AS647 - Interplay of the diet and the gut microbiome in age-related macular degeneration

Investigator Names and Contact Information

Amy Millen (aemillen@buffalo.edu)

Introduction/Intent

Background: Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in developed countries. The pathogenesis of AMD is multifactorial, and risk factors include diet, smoking, and genetic alleles for complement components, implicating aberrant chronic inflammation. Much remains to be learned about modifiable risk factors for AMD and their interactions with high-risk AMD genes. In particular, the gut microbiome modulates the systemic inflammatory milieu and nutrient metabolism, and may play an integral role in AMD development and progression.

SPECIFIC AIMS

The retinal disease of age-related macular degeneration (AMD) is a leading cause of vision loss in aging adults,^1,2 with prevalent, vision-threatening AMD estimated to increase to 5.4 million by 2050, as the population ages.³ The pathogenesis of AMD is multifactorial, involving inflammation,⁴ oxidative stress,⁵ and angiogenesis,^6,7 with major risk factors including smoking⁸ and genetic alleles for complement components.^9,10 Adherence to healthy diet patterns is consistently shown to be associated with reduced progression to late-staged AMD.^11-15 As it is well established that diet influences the gut microbiome,^16,17 researchers have begun to investigate associations between the gut microbiome and AMD,^18-21 and to date, there are four studies^18-21 with only one in humans (n=23 patients).¹⁹ These data suggest that consumption of high fat diets¹⁸ and high glycemic diets²⁰ promote the development of AMD phenotypes in mouse models through interactions with the gut microbiome. Gut bacterial composition and bacterial species’ associated metabolic pathways differed by AMD status (neovascular AMD vs. controls) in humans, ¹⁹ supporting findings from animal models. Information does not currently exist on studies of the gut microbiome inclusive of intermediate AMD. We do not know whether the composition and diversity of the gut microbiome affects AMD risk, through its ability to modulate systemic inflammation and nutrient metabolism, or other mechanisms.

Our long-term goal is to determine if the composition and diversity of the gut microbiome is associated with the development or progression of AMD, and to better understand to what extent the gut microbiome interacts with dietary intake to produce metabolites observed to be associated with AMD risk. Our overarching hypothesis is that the composition and diversity of the gut microbiome and the predicted metabolic pathways the bacteria influence, such as short chain fatty acids production, can be used to differentiate between people with and without AMD. We have a timely, but temporary, opportunity to efficiently leverage existing resources from a well-characterized, prospective cohort of postmenopausal women, the Women’s Health Initiative (WHI) Observational Study (OS), to examine associations between the gut microbiome, assessed with whole genome shotgun sequencing, and the prevalence and stage of AMD. We propose two separate, mutually exclusive studies within the WHI OS. We will conduct a nested case-control study where we will recruit 200 cases of advanced AMD and 200 age, race, and clinic center-matched controls with no AMD (n=200) from the WHI OS. In our second study we will recruit all participants of the Carotenoids in Age-Related Eye Disease Study 2 (CAREDS2) (2016-2019), which we estimate will provide an additional sample of 487 women (361 none/early AMD, n=107 intermediate AMD, n=19 advanced AMD). CAREDS is an ancillary study of the WHI OS specifically designed to investigate AMD, and has just completed a 15-year follow-up exam (CAREDS2). CAREDS2 has detailed ocular phenotypic data including graded retinal photographs to assess AMD prevalence and stage, measures of ocular coherence tomography, and measures of macular pigment density. WHI OS and CAREDS2 participants have data that allows us to characterize AMD risk factors, and all participants of both proposed studies have data on habitual dietary intake two to three times over the past 25 years. We will collect current, habitual dietary intake from the preceding 3 months on all participants. For both proposed studies, we will collect stool samples for whole genome shotgun sequencing of the gut microbiome. We have shown both collection and sequencing are feasible in the WHI OS participants, and our pilot data suggest that the gut microbiome, and the metabolic pathways influenced by it, may differ in participants with and without AMD. Specifically, we propose the following aims:

Study Aim 1: Determine the composition, diversity, and associated metabolic pathways of the gut microbiome in advanced AMD cases (n=200) and age, race, and clinic-center matched controls without AMD in the WHI OS.

Study Aim 2: Determine the composition, diversity, and associated metabolic pathways of the gut microbiome in those with any AMD (107 intermediate and 19 advanced) and in those with none or early AMD (n=361) among participants of CAREDS2.

Findings from these studies will help us to better understand which gut microbiota (e.g., phyla to species), and the metabolic pathways they influence, differ most between those with and without AMD (both intermediate and advanced). We will examine associations between the gut microbiome and dietary patterns, genotype of high risk AMD genes, obesity and smoking status which will help guide our analysis of aims 1 and 2. We will also explore to what extent the associations in aims 1 and 2 are modified by dietary pattern, high-risk AMD genotype, smoking status, and obesity. In future studies, we aim to examine the association between the gut microbiome and subsequent AMD incidence and progression, to understand if the microbiota acts as a biomarker to identify persons most likely to progress to advanced disease and whether modification of the gut microbiome, through dietary manipulation, could help reduce development or progression of AMD.