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Table of Contents
Year : 2021  |  Volume : 7  |  Issue : 1  |  Page : 26-29

Disentangling dysbiosis in chronic kidney disease

Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission20-May-2021
Date of Decision22-May-2021
Date of Acceptance25-May-2021
Date of Web Publication21-Oct-2021

Correspondence Address:
Dr. Anita Timmy Saxena
Department of Nephrology Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jrnm.jrnm_14_21

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How to cite this article:
Saxena AT. Disentangling dysbiosis in chronic kidney disease. J Renal Nutr Metab 2021;7:26-9

How to cite this URL:
Saxena AT. Disentangling dysbiosis in chronic kidney disease. J Renal Nutr Metab [serial online] 2021 [cited 2022 May 26];7:26-9. Available from: http://www.jrnm.in/text.asp?2021/7/1/26/328956

More than 2000 years ago, Hippocrates stated that “All diseases begin in the gut.” “We know that mental state influences gut as is explicit from the sensation of disquiet in the stomach prior to accomplishing an important mission.”

Microbes that live in and on the human body outnumber human cells by 10:1, with a more recent estimate suggesting that “we are essentially one part human to one part microbe in terms of cell number.”[1],[2]

“The organisms that are more prevalent in patients tend to be more pro-inflammatory in nature, while those that are less in number tend to promote anti-inflammatory responses.”[3],[4] These microorganisms have an important place in regulating human health as they break down otherwise indigestible dietary fibers to short-chain fatty acids (SCFAs are beneficial in maintaining gut health), and other components of food, produce vitamins, promote development and maturation of the immune system, and prevent pathogenic bacterial species from colonizing the gut. Humans harbours more than 1000 species of bacteria capable of surviving in the gut.[5] These microorganisms have a unique ability to exchange genetic material with one another that adds further complexity to the commensals.

Ammonium hydroxide, a metabolic by-product derived from urea hydrolysis in the intestinal lumen by urease-expressing microbes, contributes to intestinal epithelial cell toxicity and the subsequent decreases in tight junction proteins. The intestinal uremic milieu observed in chronic kidney disease (CKD) patients results in the loss of tight junction proteins, compromising the integrity of the intestinal barrier.[6]

The Human Microbiome Project and the European Metagenomics of the Human Intestinal Tract have shown that the healthy microbiome can vary from one individual to another[7] but remains relatively stable over time.[8],[9]

The microbiome–host relationship carries a spectrum of beneficial roles in energy utilization, storage and nutrition, immune system regulation and adaptation, intestinal integrity,[5],[10],[11],[12],[13] handling and processing complex carbohydrates,[14],[15] and the production and absorption of different vitamins[15],[16],[17] and also contributes to amino acid homeostasis such as synthesizing lysine and threonine by utilizing nitrogenous compounds.[18] Increased intestinal permeability is known in stress-related conditions such as anxiety and depression and constipation which are common in patients with CKD.[19],[20]

Uremic toxicity has recently gained much attention as a potential cause of CKD progression. Data are accumulating in support of intestinal microbiota playing a pivotal role in the development of CKD complications like cardiovascular disease (CVD) due to their deleterious effect on the endothelium. In CKD, impairment of endothelial function is characterized by increased oxidative stress, expression of pro-inflammatory and prothrombotic molecules, structural damage, and failure of the endothelial repair and protection mechanisms. Laminar shear stress, a hemodynamic force which plays a role in maintaining endothelial functions, also contributes to endothelial dysfunction including production of nitric oxide, vasodilation, and permeability.[20],[21],[22]

Altered microbiome in CKD is attributed to several factors, such as underlying cause of renal dysfunction (e.g., diabetic kidney disease and glomerulonephritis),[23],[24] therapeutic interventions such as use of antibiotics and immunosuppressive therapy, iron supplementation, phosphate binders,[25] and dietary restrictions.[26] Historic era for phage therapy was seen between the 1920s and the early 1950s, when German and Soviet armies, during World War II, used phages to treat dysentery. However, with the advent of antibiotics, this concept was abandoned only to be revived with treatment failures due to antibiotic-resistant bacteria.[27]

During natural progression of CKD, there is a shift in microbiome composition and the intestinal environment from a symbiotic to a dysbiotic state caused by an increase in colonic protein fermentation which results in increase microbiota-derived uremic toxins along with diminution of carbohydrate fermentation and consequently formation of SCFAs is compromised.[28]

The amounts of nutrients entering the colon mainly depend on dietary intake and the efficiency of the assimilation process in the small intestine. Pancreatic inflammation and malabsorption are often associated with impaired protein digestion in end-stage renal disease (ESRD) population,[29],[30] and consequently, changes in the composition of intestinal flora, or changes in intestinal production and absorption, alter their serum concentration.

In 1917, Félix d'Hérelle proposed the term “bacteriophages” derived from two separate words “bacteria” and “phagein” (to eat in Greek), implying “virus capable of parasitizing bacteria[27],[31] and antimicrobial peptides.”[28],[29],[32],[33],[34],[35],[36],[37] Increased intestinal urea concentrations in response to high blood urea nitrogen (BUN) together with increased colonic transit time give rise to altered carbohydrate-to-protein balance, producing dysbiosis. Further, the transcellular tight junction proteins are reduced in CKD, and alongside, there is accumulation of inflammatory cells in the lamina propria and increase in serum monocyte chemoattractant protein-1 concentrations, which ensues systemic inflammation.[38] Accumulation of toxic metabolites in blood and other metabolic compartments results from reduced renal clearance causing the progression of CKD to ESRD. The progression is also influenced by several other factors, such as dietary intake, mental stress, and medications.[39] Although medication or renal replacement therapies may delay the progression of CKD,[31] other preventable factors such as dysbiosis of gut microbiota are gaining much scientific popularity.

Literature suggests that solutes with toxic capacity are produced in the intestine.[40] Uremic toxins, p-cresol sulfate (PCS) and indoxyl sulfate (IS), both come from bacterial fermentation of the proteins in the large intestine. It is the colonic microbiota that degrades tryptophan to indole. Prolonged retention of undigested protein in the intestines (colonic lumen) triggers immune response causing discomfort and inflammation in the gut and formation of uremic toxins (PCS and IS), which play an important role in the genesis of cardiovascular complications, progression of renal damage, and mortality in CKD. Of more than known 900 toxins, IS and PCS are not only known for their involvement in the development of CVD but also are biomarkers for renal function.[41],[42]

Increased levels of IS are associated with enhanced oxidative stress in endothelial cells, vascular smooth muscle cell proliferation, vascular stiffness, peripheral vascular disease, aortic calcification, and overall and cardiovascular mortality in patients with CKD. IS exerts cardiac profibrotic effect, causing myocardiocyte hypertrophy, and predisposes to atrial fibrillation.[43],[44]

Food intake can have a significant role in BUN and urea formation. Bulgarian peasants have unusual longevity. In 1907, the immunologist Elie Metchnikoff attributed this unusual longevity Bulgarian peasant to their consumption of large quantities of fermented milk products, and proposed that replacing harmful microbes in the gut with lactic acid bacteria could improve intestinal health and prolong life.[44]

SCFAs, mainly produced by the intestinal flora from carbohydrate fermentation, with acetate (∼50% of all SCFAs), propionate, and butyrate account for more than 90% of all SCFAs. Patients with moderate to advanced CKD (or those with RTA !V who have chronic hyperkalemia) are advocated to follow strict dietary restriction to prevent hyperkalemia which limits the consumption of potassium-rich food, such as fruits, vegetables, and high fiber-containing food (also to prevent excess phosphorus intake). These restrictions decrease colonic carbohydrate/protein availability, resulting in dysbiosis, thus decreasing SCFA-producing bacteria.[27],[40],[41],[42],[43],[45],[46]

The SCFAs acetate, butyrate, and propionate have anti-inflammatory and histone deacetylase properties.[47] Therapy with SCFAs improved renal dysfunction in an ischemic acute kidney injury model, and lowered the levels of local and systemic inflammation, oxidative stress, and cell apoptosis.[48]

Butyrate and SCFAs not only serve as a primary energy source for epithelial cells of the intestinal tract,[49],[50] but also they dampen the pro-inflammatory response in intestinal epithelial cells.

This prothrombotic phenotype is ascribed to CKD-associated dysbiosis (indolic compounds induced platelet hyperactivity) giving rise to phenomenon known as thrombolome (uremic toxins that enhance thrombosis by increasing tissue factor expression, platelet hyperactivity, microparticle release, and endothelial dysfunction) which is spontaneously induced.

IS- and CKD-related anemia has been observed since it diminishes erythropoiesis, hampers the activity of erythropoietin, and enhances programmed cell death of red blood cells (eryptosis). Increased inflammatory biomarkers in Stage 3–4 CKD patients, such as glutathione peroxidase and interleukin-6, are reported. Vascular inflammation is involved in the pathogenesis of thrombotic complications. Controlling inflammation, dysbiosis, and oxidative stress can prevent the occurrence of CVD in CKD. IL-6 acts both as pro- and anti-inflammatory cytokines depending upon whether it activates signal transducers and activators of transcription (STAT1) or not.[51]

This indicates that alterations in SCFAs secondary to CKD-associated dysbiosis might negatively impact the integrity of intestinal epithelial cells, further worsening the pro-inflammatory state. Restoration of SCFAs using a high-fiber diet in an experimental autoimmune hepatitis animal model resulted in improved intestinal histological structures measured by crypt number and depth, ameliorated intestinal track permeability, and reduced bacterial translocation.[32]

Therefore, to maintain gut health pre and probotics can be considered as a adjuvant alternative for improving gut health and thereby preventing progression of CKD. Randomized controlled trials on synbiotic therapy, have shown a reduction of PCS concentration.[52],[53] Fecal microbiota transplantation (FMT) is known to be effective in attenuating metabolic complication and accumulation of uremic toxins which can potentially improve gut microbiota disturbance. Studies have shown that FMT decreases p-cresyl sulfate accumulation and improves glucose tolerance without change in kidney function.[54]

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Conflicts of interest

There are no conflicts of interest.

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