Abstract
Animals coexist in commensal, pathogenic or mutualistic relationships with complex communities of diverse organisms including microbes1. Some bacteria produce bioactive neurotransmitters which have been proposed to modulate host nervous system activity and behaviors2,3. However, the mechanistic basis of this microbiota-brain signaling and its physiological relevance is largely unknown. Here we show that in C. elegans, the neuromodulator tyramine produced by gut-colonizing commensal Providencia bacteria bypasses the requirement for host tyramine biosynthesis to manipulate a host sensory decision. Bacterially-produced tyramine is likely converted to octopamine by the host tyramine β-hydroxylase enzyme. Octopamine in turn targets the OCTR-1 octopamine receptor on the ASH nociceptive neurons to modulate an aversive olfactory response. We identify genes required for tyramine biosynthesis in Providencia, and show that these genes are necessary for modulation of host behavior. We further find that C. elegans colonized by Providencia preferentially select these bacteria in food choice assays, and that this selection bias requires bacterially produced tyramine and host octopamine signaling. Our results demonstrate that a neurotransmitter produced by gut microbiota mimics the functions of the cognate host molecule to override host control of a sensory decision, thereby promoting fitness of both host and microbe.
Highlights
Animals coexist in commensal, pathogenic or mutualistic relationships with complex communities of diverse organisms including microbes[1]
We found that feeding C. ele gans with JUb39 pre-treated with high concentrations of the antibiotic gentamicin eliminated octanol modulation (Fig. 1d), indicating that JUb39 must be alive to mediate this behavioral plasticity
While exogenous TA did not further increase octanol avoidance in wild-type JUb39-grown animals, TA supplementation was sufficient to induce octanol modulation in OP50-grown animals (Fig. 3g). These results indicate that TA produced by multiple amino acid decarboxylase enzymes (AADCs) enzymes in Providencia is both necessary and sufficient to modulate octanol avoidance by wild-type C. elegans
Summary
We performed chemotaxis assays with animals fed on mCherry-labeled JUb39, and quantified intestinal bacterial cells in animals that had navigated either toward octanol or toward the control. Mutations in the cat2 tyrosine hydroxylase[24] and tph1 tryptophan hydroxylase[25] enzymes required for the production of biogenic amines dopamine and serotonin in C. elegans, respectively, did not affect octanol modulation (Fig. 2b) These results raise the possibility that C. elegans-produced OA, but not TA, is partly necessary for JUb39-mediated octanol modulation. Tdc1 mutants grown on OP50 responded more rapidly to 30% octanol than wild-type animals (Fig. 2c) This enhanced aversion was suppressed upon growth on JUb39 (Fig. 2c). We found that growth on L-Tyr-supplemented media enhanced octanol modulation by JUb39 in SOS assays (Fig. S3) Under these conditions, mutations in tbh1 fully suppressed octanol modulation in SOS assays, whereas consistent with our observations in longrange chemotaxis assays, tdc1 mutants continued to exhibit robust octanol modulation (Fig. 2e). We infer that JUb39 TyrDC likely generates TA from tyrosine
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