Considering Probiotic in CKD: Exploring Complementary Effect on Protein Metabolism

Gut Microbiota, Protein Metabolism, and Its Interaction with CKD

The gastrointestinal tract (GIT) of humans is host to a complex community of different microorganisms whose activities significantly influence host nutrition and health through enhanced metabolic capabilities, protection against pathogens, and regulation of the gastrointestinal development and immune system.(3)

Protein and its metabolites, amino acids, are important nutrients for various human physiological processes. The gut microbiota mediates the biochemical crosstalk between protein metabolism and host immune response. The gut microbes are involved in the digestion, absorption, metabolism, and transformation of dietary protein. Amino acids can be metabolized into microbial metabolites, which may participate in various physiological processes in host health and disease. Dietary protein components influence the gut microbiome and microbial metabolites. Dietary protein source, concentration, and amino acid balance are primary factors that influence gut microbes' composition, structure, and function. (4) Patients suffering from CKD exhibit quantitative and qualitative alterations in the gut microbiota, including elevated levels of urea and ammonia in the intestine, reduced intestinal barrier integrity, and elevated markers of inflammation. (5) These factors together hamper protein metabolism in the gut.

The urea concentrations in the blood rise with the progression of CKD, which leads to changes in the intestinal flora, increases the production of gut-derived toxins and renders a compromised intestinal epithelial barrier. These processes may hasten the progression of kidney injury. When intestinal bacteria are exposed to urea via GI secretions, urea is converted to ammonia by bacterial urease. This high urea concentration promotes the growth of bacterial families that contain urease (Actinobacteria, Firmicutes, and Proteobacteria). In patients with CKD, bacterial families producing uricase, indole- and p-cresyl-forming enzymes perpetuate compared to healthy subjects. Indoxyl sulphate is derived from dietary protein. During the metabolism of tryptophan, intestinal flora produces indole, which is then metabolised by the liver to produce indoxyl sulphate. P-Cresol is a tyrosine and phenylalanine metabolite. The protein binding of these solutes is nearly 100% in healthy individuals. However, 90% of p-cresol and 85% of indoxyl sulphate are protein-bound in patients with chronic renal failure. Serum levels of p-cresol and indoxyl sulphate are increased 10- and 50-fold, respectively, among patients with chronic kidney disease. These two toxins have been indicated causative contributors to renal tubular damage, aberrations in coagulation physiology, endothelial dysfunction, leukocyte activation, and insulin resistance in various body tissues. (6)

The kidneys play an important role in protein metabolism. Renal tubules reabsorb 3g of albumin under normal conditions and exhibit a 6-fold increase in albumin reabsorption in patients with focal segmental glomerulosclerosis. The capacity of tubular lysosomal proteolysis can be increased up to 8-fold; however, proteinuria over the capacity of tubular handling may cause tubulointerstitial damage in patients with CKD. (7)

High dietary protein intake can cause intraglomerular pressure, which may result in kidney hyperfiltration, glomerular injury, and proteinuria. Excessive protein can harm the glomerular structure, resulting in or exacerbating CKD. (8)

In CKD predialysis patients fed low-protein diets, the ability to conserve protein is well maintained if metabolic acidemia is absent and there is no concomitant illness. However, dialysis promotes protein wasting, at least partly because of obligatory protein and amino acid losses into the dialysate. These protein and amino acid losses are approximately 0.06 g/kg/day for three times weekly hemodialysis and 0.2 g/kg/day for peritoneal dialysis and need to be replaced with modest increases in dietary protein intake.

Chronic inflammation and enhanced levels of cytokines may also contribute to the increased protein requirements. Patients with advanced chronic renal failure who are not undergoing chronic dialysis can maintain neutral or positive nitrogen balance with low protein intakes. However, the alteration of protein catabolic and/ or synthetic state prevents individuals from adapting physiologically to lower protein diets, so a rather modest reduction in protein intake (for example, to 0.80 to 1.0 g protein kg/day) is associated in many patients with a failure to compensate adequately. Hence, nitrogen losses exceed nitrogen intake on these lower protein diets, and the patients are driven into a state of negative nitrogen balance. (9)

Action on Kidney Physiology: Probiotic bacteria (Streptococcus thermophilus, Lactobacillus acidophilus, Bifidobacterium longum, Bacillus coagulans etc.) have grown in popularity over the last two decades as a result of growing scientific evidence pointing to their beneficial benefits on human health.(10) Probiotics reduced urea, blood urea nitrogen, ammonia levels, and plasma concentrations of p-cresol and indoxyl sulfate in CKD patients. Certain probiotic genus like Bifidobacteria are important in maintaining the intestinal mucosal barrier, lowering cytokine and endotoxin concentrations and increasing serum levels of IL-10 (5), which is important in regulating and maintaining renal function. (11)

Clinical Evidence:

• A prospective, randomized, double-blind, placebo-controlled cross-over trial analyzed the efficacy of probiotics supplementation consisting of L. acidophilus, B.longum, and S.thermophilus, for promoting kidney health in CKD patients. The study was conducted across four countries on 46 outpatients with CKD stages 3 and 4: USA (n=10), Canada (n=113), Nigeria (n=115), and Argentina (n=8) for three months. The result showed a significant decrease in BUN (blood urea nitrogen) levels in 29 patients (63%, P<0.05). Almost all subjects expressed a perceived substantial overall improvement in quality of life (86%, P<0.05). This suggests that the chosen probiotic formulation promotes kidney health in CKD patients. (12)
• A randomized, double-blind, controlled clinical trial performed on 60 patients analysed the effect probiotics (B.coagulans strain) on metabolic status with diabetic nephropathy. The result analyzed after 12 weeks of intervention showed that significantly reduced serum high-sensitivity C-reactive protein (hs-CRP) (- 1.9 ± 2.4 vs - 0.2 ± 2.7 mg/L, P=0.01) and plasma malondialdehyde (MDA) levels (- 0.1 ± 0.6 vs. + 0.6 ± 1.0 μmol/L, P=0.002). This suggests that probiotics intake benefits diabetic nephropathy. (13)
• B. coagulans has been shown to improve protein digestion in preclinical and clinical studies. B. coagulans is known for its ability to withstand the stomach's acidic environment to reach the intestine, where it germinates. Once active in the small intestine after germination, it aids the digestion of proteins. Studies also demonstrated that B. coagulans produce several enzymes that break down proteins into smaller peptide molecules and free amino acids, improving the intestinal environment of the colon and lowering toxic metabolite levels. (14, 15)

Action on Protein Metabolism: Probiotics can also stimulate host digestive protease and peptidase activity, and some can release exoenzymes, which can catalyze protein breakdown. Furthermore, probiotics can increase small peptide and amino acid uptake by boosting epithelial absorption and transport. Furthermore, probiotics can minimise detrimental protein fermentation, attenuating the toxicity of metabolites. (16)

• The gut microbiome also plays an essential role in the metabolism of proteins that are building blocks of the body.
• CKD patients have a compromised gut microbial milieu that produces high amounts of uricase, indole- and p-cresyl-forming enzymes, which can lead to multiple co-morbid processes and hamper protein metabolism.
• Probiotics help in multimodal action by increasing gut integrity, decreasing indole and p-cresyl serum levels and helping in balancing protein metabolism, thus slowing the progression of CKD.
• Using probiotic mixtures of B. longum, B.coagulans, S. thermophillus, and L. acidophillus improves kidney health in CKD patients.