Exploring mechanisms of C. elegans microbiota-mediated protection

Animals and microorganisms live together, forming a network of associations between animal hosts and their resident microorganisms, the microbiota. One important beneficial microbiota function is protecting the host against pathogen infection, termed microbiota-mediated protection. Many studies describe microbiota-mediated protection in animals; however, the underlying mechanisms remain mostly elusive. In my Ph.D. thesis project, I investigated mechanisms of microbiota-mediated protection in the nematode model Caenorhabditis elegans. To understand microbiota-mediated protection mechanisms, I first identified C. elegans natural microbiota isolates that protect the host against infection with Bacillus thuringiensis. Then, I explored the underlying mechanisms of protection by these microbiota isolates both from the bacterial and the host side. On the bacterial side, I showed that: 1) Some microbiota isolates can protect the host by directly inhibiting pathogen growth via massetolide E production, a lipopeptide of the viscosin group, while others protect the host without producing massetolide E. 2) Microbiota isolates can produce biofilm in vitro, suggesting biofilm formation as a potential protection mechanism, which merits in vivo investigation. 3) Microbiota isolates cannot protect against B. thuringiensis toxins (Cry21Aa3 and Cry14Aa2) and are rendered pathogenic under certain pathogen exposure conditions, revealing the context-dependent dual nature of microbiota protective function. Moreover, in collaboration with colleagues, we characterized a more extensive selection of natural microbiota isolates of C. elegans and elucidated their metabolic contribution to the host using whole-genome sequencing, mathematical modeling, and experimentation. We showed that C. elegans microbiota could synthesize all the essential vitamins and amino acids needed by the nematode, reinforcing its beneficial role to the host. On the host side, I used a multi-omics approach to identify host genes and pathways required for microbiota-mediated protection. To this end, I obtained transcriptomic and proteomic datasets of the infected and uninfected worms treated or untreated with the protective microbiota isolates. I showed that: 1) Protective microbiota isolates influence the worm's innate immune response and cellular structural component functions. 2) Microbiota isolates induce changes in expression and abundances on both gene and protein levels, respectively, for galectins, C-type lectins, and lysozymes, suggesting their potential roles in microbiota-mediated host protection. Altogether, these findings indicate microbiota-mediated activation of innate immune response genes, suggesting that the microbiota isolates ‘prime’ the C. elegans immune response, increasing host preparedness for subsequent pathogen attack. Overall, the findings of this thesis provide valuable insights into mechanisms of microbiota-mediated protection on the bacterial and host sides, expanding our understanding of host-microbe interactions.


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