max 350 w) 31Background: Understanding and controlling the spread of antimicrobial resistance is 32 one of the greatest challenges of modern medicine. To this end many efforts focus on 33 characterising the human resistome or the set of antibiotic resistance determinants 34 within the microbiome of an individual. Aside from antibiotic use, other host 35 environmental and genetic factors that may shape the resistome remain relatively 36 underexplored. 37Methods: Using gut metagenome data from 250 TwinsUK female twins, we quantified 38 known antibiotic resistance genes to estimate gut microbiome antibiotic resistance 39 potential for 41 types of antibiotics and resistance mechanisms. Using heritability 40 modelling, we assessed the influence of host genetic and environmental factors on the 41 gut resistome. We then explored links between gut resistome, host health and specific 42 environmental exposures using linear mixed effect models adjusted for age, BMI, 43 alpha diversity and family structure. 44
Results:We considered gut microbiome antibiotic resistance to 21 classes of 45 antibiotics, for which resistance genes were detected in over 90% of our population 46 sample. Using twin modelling, we estimated that on average about 25% of resistome 47 variability could be attributed to host genetic influences. Greatest heritability estimates 48 were observed for resistance potential to acriflavine (70%), dalfopristin (51%), 49 clindamycin (48%), aminocoumarin (48%) and the total score summing across all 50 antibiotic resistance genes (38%). As expected, the majority of resistome variability 51 was attributed to host environmental factors specific to an individual. We compared 52 antibiotic resistance profiles to multiple environmental exposures, lifestyle and health 53 factors. The strongest associations were observed with alcohol and vegetable 54 consumption, followed by high cholesterol medication and antibiotic usage. Overall, 55inter-individual variation in host environment showed modest associations with 56 antibiotic resistance profiles, and host health status had relatively minor signals. 57
Conclusion:Our results identify host genetic and environmental influences on the 58 human gut resistome. The findings improve our knowledge of human factors that 59 influence the spread of antibiotic resistance genes and may contribute towards helping 60 to attenuate it. 61 62