Bacterially produced metabolites protect C. elegans neurons from degeneration

Abstract

Caenorhabditis elegans and its cognate bacterial diet comprise a reliable, widespread 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 C. elegans strain expressing a neurotoxic allele of the mechanosensory abnormality protein 4 (MEC-4d) degenerin/epithelial Na + (DEG/ENaC) channel, which causes the progressive degeneration of the touch receptor neurons (TRNs). Using this model, our study evaluated the effect of various dietary bacteria on neurodegeneration dynamics. Although degeneration of TRNs was steady and completed at adulthood in the strain routinely used for C. elegans maintenance (Escherichia coli OP50), it was significantly reduced in environmental and other laboratory bacterial strains. Strikingly, neuroprotection reached more than 40% in the E. coli HT115 strain. HT115 protection was long lasting well into old age of animals and was not restricted to the TRNs. Small amounts of HT115 on OP50 bacteria as well as UV-killed HT115 were still sufficient to produce neuroprotection. Early growth of worms in HT115 protected neurons from degeneration during later growth in OP50. HT115 diet promoted the nuclear translocation of DAF-16 (ortholog of the FOXO family of transcription factors), a phenomenon previously reported to underlie neuroprotection caused by downregulation of the insulin receptor in this system. Moreover, a daf-16 loss-of-function mutation abolishes HT115-driven neuroprotection. Comparative genomics, transcriptomics, and metabolomics approaches pinpointed the neurotransmitter γ-aminobutyric acid (GABA) and lactate as metabolites differentially produced between E. coli HT115 and OP50. HT115 mutant lacking glutamate decarboxylase enzyme genes (gad), which catalyze the conversion of GABA from glutamate, lost the ability to produce GABA and also to stop neurodegeneration. Moreover, in situ GABA supplementation or heterologous expression of glutamate decarboxylase in E. coli OP50 conferred neuroprotective activity to this strain. Specific C. elegans GABA transporters and receptors were required for full PLOS BIOLOGY PLOS Biology | https://doi.

Dietary and environmental factors have opposite AhR-dependent effects on C. elegans healthspan

“…Interestingly, alanine and glutamate were also shown to extend C. elegans lifespan [ 72 ]. Moreover, C. elegans ahr-1 is required for cell fate specification of GABAergic neurons [ 17 ] and it was recently shown that HT115, differently from OP50, possess the enzyme (glutamate decarboxylase, GAD) necessary to convert glutamate into GABA, which is responsible to protect C. elegans neurons from degeneration [ 74 ]. Although the authors did not check whether OP50 and HT115 indeed produce different amounts of Glu, lack of GAD is expected, consistent with our data, to increase Glu production by OP50.…”

What can a worm learn in a bacteria-rich habitat?

“…In addition to its responses to pathogenic bacteria, several recent studies also reveal interesting interactions between C. elegans and its commensal bacteria species. These studies show that C. elegans utilizes neurotransmitters or vitamins produced by the environmental bacteria (O'Donnell, Fox, Chao, Schroeder, & Sengupta, 2020;Urrutia et al, 2020;Wei & Ruvkun, 2020) to maintain or modulate various physiological events and neural functions. These findings together with those investigating the interactions of C. elegans and pathogenic bacteria have established C. elegans as a promising system to probe mechanisms underlying gut-brain interactions.…”

The Heritability of Behaviors Associated With the Host Gut Microbiota

“…In females, macrophage secretion of TNF-a and interferon-g (IFN) stimulate the development and degeneration of the corpus luteum and, in so doing; regulate ovarian function (142). In the testis, Sertoli and Leydig cells produce numerous cytokines (like TNFa, IL1, IL6, and IL18), which act as a paracrine signal that regulates germ cell development and function (143)(144)(145)(146)(147). In macrophages, IFN induces chromatin remodeling and inherited transcriptional immune memory (148), and modifications of histone marks like H4ac, H3K9ac, and H3K4me3 at IFN-activated promoters (149).…”