Probiotics impact the antibiotic resistance gene reservoir along the human GI tract in a person-specific and antibiotic-dependent manner

Abstract

Antimicrobial resistance poses a substantial threat to human health. The gut microbiome is considered a reservoir for potential spread of resistance genes from commensals to pathogens, termed the gut resistome. The impact of probiotics, commonly consumed by many in health or in conjunction with the administration of antibiotics, on the gut resistome is elusive. Reanalysis of gut metagenomes from healthy antibiotics-naïve humans supplemented with an 11-probiotic-strain preparation, allowing direct assessment of the gut resistome in situ along the gastrointestinal (GI) tract, demonstrated that probiotics reduce the number of antibiotic resistance genes exclusively in the gut of colonization-permissive individuals. In mice and in a separate cohort of humans, a course of antibiotics resulted in expansion of the lower GI tract resistome, which was mitigated by autologous faecal microbiome transplantation or during spontaneous recovery. In contrast, probiotics further exacerbated resistome expansion in the GI mucosa by supporting the bloom of strains carrying vancomycin resistance genes but not resistance genes encoded by the probiotic strains. Importantly, the aforementioned effects were not reflected in stool samples, highlighting the importance of direct sampling to analyse the effect of probiotics and antibiotics on the gut resistome. Analysing antibiotic resistance gene content in additional published clinical trials with probiotics further highlighted the importance of person-specific metagenomics-based profiling of the gut resistome using direct sampling. Collectively, these findings suggest opposing person-specific and antibiotic-dependent effects of probiotics on the resistome, whose contribution to the spread of antimicrobial resistance genes along the human GI tract merit further studies.

Functional insights on probiotics activity in the gut from metagenomic data

“…The interesting metagenomic work by Montassier and colleagues thus provides elegant evidence for the mechanism by which probiotic bacteria may exert their effect: they modify the gut microbiome in such a manner that allows for the proliferation of commensal bacteria that are beneficial to the host's health. This contrasts with the conclusions drawn by the authors who point out 'opposing person-specific and antibiotic-dependent effects of probiotics on the resistome' (Montassier et al, 2021). That the observations were limited to 'permissive' individuals strongly point towards a contribution by the probiotic bacteria, who mostly reside in the lumen and do not typically adhere to the mucosa.…”

“…The description of the enrichment of these commensal bacteria by Montassier and colleagues was focussed on the antibiotic resistance genes present in these organisms; their proliferation resulted in a detected expansion of the intestinal 'resistome' (Montassier et al, 2021). However, the clinical relevance of this reported expansion would most likely be limited.…”

“…The effect was not observed in individuals who the authors described as 'resistant' , meaning the probiotic bacteria didn't multiply in their gut. Following the treatment, the 'permissive' individuals had larger numbers of AGR-carrying Blautia species and Clostridium species (Clostridium citroniae, Clostridium leptum) in their gut, and by the use of mouse experiments it was confirmed that Blautia coccoides, Blautia hominis and Blautia producta had all increased as a result of the sequential antibiotic and probiotic treatment (Montassier et al, 2021).The beneficial effects of these species, and conversely, correlations between their absence or lower abundance and diseased states, have been known for some time. Decreased levels of Blautia species have been associated with liver diseases (…”

“…To these three selection mechanisms that result in antimicrobial resistance, we can now add a fourth mechanism. It was shown that propagation of bacteria that carried ARGs had occurred in volunteers who had first been treated with a combination of antibiotics (ciprofloxacin and metronidazole) and then took a cocktail of probiotic bacteria (Bio-25, Ambrosia SupHerb Ltd., Netanya, Israël -containing 11 different species) (Montassier et al, 2021). In a small number of individuals, this resulted in proliferation of certain bacterial species in their gut that carried vancomycin resistance genes.…”

“…Importantly, and a bit worrisome, the selected ARGs were not active against the applied antibiotics. The authors warn for this unwanted effect of probiotics (Montassier et al, 2021). Do these observations actually pose a reason for concern?…”