Important efforts were made during the
Important efforts were made during the last decades in order to better understand the key pathogenic features of DR and DN, so that new and more effective therapies and preventative strategies might be developed [, , ]. Despite these, the multifactorial intervention strategies aimed to decrease the risk of microangiopathy in diabetic patients remain unsatisfactory, particularly because there are no treatment approaches able to specifically (and efficiently) target the molecular features of DR and DN. In addition, the great percentage (near 80%) of affected patients live in low-to-middle-income countries where some of the most important therapeutic options remain unavailable or strongly limited. Even though hyperglycaemia is undoubtedly a major contributor for the progression of both DR and DN, hypoglycaemic-based therapeutic strategies were unable to prove efficacy in reducing cardiovascular risk . Very exciting findings coming during the last years strongly suggest the involvement of distinct mechanisms, adding complexity to what was already known . Chronic low-grade inflammation, already recognized as a pivotal player in the development of diabetes and its complications, including DR and DN, has recently been associated with other mechanisms related with pathogen-host interactions, including gut microbiota (GM) and the innate immune system [, , ]. In a certain way, the human body may be viewed as supra(or meta)-organism because the human gastrointestinal tract (GIT), particularly the large intestine, is colonized by trillions of microbes (microbioma) which contains many hundredfold more genes (microbiome) than those present in the own genome . GM composition and activity is co-developed with the host and modulated, from birth to ageing, by a dynamic and complex interplay between host genome, factors related with life-style, namely diet, which has been increasingly considered the key modulator of microbiota activity . This microbial 2-NBDG chemicals exerts metabolic effects, referred to as co-metabolism, including vitamins synthesis and fermentation of macromolecules, namely carbohydrates, lipids, and proteins . In addition, GM plays chief functions for the host homeostasis, including structural/protective effects against pathobionts, namely protecting intestinal barrier, as well as “education” of host immunity . Normally, the intestinal barrier prevents the translocation of substances and microbes from the lumen to the bloodstream; however, deregulation or damage of the intestinal milieu and related disturbance of the gut flora composition – referred to as “intestinal dysbiosis” – may result in a “leaky gut syndrome”, with increased permeability that might activate the innate immune system and promote a state of low-grade inflammation. During the recent years, GM dysbiosis has been associated not only with intestinal disorders but also with extra-intestinal diseases, including chronic disorders that are highly prevalent in elderly individuals, such as diabetes and its major vascular complications [, , ]. Ageing is accompanied by a myriad of clinical issues; older adults (over age 65 years) have a high prevalence of co-morbid disease  and concomitant exposure to multiple medications, including antibiotics. The ageing alimentary tract is subject to a variety of changes: impaired dentition and salivary function, decreased motility with constipation, diverticular disease, and dietary modification . Together, these factors may contribute to changes in the microbiota among older adults, and may ultimately enhance susceptibility to a plethora of chronic diseases [20,22,23]. Several studies have strongly suggested that the microbiota may shape the host immune system, contribute to “inflammaging”, lead to chronic health conditions, and modulate the ageing process [21,22]. The term inflammaging, originally described as an evolutionary perspective on immunosenescence , could be seen as the pro-inflammatory environment that exists in older adults, which have high concentrations of acute phase reactants and pro-inflammatory cytokines; this impaired inflammation is accompanied by deregulated immune responses to external factors, particularly to pathogens . Inflammaging may relate to bacterial translocation from gut, which is supported by high blood levels of lipopolysaccharide (LPS) binding protein and high urinary excretion of microbial by-products among older adults [26,27]. It has becoming increasingly evident that GM dysbiosis is strongly associated with a state of chronic low-grade inflammation and to an immunosenescence phenotype, which are key signatures in the physiological process of ageing (inflammaging), as well as in the pathological mechanisms associated with chronic metabolic disorders, particularly to diabetes (“metaflammation”) and its vascular complications.