Metabolic regulation of behavior by the intestinal enzyme FMO-2

Many elements of an organism's behavior are intertwined with the organism's health. Over a long period of time, health status is also indicative of life span, with improved health correlating with a longer life. However, the relationship between longevity and behavior remains relatively unexplored. Here, we report that modification of a single longevity gene downstream of dietary restriction and hypoxia markedly alters behavior in <i>Caenorhabditis elegans</i>. We found that modified expression of flavin-containing monooxygenase (<i>fmo-2</i>) leads to altered sensory perception and decision-making in a variety of behavioral paradigms. This cell nonautonomous signaling pathway is linked to changes in tryptophan metabolism, where loss of <i>fmo-2</i> requires the tryptophan metabolite serotonin and overexpressed <i>fmo-2</i> requires the tryptophan metabolite quinolinic acid to change behavior. These results suggest a unique mechanism for gut metabolism to communicate positive satiety signals and negative depressive signals to the organism by modifying an essential amino acid. They also demonstrate the importance of examining pleiotropic effects in promising longevity interventions.