Restoring a lost microbiome to a model worm

A lost dimension of life is being restored to the laboratory worm Caenorhabditis elegans. With the promise of building yet further on its already resounding success as a model organism, research that reunites it with a microbiota resembling that found in its wild relatives, launches it as a new host-microbiome model.

A model with a celebrated history

In the early 1950s, a 1mm long transparent roundworm was plucked from mushroom compost near Bristol. Easy to breed and feed, this member of the free living nematode species Caenorhabditis elegans (C. elegans) founded the N2 strain brought to prominence by Sydney Brenner, who recognised its potential for studying how genes program development and behavior.

As Brenner reminisces in his article “In the beginning was the worm”, there was initially some scepticism as he embarked on his project to turn C. elegans into a model organism. But it was a spectacular success, leading to the 2002 Nobel Prize.

Nobel Prize 2002. "for their discoveries concerning genetic regulation of organ development and programmed cell death'"
Nobel Prize 2002. “for their discoveries concerning genetic regulation of organ development and programmed cell death'”

You can read about  those exhilarating early days in a delightful article by Bob Horvitz and John Sulston entitled “Joy of the worm”. The careful observation of cells dividing, dying, or migrating in living worms yielded fundamental new insights into how multicellular organisms develop; the connectivity of its 302 adult neurons was described; and mutant screens mapping abnormal phenotypes to genes began to illuminate how specific genes drive cell fate decisions. Later, in 1998, C. elegans was the first multicellular organism to have its genome sequenced.

How long can a model organism last?

A search on Pubmed yields 7,903 publications to date in which C. elegans appears in the title. The pace quickens from the early 1970s but plateaus in the last three years, though with an increasing breadth of issues being addressed.

A search on Pubmed yields 7,903 publications to date in which C. elegans appears in the title. The pace quickens from the early 1970s but plateaus in the last three years

We have recently published on topics as diverse as cross-tissue signaling in innate immunity, and  serotonin circuits for rapid decision making, In another area of biology, made more urgent by current demographics, the worm’s value as a simple model for protein toxicity, neurodegenerative disease and ageing looks far from being exhausted.

In one now-burgeoning area of research though – the inter-dependent interaction between multicellular organsims and their associated microbiomes – its potential is only just about to be realised.

Restoration of a lost microbiome

When Sydney Brenner received the N2 strain of C. elegans, it arrived without its microbiome, and the practice of keeping worms monoxenically – that is essentially microbiota free by bleach treatment of their eggs and a diet limited to a single bacterial strain –has continued in the many labs that have worked on C. elegans since.

Exclusive adherence to this tradition may be about to change, however.  Research just published in BMC Biology characterizes the native microbiome found in wild C. elegans worms, and using cultivable isolates to derive an experimental microbiota with a comparable taxonomic structure (albeit simplified), finds that laboratory worms propagated on this grow faster, produce more offspring, and more effectively resist pathogens.

You can see one such repopulated worm, microbes stained in red, in a video from the paper by Dirksen et al shown below. Another recent study similarly exposes  laboratory C. elegans to more naturalistic microbiomes – in this case by cultivation in soils enriched with various rotting fruits – and shows that the worms assemble a distinct microbiota from that of the different mini-habitats in which they are grown.

The significance of this new turn in the history of the model worm is explored in a commentary by Laura Clark and Jonathan Hodgkin.  From the perspective of achieving a more complete understanding of worm biology, restoring something like a natural microbiome to C. elegans may help unravel the mystery of at least some of the genes that have no apparent function in the laboratory life of a monoxenic worm.

With respect to the open question of the relationship between host genotype and microbiome composition (recently reviewed here), the results already indicate an influence of genotype, and the tractable genetics of C. elegans promise more specific insights to come.

As for the impact of the microbiota on the host, the results indicating an effect on growth, fecundity and pathogen resistance can be dissected further, and the worm offers a well-charted environment in which to explore and understand behavioural effects.

To echo the title of Hinrich Schulenburg and colleagues’ paper, we are at the gateway to a new host-microbiome model. Restoring its lost microbiome marks a new beginning for the worm.

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