CF Gut Disease Influenced by Both Immune, Epithelial CFTR Defects
Immune cell defects mostly affected small intestine; epithelial defects, the large intestine
Defects in both epithelial and immune cells contribute to changes in the gut microbiota, the populations of microbes naturally present in the gut, seen in cystic fibrosis (CF), a recent study in mice showed.
While the immune component had the greater effect in the small intestine, however, the epithelial defect mostly influenced the large intestine.
“Our current study suggests that CF immune defect contributes to gut dysbiosis [an imbalance in the gut microbial community]. This finding refines the current theory that attributes CF intestinal disease solely to the epithelial defect,” the researchers wrote.
The study, “Cftr deletion in mouse epithelial and immune cells differentially influence the intestinal microbiota,” was published in Communications Biology.
CF affects several organs, including the gut. While pulmonary complications are predominant in adults with CF, gut disease starts before birth and issues such as constipation and intestinal obstruction persist throughout life. In fact, about 60% of patients experience gut swelling, redness, or ulcerations.
CF is caused by mutations in the CFTR gene, which has the instructions to make the CFTR protein. If healthy, CFTR regulates salt and water flow into and out of cells. All major cell types lining the intestines have CFTR. As such, defects in this protein have been associated with intestinal acidification, bacterial overgrowth, and gut dysbiosis.
Other studies found that the immune system affects bacteria that’s key to gut health and that CFTR defects in immune cells compromise their function.
“Despite these functional impairments, it is not determined whether the CF immune defect is directly involved in shaping the intestinal microbiota,” the researchers wrote.
Effect of epithelial, immune defects
Scientists at Louisiana State University investigated if both epithelial and immune defects influence the gut microbiota and contribute to gut-related CF complications.
To do so, they compared populations of microbes in the gut of healthy mice versus mouse models of CF. Specifically, CF mice had CFTR deletions in the whole body or in different cells of the immune system.
Feces and intestinal samples were used to perform gene sequencing — a method to determine the exact sequence of a gene and detect mutations — to characterize the microbes in the healthy and CF mice.
Results showed CFTR deletions in the whole body led to the most pronounced changes in intestinal microbiota, with significantly less species diversity compared to controls and to CF mice with no CFTR in either neutrophils, macrophages, or in neutrophils, monocytes, and macrophages combined. CFTR deletions in macrophages or neutrophils alone had little to no impact on the microbiota, whereas the combined CFTR loss in neutrophils, monocytes, and macrophages had an effect closer to deletions in the whole body.
“These data suggest that the innate immune defect contributes to the altered CF intestinal microbiota,” the scientists wrote.
Differences in large, small intestines
Looking at how similar the gut microbiome is by intestinal location, the team found that mice with whole body CFTR deletions had the greatest differences in both small and large intestines compared to all other groups.
“As the small intestine is the site most susceptible to pathology [disease] and obstruction in CF, our data suggest that the host innate [normal] immunity plays a direct role in shaping the diverse mouse microbiomes at this location,” the researchers wrote.
In fact, an analysis of differentially abundant groups of bacteria showed that, while the immune component was a major factor in small intestine dysbiosis, the epithelial defect largely influenced changes in the large intestine.
In the small intestine, goblet cells, involved in creating a coat of mucus in the gut, showed significantly greater density in all CF groups than in control mice. Alterations in goblet cells have been associated with the severity of CF intestinal disease.
The researchers also performed a bone marrow transplant between wild-type mice (controls) and CF animals with bodywide CFTR deletion to confirm their results. This led to CFTR production only in immune cells, whereas control mice transplanted with bone marrow from other controls had CFTR in both epithelial and immune cells.
Here, results showed that altering the immune system had a greater impact in the small intestine than in the large intestine, as assessed by differences in the abundance of bacterial groups.
“From these data, we conclude that the small intestinal microbiota was more sensitive to host immune modulation than the large intestinal microbiota. Hence, CF immune defect is a major contributor to small intestine dysbiosis seen in CF,” the researchers wrote. “In summary, our study provided data to suggest that both epithelial defect and immune defect in CF collectively influence the intestinal microbiota. However, each has its own unique role in modulating the microbial community.”