Assie, Adrien et al. (2019) International Worm Meeting "Selecting for functions: metagenomic identification of essential functions of the microbiome in the C. elegans gut."

Samuel, Buck, Assie, Adrien, Weckhorst, Jessica, Zhang, Fan

[International Worm Meeting, 2019]

The gut microbiome both extends the capabilities of its host and alters its physiology. Host genetics, diet, environment, and microbe-microbe interactions influence microbiome form and function. In humans, microbiome community function is important for resilience to disease. Despite its importance, the essential functions that drive microbiome assembly and stability in remain largely unaddressed in any host. To address this challenge, we leverage the nematode Caenorhabditis elegans to explore how microbiomes of distinct scales and functional complexity assemble in different host genetic backgrounds. This system has several advantages, including (1) a simple microbiome that can be removed (bleaching) and manipulated in the lab; (2) highly conserved intestinal physiology and innate immunity; and (3) comparable microbial mechanisms for host gut persistence. Previous studies in the lab have identified host-dependent variation in the microbiome: around 40 C. elegans wild strains were exposed to a model microbiome (BIGbiome) and they form three distinct gut types that differ in dominant taxa [Ochrobactrum, Bacteroidetes or a mix]. To examine the essential functions for colonization of the C. elegans gut, we first sequenced more than 100 bacterial genomes of its microbiome to determine their functional potential. Next, bacteria in each C. elegans microbiome were mapped to their corresponding genomes and scaled by abundance (16S) to construct virtual metagenomes. In-silico metabolic reconstructions and comparative metagenomic analyses both indicate broad variation in potential functions and provide many candidate genes important for host association. Unique functions may also allow for host selection of specific taxa. Analyses of each of the genomes indicate a wide range of potential metabolic capacities from "generalists" (like Enterobacteria) that have genes for utilization of a wide range of carbohydrate substrates to "specialists" (like Ochrobactrum) that have a narrower nutrient usage potential. Interestingly, specialists thrive within the worm gut whereas generalists are less successful in a community context. To explore this further, we exposed C. elegans strains to microbiomes of increasing complexity in function and taxa diversity. Together, these studies highlight key molecular functions under host selection that may underlie assembly and stability of the microbiome.

Vidal, Daniela et al. (2021) International Worm Meeting "Host-microbiome interactions with age on Caenorhabditis elegans reproduction"

Samuel, Buck, Weckhorst, Jessica, Vidal, Daniela, Zhang, Fan

[International Worm Meeting, 2021]

Interactions with and alterations of the gut microbiome with age can have a dramatic impact on our physiology. Changes in the membership of the gut microbiome can dictate levels of immunity, stress resistance and vitality across systems. Linking changes in the microbiome to microbial factors that may influence them has been a challenge in many systems due to the complexity of the microbiomes and intractability of following these interactions over an individual's lifespan. To address this gap, we leveraged recent advances in characterization of the natural microbiome of C. elegans to examine both the gut microbiome on the aging process in C. elegans and vice versa. First, we utilized a 64-member microbiome (BIGbiome) and asked whether microbiome membership changed as animals age. Compared to E. coli OP50 controls, the BIGbiome community had several significant impacts on three genetically diverse strains (lab N2, plus wild JU1400 and ED3017), including extended lifespan (up to 10%), improved healthspans (e.g., 36% at d5) and greater reproductive output (23% higher at d1 adults). In addition, increases in the levels of Ochrobactrum BH3, a dominant colonizer of the C. elegans gut, from 0% to 25% in the BIGbiome community yielded a dose dependent promotion of reproductive rates. This indicates that specific members (such as Ochrobactrum) may promote reproductive rates and healthy aging in C. elegans. Next, we determined how C. elegans age may influence microbiome membership. To do this, we monitored gut microbiomes of single animals for each of the C. elegans strains for the first 10 days of adulthood. Each of the host strains exhibited gut microbiomes distinct from the surrounding lawn in early adulthood, though they differed in (i) dominant microbes at that age, and (ii) the extent of the lifespan with enriched microbes. This suggests that the ability to maintain a specific microbiome community may be driven by changes in host responses in C. elegans. Last, we sought to examine the genes that mediate Ochrobactrum impact on the aging process. We screened a ~1000 microbiome regulators by RNAi for defects in Ochrobactrum colonization with age, then looked for altered reproductive rates in candidates (32 clones). Hits from these studies suggest that Ochrobactrum may be promoting reproduction via germline interactions directly. Together, our results highlight use of C. elegans as a model system for investigating microbiome influence on host aging.

Maaike C. W. van den Berg et al. (2006) European Worm Meeting "Sex-Dependent Resistance to the Fungal Pathogen Cryptococcus neoformans"

Maaike C. W. van den Berg, Jessica Z. Woerlee, Robin C. May, Hansong Ma

[European Worm Meeting, 2006]

Maaike C. W. van den Berg1,2, Jessica Z. Woerlee2, Hansong Ma1,2 & Robin C. May1. Cryptococcus neoformans is the causative agent of cryptococcosis, a fatal fungal disease of immunocompromised patients. Our group and others have made use of C. elegans as an alternative host for Cryptococcus, in order to investigate the molecular basis of host-pathogen interactions. Using this system, we now report that male C. elegans show greater resistance to killing by Cryptococcus than hermaphrodite animals and that this resistance can be induced in hermaphrodite animals by inappropriate activation of the male sex-determination pathway. Resistance is molecularly determined, rather than resulting from behavioural changes or reproductive differences, and requires the activity of the stress-response transcription factor DAF-16. Finally, we demonstrate that resistance to Cryptococcus neoformans correlates broadly with longevity within the Caenorhabditis genus. Our results suggest that many of the molecular determinants of longevity and immunity are the same and that differential regulation of these determinants may underlie much sex-dependent and species-dependent variation.