This effect could originate from increased intestinal permeability to PAMPs secondary to dysbiosis (Fig5). target mechanistic pathways (Fritscheetal, 2013, 2016; Sobrin & Seddon, 2014; Black & Clark, 2016). Obesity has long been suspected as a risk element for AMD, but increased body mass index associations with AMD were inconsistent (Zhangetal, 2016). Using 21, 287 participants from the Melbourne Collaborative Cohort Study, it was recently demonstrated that each increase of 0. 1 in waist/hip ratio (a measure for abdominal obesity) was associated with a 13% increase in the odds of early AMD and a 75% increase in the odds of late AMD in men, making obesity the second most important environmental risk element for late AMD after cigarette smoking (Adamsetal, 2011). Progression of AMD is influenced by single or compounded environmental and genetic risk factors that lead to persistent lowgrade inflammation Atractylenolide I and a largely innate immune response Atractylenolide I (Combadireetal, 2007; Ambatietal, 2013; Sennlaubetal, 2013). Evidence for environmental factors predisposing to AMD is supported by the fact that Pdgfrb genetically unrelated individuals with shared longterm environmental exposure develop the disease with a concordance of 70. 2% (Gottfredsdottiretal, 1999). A consequence of cohabitation and common lifestyle habits that prospectively impact disease modifiers such as systemic inflammation is microbial exchange (Songetal, 2013). Given that commensal gut microbiota exert profound influence on digestion, dietary metabolism, endotoxemia, and immune responses (Backhedetal, 2005; Turnbaughetal, 2006; Canietal, 2008; CerfBensussan & GaboriauRouthiau, 2010), they are primary candidates to impact chronic lowgrade inflammation (Tremaroli & Backhed, 2012). Microbiotarelated lowgrade inflammation is characterized by elevated proinflammatory gene expression and is a common consequence of an altered hostmicrobiota 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 wellness (Brunetal, 2007; Mancoetal, 2010; Gerovaetal, 2011; Nevesetal, 2013; Bischoffetal, 2014). Heightened intestinal permeability can allow for an increased translocation of bacterial products such as LPS and other pathogenassociated molecular pattern molecules (PAMPs) (Canietal, 2008; CerfBensussan & GaboriauRouthiau, 2010; Mehal, 2013). These PAMPs impact proinflammatory signaling through pattern acknowledgement receptors (PRRs) of the innate immune system, especially the Tolllike receptors (TLRs) and Nodlike receptors (NLRs), inducing lowgrade systemic inflammation (Chassaing & Gewirtz, 2014). Microglia, perivascular macrophages, a small number of dendritic cells, and RPE Atractylenolide I cells express various PRRs, including TLRs and NLRs, and may predispose intended for PAMPs of intestinal origin to impact ocular inflammation (Chen & Xu, 2015). In addition , bacterial products or metabolites from gut microbiota can modulate microglia maturation, morphology, and function (Ernyetal, 2015) Atractylenolide I and trigger retinaspecific T cells that are thought to be involved in autoimmune uveitis (Horaietal, 2015). Dysbiosis in gut microbes is particularly important for the aging populace given that they modulate agingrelated changes in innate immunity, sarcopenia, cognitive function, and frailty in general (O’Toole & Jeffery, 2015). Here, we sought to evaluate the contribution of intestinal flora to progression of NV AMD, particularly in the context of obesitydriven CNV. == Results == == Highfat diet modulates gut microbiota and exacerbates CNV == In light of epidemiologic data linking obesity to CNV (Seddonetal, 2003; Zhangetal, 2016), we first investigated the propensity of diets with elevated fat content to exacerbate CNV. C57BL/6J mice were raised under sterile barrier conditions and placed on a regularchow diet (RD; 16% kcal fat) or highfat diet (HFD; 60% kcal fat), from 6 weeks of age (Fig1A). As expected, upon killing.