Prediction of the intestinal resistome by a three-dimensional structure-based method
Etienne Ruppé
(1, 2)
,
Amine Ghozlane
(1, 3, 4)
,
Julien Tap
(1)
,
Nicolas Pons
(1)
,
Anne-Sophie Alvarez
(1)
,
Nicolas Maziers
(1)
,
Trinidad Cuesta
(5)
,
Sara Hernando-Amado
(5)
,
Irene Clares
(5)
,
Jose Luís Martínez
(5)
,
Teresa Coque
(6, 7)
,
Fernando Baquero
(6, 7)
,
Val Lanza
(6, 7)
,
Luis Máiz
(8)
,
Tiphaine Goulenok
(9)
,
Victoire de Lastours
(2, 9)
,
Nawal Amor
(9)
,
Bruno Fantin
(2, 9)
,
Ingrid Wieder
(10)
,
Antoine Andremont
(2, 10)
,
Willem van Schaik
(11, 12)
,
Malbert Rogers
(11)
,
Xinglin Zhang
(11)
,
Rob Willems
(11)
,
Alexandre de Brevern
(13)
,
Jean-Michel Batto
(1)
,
Herve H. Blottiere
(1)
,
Pierre Léonard
(1)
,
Véronique Léjard
(1)
,
Aline Letur
(1)
,
Florence Levenez
(1)
,
Kevin Weiszer
(1)
,
Florence Haimet
(1)
,
Joel Dore
(1)
,
Sean Kennedy
(1, 4)
,
S. Dusko Ehrlich
(1, 14)
1
MetaGenoPolis
2 IAME (UMR_S_1137 / U1137) - Infection, Anti-microbiens, Modélisation, Evolution
3 Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB
4 Biomics
5 CNB-CSIC - Centro Nacional de Biotecnología [Madrid]
6 IRYCIS - Instituto Ramon y Cajal de Investigacion Sanitaria [Madrid, Spain]
7 CIBERESP - Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública = Consortium for Biomedical Research of Epidemiology and Public Health
8 Hospital Universitario Ramón y Cajal [Madrid]
9 Service de Médecine Interne [AP-HP, CHU Beaujon]
10 Laboratoire de Bactériologie [AP-HP Hôpital Bichat-Claude Bernard]
11 UMCU - University Medical Center [Utrecht]
12 University of Birmingham [Birmingham]
13 BIGR (UMR_S_1134 / U1134) - Biologie Intégrée du Globule Rouge
14 King‘s College London
2 IAME (UMR_S_1137 / U1137) - Infection, Anti-microbiens, Modélisation, Evolution
3 Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB
4 Biomics
5 CNB-CSIC - Centro Nacional de Biotecnología [Madrid]
6 IRYCIS - Instituto Ramon y Cajal de Investigacion Sanitaria [Madrid, Spain]
7 CIBERESP - Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública = Consortium for Biomedical Research of Epidemiology and Public Health
8 Hospital Universitario Ramón y Cajal [Madrid]
9 Service de Médecine Interne [AP-HP, CHU Beaujon]
10 Laboratoire de Bactériologie [AP-HP Hôpital Bichat-Claude Bernard]
11 UMCU - University Medical Center [Utrecht]
12 University of Birmingham [Birmingham]
13 BIGR (UMR_S_1134 / U1134) - Biologie Intégrée du Globule Rouge
14 King‘s College London
Etienne Ruppé
- Function : relator_co_first_author
- PersonId : 1068520
Amine Ghozlane
- Function : relator_co_first_author
- PersonId : 746839
- IdHAL : amine-ghozlane
- ORCID : 0000-0001-7670-6235
- IdRef : 166416460
Julien Tap
- Function : relator_co_first_author
- PersonId : 1172956
- IdHAL : julien-tap
- ORCID : 0000-0001-8998-5413
Antoine Andremont
- Function : Author
- PersonId : 948288
Alexandre de Brevern
- Function : Author
- PersonId : 9903
- IdHAL : alexandre-de-brevern
- ORCID : 0000-0001-7112-5626
- IdRef : 135431697
Herve H. Blottiere
- Function : Author
- PersonId : 747227
- IdHAL : herve-blottiere
- ORCID : 0000-0002-8390-0607
- IdRef : 076955648
Joel Dore
- Function : Author
- PersonId : 1206301
- IdHAL : joel-dore
- ORCID : 0000-0002-8756-0718
- IdRef : 069752249
S. Dusko Ehrlich
- Function : Author
- PersonId : 1068832
- ORCID : 0000-0002-7563-4046
Abstract
The intestinal microbiota is considered to be a major reservoir of antibiotic resistance determinants (ARDs) that could potentially be transferred to bacterial pathogens via mobile genetic elements. Yet, this assumption is poorly supported by empirical evidence due to the distant homologies between known ARDs (mostly from culturable bacteria) and ARDs from the intestinal microbiota. Consequently, an accurate census of intestinal ARDs (that is, the intestinal resistome) has not yet been fully determined. For this purpose, we developed and validated an annotation method (called pairwise comparative modelling) on the basis of a three-dimensional structure (homology comparative modelling), leading to the prediction of 6,095 ARDs in a catalogue of 3.9 million proteins from the human intestinal microbiota. We found that the majority of predicted ARDs (pdARDs) were distantly related to known ARDs (mean amino acid identity 29.8%) and found little evidence supporting their transfer between species. According to the composition of their resistome, we were able to cluster subjects from the MetaHIT cohort (n = 663) into six resistotypes that were connected to the previously described enterotypes. Finally, we found that the relative abundance of pdARDs was positively associated with gene richness, but not when subjects were exposed to antibiotics. Altogether, our results indicate that the majority of intestinal microbiota ARDs can be considered intrinsic to the dominant commensal microbiota and that these genes are rarely shared with bacterial pathogens.