Etienne Ruppé AP HP, Hôpital Bichat Claude Bernard UMR 1137 IAME

Transcription

1 Etienne Ruppé AP HP, Hôpital Bichat Claude Bernard UMR 1137 IAME

2 Disclosures Consultant for DaVolterra and MaaT Pharma Received funds by biomérieux 2

3 1. The intestinal microbiota 3

4 16S profiling 16S and profiling metagenomics and metagenomics allowed a more allowed in depth a more vision of our in depth microbiota vision of our microbiota 1. Huge number of bacterial cells (3.8x10 13 ) 1, pathogens are subdominant 2. Great diversity (estimated hundreds of species) 3. Mostly un(hardly)culturable bacteria A 10M genes catalogue! 2 1 Sender, R. PLoS Biol. 14, e (2016); 2 Li, J. Nat. Biotechnol. 32, (2014). 4 4

5 Is there any left condition unliked to the intestinal microbiota? Allergy Alzheimer Atherosclerosis Autism Breast cancer Celiac disease Cirrhosis Colorectal cancer Crohn sdisease Encephalopathy Frailty in seniors HIV Obesity Parkinson Rheumatoid arthritis Type 1 diabetes Type 2 diabetes Ulcerative colitis You name it! Adapted from Sommer, F. & Bäckhed, F. Nat Rev Microbiol 11, (2013) 55

6 The intestinal microbiota is the «epicentre of antibiotic resistance» Antibiotics: barrier effect concentrations of resistant bacteria Carriage of resistant bacteria Source of infection Gene transfer Excretion of resistant bacteria Cross-transmission Spread in environment Allergy Alzheimer Atherosclerosis Autism Breast cancer Celiac disease Cirrhosis Colorectal cancer Crohn sdisease Encephalopathy Frailty in seniors HIV Obesity Parkinson Rheumatoid arthritis Type 1 diabetes Type 2 diabetes Ulcerative colitis Resistance to antibiotics! Adapted from Sommer, F. & Bäckhed, F. Nat Rev Microbiol 11, (2013); Carlet, J. Antimicrob Resist Infect Control 1, 39 (2012). 6

7 2. The barrier effect 7

8 The intestinal microbiota opposes to the settlement and overgrowth of exgenous bacteria: introduction to the barrier effect or colonization resistance Pamer, E. G. Science 352, (2016). 8

9 A consortium of 4 anaerobic bacteria collaborate to eradicate VRE from the gut in mice CBBP: C. bolteae, B. producta, B. sartorii and P. distasonis Caballero, S. Cell Host & Microbe 21, e4 (2017). 1. 9

10 Some bacteria could be associated with a faster intestinal clearance of ESBL E. coli (but not with the acquisition)? RNA extracted from feces cdna synthesis and sequencing (Illumina) 16S and 23S analysis, multiple statistical analyses Leo, S. et al. In preparation. 10

11 Some bacteria could be associated with a faster intestinal clearance of ESBL E. coli (but not with the acquisition)? Leo, S. et al. In preparation. 11

12 3. Quantification of multidrug-resistant bacteria in the intestinal microbiota 12

13 Have concentrations of resistant bacteria clinical consequences? Bacterial translocation 1 Urinary-tract infection 2 Cross-transmission 3 Long-term carriage 4 Very low risk High risk 1 Berg, R.D. et al. Infect Immun 33, (1981); 2 Ruppé, E. et al. Antimicrob. Agents Chemother. 2013, 57(9):4512; 3 Donskey, C.J., et al. N Engl J Med 343, (2000); 4 Ruppé, E. et al. Clin Infect Dis. 61, (2015). 13

14 4. Actions! 14

15 be creative! 15

16 BROWN! 16

17 Inactivation of the antibiotic in the colon using engineered beta lactamases P1A beta lactamase from Bacillus subtilis and its derivative P3A manufactured in E. coli (Asp276Asn): Ribaxamase Pre-treatment (D-4) CRO+Ribaxamase (D4) CRO (D4) Connelly S. J Appl Microbiol Feb 28; 17

18 Inactivation of the antibiotic in the colon using engineered active charcoal de Gunzburg, J. et al. biorxiv (2017). 18

19 Inactivation of the antibiotic in the colon using engineered active charcoal de Gunzburg, J. et al. biorxiv (2017). 19

20 Fecal material transplantation restores the barrier effect Mice 1 Human 2 Number of antibiotic resistance genes per individual 1 Ubeda, C. et al. Infect. Immun. 81, (2013); 2 Millan, B. et al. Clin. Infect. Dis. (2016). doi: /cid/ciw185 20

21 Moving towards specific bacterial consortia 7 health donors Treatment (EtOH induced sporulation) Encapsulation and storage at 80 C SER 109 Khanna, S. et al. J Infect Dis. 214, (2016). 21

22 Already in motion (almost) The diversity of Enterobacteriaceae decreases (C), and Escherichia coli is restored as the prominent Enterobacteriaceae member. Khanna, S. et al. J Infect Dis. 214, (2016). 22

23 Interplay between pathogens, ATB, resistance and commensals is far from being understood Wrap up Indeed, lowering the concentrations of resistant bacteria could have various benefits Yet new ideas to combat multidrugresistance emerge from a better understanding of this interplay Especially, preserving/restoring the barrier effect in order to prevent the overgrowth of resistant bacteria Several, complementary methods are being developed: phages, colonic inactivation, FMT Let s not forget to be cautious with the findings of metagenomic studies! 23

24 See you in Geneva for more metagenomics! October