Products of gut microbial Toll/interleukin-1 receptor domain NADase activities in gnotobiotic mice and Bangladeshi children with malnutrition

Cell Rep. 2022 Apr 26;39(4):110738. doi: 10.1016/j.celrep.2022.110738.

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.

Trial registration: ClinicalTrials.gov NCT01889329.

Keywords: CP: Microbiology; NAD metabolism; TIR domain structure/activity relationships; childhood malnutrition; defined microbial communities; gnotobiotic mice; human gut microbiome development/functional profiling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bacteria / metabolism
  • Child
  • Cyclic ADP-Ribose
  • Gastrointestinal Microbiome*
  • Germ-Free Life
  • Humans
  • Malnutrition*
  • Mice
  • NAD / metabolism
  • NAD+ Nucleosidase / metabolism
  • Receptors, Interleukin-1

Substances

  • Receptors, Interleukin-1
  • NAD
  • Cyclic ADP-Ribose
  • NAD+ Nucleosidase

Associated data

  • ClinicalTrials.gov/NCT01889329