Abstract
Age‐related macular degeneration in its neovascular form (NV AMD) is the leading cause of vision loss among adults above the age of 60. Epidemiological data suggest that in men, overall abdominal obesity is the second most important environmental risk factor after smoking for progression to late‐stage NV AMD. To date, the mechanisms that underscore this observation remain ill‐defined. Given the impact of high‐fat diets on gut microbiota, we investigated whether commensal microbes influence the evolution of AMD. Using mouse models of NV AMD, microbiotal transplants, and other paradigms that modify the gut microbiome, we uncoupled weight gain from confounding factors and demonstrate that high‐fat diets exacerbate choroidal neovascularization (CNV) by altering gut microbiota. Gut dysbiosis leads to heightened intestinal permeability and chronic low‐grade inflammation characteristic of inflammaging with elevated production of IL‐6, IL‐1β, TNF‐α, and VEGF‐A that ultimately aggravate pathological angiogenesis.
Highlights
While AMD is the leading cause of irreversible blindness in the industrialized world (Klein & Klein, 2004; Maberley et al, 2006; Wong et al, 2014), the cellular and molecular mechanisms that precipitate disease remain incompletely understood despite significant genomewide association studies identifying susceptibility genotypes and target mechanistic pathways (Fritsche et al, 2013, 2016; Sobrin & Seddon, 2014; Black & Clark, 2016)
Quantification of fluorescein isothiocyanate (FITC)–dextran-perfused neovessels over isolectin B4 (IB4)-labeled impact area by confocal imaging 14 days after laser burn revealed a robust 60% increase in choroidal neovascularization (CNV) in high-fat diet (HFD)-fed mice when compared to regular-chow diet (RD) controls (Fig 1D and E)
Polymorphisms in genes implicated in inflammation predispose to AMD (Hageman et al, 2005) with strong linkage to single nucleotide polymorphisms in CFH factors, CFHR (CFH-related factors), ARMS2, VEGFA, and TGFBR1 (Ambati et al, 2003a; Klein et al, 2005; Yu et al, 2011; Ratnapriya & Chew, 2013), yet by themselves, no single mutation can account for disease development
Summary
While AMD is the leading cause of irreversible blindness in the industrialized world (Klein & Klein, 2004; Maberley et al, 2006; Wong et al, 2014), the cellular and molecular mechanisms that precipitate disease remain incompletely understood despite significant genomewide association studies identifying susceptibility genotypes and target mechanistic pathways (Fritsche et al, 2013, 2016; Sobrin & Seddon, 2014; Black & Clark, 2016). Progression of AMD is influenced by single or compounded environmental and genetic risk factors that lead to persistent low-grade inflammation and a largely innate immune response (Combadiere et al, 2007; Ambati et al, 2013; Sennlaub et al, 2013). Given that commensal gut microbiota exert profound influence on digestion, dietary metabolism, endotoxemia, and immune responses (Backhed et al, 2005; Turnbaugh et al, 2006; Cani et al, 2008; Cerf-Bensussan & Gaboriau-Routhiau, 2010), they are prime candidates to impact chronic low-grade inflammation (Tremaroli & Backhed, 2012). Microbiota-related low-grade inflammation is characterized by elevated pro-inflammatory gene expression and is a common consequence of an altered host–microbiota relationship caused by instigator bacteria or dietary components that influence intestinal permeability (Chassaing & Gewirtz, 2014). There is accumulating evidence that asserts the importance of intestinal permeability, a barrier aspect closely associated with the intestinal commensal microbiota as well as with the mucosal immune system, in intestinal and systemic health
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
