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Accumulating evidence suggests that cardiovascular disease (CVD) is associated with an altered gut microbiome. Our understanding of the underlying mechanisms has been hindered by lack of matched multi-omic data with diagnostic biomarkers. To comprehensively profile gut microbiome contributions to CVD, we generated stool metagenomics and metabolomics from 1,429 Framingham Heart Study participants. We identified blood lipids and cardiovascular health measurements associated with microbiome and metabolome composition. Integrated analysis revealed microbial pathways implicated in CVD, including flavonoid, γ-butyrobetaine, and cholesterol metabolism. Species from the Oscillibacter genus were associated with decreased fecal and plasma cholesterol levels. Using functional prediction and in vitro characterization of multiple representative human gut Oscillibacter isolates, we uncovered conserved cholesterol-metabolizing capabilities, including glycosylation and dehydrogenation. These findings suggest that cholesterol metabolism is a broad property of phylogenetically diverse Oscillibacter spp., with potential benefits for lipid homeostasis and cardiovascular health., Competing Interests: Declaration of interests R.J.X. is a member of the Scientific Advisory Boards at Nestlé and Magnet Biomedicine, a founder of Jnana and Celsius Therapeutics, and a board member of MoonLake Immunotherapeutics. A provisional patent application describing potential treatments for CVD using the isolates and related compositions described in this study has been filed. The authors listed on that application are R.J.X., C.L., M.S., A.M.T.M, and D.R.P., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Understanding the role of the microbiome in inflammatory diseases requires the identification of microbial effector molecules. We established an approach to link disease-associated microbes to microbial metabolites by integrating paired metagenomics, stool and plasma metabolomics, and culturomics. We identified host-microbial interactions correlated with disease activity, inflammation, and the clinical course of ulcerative colitis (UC) in the Predicting Response to Standardized Colitis Therapy (PROTECT) pediatric inception cohort. In severe disease, metabolite changes included increased dipeptides and tauro-conjugated bile acids (BAs) and decreased amino-acid-conjugated BAs in stool, whereas in plasma polyamines (N-acetylputrescine and N1-acetylspermidine) increased. Using patient samples and Veillonella parvula as a model, we uncovered nitrate- and lactate-dependent metabolic pathways, experimentally linking V. parvula expansion to immunomodulatory tryptophan metabolite production. Additionally, V. parvula metabolizes immunosuppressive thiopurine drugs through xdhA xanthine dehydrogenase, potentially impairing the therapeutic response. Our findings demonstrate that the microbiome contributes to disease-associated metabolite changes, underscoring the importance of these interactions in disease pathology and treatment., Competing Interests: Declaration of interests R.J.X. is a co-founder of Celsius Therapeutics and Jnana Therapeutics, board director at MoonLake Immunotherapeutics, and consultant to Nestlé. D.R.M. is a co-founder of MedBiome Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Fungi are consistently enriched in inflamed intestines, with elusive effects on host immunity. In a recent issue of Nature Medicine, Martini et al. identify a subset of Th1 cells able to lyse the epithelium, enriched in Crohn's disease patient samples after fungal exposure., Competing Interests: Declaration of interests R.J.X is a co-founder of Celsius Therapeutics and Jnana Therapeutics, board director at MoonLake Immunotherapeutics, and consultant to Nestlé., (Copyright © 2023 Elsevier Inc. All rights reserved.)

CD4+ T cell responses are exquisitely antigen specific and directed toward peptide epitopes displayed by human leukocyte antigen class II (HLA-II) on antigen-presenting cells. Underrepresentation of diverse alleles in ligand databases and an incomplete understanding of factors affecting antigen presentation in vivo have limited progress in defining principles of peptide immunogenicity. Here, we employed monoallelic immunopeptidomics to identify 358,024 HLA-II binders, with a particular focus on HLA-DQ and HLA-DP. We uncovered peptide-binding patterns across a spectrum of binding affinities and enrichment of structural antigen features. These aspects underpinned the development of context-aware predictor of T cell antigens (CAPTAn), a deep learning model that predicts peptide antigens based on their affinity to HLA-II and full sequence of their source proteins. CAPTAn was instrumental in discovering prevalent T cell epitopes from bacteria in the human microbiome and a pan-variant epitope from SARS-CoV-2. Together CAPTAn and associated datasets present a resource for antigen discovery and the unraveling genetic associations of HLA alleles with immunopathologies., Competing Interests: Declaration of interests R.J.X. is a co-founder of Celsius Therapeutics and Jnana Therapeutics, a member of the Scientific Advisory Board at Nestle, and a member of the Board of Directors at Moonlake Immunotherapeutics. S.A.C. is a member of the scientific advisory boards of Kymera, PTM BioLabs, Seer, and PrognomIQ., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The perinatal period represents a critical window for cognitive and immune system development, promoted by maternal and infant gut microbiomes and their metabolites. Here, we tracked the co-development of microbiomes and metabolomes from late pregnancy to 1 year of age using longitudinal multi-omics data from a cohort of 70 mother-infant dyads. We discovered large-scale mother-to-infant interspecies transfer of mobile genetic elements, frequently involving genes associated with diet-related adaptations. Infant gut metabolomes were less diverse than maternal but featured hundreds of unique metabolites and microbe-metabolite associations not detected in mothers. Metabolomes and serum cytokine signatures of infants who received regular-but not extensively hydrolyzed-formula were distinct from those of exclusively breastfed infants. Taken together, our integrative analysis expands the concept of vertical transmission of the gut microbiome and provides original insights into the development of maternal and infant microbiomes and metabolomes during late pregnancy and early life., Competing Interests: Declaration of interests R.J.X. is co-founder of Jnana Therapeutics and Celsius Therapeutics, board director at MoonLake Immunotherapeutics, and consultant to Nestlé; these organizations had no role in the study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The gut microbiome has an important role in infant health and development. We characterized the fecal microbiome and metabolome of 222 young children in Dhaka, Bangladesh during the first two years of life. A distinct Bifidobacterium longum clade expanded with introduction of solid foods and harbored enzymes for utilizing both breast milk and solid food substrates. The clade was highly prevalent in Bangladesh, present globally (at lower prevalence), and correlated with many other gut taxa and metabolites, indicating an important role in gut ecology. We also found that the B. longum clades and associated metabolites were implicated in childhood diarrhea and early growth, including positive associations between growth measures and B. longum subsp. infantis, indolelactate and N-acetylglutamate. Our data demonstrate geographic, cultural, seasonal, and ecological heterogeneity that should be accounted for when identifying microbiome factors implicated in and potentially benefiting infant development., Competing Interests: Declaration of interests L.S., C.L.B., C.I.L.R., S.D., O.D-B., C.N-B., and O.S. are employees of Société des Produits Nestlé (SPN). R.J.X. is a member of the Scientific Advisory Board at Nestlé, founder of Jnana and Celsius Therapeutics and board member of MoonLake Immunotherapeutics. We filed a patent related to findings described in this study. R.J.X., H.V., T.V., O.S., L.S., S.D., and C.N.-B. are listed as inventors (Bifidobacterium Longum Transitional Microorganisms, Compositions and Uses Thereof, PCT/US2022/035,310)., (Copyright © 2022 Elsevier Inc. All rights reserved.)