Gut Kidney Cross talk

DR ABD ELRAHMAN A MOUKHTAR

PROFFESSOR OF INTERNAL MEDICINE
MANSOURA UNIVERSITY - 2019
‫قال رسول هللا صلى هللا عليه وسلم ‪:‬‬
.The milieu interior between Entrance – Exit gates

GUT
KIDNE
Y
The gut as an entrance gate to the milieu interior .

The gastrointestinal tract (GIT) is, like the skin or the lung, a major interface organ between
the environment and interior milieu.

 It is the site with the highest load of microorganisms (also referred to as “the
microbiota”).
This is especially true in the large intestine due to substantial amounts of undigested
dietary and endogenous (e.g. mucus, enzymes) components amenable to microbial
fermentation.
 Molecular Basis

 Thus gut epithelial cells - enterocytes and colonocytes - are polarized key players
influenced by both the environment (e.g. food, pathogens, toxicants) and body metabolism and functions.
 The gut epithelium has developed over time various mechanisms for sensing not only nutrients but also
microbial structural components (e.g. lipopolysaccharide, LPS; peptidoglycan, flagellin, CpG DNA motifs),
metabolites (e.g. short chain fatty acids, SCFA) or secreted molecules (e.g. toxins, polyphosphate chains,
other compounds still unknown).
 These sensors include for example
Toll-like receptors (TLRs) and receptors to SCFA.
 All these mechanisms make the molecular basis of :
the crosstalk between the host and the gut microbiota at the epithelial level.
iHSP & IAP as an
example at both
the s.I & L.I

iHSPs and IAP display potent anti-oxidant and anti-inflammatory

properties that dynamically stimulate gut epithelial resistance to oxidative stress
and inflammation. IAP is also anti-inflammatory systemically
 Bidirectional Nature

 Despite the fact that the intestinal barrier is composed of a multilayered structure, thus
shielding the human internal environment from the colonic microbial content, there is
intense cross-talk between both compartments.

 Broadly speaking, this bidirectional communication consists of both metabolic as well as

immunological signals, aiming to maximize the win-win between commensal microbiome
and the host.
 Maintaining the symbiotic equilibrium between gut microbiome and host in different
pathological conditions remains a challenge for the physicians.
Gut barrier function
and microbiota
:The intestinal barrier is a three dimensional gate

The intestinal epithelial barrier can be divided into three components:

.Biologic barrier

.Physical barrier

.Immune barrier

Each of which can become dysfunctional and can be a potential therapeutic target.
 The intestinal barrier as a three dimensional seal.

The commensal microflora in a healthy

gut constitute approximately 103–104
different bacterial species, mostly of the
Firmicutes and Bacteroidetes phyla.
Microbial species over the length of the GI track
 The Most relevant roles of commensal bacteria includes :

1. Maintaining an intestinal epithelial barrier by various mechanisms, including:

 Pro-proliferative effects on IECs (promote enterocyte differentiation ).
 Restoration of protein tight junction structure.
 Up regulation of mucin genes driving the steady
state expression of mucus and antimicrobial factors.
 Competition with pathogenic bacteria to bind epithelial cells.
2. Maintaining the intestinal immune barrier :
 Educate the mucosal and systemic immune system
 Maintaining proper T cell functions by molecular signaling.
( Certain bacteria produce molecules that serve to direct proper T cell population balance).
 Suppressing intestinal inflammation that involves
toll‐like receptor (TLR) signaling, IAP, iHSP.
3. Vitally significant Metabolic end products :

 Involved in the generation of secondary bile acids, which promote the uptake of dietary lipids
and fat-soluble vitamins .

 The fermentation of complex carbohydrates yields short-chain fatty acids (SCFAs; e.g., butyrate) that serve as an
energy source for the host and display beneficial effects on immune cells .

 Importantly, SCFAs also mediate anti-inflammatory effects on immune cells, which involves
signaling via G-protein-coupled receptor 41 (GPR41) and GPR43.
(GPR43 signaling is anti-inflammatory in the gut).

Thus, the intestinal microbiota and its metabolic products are vital for gut homeostasis.
A fine balance of gut microbes
 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
Renal failure
&
microbiota
bidirectional
relation ?
 Unbalanced microbiota in CKD patients has higher number
of pathogens

CKD Patients
• Increased
• Actinobacteria
• Clostridia
• Proteobacteria

Kibow Biotech, Inc. Nosratola D Vaziri et al. Kidney International 19 th Sept 2012,
Kibow Biotech, Inc.
Hemodialysis Urea Accumulation Fluid retention

Urea influx into gut

Dialysis-
induced
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

 The gut‐kidney axis in chronic renal failure: A new potential target for therapy

Hemodialysis International, Volume: 21, Issue: 3, Pages: 323-334, First published: 16 September 2016, DOI: (10.1111/hdi.12486)
 ?How does a gut dysbiosis alter metabolism in the colon

Secondly small intestinal

assimilation(digestion and/or
absorption) of proteins is impaired
Chronic renal failure is
in the case of renal failure, resulting
characterized by a in an increased availability of
progressive retention of a
number of microbial
proteins for fermentation in the
metabolic end colon.
products(urea, uric acid,
creatinine,phenols, indoles
and polyamines). Fermentation of these proteins in
Short Chain Fatty Acids Tyrosine Typtophan the distal region of the colon leads
Butyrate to production of toxic metabolites
Acetate
(Phenols, thiols, indoles, amines
Propionate p-cresol indole
and ammonia)
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.

Normal Control (n=7

Dialysis Colectomy Dialysis Intact colon
Metabolite to 10)
(n=6) (n=9)

Plasma p-cresyl 0.19+0.13 0.06+0.09 4.1+1.6

sulphate (mg/dL)

Plasma indoxyl 0.06+0.02 0.08+0.06 2.8+1.3

sulphate (mg/dL)

T W Meyer et al. JASN 2011; 22:1769-1776

Kibow Biotech, Inc. Page | 25
Can therapies aimed at modulation of
gut microbiota help patients with
kidney disease?
 ?How can you change your microbiota

Antibiotics

Kill
 both good and bad bacteria
Original microbiota usually return once drugs are removed

Can allow for the growth of pathogens


Probiotics

Ingested microorganism(s) associated with beneficial effects to humans and animals
– Lacctobacillus (50 species), Bifidobacteria (30 species), Sacchoaroyces

boulardii, Streptococcus thermophilus, Enterococcus faecium,

Leuconostoc

Giving back live beneficial microorganisms

Do not colonize

?How can you change your microbiota

Prebiotics
Non-digestible food substances that provide substrate for existing beneficial
microbes already present in the gut
Increase number or activity of bifidobacteria and lactic acid bacteria(commonly
assumed)
– Bran sources
– Raw foods: chicory root, dandelion greens, raw garlic, leek, onion, asparagus
banana
?How can you change your microbiota

 Diet

Changes activity of existing microbes.

 Fecal transplants
Changing complete gut ecosystem.
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
 Clinical Trial Results
Type Strain Patient Type and Effect
Number
Open label pilot study L. acidophilus Hemodialysis Serum dimethylamine
N=8 Nitrosodimethylamine
Simenhoff Miner Electrolyte Metabol
1996

Prospective DBPRC crossover S. thermophilus, L. acidophilus, B. CKD Stages 3 and 4 BUN

longum N=13 Creatinine
Ranganathan et al. Curr Med Res Opin 90 x 109 cfu/d 6 months Uric acid
2009

Prospective DBPRC crossover S. thermophilus, L. acidophilus, B. CKD Stages 3 and 4 BUN

longum N=46 Uric acid
Ranganathan Adv Ther 2010 90 x 109 cfu/d 6 months Improved QOL

Open label single arm L. Casei Shirota Hemodialysis

B. Breve Yakult + N=8 Serum p-cresol
Nakabayashi Nephrol Dial Transplant galactooligosaccharides 4 weeks
2011 1x 108 Improved stool consistency

Randomized control trial Lactobacillus casei shirota CKD Stages 3 and 4 blood urea in high dose
8x109 N=30 group
 Gut microbiota plays a direct protective role as a biological barrier. They are closely attached to the surface of
the intestinal mucosa and compete with pathogenic bacteria and thus can inhibit the colonization and excessive
growth of pathogens.

 The intestinal epithelial layer acts as a physical barrier. TJ proteins play an important role in the establishment
and maintenance of cell polarity within tissues.

 Microbiota and epithelial cells interact with each other and regulate subsequent immune response.

 Disturbed microbiota and\ or intestinal barrier seems to be one of the great players in chronic diseases including
chronic renal failure.

 The relation between the microbiota and the internal milieu looks bidirectional .

 The understanding of their interaction, manipulation of the structure and functions of human microbiota may
allow effective prevention and treatment of many diseases including Renal disorders.
Thank
You