The mammalian gut microbiota harbors a diverse ecosystem where hundreds of bacterial species interact with each other and their host. Given that bacteria use signals to communicate and regulate group behaviors (quorum sensing), we asked whether such communication between different commensal species can influence the interactions occurring in this environment. We engineered the enteric bacterium, Escherichia coli, to manipulate the levels of the interspecies quorum sensing signal, autoinducer-2 (AI-2), in the mouse intestine and investigated the effect upon antibiotic-induced gut microbiota dysbiosis. E. coli that increased intestinal AI-2 levels altered the composition of the antibiotic-treated gut microbiota, favoring the expansion of the Firmicutes phylum. This significantly increased the Firmicutes/Bacteroidetes ratio, to oppose the strong effect of the antibiotic, which had almost cleared the Firmicutes. This demonstrates that AI-2 levels influence the abundance of the major phyla of the gut microbiota, the balance of which is known to influence human health.

Highlights d Human microbiotas were resilient and recovered rapidly during antibiotic administration d A low-fiber diet aggravated microbiota collapse and delayed recovery from ciprofloxacin d Microbiota reprogramming and transmission conferred resilience to repeated treatment d Single housing disrupted recovery, highlighting roles of reservoirs and sanitation

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19The intestinal microbiota contains beneficial microorganisms that protect against pathogen 20 colonization. Antibiotics can disrupt the microbiota and compromise colonization 21 resistance. Here, we determine how the exchange of microbes between hosts impacts the 22 resilience of the gut microbiota to resist colonization after antibiotic-induced dysbiosis. We 23 assess the functional consequences of dysbiosis using a mouse model of colonization 24 resistance against an invading Escherichia coli. Antibiotics caused the stochastic loss of 25 microbiota members, but the microbiotas of co-housed animals remained more similar to 26 each other than those among singly housed animals. Strikingly, co-housed animals 27 maintained colonization resistance after antibiotics, whereas most singly housed mice 28 were susceptible to invasion by E. coli. The ability to retain or share a particular 29 commensal, Klebsiella michiganensis, a related member of the same family 30 Enterobacteriaceae, was sufficient for colonization resistance after antibiotic-induced 31 dysbiosis. K. michiganensis generally outcompeted E. coli in vitro, but in vivo administration 32 of galactitol to bi-colonized gnotobiotic mice, a nutrient that supports only E. coli growth in 33 vitro, abolished the colonization resistance capacity of K. michiganensis against E. coli, 34 supporting nutrient competition as the primary mechanism for their interaction. K. 35 michiganensis also hampered colonization of the enteric Enterobacteriaceae pathogen 36 Salmonella enterica serovar Typhimurium and prolonged host survival. Our results address 37 the functional consequences of the stochastic effects of antibiotic treatments, whereby 38 microbial transmission through host interactions can facilitate the reacquisition of 39 beneficial commensals and thus minimize the negative impact of antibiotics. 40 57 Proteobacteria (e.g. from the Enterobacteriaceae family Escherichia and Salmonella in 58 particular) and Firmicutes (e.g. Clostridia) 4,19 . These known mechanisms of colonization 59 resistance mainly involve (1) metabolic processes 20 , involving competition for nutritional 60 niches 21-24 ; (2) production of inhibitory or signaling molecules 25-33 ; and (3) contact-61 dependent killing 34,35 . Antibiotics disrupt the microbiota and potentially affect all of these 62 mechanisms, possibly accounting for the breakdown of colonization resistance against 63 4 intestinal pathogens. Identification of environmental factors that minimize loss of 64 protective bacteria upon perturbations can facilitate the development of general strategies 65 to attenuate the negative impact of antibiotics and other drugs. 66 67 In the gut, competition for nutrients is highly shaped by diet and cross-feeding among 68 established species, to optimize the available resources 36,37 . This competition poses a 69 challenge for invading species, since unutilized niches are unlikely to exist. Dietary fiber 70 and mucus polysaccharides are mostly degraded by strict anaerobes, and the release...

The gut microbiota is a complex, densely populated community, home to many different species that collectively provide huge benefits for host health. Disruptions to this community, as can result from recurrent antibiotic exposure, alter the existing network of interactions between bacteria and can render this community susceptible to invading pathogens. Recent findings show that direct antagonistic and metabolic interactions play a critical role in shaping the microbiota. However, the part played by quorum sensing, a means of regulating bacterial behavior through secreted chemical signals, remains largely unknown. We have recently shown that the interspecies signal, autoinducer-2 (AI-2), can modulate the structure of the gut microbiota by using Escherichia coli to manipulate signal levels. Here, we discuss how AI-2 could influence bacterial behaviors to restore the balance between the 2 major bacteria phyla, the Bacteroidetes and Firmicutes, following antibiotic treatment. We explore how this may impact on host physiology, community susceptibility or resistance to pathogens, and the broader potential of AI-2 as a means to redress the imbalances in microbiota composition that feature in many infectious and non-infectious diseases.