What artificial stomachs and mini intestines reveal

Researchers led by gastroenterologist Prof. Dr. Michael Sigal are able to understand infectious diseases more precisely by studying organoids of the digestive tract. They are gaining a better insight of why some germs are followed by cancer decades later.

When Michael Sigal's team receives tissue from the clinic, they have to be quick. The small tissue samples of the stomach or intestinal wall, which are routinely removed during endoscopic examinations, are a valuable resource for research at the medical clinic specialized in hepatology and gastroenterology. "We treat them with great care so that the cells survive," says Sigal.  

His team members first separate stem cells from the tissue. These stem cells continuously produce new cells in the digestive tract. In a sense, they are constantly being replenished and as a result the stomach and intestines are given a fresh lining every one to two weeks. 

This process can be mimicked in the laboratory: Sigal's team adds a special cocktail of growth factors to the isolated stem cells. After a few days, the cells develop into stomach or intestinal epithelial cells. These are precisely the cells that line the inside of the digestive tract. Using a special method they published in Nature Communications, Sigal's team then co-cultivates epithelial organoids with so-called stromal cells that surround the epithelium in the human intestine. "By bringing these two cell types together, they form structures by themselves looking almost like a cross-section of the intestine or stomach. That's impressive," says Sigal. The tissue duo of stromal cells and epithelial cells does not simply grow flat in the culture dishes. "The cells show a three-dimensional structure, the so-called crypts, as we can find them in the stomach and intestines," describes Sigal. A picture in his office shows the crypts whose structure is reminiscent of closely spaced stalagmites. The crypts are surrounded by connective tissue stromal cells. When stromal cells and epithelial cells get into contact, they arrange themselves into crypts under certain conditions. "The two cell types even supply the growth factors to each other to some extent, so we have less work to do," says Sigal happily. 

The stomach and intestinal organoids that were cultivated out of stem cells of tissue samples can reach a size of a few millimeters. Sigal can draw a lot of insights from these miniature systems. For example, infections caused by the stomach germ Helicobacter pylori demonstrate an everlasting problem for patients. Whilst most patients only develop mild inflammation of the mucous membranes, some develop ulcers. One in a hundred will eventually develop stomach cancer decades later, a disease that is extremely difficult to treat. Infections are therefore considered as one of the most crucial risk factors in the development of stomach cancer. Researchers around and beyond Sigal are trying to find out under which conditions the bacterium becomes harmful. 

"We can infect our organoids with Helicobacter pylori and observe the effects of the infection." For a long time, researchers believed that the bacterium only spread on the surface of the stomach lining. However, a small part of the bacterial population reaches the stem cells located at the bottom of the crypts. Here, the bacteria are potentially able to genetically modify stem cells. In addition to possible damage to the DNA, cell division is also stimulated. Thus, stem cells are able to produce new tissue more quickly. "Accelerated tissue regeneration is useful in the case of a wound. However, long-term cell proliferation at this pace can also promote cancer," says Sigal, outlining the current state of knowledge. 

By using the gastric organoids, he is able to take a closer look at the interaction of the stomach germ and stem cells. Sigal's team can also genetically modify Helicobacter pylori in order to understand which characteristics make the germ so dangerous. Further, the effects of individual inflammatory substances produced during a Helicobacter pylori infection can be investigated with organoids. 

Sigal is also interested in other pathogens causing similar damage to the intestine. Certain Escherichia coli and Klebsiella bacteria are able to produce a toxin called colibactin. Roughly 20 to 30 percent out of the population have these toxin-producing microorganisms in their intestinal tract. Colibactin could be even more harmful to the genetic material of stem cells than Helicobacter pylori, according to Sigal. The toxin breaks the double strand of DNA in a specific way that pathologist have also found in cancer cells of colorectal cancer patients.  "When we add colibactin-producing bacteria to our intestinal organoids, they acquire characteristics of cancer cells. A kind of mini-cancer develops," Sigal describes, adding "Nobody needs to panic about this. It is known that not 30 percent of the population actually develops bowel cancer. So there must be protective factors against damage caused by colibactin." 

The intestinal mucosa, for example, is almost impermeable to many substances and bacteria, so that only important nutrients enter the blood circulation. A healthy, balanced diet with plenty of wholegrain products tends to keep this barrier intact. Sigal is now looking into such protective possibilities, such as the role of the microbiome, with the help of his organoids. 

Original text (German): Susanne Donner, March 2023.