The expansion of metagenomic, proteomic, and transcriptomic analyses continues to illuminate CF specific taxonomic and functional alterations

The expansion of metagenomic, proteomic, and transcriptomic analyses continues to illuminate CF specific taxonomic and functional alterations. individuals underlying microbiota, Nrp1 diet, and existing medications against the backdrop of the complex nutritional needs in CF. and have consistently been observed. In AN-3485 contrast, abundances of have been shown to be relatively increased in the CF gut [7,12,52,53,54,55,57]. Use of the CFTR modulator ivacaftor is usually associated with arguably healthier microbiome profiles, reinforcing the concept that dysbiosis is usually driven by CFTR dysfunction [58]. Recent developments in metagenomic methods have enhanced the ability to characterise the functionality of the gut microbiota, thereby elucidating the physiological effects of dysbiosis. It has been exhibited that this CF gut microbiome displays an increased capacity to metabolise nutrients, antioxidants, and short-chain fatty acids (SCFAs), as well as a relatively decreased propensity to synthesise fatty acids [7,56,59]. The key drivers of these changes to the gut microbiota involve the downstream effects of CFTR dysfunction. The production of dehydrated mucus, changes AN-3485 to intestinal pH, nutrient malabsorption, and prolonged intestinal transit secondary to intestinal dysmotility all have the potential to exert selective pressure on enteric microorganisms and ultimately alter the microbiome [60,61,62]. Notably, excess fat malabsorption following exocrine pancreatic insufficiency could also confer survival advantage to certain organisms that adapt well to high-fat intestinal environments [63]. These CFTR-related factors are further compounded by iatrogenic causes. Antibiotic exposure, which is usually prevalent in CF for the prophylaxis and treatment of respiratory tract infections, may contribute to changes in the gut microbiota. Studies in the CF populace have consistently exhibited an association between antibiotic use and decreased AN-3485 alpha diversity (within-sample species diversity) in the gut [12,53,64,65] (Physique 1). Multiple studies have also highlighted a correlation between antibiotic exposure and relative depletions of the bacterial genus [64,65,66,67]. The high-energy and high-fat diet prescribed in CF is usually another likely contributor (discussed below). 5. Intestinal Inflammation Disruption to the gut microbiota is usually associated with intestinal inflammation in CF. Chronic inflammation is usually a well-recognised feature of the CF intestine, primarily evidenced by elevated faecal inflammatory markers in patients with CF in many studies [68,69,70,71,72,73] (Physique 1). The earliest evidence of GI inflammation was elevated concentrations of inflammatory markers such as interleukin-8, interleukin-1, neutrophil elastase, and immunoglobulins on whole-gut lavage, reported by Smyth et al. [74]. Imaging techniques including endoscopy and capsule endoscopy have subsequently revealed a high prevalence of mucosal pathologies, including ulcerations and oedema in the CF GI tract [71,75,76]. Gut inflammation in CF is usually of a multifactorial aetiology. Mucus hyperviscosity and hyperacidity as a result of CFTR dysfunction likely promote gut inflammation [8,77,78]. CFTR itself is also involved in downregulating proinflammatory pathways, and hence its dysfunction in CF may contribute to the altered intestinal milieu [79] (Physique 1). Additionally, inflammation AN-3485 may be precipitated by intestinal dysmotility and the intraluminal pooling of inspissated contents [77,80]. The same iatrogenic factors that contribute to intestinal dysbiosis, namely antibiotic exposure and the high-fat CF diet, have also been shown to be correlated with intestinal inflammation in CF and other contexts [81,82,83] (Physique 1). The mechanisms by which antibiotics may induce inflammation are not well-known. However, it has been exhibited in animal models that antibiotic administration promotes the translocation of microorganisms through goblet-cell-mediated pathways, subsequently increasing the release of inflammatory AN-3485 cytokines [84]. Notably, the aforementioned dysbiosis is usually a key contributor to intestinal inflammation in CF. Reductions in the abundances of bacteria with anti-inflammatory properties, including has been widely observed in CF cohorts [7,52,53,66,70,85]. Many of these bacteria are.