089: Using the zebrafish microbiome to study development and the gut-brain axis with John Rawls

How can the humble zebrafish teach us about the human microbiome? John Rawls discusses the benefits of using animal models

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Julie's Biggest Takeaways:

Zebrafish and other model animals provide opportunities to understand host-microbe interactions. Zebrafish are particularly useful for imaging studies, due to their translucent skin and the ease of in vivo microscopy. This allows zebrafish to be used to in studies of spatial architecture or longitudinal studies (imaging the same fish specimen over time) in ways that other model organisms can't be.

Zebrafish get their first microbes from their mother, just like mammals! The chorion, a protective coating that surrounds the zebrafish embryo, is seeded with microbes from passing through the cloaca of the female zebrafish. Surface-sterilizing this chorion allows researchers to generate germ-free animals that are very useful for microbiome studies.

A gut epithelial transcription factor is regulated by a signal from the gut microbiota, and this signaling interaction is conserved among all vertebrates. The transcription factor itself, HNF4, is found in both complex and simple animals, like the sea sponge, and may serve a long-conserved function in regulating interactions between animals and their microbiota.

Enteroendocrine cells release hormones based on specific chemical cues, but they can also interact with the nervous system. This makes them an important part of the gut-brain system, and the power of in vivo imaging has made zebrafish a great model for better understanding their function. Specific members of the microbiome specifically stimulate these EECs, sending signals up the vagus nerve to the brain.

Featured Quotes:

"We know that the zebrafish functionality of its intestine is very similar to what one encounters in the mouse or human intestine and we and others have been able to translate our findings from zebrafish studies into human biology."

On genomic studies that have found similar transcription profiles in zebrafish, stickleback fish, mice, and humans: "This suggested that there is a core transcriptome that gut epithelial cell use in different vertebrate species that haven't shared an ancestor in 420 million years!"

Comparing fish and mouse: "Genes regulated by microbiota in these respective hosts display a lot of overlap. Many of the same signaling pathways and metabolic processes are affected by microbiotas in different hosts in similar ways."

"There's been a lot of interesting research documenting the role of the intestinal microbiome in promoting harvest of dietary nutrients we consume. Much of that literature has been focused on the events that occur in the distal intestine, in the colon, where recalcitrant carbohydrates and proteins that make it that far, many of which we are unable to digest, are made available to the colonic microbiome, members of which are able to digest and degrade them to things such as short chain fatty acids, which we can consume."

"Eventually, we'll have some strong candidates in terms of specific bacterial strains or communities or factors or pharmacologic agents that could be used to affect dietary fat absorption or metabolism. We're still a long ways away from that."

"One of the fascinating things about developmental biology is that the only way you get a viable animal is if the different tissues and the different cells within the body are coordinating amongst themselves for energy, for nutrients, for oxygen, et cetera. As you're building an animal and as you're sustaining an animal, the different tissues have to cooperate. When that doesn't happen, when tissues or cells become selfish or don't play by the rules, you get things like cancer and other diseases as well...when I began learning about the field of microbiome science and some of the work that was coming out from that field, it sounded to me like the microbiome was going to be a really important part of that. Not only can we think of the microbiome as a 'microbial organ,' as it is sometimes called, and therefore worthy of consideration within the context of developmental biology, but also the influence of the microbiome on any one tissue is going to modify its need and its ability to cooperate within the integrated system."

Links for this Episode:

• John Rawls' lab website
• More amazing zebrafish images from the Rawls lab
• Duke University Microbiome Center
• Genome Research article on HNF4 regulation
• Cell Host and Microbe article on microbial influence on fatty acid absorption