Neutropenia is the depletion of neutrophils, a type of white blood cell, which is a typical side effect of cytotoxic cancer treatments like chemotherapy and radiation. Patients with severe neutropenia often experience fever. The mucus-degrading commensal bacterium Akkermansia muciniphila was identified as the possible causative agent of this fever, according to research published on November 16 in Science Translational Medicine. The results of this study demonstrate that these microbes reduce the thickness of the mucus layer in mice, leaving the animals more susceptible to secondary bacterial infections; this finding may lead to strategies for preventing treatment-induced fevers in humans.
Scientists have found connections between changes in gut microbiota and neutropenic fever, suggesting that infections arising in the gut can be a key source of bacterial infections in the blood. To learn more about this connection, s cientists at the University of Texas MD Anderson Cancer Center studied fecal samples from 119 patients having stem cell transplantation, a process that is followed by radiation and chemotherapy. Many patients who experienced fever during the first few days of neutropenia were shown to have a higher relative abundance of A. muciniphila and Bacteroides species in their gut. These bacteria are able to break down mucin, an important part of the mucus layer.
Thereafter, researchers looked into whether or not mice’s microbiomes are affected by radiation therapy or chemotherapy. Finding that the mice group exposed to these radiation therapy began eating less food encouraged the researchers to undertake a third experimental part of the study, as loss of appetite is a common side effect of cancer treatments. Microbiomes of healthy mice that were not given cytotoxic cancer treatment but were placed on a calorie-restricted diet were studied in the third group. Compared to control mice, Akkermansia and Bacteroides levels increased six days after radiation or chemotherapy, or after one week on the restriction diet. Histological examinations demonstrated that along with these alterations in the composition of the microbiome, the mucus layer in the colon became noticeably thinner.
MD Anderson researcher Jennifer Karmouch, a co-author of the study, explains that a decreased mucus layer in the intestine makes it more likely for bacteria to enter the bloodstream and cause infection. That’s why the team believes some patients spike a fever in the first place.
Karmouch and colleagues wanted to know if they could stop Akkermansia from proliferating and stop the subsequent reduction in the thickness of the colonic mucus layer. They did this by administering one of two medications to mice. Azithromycin, an antibiotic that specifically targets Akkermansia, was given to some of the mice, while others were given propionate, a metabolite that has been observed to be deficient in the colonic lumen of calorie-restricted mice. The group also found that propionate inhibits mucin consumption by Akkermansia in an in vitro experiment.
The mucus layer in the colons of irradiated mice was maintained by both therapies. As the FDA currently does not recommend azithromycin for cancer patients, propionate may provide some hope, as Karmouch suggests. Karmouch said that she and her team are trying to figure out how to deliver it more directly to the colon because the metabolite’s low absorbability limits its potential clinical application.
More than half of the patients who developed a neutropenic fever had higher-than-average levels of Akkermansia in their gut microbiomes, but the study shows that Akkermansia levels alone cannot predict if a patient with neutropenia will develop fever, as some cancer patients with fevers had low Akkermansia counts. Karmouch speculates that there may be functional variations between A. muciniphila strains, and that this may affect the bacteria’s ability to thin mucus.
There could be other factors to take into account, though. The work demonstrates a really fascinating link, says Ami Bhatt, a microbiome scientist at Stanford University. However, she adds, it does not prove that Akkermansia is essential or sufficient for the thinning of the mucus, and other mucin-degrading organisms can occupy that niche. While Bhatt did not contribute to this study, she is on the scientific advisory board of Cantata Bio, a startup focused on infectious diseases, and has worked with one of the coauthors in the past.
Nevertheless, as Bhatt notes, this study adds to the growing body of evidence that the gut microbiota affects the possibility of potential pathobionts making it into the blood system and causing illnesses.
Sources:
Schwabkey, Z. I., Wiesnoski, D. H., Chang, C. C., Tsai, W. B., Pham, D., Ahmed, S. S., Hayase, T., Ortega Turrubiates, M. R., El-Himri, R. K., Sanchez, C. A., Hayase, E., Frenk Oquendo, A. C., Miyama, T., Halsey, T. M., Heckel, B. E., Brown, A. N., Jin, Y., Raybaud, M., Prasad, R., Flores, I., … Jenq, R. R. (2022). Diet-derived metabolites and mucus link the gut microbiome to fever after cytotoxic cancer treatment. Science translational medicine, 14(671), eabo3445. https://doi.org/10.1126/scitranslmed.abo3445
