The gut microbiota exist in a symbiotic relationship with the human organism. Under physiologic conditions, interactions between the gut microbiome and the host contribute to maintain normal nutrition, metabolism and immune function (1, 2). Great progress in characterizing the structure of microbiome has led to highlight the role of colon bacteria in health and in disease. Disturbances in normal gut microbiota is called dysbiosis and growing evidence is linking dysbiosis with pathogenesis of multiple diseases, including kidney diseases. In this review we will focus on the potential role of gut microbiome in nephrology and discus the new emerging concept of microbiome targeted therapeutic interventions in management of renal diseases.
The human gut is home to a very complex environment comprising of approximately 1 kg of microbes (mainly bacteria but also archaea, viruses and eukaryotes). Genes within those organisms are termed the microbiome.
In the few recent years there has been a tremendous interest in the role of gut bacteria in health and disease. This has resulted in two large projects aiming to characterize the human microbiome: the European Metagenomic of the Human Intestinal Tract (MetaHIT) (3) and the Human Microbiome Project (HMP) (4). MetaHIT catalogued 3.3 million microbial genes (from a cohort of 124 European individuals) – 150-fold more than the human gene complement (3), HMP obtained samples from 300 American individuals (4). In 2014 the aforementioned data were combined with that from a Chinese project resulting in an integrated gene catalogue comprising of more than 9 million genes (5). Findings from these studies suggest that each and every person harbours a unique ecosystem of microbes which has the potential to change adaptively to our needs (depending on the surrounding environment, diet) and greatly influences our well-being. On average we host a few hundred species, mainly bacterial, with the predominant ones being Bacteroidetes, Firmicutes and Actinobacteria (6).
At birth the colon (where the microbiome is most abundant) is largely sterile (although some bacteria can be transmitted from the mother during pregnancy (7)). Bacterial colonization occurs during birth (especially vaginal) and continues afterwards depending on many factors (antibiotic treatment, mode of feeding etc.). The microbiome resembles that of an adult before the third year of age, remains relatively stable (8) and plays an important role in the development of the nervous system and immune response. It also participates in the synthesis of vitamins (vitamin K), degradation of dietary oxalates (Oxalobacter formigenes), indigestible plant polysaccharides, metabolism of bile acids (9).
The impact of gut microbiome on kidney diseases is a novel area of interest – PubMed search reveals 77 publications with the keywords gut microbiome and kidney disease, of which only 3 are older than 5 years. The impact of colonic bacteria on renal pathophysiology seems to be ubiquitous as suggested by more and more data each day.
Hypertension is probably also influenced by the composition of the human microbiome through gastrointestinal sodium handling (10), modification of expression of hypertensive phenotype (11) and other mechanisms. Recent studies have shown that both in rat models of hypertension and in a small sample of patients there is a decrease in the microbial abundance, diversity and an increased Firmicutes/Bacteroidetes ratio. A microbiome-oriented intervention (minocycline in this case) reduces blood pressure suggesting a therapeutic possibility (12). Another new study reveals a relationship between gut dysbiosis and blood pressure in obstructive sleep apnea-induced hypertension (13).
IgA nephropathy (IgAN) has also been associated with intestinal immunity (IgA is present in mucosal secretions – gastrointestinal fluid). Studies show that the microbiome composition is different in patients with IgA nephropathy and healthy controls and also in patients in which disease progresses and non-progressors (14). In animal models B-cell activation factor transgenic mice were shown to exhibit IgA mesangial deposition which did not occur without the presence of specific gut microbiota and circulation of specific IgA antibodies (15). Genome-wide association studies suggest a tight link between IgAN and inflammatory bowel diseases (16) therefore strengthening the hypothesis for a strong intestine-kidney connection possibly mediated by the gut microbiome.
In animal models of kidney ischemia-reperfusion injury the extent of damage differs between germ-free and control mice being more severe in “sterile” animals and becoming equivalent after addition of bacteria to diet suggesting a potential therapeutic intervention (17).
Another acute kidney injury (AKI) study evaluated the relationship between short-chain fatty acids (SCFAs) and the extent of renal dysfunction. In health SCFAs are fermentation end products (derived from dietary fiber) of gut microbiota which exhibit anti-inflammatory properties. Mice subjected to ischemia-reperfusion injury treated with butyrate, propionate and acetate 30 minutes before ischemia and at the moment of reperfusion which modulated the inflammatory process, ameliorated the effects of hypoxia and improved outcomes (18).
The emerging role of gut bacteria in chronic kidney disease (CKD), which has been termed “kidney-gut axis” or “microbiome-centric theory of CKD progression” (19, 20), has been gaining importance in recent years. The fact that some of the uremic toxins are of colonic origin and that in the face of disease the gut excretes some metabolites e.g. potassium has been known for years.
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