Abstract

C. elegans and its cognate bacterial diet comprise a widespread, reliable model to study diet and microbiota effects on host physiology. Nonetheless, how diet influences the rate at which neurons die remains largely unknown. A number of models have been used in C. elegans as surrogates for neurodegeneration. One of these is a strain expressing a neurotoxic allele of the MEC-4(d) DEG/ENaC channel which causes the progressive degeneration of the touch receptor neurons (TRN, Driscoll and Chalfie, 1991). Using such a model, this study evaluated the effect of various dietary bacteria on neurodegeneration dynamics and TRN function. While degeneration of TRNs was completed at adulthood in E. coli OP50, it was significantly reduced in environmental and other laboratory strains. Strikingly, E. coli HT115 was the most neuroprotective. This protection was long-lasting well into the old age of animals and not restricted to the touch receptor neurons. Additionally, the early growth of worms in HT115 protected neurons from degeneration during later growth in OP50. HT115 diet promoted the nuclear translocation of the DAF-16 transcription factor and a loss of function daf-16 mutation abolishes HT115-driven neuroprotection. Comparative genomics, transcriptomics, and metabolomics approaches pinpointed the neurotransmitter γ-aminobutyric acid (GABA) as the metabolite differentially produced between OP50 and HT115. HT115 mutant lacking glutamate decarboxylase enzyme genes (Gad), which catalyze the production of GABA from glutamate, lost the ability to produce GABA and also to stop neurodegeneration. Moreover, in situ GABA supplementation or heterologous expression of Gad in E. coli OP50 conferred neuroprotective activity to this strain. Together, these results demonstrate that bacterially produced GABA exerts an effect of neuroprotection in the host, highlighting the role of metabolite composition of the diet in nervous system homeostasis.