Probiotics and Gastrointestinal Concerns of
the Dialysis Patient
Karen Madsen, PhD
University of Alberta
Karen Madsen, PhD
University of Alberta
Edmonton, Alberta, Canada
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
Welcome to your
microbial life!
Presentation Title Here | 3
What kinds of microbes are foundBacteria
in the gut?
>50 different phyla
~5 phyla found in gut
• Over 50 known bacterial phyla
• Generally only 6 phyla found in gut
• Bacteroidetes*
• Firmicutes*
• Actinobacteria
• Proteobacteria
• Verrucomicrobria
• Fusobacteria
• 10-100 trillion organisms
• >1000 different species
• Bacteria, fungi, viruses
Microbial species and abundance change over the
length of the GI track
Microbial Ecology of the Gut

Species have a characteristic geographic distribution along
both the length and the diameter of the gut
Bacterial phyla have specific site-distribution
in healthy humans
MOUTH
SKIN
ESOPHAGUS
COLON
STOMACH
Bacteroidetes
VAGINA
Firmicutes
Nature 449, 811-818. 2007
Gut Microbiota have a Role in Health and Disease
A fine balance of gut microbes
COMMENSALS
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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
PATHOGENS

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Sepsis, infection
Inflammation
Liver damage
Production of carcinogens
Diarrhea, constipation
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
A “dysbiosis” of the gut microbiota can
result from different mechanisms…
Anti
Healthy
Excess “bad”
bacteria
Too few “good”
bacteria
Pro
Balanced
Proinflammatory
microbes
Antiinflammatory
microbes
GUT BARRIER FUNCTION
AND MICROBIOTA
A barrier exists between microbes and the immune
system
TOLERANCE
Components of the intestinal barrier
Microbial barrier
(commensal bacteria)
Chemical barrier
(mucus layer)
Physical barrier
(the epithelium)
Immunological
barrier
(immune cells of the lamina
propria)
Muscle layers
(smooth muscle intestinal
wall)
Image adapted from: Hooper LV (2009) Nat Rev Microbiol 7(5):367-74
Tight junctions maintain barrier between
epithelial cells
A breakdown in gut barrier function has been
linked with numerous diseases
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Inflammatory bowel disease
Chronic kidney disease
Sepsis
Necrotizing pancreatitis
Celiac disease
Type 1 diabetes
Food allergies
Alcoholic liver disease
WHAT IS THE ROLE OF THE MICROBIOTA
AND GUT PERMEABILITY IN KIDNEY
DISEASE?
Kidney Function
Secretory
Erythropoietin Vitamin D,
Renin
Excretory
Urea, uric acid,
creatinine,
nitrogenous wastes
Kibow Biotech, Inc.
Regulatory
Maintains homeostasis;
Na, K, Po4,trace
elements.
Impaired Kidney Function results in Waste
Accumulation
Toxins Retained
Blood with waste
Renal artery
Filtered blood
Renal vein
Water
Toxins\
Waste in urine
Kibow Biotech, Inc.
•Urea
•Uric acid
•Creatinine
•Indoxyl sulphate
•Parathyroid hormone
•Para cresyl sulphate
•Phenol
•P-cresol
•Oxalate
Page | 20
Hemodialysis
Urea Accumulation
Fluid retention
Urea influx into gut
Dialysisinduced
hypotension
Increase urease-expressing microbes
Generation of urea-derived ammonia
Bowel ischemia
Disruption of epithelial tight junctions
Bowel edema
Translocation of endotoxin and microbial components
Local and systemic inflammation
Wong et al. Am J Nephrology 39:230. 2014
Unbalanced microbiota in CKD patients has higher
number of pathogens
CKD Patients
• Increased
•Actinobacteria
•Clostridia
•Proteobacteria
Nosratola D Vaziri et al. Kidney International 19th Sept 2012,
Kibow
Biotech,
Inc.
Kibow
KibowBiotech,
Biotech,Inc.
Inc.
How does a gut dysbiosis alter metabolism in the
colon?
Short Chain Fatty Acids
Butyrate
Acetate
Propionate
Tyrosine Typtophan
p-cresol
indole
p-Cresyl sulphate and indoxyl sulphate originate from
dietary amino acid bacterial fermentation the colon
CKD
• Decreased protein absorption in small intestine
• Prolonged colonic transit time
• Increased luminal pH secondary to increased colonic urea diffusion
Meijers et al Nephrol. Dial. Transplant. 2011;26:759-761
Page | 24
Role of the colon in systemic levels of uremic
solutes

Dialysis patients with intact colon and colectomized patients
were studied.
Metabolite
Normal Control
(n=7 to 10)
Dialysis Colectomy
(n=6)
Dialysis Intact colon
(n=9)
Plasma p-cresyl
sulphate (mg/dL)
0.19+0.13
0.06+0.09
4.1+1.6
Plasma indoxyl
sulphate (mg/dL)
0.06+0.02
0.08+0.06
2.8+1.3
Kibow Biotech, Inc.
T W Meyer et al. JASN 2011; 22:1769-1776
Page | 25
Healthy Kidney
Anders et al. Kidney Int Jan 16, 2013
Uremia/ CKD/ ESRD
How does CKD/ESRD induce a gut dysbiosis?
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Metabolic acidosis
Retention of uremic toxins
Volume overload with intestinal
wall congestion
Frequent use of antibiotics
Immune dysfunction
Diet restrictions
Oral iron usage
Can therapies aimed
at modulation of gut
microbiota help
patients with kidney
disease?
How can you change your microbiota?

Antibiotics
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Probiotics
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Non-digestible food substances that provide substrate for existing
beneficial microbes already present in the gut
Diet


Giving back live beneficial microorganisms
Do not colonize
Prebiotics
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Kill both good and bad bacteria
Original microbiota usually return once drugs are removed
Can allow for the growth of pathogens
Changes activity of existing microbes
Fecal transplants
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Changing complete gut ecosystem
Names of Probiotics
Lactobacillius rhamnosus GG
Brand name
• Lactobacillus rhamnosus St11 = Lactobacillus fortis
Scientific name
Kibow Biotech, Inc.
Commercial name
Page | 30
Common Probiotics
Lactobacillus
Bifidobacteria
Streptococcus
Others
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
Some examples of food with probiotics….
1 billion/100 gm
B. Lactis and L.
acidophilus
1 billion/100 gm
B. lactis
(B. regularis)
10 billion/100 ml
1 billion/100 gm
L casei
B. Lactis and L.
acidophilus
Some Probiotic Supplements
1 billion
CFU
Bifidobacterium infantis 35624.
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
1.5 billion
CFU
30 billion CFU
Lactobacillus gasseri (KS-13)
Bifidobacterium bifidum (G9-1)
Bifidobacterium longum (MM-2)
S. Thermophilus KB19
L. Acidophilus KB27
B. Longum KN31
450 billion CFU
B. breve
B. longum
B. infantis
L. acidophilus
L. plantarum
L. paracasei
L. bulgaricus
S. thermophilus
Effects of probiotics are strain-specific
Strain
Benefit
Product
Bifidobacterium animalis DN173 010 (marketed as Bifidis
Regularis)
Decreased transit time – help
with constipation
Dannon Activia yogurt
Lactobacillus casei DN-114 001
(marketed as L. casei
immuntas)
Stimulates immune system
Dannon’s DanActive dairy drink
Bifidobacterium infantis 35624
Alleviates symptoms of irritable
bowel syndrome
Procter and Gambles ALIGN
supplement
Bifidobacterium lactis Bb-12
Stimulates immune system
Yo-Plus yogurt, Nestle Good
Start Infant Formula
Lactobacillus casei Shirota
Stimulates immune system
Yakult fermented dairy drink
Lactobacillus rhamnosus GR-1
in combination with L. reuteri
Helps eradicate vaginal
infections
RepHresh Pro-B and FemDophilus dietary supplements
BB-12® Bifidobacterium lactis,
and LA-5® Lactobacillus
acidophilus
Stimulates immune system
Iogo Yogurt
Lactobacillus reuteri 55730
Reduce antibiotic-associated
diarrhea
BioGaia tablets, drops, and
lozenges
Saccharomyces boulardii
Reduces antibiotic-associated
diarrhea
Florastor dietary supplement
Probiotics interact with cells along the entire
intestinal tract but they do not colonize
Probiotics
Immune Function
Immune cells
Epithelial cells
Microflora
Barrier Function
Metabolism
Probiotics interact with all components of the
gut barrier
Modulate neural-muscular system
•
•
Induce the expression of µ-opioid and
cannabinoid receptors
Modulate visceral hypersensitivity
Ohland C L Am J Physiol 2010;298:G807-G819
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
PROBIOTICS ALSO MODULATE
IMMUNE FUNCTION
Probiotic Effects on Immune Cells
Effects of probiotics on immune function

Depending on the strain and host environment,
probiotics can:
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Stimulate immune function
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Have an anti-inflammatory effect
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Increase phagocytosis (Lactobacillus casei, L. acidophilus, B. breve)
Increase sIgA secretion
Reduce secretion of pro-inflammatory cytokines
Increase secretion of anti-inflammatory cytokines
Modulate NF-κ activity
Have no effect at all
PROBIOTICS CAN
ALTER BOTH EXISTING
MICROBE AND HOST
METABOLISM
Probiotics rapidly alter microbial and host
metabolic activity
Gut microbial
activity
Altered Metabolites
Host Metabolism
Systemic Effects
How could probiotics help patients with
kidney disease?
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Altering bacterial composition to reduce production of
metabolites
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Reducing colonic transit time
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Some strains have direct effect on gut motility
Improving gut barrier function
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Probiotics could increase SCFA and decrease colonic pH
Probiotics could repress activity of bacteria that produce toxic
metabolites
Through effects on tight junction proteins and mucous production
Modulating immune function
Are probiotics safe?
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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)
Clinical applications
What is the evidence?
Meta-analysis for pre-pro- and synbiotic therapy on serum indoxyl-sulfate
in patients undergoing haemodialysis for ESKD
Int J Nephrol. 2012; 2012: 673631.
Clinical Trial Results
Type
Open label pilot study
Strain
Patient Type and
Number
Effect
L. acidophilus
Hemodialysis
N=8
Serum dimethylamine
Nitrosodimethylamine
S. thermophilus, L.
acidophilus, B. longum
90 x 109 cfu/d
CKD Stages 3 and 4
N=13
6 months
BUN
Creatinine
Uric acid
S. thermophilus, L.
acidophilus, B. longum
90 x 109 cfu/d
CKD Stages 3 and 4
N=46
6 months
BUN
Uric acid
Improved QOL
L. Casei Shirota
B. Breve Yakult +
galactooligosaccharides
1x 108
Hemodialysis
N=8
4 weeks
Serum p-cresol
Lactobacillus casei shirota
8x109
16x109
CKD Stages 3 and 4
N=30
8 weeks
Simenhoff Miner Electrolyte
Metabol 1996
Prospective DBPRC
crossover
Ranganathan et al. Curr Med
Res Opin 2009
Prospective DBPRC
crossover
Ranganathan Adv Ther 2010
Open label single arm
Nakabayashi Nephrol Dial
Transplant 2011
Randomized control trial
Alatriste Nutr Hosp 2014
Improved stool consistency
blood urea in high dose
group
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
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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
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Limitations due to sample size, varying concentrations and types of proand prebiotics used, dietary confounders
THE END