TRPM channels mediate learned pathogen avoidance following intestinal distention

Abstract

Upon exposure to harmful microorganisms, hosts engage in protective molecular and behavioral immune responses, both of which are ultimately regulated by the nervous system. Using the nematode Caenorhabditis elegans, we show that ingestion of E. faecalis leads to a fast pathogen avoidance behavior that results in aversive learning. We have identified multiple sensory mechanisms involved in the regulation of avoidance of E. faecalis. The G-protein coupled receptor NPR-1-dependent oxygen-sensing pathway opposes this avoidance behavior, while an ASE neuron-dependent pathway and an AWB and AWC neuron-dependent pathway are directly required for avoidance. Colonization of the anterior part of the intestine by E. faecalis leads to AWB and AWC mediated olfactory aversive learning. Finally, two transient receptor potential melastatin (TRPM) channels, GON-2 and GTL-2, mediate this newly described rapid pathogen avoidance. These results suggest a mechanism by which TRPM channels may sense the intestinal distension caused by bacterial colonization to elicit pathogen avoidance and aversive learning by detecting changes in host physiology.

Preconditioning With Natural Microbiota Strain Ochrobactrum vermis MYb71 Influences Caenorhabditis elegans Behavior

“…On the microbe side, bacterial secondary metabolites and non-coding RNAs (Kaletsky et al, 2020) trigger the learned behavioral responsein the case of non-coding RNA even across multiple worm generations (Kaletsky et al, 2020). Interestingly, so far only pathogenic bacteria such as PA14, Serratia marcescens ATCC 13880 (Zhang et al, 2005;Zhang and Zhang, 2012), or Enterococcus faecalis (Filipowicz et al, 2021) were known to elicit the learned avoidance behavior. Ochrobactrum, however, has been repeatedly isolated from wild C. elegans and has positive or neutral effects on C. elegans life-history traits such as population growth (Zimmermann et al, 2020), animal growth rates, and body size (Dirksen et al, 2020;Zhang et al, 2021).…”

“…Moreover, the colonization with MYb71 might lead to a gut distention provoking the late microbiota avoidance response. The learned pathogen avoidance response against E. faecalis is caused by its accumulation in the anterior worm gut mediated by two transient receptor potential melastatin channelseven with an attenuated pathogen (Filipowicz et al, 2021).…”

Dissection of a sensorimotor circuit underlying pathogen aversion in C. elegans

“…The pathogenic bacteria P. aeruginosa and E. faecalis are initially attractive to C. elegans and only induce an avoidance response after many hours of exposure [ 4 , 9 , 10 , 13 ]. This learning process involves the association of infection and subsequent physiological responses, including intestinal distention, engagement of RNAi pathways, and immune activation, with bacterial cues, resulting in avoidance of the bacteria [ 10 , 12 , 25 ]. Using the reflexive aversion assay, we found that naïve animals do not respond to drops of P. aeruginosa (Fig.…”

“…Because we noticed a significant variation in the reflexive aversion of trained animals, we wondered whether varying levels of intestinal distention, which can trigger learned avoidance [ 10 , 25 ], accounted for the variation in the responses. Intestinal distention on P. aeruginosa , measured by either PA14-GFP signal in the intestinal lumen or intestine diameter, correlated with the trained response index to a weak, but significant, amount (Additional file 7 : Fig.…”

“…These behaviors range from aversive reflexes to learned avoidance. Studies using pathogenic bacteria such as Pseudomonas aeruginosa and Enterococcus faecalis , for example, have shown that these bacteria are initially attractive to C. elegans , and it is only after hour-long exposure to the pathogens that the valence of the bacteria switches from attractive to aversive [ 9 , 10 ]. This is in contrast to the C. elegans avoidance of the toxins produced by Streptomyces , which takes place in a matter of seconds [ 7 ].…”