding, and gut bacterial metabolic pathways.
Who was included in the study?
A total of 85 cases of advanced AMD and 49 age-matched controls were recruited from the Oregon Health & Science University’s ophthalmology clinics.
Advanced AMD was defined as vision loss from geographic atrophy (GA) or choroidal neovascularization.
Inclusion criteria consisted of:
- Age > 65
- Capacity to provide consent
- Capacity to answer a questionnaire
- Willingness to provide a fecal sample
Exclusion criteria consisted of history of bowel surgery or disease, history of ocular disease (however, cataract and epiretinal membrane were not considered exclusionary), and antibiotic use within the last 3 months.
Now to the findings.
The AMD group had a higher percentage of females than males (p=0.29) and were more likely to have multiple comorbidities compared to the control group (p=0.06)—though neither of these were significant.
- As expected, the AMD group was more likely to have AMD genetic risk variants, including age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH), compared to the control group (p=0.007).
- ARMS2 and CFH are thought to activate and execute the complement cascade in inflammatory processes, respectively..
And in regards to the gut microbiome?
This was also found to be significantly different at all levels of taxonomic classification between AMD and controls.
For instance: Patients with AMD had elevated levels of: Proteobacteria (phyla), Gammaproteobacteria (class), Clostridium (genus), Prevotella-9 (genus), Prevotella-7 (genus), Shigella (genus), and Desulfovibrio (genus).
- Meanwhile, the study’s controls presented with elevated levels of: Firmicutes (phyla), Clostridia (class), Ruminococcaceae (genus), UCG-013 (genus), Oscillospira (genus), and Eisenbergiella (genus).
Go on …
In particular, the genera CAG-352, Desulfovibrio, and Oscillospira were found to be associated with the AMD risk genetic alleles (different versions of the same gene) ARMS2 and CFH.
- Furthermore, patients with AMD were more likely to have immunoglobulin A (IgA)-coated bacteria, higher levels of which were also associated with ARMS2.
Lastly, AMD bacterial metabolic profiles (namely lipid metabolism, fatty acid biosynthesis, terpenoid metabolism, carotenoid biosynthesis, metabolism of various amino acids, and drug metabolism) were significantly different from the control bacterial metabolic profiles
Tell me more.
In the analysis of the gut microbiome, makeup, gender and sample tissue type (fecal swab versus stool) were controlled for.
The impact of AREDS supplementation on gut microbiota was also accounted for by running a subgroup analysis on patients not taking AREDS. The overall trends remained largely consistent.
Limitations?
A few … to start, this study had a small sample size and used a cross-sectional design rather than a longitudinal design, so it proved difficult to elucidate how gut microbiome differences may be related to AMD progression.
Additionally, the specific microbial compositions found in this study may not be generalizable to populations in other parts of the world.
- Gut microbial biodiversity likely varies depending on geographical location, as previous studies conducted in Switzerland and China had differing microbe profiles.
Lastly, age and AREDS use were major confounding variables, as both variables were higher in the AMD group compared to the control group.
So with all of this in mind, what do we know?
Overall, patients with advanced AMD were found to have decreased gut microbial diversity, which was associated with increased likelihood of carrying AMD-predisposing alleles ARMS2 and CFH.
Several of these bacteria are also implicated in other disease pathophysiology, such as inflammatory bowel disease (IBD), multiple sclerosis (MS), rheumatoid arthritis (RA), and uveitis.
- To note: This is consistent with study findings that AMD patients were more likely to have comorbidities than controls.
And lastly?
Elevated levels of IgA-coated bacteria and metabolic differences in AMD patients highlight the need for further research into immune modulation and functional differences in AMD pathogenesis.
As such: While this study has uncovered a correlation between gut microbiome diversity and AMD development, further longitudinal investigation of pathogenesis is needed using a larger, and more geographically diverse, sample size.