Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease

Host-Microbiota Interactions in the Pathogenesis of Antibiotic-Associated Diseases

Summary: Improved understanding of the interplay between host and microbes stands to illuminate new avenues for disease diagnosis, treatment, and prevention. Here, we provide a high-resolution view of the dynamics between host and gut microbiota during antibiotic-induced intestinal microbiota depletion, opportunistic Salmonella typhimurium and Clostridium difficile pathogenesis, and recovery from these perturbed states in a mouse model. Host-centric proteome and microbial community profiles provide a nuanced longitudinal view, revealing the interdependence between host and microbiota in evolving dysbioses. Time- and condition-specific molecular and microbial signatures are evident and clearly distinguished from pathogen-independent inflammatory fingerprints. Our data reveal that mice recovering from antibiotic treatment or C. difficile infection retain lingering signatures of inflammation, despite compositional normalization of the microbiota, and host responses could be rapidly and durably relieved through fecal transplant. These experiments demonstrate insights that emerge from the combination of these orthogonal, untargeted approaches to the gastrointestinal ecosystem. : Lichtman et al. compared longitudinal mouse models of antibiotic-associated inflammation. By concurrently measuring gut microbes and secreted host proteins with 16S rRNA sequencing and mass spectrometry, they found dynamic, yet distinct, microbe and proteome profiles. Inflammation-regulated proteases, antimicrobial proteins, and immunoglobulins marked multiple pathways actively shaping host responses to dysbiosis

Seasonal cycling in the gut microbiome of the Hadza hunter-gatherers of Tanzania

Although humans have cospeciated with their gut-resident microbes, it is difficult to infer features of our ancestral microbiome. Here, we examine the microbiome profile of 350 stool samples collected longitudinally for more than a year from the Hadza hunter-gatherers of Tanzania. The data reveal annual cyclic reconfiguration of the microbiome, in which some taxa become undetectable only to reappear in a subsequent season. Comparison of the Hadza data set with data collected from 18 populations in 16 countries with varying lifestyles reveals that gut community membership corresponds to modernization: Notably, the taxa within the Hadza that are the most seasonally volatile similarly differentiate industrialized and traditional populations. These data indicate that some dynamic lineages of microbes have decreased in prevalence and abundance in modernized populations

The effect of microbial colonization on the host proteome varies by gastrointestinal location

Endogenous intestinal microbiota have wide-ranging and largely uncharacterized effects on host physiology. Here, we used reverse-phase liquid chromatography-coupled tandem mass spectrometry to define the mouse intestinal proteome in the stomach, jejunum, ileum, cecum and proximal colon under three colonization states: germ-free (GF), monocolonized with Bacteroides thetaiotaomicron and conventionally raised (CR). Our analysis revealed distinct proteomic abundance profiles along the gastrointestinal (GI) tract. Unsupervised clustering showed that host protein abundance primarily depended on GI location rather than colonization state and specific proteins and functions that defined these locations were identified by random forest classifications. K-means clustering of protein abundance across locations revealed substantial differences in host protein production between CR mice relative to GF and monocolonized mice. Finally, comparison with fecal proteomic data sets suggested that the identities of stool proteins are not biased to any region of the GI tract, but are substantially impacted by the microbiota in the distal colon