Liver disease related to CF linked to changes in fecal bacteria

Data further support the gut-liver axis hypothesis as a cause of CFLD

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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People with advanced liver disease associated with cystic fibrosis (CF) have more pro-inflammatory bacteria in their feces relative to those without CF- associated liver disease, a study shows.

The findings suggest similar changes in the gut microbiota, or the populations of friendly microbes that naturally live in the intestines. This microbial community helps maintain a balanced gut function, protect against disease-causing organisms, and influences a person’s metabolism and immune system.

Six months of treatment with Trikafta (elexacaftor/tezacaftor/ivacaftor) reduced the abundance of pro-inflammatory fecal bacteria and intestinal inflammation in people with CF-related liver disease (CFLD).

The data further support the gut-liver axis hypothesis as a cause of CFLD. The hypothesis considers that a CF-associated gut microbiota imbalance promotes intestinal inflammation and leakage that allows pro-inflammatory bacteria to enter the liver, causing liver inflammation and damage.

The study, “Alterations in the fecal microbiota in patients with advanced cystic fibrosis liver disease after 6 months of elexacaftor/tezacaftor/ivacaftor,” was published in the Journal of Cystic Fibrosis.

CF is caused by mutations in the CFTR gene that result in a faulty or missing CFTR protein. As a result, cells cannot properly regulate the flow of salt and water, leading to a thick and sticky mucus being produced that accumulates in organs.

About 10-15% of patients develop CFLD, which is associated with a significant disease burden and for which there are no effective preventive treatments. The underlying mechanisms of CFLD remain poorly known, but growing evidence supports the gut-liver hypothesis.

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Effects of Trikafta on liver disease

Trikafta, a next-generation CFTR-modulator therapy, can improve lung function and nutritional status in CF, so researchers in the U.S. sought to characterize the the fecal microbiota in people with or without advanced CFLD, before and after starting Trikafta, to learn more about its effects on liver disease or fecal microbiota. The samples belonged to CF patients, ages 12 and older, enrolled in PROMISE (NCT04038047), a multicenter, observational study of Trikafta’s long-term clinical effects.

“Evaluating the effect of [Trikafta] on the natural history of CFLD may … help determine which model best explains CFLD [mechanisms], a critical step towards developing better therapies for this morbid complication,” the researchers wrote.

The analysis included 11 CF patients with advanced CFLD, classified as elevated blood pressure in the major liver vein and/or liver scarring, that is, cirrhosis,  and 23 aged-matched CF patients without liver disease. The patients’ stool samples were collected within 30 days before treatment as a baseline and at one and six months after treatment started. A total of 93 samples were collected.

Most patients carried F508 del, the most common CF-causing mutation, in one copy of the CFTR gene and hadn’t received treatment with other CFTR-modulator therapies.

Compared with those without liver disease, those with advanced CFLD had significantly higher baseline amounts of potential pro-inflammatory Streptococcus salivarius and Veillonella parvula, and a significantly lower abundance of Ruminococcus torques. After six months of Trikafta, relative abundances of S. salivarius and V. parvula were significantly lower in CFLD patients, but not in those without liver disease.

Eight CFLD patients (72%) had decreased fecal calprotectin, a marker of gut inflammation, six months after starting treatment. Of these, half had abnormal calprotectin at baseline, which was normalized after six months. This effect was associated with a significant decrease in S. salivarius and a trend towards decreasing V. parvula.

Of the 23 CF patients without liver disease, most (70%) also had a decrease in fecal calprotectin after six months on Trikafta and half had abnormal fecal calprotectin levels at baseline.

“These results support an association between dysbiosis and intestinal inflammation in CFLD with improvements in both [post-Trikafta], lending further support to the gut-liver axis in [advanced] CFLD,” wrote the researchers, who said future research should characterize fecal microbiota at later timepoints and evaluate its correlation with markers of intestinal integrity and liver function.