Leak in the test tube
Leaky gut syndrome is still a presumptive condition from the point of view of official medicine, in which microorganisms and various substances leak from the intestine into the surrounding tissues and blood vessels. Most often it affects elderly people, cancer patients or patients with other chronic diseases, as well as healthy people who lead a particularly stressful lifestyle. Stressors destroy the connections between the cells forming the intestinal mucosa. Microorganisms and molecules seep through these cellular gaps and can provoke an immune response, leading to the development of various diseases associated with chronic inflammation (inflammatory bowel diseases, dementia, atherosclerosis, liver fibrosis, cancer, diabetes, arthrosis). Clinicians do not have a reliable tool for detecting leaky gut syndrome; in addition, there are no ways to treat it.
Researchers from the University of California, San Diego School of Medicine were able to simulate leaky gut syndrome using three-dimensional models of the gut created from human cells. These small organoids, or "mini-guts", helped to identify new biomarkers that characterize a leaky gut. The detected molecular signals will help doctors better diagnose the condition, track its progression and assess the success or failure of treatment. The group also used the model to find ways to repair the mucous membrane.
The group has previously identified a specialized molecular mechanism that helps tighten the gaps between intestinal cells – the so-called voltage polarity signaling pathway. They found that the connections between cells are destroyed when this pathway is overloaded. They also suggested that the drug metformin, prescribed for type 2 diabetes, can activate the signaling pathway and makes connections between cells stronger. The researchers made these fundamental discoveries on cell lines grown in Petri dishes.
The new study used three-dimensional models of intestinal organoids created from human intestinal cells. The inner wall of the intestine is not smooth, it looks like a rough terrain with hills and valleys. At the bottom of each "valley" – crypts – there are small reservoirs of stem cells. To produce intestinal organoids, the researchers collected a small number of these stem cells from patients' biopsies and grew them in the laboratory. In the intestine, stem cells differentiate into four different types of cells that make up the intestinal mucosa. But outside the body, in laboratory dishes, they curled up into a ball and formed crypts, or "mini-guts".
To simulate leaky gut syndrome, the researchers straightened the mini-intestines to expose the surface of the inner (mucous) lining of the intestine. Then they planted several types of bacteria in them, which led to the rupture of connections between intestinal cells.
The new model of the intestine allowed us to show that intercellular connections are controlled by a previously identified voltage polarity signaling pathway. Researchers have found that the signaling pathway that keeps the inner lining of the intestine intact begins to break down during the aging process of the body and as colorectal tumors develop. In addition, they noted an increase in the level of inflammatory markers with the destruction of the intestinal barrier. The group found that this signaling pathway could be restored. The drug for the treatment of type 2 diabetes mellitus metformin activates AMPK (AMP-activated protein kinase), an enzyme that plays a key role in the voltage polarity signaling pathway.
On the left – relatively dense intercellular connections of the young mini-intestine; in the middle – collapsing cellular connections in the old mini-intestine (marked with an asterisk); on the right – destroyed cellular connections in the old mini-intestine, restored by metformin.
Researchers have shown that metformin makes contacts between cells stronger by restoring mucosa damaged by bacteria, age-related processes or tumors. One of the markers of the voltage polarity signaling pathway is the protein occludin. In experiments, metformin increased the level of occludin by six times compared to untreated cells.
In the future, researchers plan to deepen their knowledge of diseases associated with leaky gut syndrome and test various ways of mucosal repair in the context of aging, inflammatory bowel diseases, cancer and other conditions to see if it is possible to reduce or prevent the occurrence and progression of these diseases.
Article P.Ghosh et al. The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer is published in the journal Life Science Alliance.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru Based on UC San Diego News Center: Human Gut-in-a-Dish Model Helps Define 'Leaky Gut,' and Outline a Pathway to Treatment.