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Probiotics and Gastrointestinal Concerns of the Dialysis Patient Karen Madsen, PhD University of Alberta Karen Madsen, PhD University of Alberta Edmonton,

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Presentation on theme: "Probiotics and Gastrointestinal Concerns of the Dialysis Patient Karen Madsen, PhD University of Alberta Karen Madsen, PhD University of Alberta Edmonton,"— Presentation transcript:

1 Probiotics and Gastrointestinal Concerns of the Dialysis Patient Karen Madsen, PhD University of Alberta Karen Madsen, PhD University of Alberta Edmonton, Alberta, Canada

2 Objectives To gain an understanding of the human gut microbiome and how it can influence human health To learn what probiotics are and their mechanisms of action To gain knowledge of the efficacy of probiotic therapy in patients with renal disease

3 3Presentation Title Here | Welcome to your microbial life!

4 Bacteria >50 different phyla ~5 phyla found in gut What kinds of microbes are found in the gut? Over 50 known bacterial phyla Generally only 6 phyla found in gut Bacteroidetes* Firmicutes* Actinobacteria Proteobacteria Verrucomicrobria Fusobacteria trillion organisms >1000 different species Bacteria, fungi, viruses

5 Microbial species and abundance change over the length of the GI track

6 Microbial Ecology of the Gut  Species have a characteristic geographic distribution along both the length and the diameter of the gut

7 Bacterial phyla have specific site-distribution in healthy humans Nature 449, Bacteroidetes Firmicutes COLON SKIN MOUTH ESOPHAGUS STOMACH VAGINA

8 Gut Microbiota have a Role in Health and Disease


10 A fine balance of gut microbes PATHOGENS Sepsis, infection Inflammation Liver damage Production of carcinogens Diarrhea, constipation COMMENSALS Inhibit pathogen growth Convert pro-drugs to active metabolites Degrade polysaccharides of plant origin Produce folate and Vitamin K Produce short-chain fatty acids Stimulate and modulate immune function Regulate body fat storage Maintain barrier function and stimulate epithelial repair Stimulate gut motility

11 Low diversity and imbalances in gut microbiota are associated with human disease states Health High biodiversity and richness Stable Primarily Bacteroides and Firmicutes Disease Low biodiversity Unstable Increased abundances of Proteobacteria, Fusobacteria, Verrucomicrobia C. Difficile colitis, IBD, IBS, obesity, metabolic syndrome, peripheral vascular disease, renal disease, diabetes

12 A “dysbiosis” of the gut microbiota can result from different mechanisms… Anti Pro Pro- inflammatory microbes Anti- inflammatory microbes Healthy Excess “bad” bacteria Too few “good” bacteria Balanced


14 A barrier exists between microbes and the immune system TOLERANCE

15 Components of the intestinal barrier Image adapted from: Hooper LV (2009) Nat Rev Microbiol 7(5): Physical barrier (the epithelium) Physical barrier (the epithelium) Chemical barrier (mucus layer) Chemical barrier (mucus layer) Immunological barrier (immune cells of the lamina propria) Immunological barrier (immune cells of the lamina propria) Microbial barrier (commensal bacteria) Microbial barrier (commensal bacteria) Muscle layers (smooth muscle intestinal wall) Muscle layers (smooth muscle intestinal wall)

16 Tight junctions maintain barrier between epithelial cells

17 A breakdown in gut barrier function has been linked with numerous diseases Inflammatory bowel disease Chronic kidney disease Sepsis Necrotizing pancreatitis Celiac disease Type 1 diabetes Food allergies Alcoholic liver disease


19 Secretory Erythropoietin Vitamin D, Renin Excretory Urea, uric acid, creatinine, nitrogenous wastes Regulatory Maintains homeostasis; Na, K, Po 4, trace elements. Kidney Function Kibow Biotech, Inc.

20 Page | 20 Impaired Kidney Function results in Waste Accumulation Kibow Biotech, Inc. Toxins Retained Urea Uric acid Creatinine Indoxyl sulphate Parathyroid hormone Para cresyl sulphate Phenol P-cresol Oxalate Blood with waste Renal artery Filtered blood Renal vein Water Toxins\ Waste in urine

21 Urea AccumulationFluid retention Hemodialysis Urea influx into gut Increase urease-expressing microbes Generation of urea-derived ammonia Disruption of epithelial tight junctions Translocation of endotoxin and microbial components Local and systemic inflammation Bowel edema Dialysis- induced hypotension Bowel ischemia Wong et al. Am J Nephrology 39:

22 Kibow Biotech, Inc. Unbalanced microbiota in CKD patients has higher number of pathogens CKD Patients Increased Actinobacteria Clostridia Proteobacteria Nosratola D Vaziri et al. Kidney International 19 th Sept 2012, Kibow Biotech, Inc.

23 How does a gut dysbiosis alter metabolism in the colon? Short Chain Fatty Acids Butyrate Acetate Propionate Tyrosine Typtophan p-cresol indole

24 Page | 24 p-Cresyl sulphate and indoxyl sulphate originate from dietary amino acid bacterial fermentation the colon Meijers et al Nephrol. Dial. Transplant. 2011;26: Decreased protein absorption in small intestine Prolonged colonic transit time Increased luminal pH secondary to increased colonic urea diffusion CKD

25 Dialysis patients with intact colon and colectomized patients were studied. Page | 25 Role of the colon in systemic levels of uremic solutes Kibow Biotech, Inc. T W Meyer et al. JASN 2011; 22:

26 Healthy Kidney Uremia/ CKD/ ESRD Anders et al. Kidney Int Jan 16, 2013

27 How does CKD/ESRD induce a gut dysbiosis? Metabolic acidosis Retention of uremic toxins Volume overload with intestinal wall congestion Frequent use of antibiotics Immune dysfunction Diet restrictions Oral iron usage

28 Can therapies aimed at modulation of gut microbiota help patients with kidney disease?

29 Antibiotics  Kill both good and bad bacteria  Original microbiota usually return once drugs are removed  Can allow for the growth of pathogens Probiotics  Giving back live beneficial microorganisms  Do not colonize Prebiotics  Non-digestible food substances that provide substrate for existing beneficial microbes already present in the gut Diet  Changes activity of existing microbes Fecal transplants  Changing complete gut ecosystem How can you change your microbiota?

30 Names of Probiotics Kibow Biotech, Inc. Brand name Lactobacillus rhamnosus St11 = Lactobacillus fortis Scientific name Commercial name Lactobacillius rhamnosus GG Page | 30

31 LactobacillusBifidobacteriaStreptococcusOthers L acidophilus L casei GG L rhamnosom L salavarius L delbruecki L reuteri L brevis L plantarum L. bulgaricus B bifidum B infantis B longum B thermophilum B adolescents B. Lactis B. breve S thermophilus S lactis S salivarius E. Coli Nissle 1917 Serotype O6:K5:H1 Saccharomyces boulardi Common Probiotics

32 Some examples of food with probiotics…. 1 billion/100 gm B. Lactis and L. acidophilus 10 billion/100 ml L casei 1 billion/100 gm B. lactis (B. regularis) 1 billion/100 gm B. Lactis and L. acidophilus

33 Some Probiotic Supplements 1 billion CFU Bifidobacterium infantis billion CFU Lactobacillus gasseri (KS-13) Bifidobacterium bifidum (G9-1) Bifidobacterium longum (MM-2) 30 billion CFU S. Thermophilus KB19 L. Acidophilus KB27 B. Longum KN billion CFU B. breve B. longum B. infantis L. acidophilus L. plantarum L. paracasei L. bulgaricus S. thermophilus 15 billion CFU L. acidophilus, B. lactis L. Bulgaricus, B. longum L. rhamnosus, L. brevis, S. thermophilus, L. casei, L. salivarius L. lactis, B. breve, L. plantarum L. paracasei, B. bifidum

34 Effects of probiotics are strain-specific StrainBenefitProduct Bifidobacterium animalis DN (marketed as Bifidis Regularis) Decreased transit time – help with constipation Dannon Activia yogurt Lactobacillus casei DN (marketed as L. casei immuntas) Stimulates immune systemDannon’s DanActive dairy drink Bifidobacterium infantis 35624Alleviates symptoms of irritable bowel syndrome Procter and Gambles ALIGN supplement Bifidobacterium lactis Bb-12Stimulates immune systemYo-Plus yogurt, Nestle Good Start Infant Formula Lactobacillus casei ShirotaStimulates immune systemYakult fermented dairy drink Lactobacillus rhamnosus GR-1 in combination with L. reuteri Helps eradicate vaginal infections RepHresh Pro-B and Fem- Dophilus dietary supplements BB-12® Bifidobacterium lactis, and LA-5® Lactobacillus acidophilus Stimulates immune systemIogo Yogurt Lactobacillus reuteri 55730Reduce antibiotic-associated diarrhea BioGaia tablets, drops, and lozenges Saccharomyces boulardiiReduces antibiotic-associated diarrhea Florastor dietary supplement

35 Probiotics interact with cells along the entire intestinal tract but they do not colonize Probiotics Immune cells Epithelial cells Microflora Immune Function Barrier Function Metabolism

36 Ohland C L Am J Physiol 2010;298:G807-G819 Modulate neural-muscular system Induce the expression of µ-opioid and cannabinoid receptors Modulate visceral hypersensitivity Probiotics interact with all components of the gut barrier

37 Gut Microbes Modulate Gut Permeability The type and quantity of bacterial species present in the gut has a definitive role in modulating intestinal permeability Some microbes enhance barrier function Bifidobacterium infantis, Lactobacillus plantarum Some microbes decrease barrier function


39 Probiotic Effects on Immune Cells

40 Effects of probiotics on immune function Depending on the strain and host environment, probiotics can:  Stimulate immune function Increase phagocytosis ( Lactobacillus casei, L. acidophilus, B. breve ) Increase sIgA secretion  Have an anti-inflammatory effect Reduce secretion of pro-inflammatory cytokines Increase secretion of anti-inflammatory cytokines Modulate NF-κ activity  Have no effect at all


42 Probiotics rapidly alter microbial and host metabolic activity Gut microbial activity Systemic Effects Host Metabolism Altered Metabolites

43 How could probiotics help patients with kidney disease? Altering bacterial composition to reduce production of metabolites  Probiotics could increase SCFA and decrease colonic pH  Probiotics could repress activity of bacteria that produce toxic metabolites Reducing colonic transit time  Some strains have direct effect on gut motility Improving gut barrier function  Through effects on tight junction proteins and mucous production Modulating immune function

44 Are probiotics safe? Commercially available probiotic strains are considered to be GRAS (Generally regarded as safe) due to their long term usage in fermented foods Risks appear to be minimal in most patients Few side effects – primarily gas and bloating which are usually temporary Isolated case reports of systemic infections linked to Lactobacillus rhamnosus ( critically ill; severely immunosuppressed ) and S. boulardii ( intravenous catheters )

45 Clinical applications What is the evidence?

46 Int J Nephrol. 2012; 2012: Meta-analysis for pre-pro- and synbiotic therapy on serum indoxyl-sulfate in patients undergoing haemodialysis for ESKD

47 TypeStrainPatient Type and Number Effect Open label pilot study Simenhoff Miner Electrolyte Metabol 1996 L. acidophilusHemodialysis N=8 Serum dimethylamine Nitrosodimethylamine Prospective DBPRC crossover Ranganathan et al. Curr Med Res Opin 2009 S. thermophilus, L. acidophilus, B. longum 90 x 10 9 cfu/d CKD Stages 3 and 4 N=13 6 months BUN Creatinine Uric acid Prospective DBPRC crossover Ranganathan Adv Ther 2010 S. thermophilus, L. acidophilus, B. longum 90 x 10 9 cfu/d CKD Stages 3 and 4 N=46 6 months BUN Uric acid Improved QOL Open label single arm Nakabayashi Nephrol Dial Transplant 2011 L. Casei Shirota B. Breve Yakult + galactooligosaccharides 1x 10 8 Hemodialysis N=8 4 weeks Serum p-cresol Improved stool consistency Randomized control trial Alatriste Nutr Hosp 2014 Lactobacillus casei shirota 8x x10 9 CKD Stages 3 and 4 N=30 8 weeks blood urea in high dose group Clinical Trial Results

48 Conclusions The gut microbiota has an important role in human health and in pathogenesis of disease Evidence is supportive of a role for colonic metabolism contributing to uremia Manipulation of the gut microbiota is a promising new therapeutic strategy for patients with renal disease However, to date, limited clinical trials have been done  Limitations due to sample size, varying concentrations and types of pro- and prebiotics used, dietary confounders


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