hiv dysbiosis engraftment - virology...
TRANSCRIPT
Outline
• Clinical impact gut microbes
• HIV dysbiosis
• Engraftment
Microbiome as space occupying communityC. difficile infection (CDI)
• Disease associated with exposure to antibiotics– Antibiotic is first-line tx
• Recurrence rate of 30% after first episode – 50% after 2nd episode
• Fecal transplant (FMT) is curative in 90+%
Van Nood et al., NEJM 2013; Seekatz AM Mbio, 2014
Microbes process diet to produce metabolites that affect CV disease
Koeth et al., Nat Med 2013; Tang et al., NEJM 2013
Inhibiting microbial TMA lyase to treat atherosclerosis
Wang Z et al. Cell, 2015
Foamy macrophage
Atherosclerotic lesions
Microbiome and nutrition/metabolism
Ridaura et al. Science, 2013
OFID, 2015
Microbiome as a pharmacoactive agent
• Digoxin (unsaturated lactone) levels vary by patients
– 20% of patients have excess dihydrolactone
– Antibiotics increase serum levels of active agent
• Eggerthella lenta + cardiac glycoside reductase (cgr) alters digoxin levels
» Haiser & Turnbaugh et al. Science 2013
Brief Summary
• Microbiota – as a community e.g., C diff.
– as a metabolic agent e.g., TMAO, insulin resistance
– as a pharmacoactive agent e.g., digoxin, lovastatin
– as an immunomodulatory e.g., CTLA4, PD-1
• Consider the microbiota in clinical conditions that vary by: – Antibiotics / diet
– Intravenous vs. oral formulation
– Altered pharmacokinetics
Microbiome
• Clinical impact
• HIV dysbiosis
• Engraftment
Morbidity
MortalityHIV Inflammation
Immune activation
(IL-6, sCD14, K/T, D-
dimer, CD38+ etc.)
Microbiome as a potential source of persistent immune activation
Gut CD4 cells are eliminated during HIV infection
Sanos Immunology, 2011
Sato et al. Nature, 2011
• CD4 (Th17/22) subsets preferentially eliminated
• CD4 provides immunity to bacteria & maintain the epithelial barrier– Stimulates epithelial cells to make
mucins & antimicrobial peptides
– Absence leads to mucocutaneouscandidiasis and S. aureus infection
Microbiota profile linked to HIV infection
Vujkovic & Somsouk. Current HIV AIDS Rpts, 2019
Dysbiosis during treated HIV associate with markers of inflammation
Vujkovic-Cvijin I, Dunham RM, Iwai S, Maher MC, Albright RG,
Broadhurst MJ, Hernandez RD, Lederman MM, Huang Y, Somsouk M,
Deeks SG, Hunt PW, Lynch SV, McCune JM. Sci Trans Med, 2013
Enzymatic pathways for tryptophan catabolism (IDO) overrepresented in HIV microbiota
Vujkovic-Cvijin I, Dunham RM, Iwai S, Maher MC, Albright RG,
Broadhurst MJ, Hernandez RD, Lederman MM, Huang Y, Somsouk M,
Deeks SG, Hunt PW, Lynch SV, McCune JM. Sci Trans Med, 2013
Microbes or their metabolites may affect host immune function
• Can a ‘healthy’ microbiome reduce systemic inflammation?
• How can a microbiome be altered and stably reconstituted?
– Rifaxamin had no significant effect on T cell activation / microbial translocation
» Tenorio et al. J Infect Disease, 2015
– Abtx + FMT in SIV macaques reduced immune activation» Hensley McBain et al. J Virol, 2016
– Vancomycin induced dysbiosis did not accelerate untreated SIV disease progression
» Ortiz AM et al. Nat Med, 2018
– Cotrimoxazole reduced systemic (CRP) and intestinal inflammation (myeloperoxidase)
» Bourke et al. Sci Trans Med, 2019
Questions
Fecal transplant study in patients with HIV
Inclusion criteria HIV-infected, ART for >= 1 year Favored CD4 T cell < 500 cells/mL, CD4:CD8 ratio < 1.0
Donors Selected for low Proteobacteria and low Prevotella abundance
ClinicalTrials.gov Identifier: NCT02256592
Vujkovic-Cvijin & Somsouk et al. Gut Microbes, 2017
Shift in microbiome towards donor communityoccurs post-FMT
-0.2
-0.1
0.0
0.1
0.2
0.3
-0.2 -0.1 0.0 0.1 0.2
PC1 (21.76%)
PC
2 (
19
.89
%)
Recipients
P1713 (donor: D01)
P2112 (donor: D37)
P2150 (donor: D01)
P2294 (donor: D01)
P2356 (donor: D37)
P3164 (donor: D37)
Donors
D01
D37
DONOR
RECIPIENTS
After FMT, recipient microbiome profiles remained distinctly separated from the donors
FMT for C. difficile infection results in large microbial shifts
Vujkovic-Cvijin & Somsouk et al. Gut Microbes, 2017
Why is engraftment limited?
C. difficile infection with drastically reduced alpha diversity
Infection /
Antibiotics?
Antibiotic conditioning pre-FMT
Cipro/Flagyl x 5d
-7
Pre-antibiotic treatment
After antibiotic treatment
22
After FMT
23
Engraftment remained variable & modest
Very low alpha diversity associated with greater degree of engraftment (n=1)
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30
40
50
Faith's
Phylo
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ivers
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Microbiome
• Clinical impact
• HIV dysbiosis
• Engraftment (learn from other studies)
Lessons from other interventions
• Mucosal vs. stool microbes
• Anaerobic processing
• Pooled donors
• Antibiotic pre-tx
• Prebiotics, probiotics, and synbiotics
Stool
Mucus
Colon
Clostridia
Bacteroidiaα-proteobacteria
β-proteobacteria
γ-proteobacteria
δ-proteobacteria
Bacterial Taxonomic Class
Actinobacteria
Bacilli
Sphingobacteriia ErysipelotrichiaCoriobacteriia
Microbial profile varies across stool, mucus, and colonic lining
Keir & Somsouk, Courtesy of GenentechWilliams BB et al. Path & Immunity, 2019.
Abundance of live species altered during aerobic processing
Bacteroidaceae
O2 tolerant orgs enriched O2 sensitive orgs depleted
Veillonellaceae
Courtesy of OpenBiome
Anaerobically processed FMT for ulcerative colitis
• Early trials using FMT for UC– Generally negative but promising
– No antibiotics
– Superdonor with f. Lachnospiraceaeand g. Ruminococcus
Costello SP JAMA, 2019; Moayyedi Gastro, 2015; Rossen Gastro, 2015; Lloyd-Price Nature, 2019
• 2019, anaerobic processing from pooled donor vs. autologous FMT– 32% vs. 9% response, P=0.03
– Fecalibacterium prausnitzii and other obligate anaerobes preserved
Probiotics
• Intact microbial community resists probiotic colonization» Zmora N et al. Cell, 2018
» Kristensen NB et al. Genome Medicine, 2016
• May be effective in prevention of infant sepsis– L. plantarum + fructooligosaccharide effective
» Panigrahi P et al. Nature, 2017
– Strep thermophlus, B. infantis, B. lactis» Jacobs SE et al. Pediatrics 2013
– B. breve BBG001» Costeloe K et al. Lancet, 2016
– VSL#3» Sinha A et al. BMJ Open, 2015
What is the natural history of the microbiome after abtx?
• Microbiome spontaneously reconstitutes over time
• FMT accelerates microbial reconstitution
• Probiotics delay reconstitution
Suez J et al. Cell, 2018
Human
Summary
• Microbiome well described in specific health conditions
– Microbial community naturally resists infection and probiotic supplements
– Enzymatic pathways a target for drug development
– Metabolic and immune pathways continue to be advanced
• Fecal transplantation is an evidence based intervention (but inconsistent) for engraftment
– Lack of microbial diversity may predict engraftment
– Super donor, anaerobic preparation, repeat dosing can enhance engraftment