Bifidobacteria metabolize lactulose to optimize gut metabolites and prevent systemic infection in patients with liver disease.

Progression of chronic liver disease is precipitated by hepatocyte loss, inflammation and fibrosis. This process results in the loss of critical hepatic functions, increasing morbidity and the risk of infection. Medical interventions that treat complications of hepatic failure, including antibiotic administration for systemic infections and lactulose treatment for hepatic encephalopathy, can impact gut microbiome composition and metabolite production. Here, using shotgun metagenomic sequencing and targeted metabolomic analyses on 847 faecal samples from 262 patients with acute or chronic liver disease, we demonstrate that patients hospitalized for liver disease have reduced microbiome diversity and a paucity of bioactive metabolites, including short-chain fatty acids and bile acid derivatives, that impact immune defences and epithelial barrier integrity. We find that patients treated with the orally administered but non-absorbable disaccharide lactulose have increased densities of intestinal bifidobacteria and reduced incidence of systemic infections and mortality. Bifidobacteria metabolize lactulose, produce high concentrations of acetate and acidify the gut lumen in humans and mice, which, in combination, can reduce the growth of antibiotic-resistant bacteria such as vancomycin-resistant Enterococcus faecium in vitro. Our studies suggest that lactulose and bifidobacteria serve as a synbiotic to reduce rates of infection in patients with severe liver disease.

Assembling symbiotic bacterial species into live therapeutic consortia that reconstitute microbiome functions.

Increasing experimental evidence suggests that administering live commensal bacterial species can optimize microbiome composition and lead to reduced disease severity and enhanced health. Our understanding of the intestinal microbiome and its functions has increased over the past two decades largely due to deep sequence analyses of fecal nucleic acids, metabolomic and proteomic assays to measure nutrient use and metabolite production, and extensive studies on the metabolism and ecological interactions of a wide range of commensal bacterial species inhabiting the intestine. Herein, we review new and important findings that have emerged from this work and provide thoughts and considerations on approaches to re-establish and optimize microbiome functions by assembling and administering commensal bacterial consortia.

Deciphering the quorum-sensing lexicon of the gut microbiota.

The enduring coexistence between the gut microbiota and the host has led to a symbiotic relationship that benefits both parties. In this complex, multispecies environment, bacteria can communicate through chemical molecules to sense and respond to the chemical, physical, and ecological properties of the surrounding environment. One of the best-studied cell-to-cell communication mechanisms is quorum sensing. Chemical signaling through quorum sensing is involved in regulating the bacterial group behaviors, often required for host colonization. However, most microbial-host interactions regulated by quorum sensing are studied in pathogens. Here, we will focus on the latest reports on the emerging studies of quorum sensing in the gut microbiota symbionts and on group behaviors adopted by these bacteria to colonize the mammalian gut. Moreover, we address the challenges and approaches to uncover molecule-mediated communication mechanisms, which will allow us to unravel the processes that drive the establishment of gut microbiota.

Klebsiella michiganensis transmission enhances resistance to Enterobacteriaceae gut invasion by nutrition competition.

Intestinal microbiotas contain beneficial microorganisms that protect against pathogen colonization; treatment with antibiotics disrupts the microbiota and compromises colonization resistance. Here, we determine the impact of exchanging microorganisms between hosts on resilience to the colonization of invaders after antibiotic-induced dysbiosis. We assess the functional consequences of dysbiosis using a mouse model of colonization resistance against Escherichia coli. Antibiotics caused stochastic loss of members of the microbiota, but the microbiotas of co-housed mice remained more similar to each other compared with the microbiotas among singly housed animals. Strikingly, co-housed mice maintained colonization resistance after treatment with antibiotics, whereas most singly housed mice were susceptible to E. coli. The ability to retain or share the commensal Klebsiella michiganensis, a member of the Enterobacteriaceae family, was sufficient for colonization resistance after treatment with antibiotics. K. michiganensis generally outcompeted E. coli in vitro, but in vivo administration of galactitol-a nutrient that supports the growth of only E. coli-to bi-colonized gnotobiotic mice abolished the colonization-resistance capacity of K. michiganensis against E. coli, supporting the idea that nutrient competition is the primary interaction mechanism. K. michiganensis also hampered colonization of the pathogen Salmonella, prolonging host survival. Our results address functional consequences of the stochastic effects of microbiota perturbations, whereby microbial transmission through host interactions can facilitate reacquisition of beneficial commensals, minimizing the negative impact of antibiotics.

Chemical conversations in the gut microbiota.

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.