Probiotics Reduce CKD Progression and Improve Survival Outcomes

Recent studies have corroborated that gut dysbiosis has been recognised as a new risk factor for the development of CKD and its sequels. Dysbiosis can aggravate systemic inflammation, which has been linked to the progression of CKD and its complications. As a result, improving the gut milieu may slow the progression of CKD. Thus, probiotics may have the potential to help CKD patients and prevent its disease progression [5,6]

Decoding Gut Microbiome & CKD: The Intricate Link

The gut microbiota is critical for good intestinal barrier function as it substantially impacts host nutrition and health via enhanced metabolic capacities, pathogen defence, gastrointestinal development and immune system modulation. As a result, the idea that disruption of intestinal microbiota may play a key role in cancer and metabolic and inflammatory digestive disorders has developed. It has recently been proven that CKD is linked to dysbiotic gut microbiota. [7,8]

Patients with end-stage renal disease (ESRD) and CKD have quantitative and qualitative changes in their gut microbiota.[9] In CKD, waste by-products normally released by the kidney, termed collectively as "uremic toxins," are gradually retained, many of which have detrimental effects on numerous organs. Uremic toxins have been shown to indirectly and directly disrupt cellular activity by raising oxidative stress, decreasing glucose absorption in adipocytes, lowering tight junctions in intestinal cells, and instigating endothelial dysfunction.[10]

Uremic toxins promote the growth of proteolytic bacteria (Actinobacteria, Proteobacteria, and Firmicutes), which causes the translocation of bacteria or their fractions into the bloodstream and increases intestinal permeability, resulting in accelerated atherosclerosis and systemic inflammation. The accumulation of uremic toxins continues with the advancement of renal failure.[11] P-cresyl sulphate (PCS) and indoxyl sulphate (IS), produced following dietary protein metabolism, can also aggravate CKD progression and mortality outcomes. [12]

Introducing Probiotics Therapy in CKD Patients

Probiotics are the subject of extensive research as a natural biotreatment due to their numerous health-promoting benefits and intrinsic potential to combat certain ailments such as CKD. Furthermore, the gut microbiota has recently been identified as a key factor in the progression and complications of CKD. [8]

Intestinal microbes can promote health by breaking down toxins and guarding against infection. Probiotics can lessen the toxic waste burden in CKD patients.[13] Probiotics also promote the growth of Bifidobacteria populations, a genus recognised to be vital in the function of the intestinal mucosal barrier. Probiotics also help decrease cytokine and endotoxin concentrations and increase serum levels IL-10. The creation of short-chain fatty acids (SCFA) done by probiotics appears to be connected with large reductions in serum levels of proinflammatory cytokines TNF-, IL-5, and IL-6, as well as endotoxins and higher levels of anti-inflammatory cytokine IL-10.[9] Probiotics' beneficial effects on CKD are as follows

• Enhanced gut barrier by increasing mucus integrity, epithelial tight junction (ETJ), and epithelial cells survival.
• Antimicrobial through a reduction in local pH, a production of antimicrobial peptides (AMPs), and defensins by probiotics, which control pathobionts overgrowth. Probiotics could stimulate the production of secretory immunoglobin A (IgA), providing additional protection from the luminal microbiota.
• Anti-inflammatory effect and improved immunity tolerance. Symbionts and probiotics interact with dendritic cells (DCs) and macrophages through pattern-recognition receptors such as Toll-like receptors (TLRs), which signal to the adaptive immune cell as regulatory T cells (TReg) and B cells. The decrease in lipopolysaccharide (LPS) production reduces the activation of macrophages and the nuclear factor-kappa B (NF-κB) cascade.
• Competition for nutrients and bile acid metabolism. The reduction in pathobionts limits the production of gut-derived uremic toxins. Probiotics increase bile salt hydrolase (BSH) activity, decreasing the abundance of TbMCA (tauro-beta-muricholic acid) and SCFA production.

Using this mechanism, probiotics can decrease CKD progression [8] and increase patient life expectancy.

• CKD poses a humongous threat to the life expectancy of patients and is predicted to be the 5th largest cause of death in the coming decades.
• CKD is a progressive systemic disease, paving the way for other cardiovascular, immunological, and musculoskeletal diseases.
• Researchers have come to a common ground that there's an intricate link between the gut microbiome and CKD progression. Patients suffering from CKD have high levels of uremic toxins and lose gut integrity, making more gut microbes enter the systemic circulation and causing inflammation.
• Administration of probiotics could be scientifically rational in CKD. Several studies substantiate this claim as they can feed on uremic toxins and strengthen gut integrity. Thus, probiotics may help in decreasing the progression of CKD.

insulin secretion in chronic kidney disease. J Clin Invest. 2016 Sep 1;126(9):3598-612.

11. Tian, N.; Li, L.; Ng, J.K.-C.; Li, P.K.-T. The Potential Benefits and Controversies of Probiotics Use in Patients at Different Stages of Chronic Kidney Disease. Nutrients 2022, 14, 4044.

12. De Mauri, A.; Carrera, D.; Bagnati, M.; Rolla, R.; Vidali, M.; Chiarinotti, D.; Pane, M.; Amoruso, A.; Del Piano, M. Probiotics-Supplemented Low-Protein Diet for Microbiota Modulation in Patients with Advanced Chronic Kidney Disease (ProLowCKD): Results from a Placebo-Controlled Randomized Trial. Nutrients 2022, 14, 1637.

13. Gharat, P.R., Vakharia, M.P., & Ranganathan, D.N. (2019). Specific Probiotics for Chronic Kidney Disease: A Review.

14. Rossi, M.; Johnson, D.W.; Morrison, M.; Pascoe, E.M.; Coombes, J.S.; Forbes, J.M.; Szeto, C.-C.; McWhinney, B.C.; Ungerer, J.P.J.; Campbell, K.L. Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY): A Randomized Trial. Clin. J. Am. Soc. Nephrol. 2016, 11, 223–231