Effects of gut microbiota-host Kynurenine Pathway interactions on Caenorhabditis elegans early ageing

Patel, Rajal and Benedetto, Alexandre (2025) Effects of gut microbiota-host Kynurenine Pathway interactions on Caenorhabditis elegans early ageing. Masters thesis, Lancaster University.

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Abstract

Aging is a multifactorial process characterized by physiological decline and the onset of age- related pathologies. The gut microbiota has emerged as a major modulator of health span and longevity, influencing host biological processes. The kynurenine pathway (KP), a primary catabolic route of tryptophan, produces metabolites with roles in immune regulation and neurotoxicity, making it a potential target for aging interventions. This study investigates the interplay between gut microbiota and the KP in Caenorhabditis elegans, hypothesizing that KP activity influences microbial colonization dynamics and aging-related pathologies. This study also focuses on lifespan modulation, and metabolic activity. Using fluorescently tagged isolates of the CeMbio+ bacterial community i.e. Enterobacter cloacae (CEent1-mPlum), Ochrobactrum vermis (MYb71-sfGFP), Stenotrophomonas indicatrix (JUb19-RFP2), Pantoea nemavictus (BIGb0393a-mPlum), and Enterobacter ludwigii (MYb174-dTom), we studied colonization patterns in wild-type and KP mutant (kmo-1, kynu-1, haao-1, tdo-2 and afmd-1) worms under monoxenic and polyxenic conditions. It was observed that bacterial colonization is influenced by host genetic background and inter-bacterial competition. kmo-1 and haao-1 mutants exhibited enhanced bacterial loads and prolonged colonization, across most bacterial conditons. Certain bacterial strains (E. cloacae, O. vermis, E. ludwigii) were efficient colonizers, while others (P. nemavictus, S. indicatrix) showed lower colonization. Bacterial colonization also influenced aging pathologies, including intestinal atrophy, pharyngeal enlargement and uterine tumour formation, with monoxenic condition (E. cloacae and E. ludwigii) as well as polyxenic condition showing tissue-specific deterioration in KP mutants. Progressive pharyngeal enlargement was observed with most bacterial strains, with E. ludwigii showing a positive correlation between gut colonization and pharyngeal swelling. Uterine tumors appeared earlier (around 48 hours) and were generally larger under polyxenic conditions compared to monoxenic conditions. Lifespan assays showed kmo-1 mutation affects longevity of C. elegans on O. vermis as well as on E. coli. Biolog Ecoplate metabolic profiling revealed that most of transformed bacterial strains phenotypically match their parental strains, maintaining strain-specific activity linked to colonization efficiency and host impact. This study underscores the complex interplay between gut microbiota, Kynurenine pathway mutations, aging and age-associated pathologies.