@article{7f36a566d8494c0188fc738cf3f1d550,
title = "Products of gut microbial Toll/interleukin-1 receptor domain NADase activities in gnotobiotic mice and Bangladeshi children with malnutrition",
abstract = "Perturbed gut microbiome development has been linked to childhood malnutrition. Here, we characterize bacterial Toll/interleukin-1 receptor (TIR) protein domains that metabolize nicotinamide adenine dinucleotide (NAD), a co-enzyme with far-reaching effects on human physiology. A consortium of 26 human gut bacterial strains, representing the diversity of TIRs observed in the microbiome and the NAD hydrolase (NADase) activities of a subset of 152 bacterial TIRs assayed in vitro, was introduced into germ-free mice. Integrating mass spectrometry and microbial RNA sequencing (RNA-seq) with consortium membership manipulation disclosed that a variant of cyclic-ADPR (v-cADPR-x) is a specific product of TIR NADase activity and a prominent, colonization-discriminatory, taxon-specific metabolite. Guided by bioinformatic analyses of biochemically validated TIRs, we find that acute malnutrition is associated with decreased fecal levels of genes encoding TIRs known or predicted to generate v-cADPR-x, as well as decreased levels of the metabolite itself. These results underscore the need to consider microbiome TIR NADases when evaluating NAD metabolism in the human holobiont.",
keywords = "CP: Microbiology, NAD metabolism, TIR domain structure/activity relationships, childhood malnutrition, defined microbial communities, gnotobiotic mice, human gut microbiome development/functional profiling",
author = "Weagley, {James S.} and Mark Zaydman and Siddarth Venkatesh and Yo Sasaki and Neha Damaraju and Alex Yenkin and William Buchser and Rodionov, {Dmitry A.} and Andrei Osterman and Tahmeed Ahmed and Barratt, {Michael J.} and Aaron DiAntonio and Jeffrey Milbrandt and Gordon, {Jeffrey I.}",
note = "Funding Information: We thank David O{\textquoteright}Donnell, Maria Karlsson, Justin Serugo, Marty Meier, Janaki Guruge, Alicia Neiner, and Kow Essuman for invaluable technical assistance; Kelli Simburger for help generating recombinant plasmids for in vitro expression of TIR domains; and Jiye Cheng for LC-QTOF-MS of cADPR, v-cADPR-x, and v-cADPR-y. In addition, we are grateful to Shin Imai (Department of Developmental Biology, Washington University School of Medicine) for providing the NMN used in the NAD-precursor-sufficient diet. This work was supported by grants from the Bill & Melinda Gates Foundation ( OPP1191864 and OPP1196579 ) and the NIH ( DK30292 ). J.S.W. is the recipient of a pre-doctoral fellowship from the NSF ( DGE - 1745038 ). J.I.G. is the recipient of a Thought Leader Award from Agilent Technologies. This work is also supported by NIH grants R01NS119812 to A.J.B., A.D., and J.M.; R01NS087632 to A.D. and J.M.; R37NS065053 to A.D.; and RF1AG013730 to J.M. The National Metabolomics Data Repository ( NMDR ) is supported by NIH grant U2C-DK119886 (reference: PMID: 26467476 ). Funding Information: We thank David O'Donnell, Maria Karlsson, Justin Serugo, Marty Meier, Janaki Guruge, Alicia Neiner, and Kow Essuman for invaluable technical assistance; Kelli Simburger for help generating recombinant plasmids for in vitro expression of TIR domains; and Jiye Cheng for LC-QTOF-MS of cADPR, v-cADPR-x, and v-cADPR-y. In addition, we are grateful to Shin Imai (Department of Developmental Biology, Washington University School of Medicine) for providing the NMN used in the NAD-precursor-sufficient diet. This work was supported by grants from the Bill & Melinda Gates Foundation (OPP1191864 and OPP1196579) and the NIH (DK30292). J.S.W. is the recipient of a pre-doctoral fellowship from the NSF (DGE-1745038). J.I.G. is the recipient of a Thought Leader Award from Agilent Technologies. This work is also supported by NIH grants R01NS119812 to A.J.B. A.D. and J.M.; R01NS087632 to A.D. and J.M.; R37NS065053 to A.D.; and RF1AG013730 to J.M. The National Metabolomics Data Repository (NMDR) is supported by NIH grant U2C-DK119886 (reference: PMID: 26467476). J.S.W. conducted bioinformatic analyses of TIR domains and pathways of bacterial NAD metabolism together with M.Z. with invaluable input from W.B. A.Y. D.A.R. and A.O. J.S.W. N.D. and M.Z. performed in vitro assays of TIR domain NADase activity. J.S.W. and J.I.G. designed gnotobiotic mouse experiments, with community profiling by shotgun sequencing (COPRO-seq) and microbial RNA-seq analyses of collected biospecimens carried out by J.S.W. and S.V. Mass spectrometric analysis of metabolites generated during in vitro and in vivo experiments were performed by Y.S. Fecal samples collected from Bangladeshi children from a previously published study were supplied by T.A. and maintained in a biospecimen archive overseen by M.J.B. This manuscript was written by J.S.W. and J.I.G. with contributions from M.Z. A.O. A.D. and J.M. A.O. and D.A.R. are co-founders of Phenobiome, Inc. a company pursuing development and biomedical applications of computational tools for predictive phenotype profiling of microbial communities. A.D. and J.M. are co-founders of, and Y.S. served as a consultant to, Disarm Therapeutics, a company dedicated to developing therapeutics for neurodegenerative conditions that is now part of Eli Lilly and Company. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = apr,
day = "26",
doi = "10.1016/j.celrep.2022.110738",
language = "English",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
number = "4",
}