Pseudomonas plecoglossicida disrupts intestinal homeostasis through manipulation of palmitoleic acid microbial metabolism.

Sickness-associated anorexia (SAA) is a common symptom during bacterial infections in fish that complicates treatment due to reduced oral drug uptake and efficacy. While current research has largely focused on cytokine-mediated pathways affecting the central nervous system, the role of gut microbiota and metabolic homeostasis in SAA remains poorly understood. Here, we used an integrated approach including single-cell sequencing, 16S rDNA sequencing, and metabolomics to investigate appetite suppression in Epinephelus coioides infected with Pseudomonas plecoglossicida, a non-intestinal pathogen. Infection severely disrupted intestinal epithelial turnover and homeostasis, marked by loss of epithelial and goblet cells, and altered microbiota composition. Although no key bacteria linked to tryptophan-derived metabolite metabolism were detected, we identified three microbiota members and several metabolites, including cimetidine, palmitoleic acid (PA), 16-hydroxypalmitate, imidazoleacetic acid, quinolinic acid, and glycerol, associated with homeostasis disruption. Notably, PA depletion correlated strongly with reduced intestinal cells and upregulation of senescence and apoptosis genes, leading to SAA. Exogenous PA supplementation mitigated infection-induced appetite loss, restored microbial balance, and improved epithelial integrity. These findings reveal that non-intestinal pathogens can disturb gut homeostasis and promote SAA via reduced PA levels, suggesting dietary PA supplementation as a potential therapeutic strategy to enhance appetite and recovery in infected fish.