In this study, we compared the fecal microbiota and metabolomes of 26 healthy subjects before (HS) and after (HSB) 2 months of diet intervention based on the administration of durum wheat flour and whole-grain barley pasta containing the minimum recommended daily intake (3 g) of barley β-glucans. Metabolically active bacteria were analyzed through pyrosequencing of the 16S rRNA gene and community-level catabolic profiles. Pyrosequencing data showed that levels of Clostridiaceae ( Clostridium orbiscindens and Clostridium sp.), Roseburia hominis , and Ruminococcus sp. increased, while levels of other Firmicutes and Fusobacteria decreased, from the HSB samples to the HS fecal samples. Community-level catabolic profiles were lower in HSB samples. Compared to the results for HS samples, cultivable lactobacilli increased in HSB fecal samples, while the numbers of Enterobacteriaceae , total coliforms, and Bacteroides , Porphyromonas , Prevotella , Pseudomonas , Alcaligenes , and Aeromonas bacteria decreased. Metabolome analyses were performed using an amino acid analyzer and gas chromatography-mass spectrometry solid-phase microextraction. A marked increase in short-chain fatty acids (SCFA), such as 2-methyl-propanoic, acetic, butyric, and propionic acids, was found in HSB samples with respect to the HS fecal samples. Durum wheat flour and whole-grain barley pasta containing 3% barley β-glucans appeared to be effective in modulating the composition and metabolic pathways of the intestinal microbiota, leading to an increased level of SCFA in the HSB samples.

In chronic kidney disease (CKD), the gut-microbiota metabolites indoxyl sulfate (IS) and p-cresyl sulfate (PCS) progressively accumulate due to their high albumin-binding capacity, leading to clinical complications. In a prospective crossover controlled trial, 60 patients with CKD grades 3B–4 (GFR = 21.6 ± 13.2 mL/min) were randomly assigned to two dietary regimens: (i) 3 months of free diet (FD) (FD is the diet usually used by the patient before being enrolled in the Medika study), 6 months of very low protein diet (VLPD), 3 months of FD and 6 months of Mediterranean diet (MD); (ii) 3 months of FD, 6 months of MD, 3 months of FD, and 6 months of VLPD. VLPD reduced inflammatory Proteobacteria and increased Actinobacteria phyla. MD and VLPD increased some butyrate-forming species of Lachnospiraceae, Ruminococcaceae, Prevotellaceae, Bifidobacteriaceae, and decrease the pathobionts Enterobacteriaceae. The increased level of potential anti-inflammatory Blautia and Faecalibacterium, as well as butyrate-forming Coprococcus and Roseburia species in VLPD was positively associated with dietary intakes and it was negatively correlated with IS and PCS. Compared to FD and MD, VLPD showed a lower amount of some Lactobacillus, Akkermansia, Streptococcus, and Escherichia species. MD and VLPD reduced both the total and free serum IS (MD −36%, −40% and VLPD −69%, −73%, respectively) and PCS (MD −38%, −44% and VLPD −58%, −71%, respectively) compared to FD. VLPD reduced serum D-lactate compared to MD and FD. MD and, to a greater extent, VLPD are effective in the beneficial modulation of gut microbiota, reducing IS and PCS serum levels, and restoring intestinal permeability in CKD patients.

In chronic kidney disease (CKD), cardiovascular (CV) damage is present in parallel which leads to an increased risk of CV disease. Both traditional and non-traditional risk factors contribute to CV damage in CKD. The systemic role of the microbiota as a central player in the pathophysiology of many organs is progressively emerging in the literature: the microbiota is indeed involved in a complex, bi-directional network between many organs, including the kidney and heart connection, although many of these relationships still need to be elucidated through in-depth mechanistic studies. The aim of this review is to provide evidence that microbiota metabolites influence non-traditional risk factors, such as inflammation and endothelial dysfunction in CKD-associated CV damage. Here, we report our current understanding and hypotheses on the gut-kidney and gut-heart axes and provide details on the potential mechanisms mediated by microbial metabolites. More specifically, we summarize some novel hypotheses linking the microbiota to blood pressure regulation and hypertension. We also emphasise the idea that the nutritional management of CKD should be redesigned and include the new findings from research on the intrinsic plasticity of the microbiota and its metabolites in response to food intake. The need is felt to integrate the classical salt and protein restriction approach for CKD patients with foods that enhance intestinal wellness. Finally, we discuss the new perspectives, especially the importance of taking care of the microbiota in order to prevent the risk of developing CKD and hypertension, as well as the still not tested but very promising CKD innovative treatments, such as postbiotic supplementation and bacteriotherapy. This interesting area of research offers potential complementary approaches to the management of CKD and CV damage assuming that the causal mechanisms underlying the gut-kidney and gut-heart axes are clarified. This will pave the way to the design of new personalized therapies targeting gut microbiota.

In this review we elucidate the role of gut microbiota as the plausible missing link between food and health, focusing on chronic kidney disease (CKD). Microbiota, the microbial community harboured in the large intestine, is considered a symbiotic “supplementary organ”. It contributes to digestion, mainly through two catabolic pathways: saccharolytic (fermentation) or proteolytic (putrefaction). It also interacts with host influencing immunity, metabolism, and health status. It is believed that a balanced healthy microbiota is primarily saccharolytic and diet has a deep effect on its composition. Mediterranean Diet, UNESCO “Intangible Cultural Heritage of Humanity”, prevents cardiovascular and metabolic systemic diseases, thanks to the high supply of fibres and antioxidants. Mediterranean Diet also favours the prevalence of saccharolytic species, while Western Diet promotes the shift towards a proteolytic profile (dysbiosis). Emerging evidences highlight the association between a wide range of diseases and dysbiosis. In CKD a vicious circle exists, in which proteolytic-derived microbial metabolites (p-cresol and indoxyl sulphate), represent the main circulating uremic toxins: their accumulation worsens dysbiosis and promotes CKD progression. Gut microbiota shaping through non-pharmacologic nutritional treatments, based on Mediterranean Diet, represents an innovative approach in CKD, potentially restoring microbiota balance, ameliorating CKD conditions and slowing down disease progression.

In chronic kidney disease (CKD), the progressive decline in the renal excretory function leads to accumulation of urea and toxins in the blood. The CKD-associated dysbiosis of gut microbiota further contributes to uremia by increasing intestinal toxins production. Gut microbiota is involved in a complex network of human organs, mediated by microbial metabolites: in CKD, gut–heart and gut–brain axes may have a role in increased cardiovascular risk and neuropsychiatric disorders. While the cardiovascular toxicity of some microbial molecules is well known, their presumptive neurotoxicity needs to be confirmed by specific studies. In this review, we describe gut–heart and gut–brain axes in CKD, with an overview of the experimental and human studies characterizing CKD-associated gut microbiota, and we discuss the benefits coming from new approaches aimed at gut manipulation. Microbiota metabolism is emerging as a modifiable non-traditional risk factor in nephrology. In order to take advantage of this issue, it is necessary to consider the microbiota manipulation as part of the nutritional management of CKD. Integrating the low-protein nutritional approach with prebiotic, probiotic and synbiotic supplementation is a promising tool to control disease progression and comorbidities, though an extensive validation in large-scale clinical trials is still required.

Proteolytic dysbiosis of the gut microbiota has been recognized as both a typical feature of chronic kidney disease (CKD) and a risk factor for its progression. Blood accumulation of gut-derived uremic toxins (UTs) like indoxyl sulfate (IS) and p-cresyl sulfate (PCS), intestinal permeability and constipation are typical features accompanying CKD progression and triggering chronic inflammation. In order to verify the efficacy of the innovative synbiotic formulation NATUREN G^® in modulating the levels of circulating UTs, intestinal permeability and gastrointestinal symptoms, we set up a randomized, single-blind, placebo-controlled, pilot trial in stage IIIb-IV CKD patients and in healthy controls. Two-month administration of the synbiotic resulted in a decrease of free IS, as compared with the placebo-treated arm, only in the CKD group. The other UTs did not significantly change, although different trends in time (increase in the placebo arm and decrease in the synbiotic arm) were observed. Moreover, after supplementation, reduction of small intestinal permeability and amelioration of abdominal pain and constipation syndromes were observed only in the CKD group. The obtained results suggest the specificity of action of NATUREN G^® in CKD and justify further validation in a wider study population.