A mini-gut organoid generated in the lab from human stem cells. Photo via ucsdnews.ucsd.edu

A team of UC San Diego School of Medicine researchers created a miniature gut in a lab to simulate and pinpoint the causes of a mysterious malady known as “leaky gut,” the school announced Monday.

The condition occurs frequently in older patients, those with cancer or chronic illnesses and those with stressful lifestyles.

Essentially, the lining of intestines becomes more permeable, allowing bacteria and microbes to pass through the gut and contribute to diseases driven by chronic inflammation, such as inflammatory bowel disease, dementia, atherosclerosis and liver fibrosis, among others.

UCSD officials said it is difficult for physicians to tell who has leaky gut, and there are no treatments for it.

By taking biopsies from patients, researchers were able to take stem cells to create 3D models of human intestines to study the ailment. The organoids, or “mini-guts,” tell the story of the condition — including revealing biomarkers which doctors could eventually use to diagnose and treat the condition, school officials said.

Dr. Pradipta Ghosh, professor of cellular and molecular medicine at UCSD School of Medicine and Moores Cancer Center, was first author of the report published in Life Science Alliance. Dr. Soumita Das, associate professor of pathology at UCSD School of Medicine, was the senior author.

According to the researchers, they rolled open the mini-gut balls to expose the surface of the intestinal lining. They then sprinkled on several types of bacteria, which stressed the gut lining junctions and caused them to fall apart. Those junctions between gut cells break down with aging and in the presence of colorectal tumors.

Each model gut differed from patient to patient, which Ghosh said was helpful to the research but also imposed limits.

“Lots of research is done in mice that are inbred so that they are genetically identical, all in the same cage, eating the same diet, in order to remove these variables from the studies,” she said. “But lab mice are far more standardized than the same human from day to day, or patients we see in the clinics. Here, our model is a better representation of humanity. On the other hand, it also means that each organoid is its own unique experiment. We have to test many organoids to be able to make any claim, which we did in our study.”

The researchers found that diabetes drug metformin activates an enzyme which helps tighten the cell junctions back up — a potentially effective treatment for the condition.

The next step will be to look at diseases driven by leaky gut and to test various ways to tighten up those cell junctions.

“I think you’d be hard pressed to find a disease in which systemic inflammation is not a driver,” Das said. “That’s why, even though there are so many things we still don’t know, we’re excited about the broad potential this model and these findings open for developing personalized leaky gut therapeutics.”

To further advance these studies and others like it, Ghosh and Das lead HUMANOID, a core facility based at UCSD School of Medicine where researchers can access a number of different human organoids, including healthy or Alzheimer’s disease mini-brains and healthy or inflammatory bowel disease mini-guts, from both male and female patients at a variety of ages.

— City News Service

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