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Intestinal organoid or mini gut (Credit: Meritxell Huch, originally from the paper titled The Renaissance of Developmental Biology. PLoS Biol 13(5): e1002149. By way of WikiCommons.)

The potential of lab-grown mini organs goes beyond learning how to manufacture replacement body parts to undo disease; it could allow researchers to glimpse, for the first time, the swaths of microorganisms that live inside us and shape our health.

A deeply entrenched belief that microbes are universally bad is shifting as a result of mounting evidence that some players of the microbiome – the body’s resident bacteria – might even hold the key to good health. Yet we have no idea what most of these microbes look like as previously there were no good ways to grow them in the lab. Mini organs, or organoids, grown from stem cells or tissue biopsies, are emerging as a useful tool to study elusive bacteria thanks to faithfully mimicking the microbes’ natural environment.

Tricking bacteria to grow in the lab is no mean feat. The inability to culture microbes at will has frustrated scientists since the dawn of modern microbiology in the 19th century. When in the 1880s, the pioneering German microbiologist Robert Koch first succeeded in culturing bacteria on potato slices, and later on gelatin before settling on agar media, he unwittingly set the course for the next 150 years for how to isolate and grow pure cultures of microbes. But the standard method sufficed for only a tiny proportion of the microbial life, leaving the vast majority of bacteria unknown to us. To recreate, say, living conditions in the gut, it’s not enough to grow microbes at body temperature with no oxygen; researchers need to consider the entire tapestry of the gut ecosystem that the various types of human and bacterial cells are intricately woven into.

Unpicking the microbiome world

 According to the latest estimate, the human body contains more or less equal numbers of bacterial and human cells—or, some 39 trillion bacteria that live alongside 30 trillion human cells. These microbes sprawl on the skin and inside body crevices and internal organs, most of them making a home in the gut. From indigestion, to Multiple Sclerosis (MS), to cancer and behavioural disorders such as autism – or even the selection of a breeding mate – gut bacteria have been linked to just about every disease, accompanied by a varying degree of media hype and scientific evidence.

Perhaps least surprisingly, these bugs help us digest food. But their roles stretch beyond dicing up stubborn molecules with their fancy enzymes. A lot of research has shown that some gut bacteria help calibrate the developing immune system so that it learns to appropriately recognize and attack foreign invaders and fight off infections. Consequently, many autoimmune diseases – childhood diabetes, allergies, MS, to name a few – are thought to be spurred by the lack of protective bacteria in the gut.

Our life-long partnership with microbes begins at birth when we sample multitudes of bacteria first from our mothers and hospital birth wards and then through all other life encounters. A few years ago, the Human Microbiome Project (HMP), which sought to identify all human-dwelling microbes, revealed that there are between 300 and 1,000 different bacterial species in the gut of an average human (which in this case happens to be a 25-year-old male, who is 1.7m tall and weighs 70 kg).

The only reason we know these bugs exist is thanks to new sequencing methods that have outpaced the classical approach where microbes first have to be cultured in order to be studied. By mashing up the gut tissue, it’s possible to selectively sequence the bacterial DNA to find out what species are present. These kinds of studies have also revealed that while the microbiome composition is similar between people, no two microbiomes are the same.

But to really understand how the bacterial cells influence our own, scientists need a way to study the microbiome as a whole system, comprising not only different kinds of human cells, but also other microbes that keep each other’s community size in check.

So far, studies looking into the interactions between host and bacterial cells have largely been done using germ-free mice raised in a laboratory bubble devoid of all microorganisms. By infecting these animals with certain types of bacteria in a tightly controlled fashion, it is possible to tease out each microbe’s effect on health. But these experiments are hard to do, costly, and take a long time. For medical implications, more desirable approaches would be those allowing for high-throughput studies of a patient’s unique combination of microbes.

And organoids, especially mini-guts, could be the way forward. These self-assembling balls of tissue, the size of a peppercorn, are replete with different cell types that confer basic features of a gut including contractions that help digest food. First created in 2009, mini-guts were initially seen as a prototype of future transplant organs, grown solely in the dish. Since then, they have taken the research world by storm by becoming a key tool to study development and model disease, screen for new drugs as well as target treatment to a person’s genetic makeup.

All this makes organoids ideally suited for personalized medicine; for example, a patient-derived mini-gut could be used to test individual responses to shifting balances in microbial communities that can cause disease, but also be potential therapies.

This research is still in its infancy, but it’s already shining light on previously elusive human-microbe interactions. For example, mini-guts have revealed that the E.coli bacterium, which is linked to necrotizing enterocolitis, a deadly disease common in preterm babies, sticks differently to host cells depending on which part of the digestive system it is in. In other studies, researchers injected Salmonella or the notorious pathogen C. difficile directly into gut organoids to reveal how they subvert human cells to help spread the infection. Organoids also revealed how Helicobacter pylori, a bacterium behind stomach ulcers, spurs cell proliferation in gastric glands, which could explain the link between ulcers and stomach cancers.

Although it is early days, it’s not too far-fetched to imagine that if we had a clearer picture of the interactions occurring between bacterial and human cells, we might be able to one day treat, or even prevent, diseases by way of probiotics. Imagine, without getting too carried away, of staving off MS with a yogurt tailored to boost disease-fighting bacteria in your microbiome.

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Jovana Drinjakovic

Jovana Drinjakovic

Jovana Drinjakovic is a science writer with a background in cell and developmental biology. After completing her PhD in Cambridge (the old one) and a postdoc at the Hospital for Sick Children in Toronto, Jovana decided to switch gears and enrolled into a journalism course at the University of Toronto’s Munk School of Global Affairs. Her writing appeared in the Globe and Mail, the National Post, Dallas Morning News and U of T Magazine. Most days Jovana writes about discoveries at U of T’s Donnelly Centre, where she works as a communication specialist.
Jovana Drinjakovic

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