Altered colon collagen may explain mcEDS digestive signs: Study
Mice with condition had fewer, smaller collagen fibrils, researchers find
Abnormally arranged collagen fibrils, the protein building blocks of connective tissue, in the colon may help explain gastrointestinal problems in people with the rare musculocontractural form of Ehlers-Danlos syndrome (EDS), a mouse study suggested. Researchers noted that the defective collagen assembly seen in the colon of these mice is thought to cause fragile skin in human patients.
“This study sheds light on the … potential mechanisms underlying gastrointestinal symptoms in patients with mcEDS,” wrote researchers in the study, “Carbohydrate sulfotransferase 14 gene deletion induces dermatan sulfate deficiency and affects collagen structure and bowel contraction,” published in PLOS One.
Musculocontractural EDS, or mcEDS, is a rare EDS subtype caused by mutations in both copies of the CHST14 or DSE genes. Such mutations lead to a deficiency in dermatan sulfate, a complex sugar molecule that supports and stabilizes connective tissue, which provides structure to joints, skin, blood vessels, and other organs.
As in all types of EDS, mcEDS is generally characterized by fragile tissue, hypermobile joints, and soft, stretchy skin. The rare EDS subtype also features adducted thumbs, or a thumb lying toward the palm, and clubfoot, a foot that’s twisted out of shape so that it points down and inward. Other signs include muscle weakness with low muscle tone, developmental motor delays, heart and kidney involvement, abnormal facial and head features, and long, slender fingers.
Gastrointestinal problems, including constipation, diverticula (irregular, bulging pouches in the colon wall), inflammation of diverticula (diverticulitis), and bowel perforation have also been reported in people with mcEDS.
Underlying mcEDS
Because the underlying mechanisms of these symptoms have not been thoroughly investigated, a research team in Japan set out to determine the effects of dermatan sulfate deficiency on the colon in mice lacking both CHST14 gene copies.
The team first examined decorin, a protein in the colon that carries dermatan sulfate or a similar molecule called chondroitin sulfate. As expected, decorin in healthy mice is predominantly modified by dermatan sulfate. In mice lacking CHST14, dermatan sulfate on decorin was significantly reduced and replaced by chondroitin sulfate.
“The compensatory increase in [chondroitin sulfate] was thought to be due to accumulation of dermatan caused by loss of [CHST14] and promotion of chondroitin synthesis,” the researchers wrote.
The colons of 10-week-old mcEDS mice were shorter and more contracted than those of healthy mice, even after adjusting for weight differences. Still, no other anatomical abnormalities or diverticula were observed in the colons of these mice.
Looking more closely, the researchers found mcEDS mice had fewer collagen fibrils, the fundamental protein building blocks of connective tissue. Moreover, the collagen fibrils had significantly smaller diameters in mcEDS than in healthy mice.
Despite these changes, there were no differences in daily food consumption, the time it took food to move through the colon, or the amount of feces between mcEDS and healthy mice. Susceptibility to colon rupture was also similar between the two groups.
A lack of constipation in mcEDS mice “may be influenced by the fact that mice do not withhold defecation,” the scientists wrote.
Colitis, or inflammation of the colon, was induced in mice. Though colitis is known to promote weight loss, diarrhea, and bloody stools, there were no differences between mcEDS and healthy mice in body weight and disease activity index scores, a composite measure of weight loss, stool bleeding, and stool consistency. Ulcer formation and swelling were also similar in the colon tissue between the two groups of mice.
In line with these findings, the infiltration of immune neutrophils into colon tissue was generally comparable between mcEDS and healthy mice, with matching levels of signaling proteins that promote inflammation.
“We found that [dermatan sulfate] deficiency affects collagen assembly and intestinal contraction,” the authors concluded. “However, unlike humans, no significant alterations in physiological function of the colon were observed” in mice, they wrote.
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