Stem cell-derived mini-intestines reveal bacteria’s key role in building up a newborn’s gut

The following factoid may induce an identity crisis for some people but it is true that our bodies carry more microbes than human cells. Some studies in 1970’s estimated the ratio at 10:1 though more recent calculations suggest we’re merely half microbe, half human.

Because microbes are much smaller than human cells they make up only about 1 or 2 percent of our total body mass. But that still amounts to trillions of micro-organisms, mostly bacteria, that live on and inside our bodies. The gut is one part of our body that is teeming with bacteria. Though that may sound gross, you’re very life depends on them. For example, these bacteria allow us to digest foods and take up nutrients that we wouldn’t be able to otherwise.

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E. coli bacteria, visible in this enhanced microscope image as tiny green rods, were injected into the center of a germ-free hollow ball of cells called a human intestinal organoid (inset image, top right). Within 48 hours, the cells formed much tighter connections with one another, visible as red in this image. Image courtesy of University of Michigan.

When we’re first born our intestines are germ-free but overtime helpful bacteria gain access to our gut and help it function, protecting it from infection by the continual exposure to harmful bacteria and viruses. New research out of the University of Michigan Medical School reported in eLife now shows that the initial bacterial infiltration is even more important than scientists previously thought. It appears to play a key role in stimulating human gut cells to shore up the intestine in preparation for the full wave of both micro-organisms and pathogens that are present throughout a person’s lifetime. The finding could help researchers discover methods to protect the gut from diseases like necrotizing enterocolitis, a rare but dangerous infection that strikes newborns.

To reach these conclusions, the research team grew human embryonic stem cells into miniature intestines in the lab. These so-called human intestinal organoids, or HIOs, are structures made up of a few thousand cells that form hollow tubes with many of the hallmarks of a bona fide intestine. The HIOs were first kept in a germ-free environment to mimic a newborn’s intestine. Then a form of helpful E. Coli bacteria, the same that’s often found in an infant’s diaper, was injected into the HIO and allowed to colonize the inside of the intestine.

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A single human intestinal organoid, or HIO — a hollow ball of cells grown from human embryonic stem cells and coaxed to become gut-lining cells. Scientists can use it to study basic gut development, and the effect of microbes on the cells, in a way that mimics the guts of newborn babies. Image courtesy of University of Michigan

The team observed several changes in gene activity shortly after the bacteria was introduced. Within a day or two, genes involved in producing proteins that fight off harmful microbes increased as well as genes that encode mucus production, a key part of protecting the cells that face the inside of the intestine. Other key features of a maturing intestine, such as tighter cell-to-cell connections and lowered oxygen levels were also stimulated by the presence of the bacteria. As co-senior author Vincent Young, M.D., Ph.D. explained in a press release, these results put the team in a position to uncover new insights about intestinal biology and disease:

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Vincent Young

“We have developed a system that faithfully reproduces the physiology of the immature human intestine, and will now make it possible to study a range of host-microbe interactions in the intestine to understand their functional role in health and disease.”

 

The particular mix of microbes found in one person versus another can differ a lot. And the impact of these differences on an individual’s health has been a trending topic in the media. Lead author David Hill, Ph.D., a postdoctoral fellow in the lab of Jason Spence, Ph.D., thinks that’s one specific research path that they aim to investigate with their HIO system:

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David Hill

“We hope to examine whether different bacteria produce different types of responses in the gut. This type of work might help to explain why different types of gut bacteria seem to be associated with positive or negative health outcomes.”

 

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