Presentation on theme: "Probiotics and Gastrointestinal Concerns of the Dialysis Patient"— Presentation transcript:
1 Probiotics and Gastrointestinal Concerns of the Dialysis Patient Karen Madsen, PhDUniversity of AlbertaKaren Madsen, PhDUniversity of AlbertaEdmonton, Alberta, Canada
2 ObjectivesTo gain an understanding of the human gut microbiome and how it can influence human healthTo learn what probiotics are and their mechanisms of actionTo gain knowledge of the efficacy of probiotic therapy in patients with renal disease
3 Welcome to your microbial life! Presentation Title Here |
4 What kinds of microbes are found in the gut? Bacteria>50 different phyla~5 phyla found in gutOver 50 known bacterial phylaGenerally only 6 phyla found in gutBacteroidetes*Firmicutes*ActinobacteriaProteobacteriaVerrucomicrobriaFusobacteriatrillion organisms>1000 different speciesBacteria, 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 MOUTHSKINESOPHAGUSSTOMACHVAGINACOLONThe area of the chart for each site represents the average number of distinct phylotypes (approximate species-level taxa, based on 16S rRNA gene-sequence analysis) per individual. (The mean number of phylotypes per individual is shown in parentheses; 3–11 individuals were studied per habitat.) The coloured wedges represent the proportion of phylotypes belonging to different phyla. More than 50 bacteria phyla exist, but human microbial communities are overwhelmingly dominated by the 4 that are shown. The relative abundance of these phyla at most sites tends to be consistent across individuals: for example, in almost all humans studied so far, Bacteroidetes and Firmicutes predominate in the colon. By contrast, the composition of the vaginal microbiota is more variable; most women have a preponderance of Firmicutes with few other representatives, whereas a minority of women have a preponderance of Actinobacteria with few other representatives. An estimated 20–80% of human-associated phylotypes (depending on habitat) are thought to have eluded cultivation so far. Data taken from refs 1An ecological and evolutionary perspective on human–microbe mutualism and diseaseLes Dethlefsen, Margaret McFall-Ngai & David A. RelmanNature 449, (18 October 2007)BacteroidetesFirmicutesNature 449,
8 Gut Microbiota have a Role in Health and Disease
11 Low diversity and imbalances in gut microbiota are associated with human disease states HealthHigh biodiversity and richnessStablePrimarily Bacteroides and FirmicutesDiseaseLow biodiversityUnstableIncreased abundances of Proteobacteria, Fusobacteria, VerrucomicrobiaC. 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 ProHealthyBalancedPro-inflammatory microbesExcess “bad”bacteriaHow the microbiome and the human genome contribute to inflammatory disease. In a simplified model, the community composition of the human microbiome helps to shape the balance between immuneregulatory (Treg) and pro-inflammatory (Th17) T cells. The molecules produced by a given microbiome network work with the molecules produced by the human genome to determine this equilibrium. (A) In a healthy microbiome, there is an optimal proportion of both pro- and anti-inflammatory organisms (represented here by SFBs and B. fragilis), which provide signals to the developing immune system (controlled by the host genome) that leads to a balance of Treg and Th17 cell activities. In this scenario, the host genome can contain ‘autoimmune specific’ mutations (represented by the stars), but disease does not develop. (B, C) The genome of patients with multiple sclerosis, type I diabetes, rheumatoid arthritis and Crohn’s disease contain a spectrum of variants that are linked to disease by genome wide association studies (reviewed in (61)). Environmental influences, however, are risk factors in all of these diseases. Altered community composition of the microbiome due to lifestyle, known as dysbiosis, may represent this disease modifying component. An increase in pro-inflammatory microbes, for example SFBs in animal models, may promote Th17 cell activity to increase and thus predispose genetically susceptible people to Th17-mediated autoimmunity (B). Alternatively, a decrease or absence in anti-inflammatory microbes, for example B. fragilis in animal models, may lead to an under-development of Treg cell subsets (C). The imbalance between Th17 cells and Tregs ultimately leads to autoimmunity. Science December 24; 330(6012): 1768–1773.doi: /sciencePMCID: PMCNIHMSID: NIHMS314237Has the microbiota played a critical role in the evolution of the adaptive immune system?Yun Kyung Lee and Sarkis K. Mazmanian*Anti-inflammatorymicrobesToo few “good”bacteria
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):367-74Physical barrier(the epithelium)Chemical barrier(mucus layer)Immunological barrier(immune cells of the lamina propria)Microbial barrier(commensal bacteria)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 diseaseChronic kidney diseaseSepsisNecrotizing pancreatitisCeliac diseaseType 1 diabetesFood allergiesAlcoholic liver disease
18 What is the role of the microbiota and gut permeability in kidney disease?
20 Impaired Kidney Function results in Waste Accumulation Toxins RetainedUreaUric acidCreatinineIndoxyl sulphateParathyroid hormonePara cresyl sulphatePhenolP-cresolOxalateBlood with wasteRenal arteryFiltered bloodRenal veinWaterToxins\Waste in urineKibow Biotech, Inc.
21 Dialysis-induced hypotension HemodialysisUrea AccumulationFluid retentionUrea influx into gutDialysis-induced hypotensionIncrease urease-expressing microbesGeneration of urea-derived ammoniaBowel ischemiaDisruption of epithelial tight junctionsBowel edemaEnd-stage renal disease results in: (1) accumulation of urea in the body fluids and its diffusion into the gastro-intestinal tract, expanding urease-expressing bacterial species, forming urea-derived ammonia and ammonium hydroxide, a caustic product that damages tight junctions, (2) fluid retention causing generalized and bowel edema which can impair intestinal epithelial barrier function, (3) intermittent hemodialysis complicated by intra-dialytic and post-dialytic hypotension associated with bowel ischemia impairs intestinal epithelial barrier function and facilitates influx of endotoxin and bacterial translocation and (4) influx of endotoxin and translocation of microbial components trigger local and systemic inflammation which further amplifies epithelial barrier dysfunctionTranslocation of endotoxin and microbial componentsLocal and systemic inflammationWong et al. Am J Nephrology 39:
22 Nosratola D Vaziri et al. Kidney International 19th Sept 2012, Unbalanced microbiota in CKD patients has higher number of pathogensCKD PatientsIncreasedActinobacteriaClostridiaProteobacteriaRelative richness of the gut microbiome in the study groups. Relative richness comprised of the average number of (a) subfamilies per subphylum for control (CTL) or end-stage renal disease (ESRD) patients or (b) species per class for control (CTL) and chronic renal failure (CRF) rats. A subfamily or species had to be present in at least three replicates of a treatment group and also had to have an average of four subfamilies or species present in a subphylum or class to be included in the figure.Kibow Biotech, Inc.Nosratola D Vaziri et al. Kidney International 19th Sept 2012,Kibow Biotech, Inc.Kibow Biotech, Inc.
23 How does a gut dysbiosis alter metabolism in the colon? Chronic renal failure is characterized by a progressive retention of a number of microbial metabolic end products(urea, uric acid, creatinine,phenols, indoles and polyamines).Secondly small intestinal assimilation(digestion and/or absorption) of proteins is impaired in the case of renal failure, resulting in an increased availability of proteins for fermentation in the colon.Fermentation of these proteins in the distal region of the colon leads to production of toxic metabolites (Phenols, thiols, indoles, amines and ammonia)Short Chain Fatty AcidsButyrateAcetatePropionateTyrosine Typtophanp-cresolindole
24 p-Cresyl sulphate and indoxyl sulphate originate from dietary amino acid bacterial fermentation the colonCKDDecreased protein absorption in small intestineProlonged colonic transit timeIncreased luminal pH secondary to increased colonic urea diffusionMeijers et al Nephrol. Dial. Transplant. 2011;26:
25 Role of the colon in systemic levels of uremic solutes Dialysis patients with intact colon and colectomized patients were studied.MetaboliteNormal Control (n=7 to 10)Dialysis Colectomy (n=6)Dialysis Intact colon (n=9)Plasma p-cresyl sulphate (mg/dL)Plasma indoxyl sulphate (mg/dL)T W Meyer et al. JASN 2011; 22:Kibow Biotech, Inc.
26 Healthy Kidney Uremia/ CKD/ ESRD Hypothetical concept about how a failing kidney and the intestinal microbiota affect each other. (Left part) Under physiological conditions, the predominance of symbiotic bacteria, an intact intestinal barrier, defensins production, mucus integrity, and immunoglobulin A (IgA) secretion support the symbiosis between the host and its gut microbiota. An intramural innate immunity controls pathobiont overgrowth inside the lumen of the intestinal tract. (Right part) The metabolic changes that are associated with the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD) change the balance of symbionts and pathobionts in a way that favors pathobiont overgrowth, that is dysbiosis. Pathobiont overgrowth induces inflammation and loss of barrier function that in turn promotes increased translocation of bacterial components and even living bacteria into the host’s internal environment. This process will activate innate immunity characterized by production of proinflammatory cytokines that define a state of systemic inflammation. This process potentially modulates a number of clinically relevant processes in CKD such as the progression of CKD, accelerated atherogenesis, and protein wasting.Anders et al. Kidney Int Jan 16, 2013
27 How does CKD/ESRD induce a gut dysbiosis? Metabolic acidosisRetention of uremic toxinsVolume overload with intestinal wall congestionFrequent use of antibioticsImmune dysfunctionDiet restrictionsOral iron usage
28 Can therapies aimed at modulation of gut microbiota help patients with kidney disease?
29 How can you change your microbiota? AntibioticsKill both good and bad bacteriaOriginal microbiota usually return once drugs are removedCan allow for the growth of pathogensProbioticsGiving back live beneficial microorganismsDo not colonizePrebioticsNon-digestible food substances that provide substrate for existing beneficial microbes already present in the gutDietChanges activity of existing microbesFecal transplantsChanging complete gut ecosystem
30 Lactobacillius rhamnosus GG Names of ProbioticsBrand nameLactobacillus rhamnosus St11 = Lactobacillus fortisScientific nameCommercial nameLactobacillius rhamnosus GGKibow Biotech, Inc.
32 Some examples of food with probiotics…. 1 billion/100 gmB. lactis(B. regularis)1 billion/100 gmB. Lactis and L. acidophilus10 billion/100 mlL casei1 billion/100 gmB. Lactis and L. acidophilus
33 Some Probiotic Supplements 15 billionCFUL. acidophilus, B. lactisL. Bulgaricus, B. longumL. rhamnosus, L. brevis,S. thermophilus, L. casei, L. salivariusL. lactis, B. breve, L. plantarumL. paracasei, B. bifidum450 billion CFUB. breve B. longum B. infantis L. acidophilus L. plantarum L. paracasei L. bulgaricus S. thermophilus1 billionCFUBifidobacterium infantis1.5 billionCFULactobacillus gasseri (KS-13) Bifidobacterium bifidum (G9-1) Bifidobacterium longum (MM-2)30 billion CFUS. Thermophilus KB19L. Acidophilus KB27B. Longum KN31
34 Effects of probiotics are strain-specific BenefitProductBifidobacterium animalis DN (marketed as Bifidis Regularis)Decreased transit time – help with constipationDannon Activia yogurtLactobacillus casei DN (marketed as L. casei immuntas)Stimulates immune systemDannon’s DanActive dairy drinkBifidobacterium infantis 35624Alleviates symptoms of irritable bowel syndromeProcter and Gambles ALIGN supplementBifidobacterium lactis Bb-12Yo-Plus yogurt, Nestle Good Start Infant FormulaLactobacillus casei ShirotaYakult fermented dairy drinkLactobacillus rhamnosus GR-1 in combination with L. reuteriHelps eradicate vaginal infectionsRepHresh Pro-B and Fem-Dophilus dietary supplementsBB-12® Bifidobacterium lactis, and LA-5® Lactobacillus acidophilusIogo YogurtLactobacillus reuteri 55730Reduce antibiotic-associated diarrheaBioGaia tablets, drops, and lozengesSaccharomyces boulardiiReduces antibiotic-associated diarrheaFlorastor dietary supplement
35 Probiotics interact with cells along the entire intestinal tract but they do not colonize Immune cellsEpithelial cellsMicrofloraImmune FunctionBarrier FunctionMetabolism
36 Probiotics interact with all components of the gut barrier Effects of probiotic bacteria and yeast on intestinal epithelial barrier function. Probiotics affect the epithelial barrier in numerous, diverse ways. This multifactorial approach to enhancing intestinal barrier function aids in developing and maintaining homeostasis. Depending on the strain of bacteria or yeast and the model used, probiotics target the epithelial barrier in the following 3 areas. A: direct effects on the epithelium. Probiotics can increase mucin expression and secretion by goblet cells, thereby limiting bacterial movement across the mucous layer. Augmentation of β-defensin expression and secretion into the mucus by epithelial cells can prevent the proliferation of commensals and pathogens, thus also contributing to barrier integrity. Finally, probiotics can enhance tight junction stability, which decreases epithelial permeability to pathogens and their products. B: effects on mucosal immunity. Probiotics can increase levels of IgA-producing cells in the lamina propria and promote secretory IgA (sIgA) secretion into the luminal mucous layer. These antibodies limit epithelial colonization by binding bacteria and their antigens, thus contributing to gut homeostasis. C: effects on other surrounding or infecting bacteria. Probiotics can alter the microbiota composition and/or gene expression, leading to indirect enhancement of the barrier through the commensal bacteria. Furthermore, some probiotics can directly kill or inhibit growth of pathogenic bacteria via expression of antimicrobial factors such as bacteriocins. Probiotics can also compete with pathogens or commensals for binding sites on mucins or epithelial cells, thereby preventing detrimental colonization and contributing to barrier function.Modulate neural-muscular systemInduce the expression of µ-opioid and cannabinoid receptorsModulate visceral hypersensitivityOhland C L Am J Physiol 2010;298:G807-G819
37 Gut Microbes Modulate Gut Permeability The type and quantity of bacterial species present in the gut has a definitive role in modulating intestinal permeabilitySome microbes enhance barrier functionBifidobacterium infantis, Lactobacillus plantarumSome microbes decrease barrier function
40 Effects of probiotics on immune function Depending on the strain and host environment, probiotics can:Stimulate immune functionIncrease phagocytosis (Lactobacillus casei, L. acidophilus, B. breve)Increase sIgA secretionHave an anti-inflammatory effectReduce secretion of pro-inflammatory cytokinesIncrease secretion of anti-inflammatory cytokinesModulate NF-κ activityHave no effect at all
41 Probiotics can alter both existing microbe and host metabolism
42 Probiotics rapidly alter microbial and host metabolic activity Gut microbialactivityHost MetabolismAltered MetabolitesSystemic Effects
43 How could probiotics help patients with kidney disease? Altering bacterial composition to reduce production of metabolitesProbiotics could increase SCFA and decrease colonic pHProbiotics could repress activity of bacteria that produce toxic metabolitesReducing colonic transit timeSome strains have direct effect on gut motilityImproving gut barrier functionThrough effects on tight junction proteins and mucous productionModulating 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 foodsRisks appear to be minimal in most patientsFew side effects – primarily gas and bloating which are usually temporaryIsolated case reports of systemic infections linked to Lactobacillus rhamnosus (critically ill; severely immunosuppressed) and S. boulardii (intravenous catheters)Richard N Fedorak, MD 2007
46 Meta-analysis for pre-pro- and synbiotic therapy on serum indoxyl-sulfate in patients undergoing haemodialysis for ESKDInt J Nephrol. 2012; 2012:
47 Clinical Trial Results TypeStrainPatient Type and NumberEffectOpen label pilot studySimenhoff Miner Electrolyte Metabol 1996L. acidophilusHemodialysisN=8Serum dimethylamineNitrosodimethylamineProspective DBPRC crossoverRanganathan et al. Curr Med Res Opin 2009S. thermophilus, L. acidophilus, B. longum90 x 109 cfu/dCKD Stages 3 and 4N=136 monthsBUNCreatinineUric acidRanganathan Adv Ther 2010N=46Improved QOLOpen label single armNakabayashi Nephrol Dial Transplant 2011L. Casei ShirotaB. Breve Yakult + galactooligosaccharides1x 1084 weeksSerum p-cresolImproved stool consistencyRandomized control trialAlatriste Nutr Hosp 2014Lactobacillus casei shirota8x10916x109N=308 weeksblood urea in high dose group
48 ConclusionsThe gut microbiota has an important role in human health and in pathogenesis of diseaseEvidence is supportive of a role for colonic metabolism contributing to uremiaManipulation of the gut microbiota is a promising new therapeutic strategy for patients with renal diseaseHowever, to date, limited clinical trials have been doneLimitations due to sample size, varying concentrations and types of pro- and prebiotics used, dietary confounders