Transcript The microbiota and solid organ transplantation

Disclosures
• Speakers Fees; Sandoz, Astellas, Chiesi.
• Advisory Board Fees; Astellas, Chiesi,Nordic Pharma
• Grants; Dutch Kidney Foundation, Astellas, Eu FP-7
“There’s an awful lot of
money in shit.”
(Roy, House of God, Chapter3, Page 35)
Feces transplantation in
nephrology
No guts no glory
Frederike Bemelman
Internist-nephrologist, Clinical Immunologist
[email protected]
The gut microbiota: extremely popular and
associated to a wide range of diseases
A role in obesity
Backhed PNAS 2007
Insulin
resistance
ChristophePlosOne 2011
Outline presentation gut and its microbiota
• Terminology and normal function
• Changes in renal failure
• Solid organ transplantation
• Evidence and therapeutic potential
• Conclusions
Terminology (1)
• Microbiota: collective microbial community inhabiting
a special environment
• Microbiome
- Genome of the microbiota
- Synonym of microbiota
• Metagenome: total of DNA extracted from an
environment
• Metagenomics: study of the metagenome
- Targeted: 16S ribosomal RNA en DNA
- Untargeted: shotgun sequencing
- Deep sequencing
Terminology (2)
Probiotics live
micro organisms
Prebiotics non
digestible food ingredients
Taxonomic ranking:
Different techniques yield different resolutions
Kingdom
Phylum
Class
Order
Family
Genus
Species
> 75%
> 80%
> 85%
> 90%
> 95%
> 95%
Tremendous phyla diversity but functional homogeneity
16S rRNA analysis of the
mouth and gut:
phylum level
Shotgun
Metagenomics:
Functional homogeneity
Lozupone, Nature
2012
The gut microbiota
• Remarkable variety within and between individuals
• Intra individual variations might be more important than inter
individual
• Number of unique configurations is large
• No easy classification in a manageable number of distinct
phenotypes
The human gut microbiota a mutually beneficial
co-existence
• Digestion capabilities
• Production of and increasing access to essential nutrients
• Shapes the immune system
The microbiota shapes the immune system of
our gut
Neonatal maturation of Peyers Patches
mesenterial lymphnodes, IgA producing B cells
Differentiation of effector T and regulatory T cells
Enhancement of bactericidal function of
neutrophils
Reduction of threshold for Dendritic Cell
activation
Alegre AJT 2014
> 1012/ml bacteria separated by 10 μm over a
surface area of 200 m2
Components of the functional Barrier;
commensal bacteria have an essential role
• Stratification
- Mucus production by goblet cells
- Anti Microbial Peptides
- IgA molecules formed by plasma cells in
the lamina propria
• Maintenance of tight junctions
• Competition with pathogenic strains
• Suppression of innate responses
Bacterial products can induce regulatory T cells
Outline presentation gut and its microbiota
• Terminology and normal function
• Changes in renal failure
• Solid organ transplantation
• Evidence and therapeutic potential
• Conclusions
Renal failure
• Increased oxalate and uric acid secretion by colonic epithelium
• Increased uremic toxins resulting in dysbiosis
• Increased NH4OH production
• Enhanced proteolytic fermentation
pathway
• Th1 type response by direct
binding of LPS to macrophages
driving a TH1 and a TH17 response
• Decreased barrier function
- Frequent endotoxemia
- Translocation of micro organism
Uremia: intestinal barrier dysfunction
• Frequent endotoxemia in the absence of overt infection
• Detection of bacteria in mesenteric lymph nodes of uremic rats
• Increased intestinal permeability to uremic solutes
Curr Opin Nephrol Hypertens 2012, 21:587–592
Uremic solutes are associated with
• Increased mortality in CKD
• Cardiovascular disease
• Progression of CKD
• Endothelial dysfunction
• Oxidative stress
Microbiota in CKD
Decreased diversity
Associations IgA and IBD
• Coeliakie and dermatitis herpetiformis both associates with
HLA-DQ2 and or DQ8
• Glutenpeptides (gliadine) HLA-DQ2/8 complexes evoke
specific CD4 T cells resulting in inflammation and increased
permeabilitiy for all other antigens
- Tissue transglutaminase 2 beaks giladin down inimmunodominant peptides
• IgAN patients have increased intestinal permeability,
increased IgA reactive with gliadine and other alimentary
antigens (bovine, lactoglobulin) 20-30%
• IGAN in mice can be elicited by ovalbumin, bovine gamma
globulin and horse spleen ferritin
Outline presentation gut and its microbiota
• Terminology and normal function
• Changes in renal failure
• Solid organ transplantation
• Therapeutic potential
• Conclusions
The microbiota and solid organ transplantation:
an unexplored area
90
80
70
60
50
40
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0
2015
2014
2012
2010
Pubme
d Hits
2008
Search for microbiota
Search for organ
transplantation AND microbiota
The microbiota and solid organ transplantation:
only few facts
• Substantial changes prior and 6 months after renal and liver
transplantation but wide inter-individual variation
• Decreased diversity in renal, lung, liver transplantation
• In gut transplantation Firmicutes abundance was correlated to
rejection
Fricke AJT 2013
Borewicz Microbiol Lett 2013
Wu Microb Ecol 2013
Oh AJT 2012
Analysis of the microbiota in renal allograft recipients
Lee et al Transplantation 2014
Less diversity as compared to references
More lactobacillus in rejection
Fewer bacteroidetes in diarrhea
Enterococci in gut and urinary tract
Lee Transplantation 2014
Important fields to explore in nephrology
and solid organ transplantation
• Is there a link between the local gut alloresponse and the
systemic alloresponse
- Do intestinal Tregs recognizing microbial peptides give rise to systemic effects?
- Is there cross reactivity ?
• Ischemia reperfusion damage might be attenuated by short
chain fatty acids Andrade–Oliveira J Am Soc Nephrol 2015
• Microbiota might affect (immunosuppressive)
drug metabolism
Outline presentation gut and its microbiota
• Terminology and normal function
• Changes in renal failure
• Solid organ transplantation
• Therapeutic potential
• Conclusions
Prebiotics
Therapeutic
arsenal
Probiotics
Postbiotics
Fecal Microbiota
Transplantation
Fecal Microbiota Transplantation
• First report by Ge Hong 4th century in Zhou
Hou Bei Ji Fang (Handy medicines in
emergencies)
• Ralph Lewin: “fresh warm
camel feces as Bedouin
remedy against dysentery”
• Eiseman et al 1958: pseudomembranous
colitis
Efficacy > 90 %
Minor side effects
Two renal transplant recipients
Can FMT eradicate the gut of ESBL E.Coli?
• Urinary tract infection the most frequent infection after renal
transplantation
• Associated with loss of transplant function
• The incidence of ESBL E.Coli is rising, resulting in longterm
admission for intravenous administration of antibiotics
• Feasibility Analysis of Nasoduodenal Feces Administration to
eradicate Resistant Enterobacteriaeceae (FANFARE)
• Aim: Eradication of the gut of renal tranplant
recipients from pathogenic E.coli
♀ 59y
1982 postmortal renal transplantation
Recurrent urinary tract infections (≥4x/y)
Despite antibiotic treatment / prophylaxis
Tx
1-1-1985
1-1-1990
1-1-1995
1-1-2000
1-1-2005
1-1-2010
1-1-2015
Urine
Feces
E.coli
K.pneumoniae
E.faecalis
ESBL
Non-ESBL
Negative culture
KEY POINTS
• Renal failure and solid organ transplantation are associated
with profound changes in the gut microbiota
- Decreased diversity
- Enhanced permeability
- Possibly enhanced systemic toxins
• Fecal Microbiota Transplantation
- effective eradication of Clostridium difficile
(and possibly of other pathogenic strains)
- Increases insulin sensitivity
• Microbiota and the alloresponse?
Work in progress
Safety
• Retrospective multicenter study
• 80 subjects
-
HIV/AIDS (3)
IBD (36)
SOT (19)
Oncologic condition (7)
Other (15)
• Efficacy after a single (78%) or double FMT (89%)
Side effects : 1 death after sedation for colonoscopy, one
unrelated
Kelly American Journal of Gastroenterology 2014
SCFA functions
• Improvement of renal function after injury (IR)
• Less systemic inflammation, oxidative stress an apoptosis
• More autophagy
• In vivo:
-
Less HDAC activity
Less maturation of DC
Less CD4 and CD8 cell proliferation
Better mitochondrial biogenesis of kidney epithelium