Probiotics in CKD-Complimentary Role in Glycemic Regulation

There is enough evidence which points out that diseases like diabetes, in the long run, can adversely affect kidneys and can cause chronic kidney disease. Almost 40% of patients who have diabetes also develop kidney disease, and its prevalence is rising in tandem with the prevalence of type 2 diabetes.[4]

Although there is no clear-cut pharmacological therapy to cure chronic kidney disease, we can reduce the progression of the disease [5]. Studies have indicated that the intake of probiotics can help reduce the progression of CKD in individuals and also help in glycemic regulation. [6,7]

This article focuses on the scope of probiotics as a novel intervention to help both CKD and mitigate associated glycemic aberrations.

Uremic toxins: A progenitor for causing systemic damage in CKD patient

Chronic kidney disease (CKD) is defined by the gradual retention of waste by-products typically discharged by the kidney, known collectively as "uremic toxins," many of which have negative consequences on various organs. Uremic toxins have been demonstrated to alter cellular functioning indirectly and directly by affecting serum or tissue components by increasing oxidative stress, inhibiting glucose absorption in adipocytes, lowering tight junctions in intestinal cells, and inciting endothelial dysfunction.[8]

• Uremic toxins help in the proliferation of proteolytic bacteria (Actinobacteria, Proteobacteria, and Firmicutes), which causes the translocation of bacteria or their fractions into the bloodstream and increases intestinal permeability leading to accelerated atherosclerosis and systemic inflammation. With the progression of renal failure, the accumulation of uremic toxins continues and may worsen the quality of life among CKD patients. (9)
• P-cresyl sulphate and indoxyl sulphate, which are formed after metabolization of dietary protein intake, can also worsen chronic kidney disease progression and mortality outcomes [10]

Gut microbiome and Interactions Leading to Type 2 Diabetes Mellitus [2]

Type 2 diabetes mellitus (T2DM) has also been connected to the composition of the gut microbiota and is directly linked to the development of low-grade inflammation. Furthermore, the intestinal microbiota composition influences the development of prediabetes states like insulin resistance.

• The main characteristics of T2DM patients' microbiota are decreased butyrate-producing bacteria (particularly Roseburia intestinalis and Faecalibacterium prausnitzii), moderate dysbiosis, a pro-inflammatory environment with increased expression of microbial genes involved in oxidative stress, decreased expression of genes involved in vitamin synthesis, increased serum bacteria's lipopolysaccharide [LPS] concentration and increased intestinal permeability.
• Dysbiosis in T2DM patients is caused by the interaction of the intestinal microbiota with environmental and genetic factors, which leads to increased intestinal permeability and altered mucosal immune response, which may result in the development or exacerbation of T2DM. Gram-negative bacteria's lipopolysaccharide (LPS) can activate the dormant immune system by activating toll-like receptors and causing the release of inflammatory cytokines. Furthermore, LPS stimulates the nuclear factor kappa-B and c-Jun N-terminal kinase pathways, which are connected to the development of insulin resistance and a lack of insulin signalling in the muscle, adipose tissue, liver, and hypothalamus.
• Gut microbiota is also responsible for producing and contributing to energy via short-chain fatty acid (SCFA) production, which involves the anaerobic digestion of dietary fibre, protein, and peptides. Dysbiosis of the gut microbiota is directly associated with changes in SCFA production. SCFA, particularly butyrate, enhances insulin sensitivity and secretion by promoting the release of peptide 1 like glucagon (GLP-1) and lowering adipocyte inflammation. Studies substantiate that SCFA-producing bacteria, namely butyrate-producing bacteria, were reduced in Asian patients with T2DM.

Probiotics: Utility in CKD and Hyperglycemia

Probiotics are a diverse group of substances containing living microorganisms to improve intestinal microbial balance and produce health benefits. To attain this, the appropriate dosages must be administered.[11] Lactobacillus acidophilus and Bifidobacterium longum species of probiotics have been linked to decreased blood urea nitrogen, ammonia levels, and plasma concentrations of p-cresol and indoxyl sulfate. Another advantage of these probiotic species is that they help boost bifidobacteria populations, a genus which plays an essential role in the operation of the intestinal mucosal barrier integrity. Administration of probiotics reportedly lowered blood urea levels in patients with CKD stages 3 and 4. [6]

Clinical evidence [12]

1. A Single-center, non-randomized-placebo controlled trial conducted on 22 individuals for a period of 5 weeks by Takayama et al. concluded that probiotics such as B. longum can decrease the concentration of Indoxyl sulphate (3.5 +/- 1.3 mg/dL vs 4.9 +/- 1.7 mg/dL, P < 0.005).

2. A single-centre, prospective, randomized, double-blind, cross-over, placebo control trial conducted on 16 CKD patients of stage 3-4 was assessed by Ranganathan et al. The study was done for a period of 6 months. It concluded that L. acidophilus, S. thermophilus and B. longum administration in CKD patients decreased Blood urea nitrogen (-2.93 mmol/L vs 4.52 mmol/L, p = 0.002), uric acid concentration (24.70 micromol/L vs 50.62 micromol/L, p = 0.050)

Probiotics have also been demonstrated to be beneficial through multiple postulated pathways for T2DM. Probiotics typically lead to enhanced intestinal integrity, decreased systemic lipopolysaccharide (LPS) levels, decreased endoplasmic reticulum stress, and improved peripheral insulin sensitivity. LPS levels are tightly linked to gut integrity. Thus, it is known that the intestinal barrier prevents LPS transfer from the intestinal lumen to the circulatory system during homeostasis. Evidence suggests that 6 weeks of treatment with the probiotic Bifidobacteria can reduce metabolic endotoxemia, inflammation, and lead to LPS translocation and enhance overall metabolism. Probiotic administration also aids in lowering plasma lipids and pro-inflammatory genes (TNF-alpha, IL-6, IL-beta) and the rise of short-chain fatty acid synthesis (SCFA). Probiotics may influence the gut microbiota, resulting in lower fasting glucose levels, haemoglobin A1c levels, and C-reactive protein (CRP) levels via cascading metabolic processes [2]

Clinical evidence

1. A study conducted by Razmpoosh et al. over a period of 6 weeks assessed 30 people with diabetes 2 type, and the study concluded that administration of L. acidophilus, B. longum and Streptococcus thermophilus could reduce the fasting plasma glucose (FPG) level significantly (FPG after 6 weeks of probiotic administration v/s FPG before probiotic administration- 131.7±31.1 vs 145.5±40.7, p=0.001) [2]

2. A study conducted by Ejtahed et al. on 64 people with T2DM over a period of 6 weeks concluded that administration of probiotics such as L. acidophilus could decrease fasting blood glucose level (after v/s baseline- 7.36±2.41vs 8.06±2.49 mmol/L, P < 0.01] and HbA1c levels [after intervention v/s baseline- 7.29 ±1.21 vs 7.17 ±1.4%, P < 0.05).[2]

3. Madempudi, R. S et al. conducted a randomized, double-blind, placebo-controlled clinical trial to assess the role of multi-strain probiotic formulations, including Bacillus coagulans, on seventy-nine individuals with T2DM. The study kept a change in HbA1c as a primary endpoint. The twelve-week-long study concluded that multi-strain probiotic supplementation, including B. coagulans, significantly reduced HbA1c (7.70 ± 0.79%; p = 0.0023) compared to placebo (HbA1c: 8.30 ± 1.35%). [13]

Points to Remember

• Chronic kidney disease is a debilitating condition, and its prevalence is going to increase in the coming times. It has been estimated that CKD will be the 5^th leading cause of death by 2040, according to the global burden of diseases.
• CKD is the pandora’s box of diseases and brings about a plethora of diseases with it, such as diabetes, cardiovascular diseases etc.
• Uremic toxins such as urea accumulate in a CKD patient, which can trigger glycemic dysregulation.
• Using probiotics such asL. acidophilus, B. longum, S. thermophilus, and B. coagulanscan help reduce serum urea, p-cresol and indoxyl sulfate, which can slow the progression of CKD.
  
• Probiotics have also been linked to glycemic control by regulating cell signalling, decreasing inflammatory markers, and reducing oxidative stress.

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References

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8. Koppe L, Nyam E, Vivot K, Manning Fox JE, Dai XQ, Nguyen BN, Trudel D, Attané C,Moullé VS, MacDonald PE, Ghislain J, Poitout V. Urea impairs β cell glycolysis and

insulin secretion in chronic kidney disease. J Clin Invest. 2016 Sep 1;126(9):3598-612.doi: 10.1172/JCI86181. Epub 2016 Aug 15.

9. 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. doi:10.3390/nu14194044

10. 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. doi:10.3390/ nu14081637.

11. Kechagia M, Basoulis D, Konstantopoulou S, Dimitriadi D, Gyftopoulou K, Skarmoutsou N, Fakiri EM. Health benefits of probiotics: a review. ISRN Nutr. 2013 Jan 2;2013:481651. doi: 10.5402/2013/481651.

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13. Madempudi, R. S., Ahire, J. J., Neelamraju, J., Tripathi, A., & Nanal, S. (2019). Efficacy of UB0316, a multi-strain probiotic formulation in patients with type 2 diabetes mellitus: A double blind, randomized, placebo controlled study. PloS one, 14(11), e0225168. https://doi.org/10.1371/journal.pone.0225168