The composition of the gut microbiota following early-life antibiotic exposure affects host health and longevity in later life.

Studies investigating whether there is a causative link between the gut microbiota and lifespan have largely been restricted to invertebrates or to mice with a reduced lifespan because of a genetic deficiency. We investigate the effect of early-life antibiotic exposure on otherwise healthy, normal chow-fed, wild-type mice, monitoring these mice for more than 700 days in comparison with untreated control mice. We demonstrate the emergence of two different low-diversity community types, post-antibiotic microbiota (PAM) I and PAM II, following antibiotic exposure. PAM II but not PAM I mice have impaired immunity, increased insulin resistance, and evidence of increased inflammaging in later life as well as a reduced lifespan. Our data suggest that differences in the composition of the gut microbiota following antibiotic exposure differentially affect host health and longevity in later life.

The immunotoxicity, but not anti-tumor efficacy, of anti-CD40 and anti-CD137 immunotherapies is dependent on the gut microbiota.

Immune agonist antibodies (IAAs) are promising immunotherapies that target co-stimulatory receptors to induce potent anti-tumor immune responses, particularly when combined with checkpoint inhibitors. Unfortunately, their clinical translation is hampered by serious dose-limiting, immune-mediated toxicities, including high-grade and sometimes fatal liver damage, cytokine release syndrome (CRS), and colitis. We show that the immunotoxicity, induced by the IAAs anti-CD40 and anti-CD137, is dependent on the gut microbiota. Germ-free or antibiotic-treated mice have significantly reduced colitis, CRS, and liver damage following IAA treatment compared with conventional mice or germ-free mice recolonized via fecal microbiota transplant. MyD88 signaling is required for IAA-induced CRS and for anti-CD137-induced, but not anti-CD40-induced, liver damage. Importantly, antibiotic treatment does not impair IAA anti-tumor efficacy, alone or in combination with anti-PD1. Our results suggest that microbiota-targeted therapies could overcome the toxicity induced by IAAs without impairing their anti-tumor activity.

Changes in the Composition of the Gut Microbiota and the Blood Transcriptome in Preterm Infants at Less than 29 Weeks Gestation Diagnosed with Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a common chronic lung condition in preterm infants that results in abnormal lung development and leads to considerable morbidity and mortality, making BPD one of the most common complications of preterm birth. We employed RNA sequencing and 16S rRNA gene sequencing to profile gene expression in blood and the composition of the fecal microbiota in infants born at <29 weeks gestational age and diagnosed with BPD in comparison to those of preterm infants that were not diagnosed with BPD. 16S rRNA gene sequencing, performed longitudinally on 255 fecal samples collected from 50 infants in the first months of life, identified significant differences in the relative levels of abundance of Klebsiella, Salmonella, Escherichia/Shigella, and Bifidobacterium in the BPD infants in a manner that was birth mode dependent. Transcriptome sequencing (RNA-Seq) analysis revealed that more than 400 genes were upregulated in infants with BPD. Genes upregulated in BPD infants were significantly enriched for functions related to red blood cell development and oxygen transport, while several immune-related pathways were downregulated. We also identified a gene expression signature consistent with an enrichment of immunosuppressive CD71+ early erythroid cells in infants with BPD. Intriguingly, genes that were correlated in their expression with the relative abundances of specific taxa in the microbiota were significantly enriched for roles in the immune system, suggesting that changes in the microbiota might influence immune gene expression systemically.IMPORTANCE Bronchopulmonary dysplasia (BPD) is a serious inflammatory condition of the lung and is the most common complication associated with preterm birth. A large body of evidence now suggests that the gut microbiota can influence immunity and inflammation systemically; however, the role of the gut microbiota in BPD has not been evaluated to date. Here, we report that there are significant differences in the gut microbiota of infants born at <29 weeks gestation and subsequently diagnosed with BPD, which are particularly pronounced when infants are stratified by birth mode. We also show that erythroid and immune gene expression levels are significantly altered in BPD infants. Interestingly, we identified an association between the composition of the microbiota and immune gene expression in blood in early life. Together, these findings suggest that the composition of the microbiota may influence the risk of developing BPD and, more generally, may shape systemic immune gene expression.

Early-Life Antibiotic-Driven Dysbiosis Leads to Dysregulated Vaccine Immune Responses in Mice.

Antibody-mediated responses play a critical role in vaccine-mediated immunity. However, for reasons that are poorly understood, these responses are highly variable between individuals. Using a mouse model, we report that antibiotic-driven intestinal dysbiosis, specifically in early life, leads to significantly impaired antibody responses to five different adjuvanted and live vaccines. Restoration of the commensal microbiota following antibiotic exposure rescues these impaired responses. In contrast, antibiotic-treated adult mice do not exhibit impaired antibody responses to vaccination. Interestingly, in contrast to impaired antibody responses, immunized mice exposed to early-life antibiotics display significantly enhanced T cell cytokine recall responses upon ex vivo restimulation with the vaccine antigen. Our results demonstrate that, in mice, antibiotic-driven dysregulation of the gut microbiota in early life can modulate immune responses to vaccines that are routinely administered to infants worldwide.

InnateDB: systems biology of innate immunity and beyond--recent updates and continuing curation.

InnateDB (http://www.innatedb.com) is an integrated analysis platform that has been specifically designed to facilitate systems-level analyses of mammalian innate immunity networks, pathways and genes. In this article, we provide details of recent updates and improvements to the database. InnateDB now contains >196 000 human, mouse and bovine experimentally validated molecular interactions and 3000 pathway annotations of relevance to all mammalian cellular systems (i.e. not just immune relevant pathways and interactions). In addition, the InnateDB team has, to date, manually curated in excess of 18 000 molecular interactions of relevance to innate immunity, providing unprecedented insight into innate immunity networks, pathways and their component molecules. More recently, InnateDB has also initiated the curation of allergy- and asthma-related interactions. Furthermore, we report a range of improvements to our integrated bioinformatics solutions including web service access to InnateDB interaction data using Proteomics Standards Initiative Common Query Interface, enhanced Gene Ontology analysis for innate immunity, and the availability of new network visualizations tools. Finally, the recent integration of bovine data makes InnateDB the first integrated network analysis platform for this agriculturally important model organism.

Curating the innate immunity interactome.

BACKGROUND: The innate immune response is the first line of defence against invading pathogens and is regulated by complex signalling and transcriptional networks. Systems biology approaches promise to shed new light on the regulation of innate immunity through the analysis and modelling of these networks. A key initial step in this process is the contextual cataloguing of the components of this system and the molecular interactions that comprise these networks. InnateDB (http://www.innatedb.com) is a molecular interaction and pathway database developed to facilitate systems-level analyses of innate immunity. RESULTS: Here, we describe the InnateDB curation project, which is manually annotating the human and mouse innate immunity interactome in rich contextual detail, and present our novel curation software system, which has been developed to ensure interactions are curated in a highly accurate and data-standards compliant manner. To date, over 13,000 interactions (protein, DNA and RNA) have been curated from the biomedical literature. Here, we present data, illustrating how InnateDB curation of the innate immunity interactome has greatly enhanced network and pathway annotation available for systems-level analysis and discuss the challenges that face such curation efforts. Significantly, we provide several lines of evidence that analysis of the innate immunity interactome has the potential to identify novel signalling, transcriptional and post-transcriptional regulators of innate immunity. Additionally, these analyses also provide insight into the cross-talk between innate immunity pathways and other biological processes, such as adaptive immunity, cancer and diabetes, and intriguingly, suggests links to other pathways, which as yet, have not been implicated in the innate immune response. CONCLUSIONS: In summary, curation of the InnateDB interactome provides a wealth of information to enable systems-level analysis of innate immunity.