Frontline Science: Microbiota reconstitution restores intestinal integrity after cisplatin therapy

Abstract

Due to their cytotoxic activities, many anticancer drugs cause extensive damage to the intestinal mucosa and have antibiotic activities. Here, we show that cisplatin induces significant changes in the repertoire of intestinal commensal bacteria that exacerbate mucosal damage. Restoration of the microbiota through fecal-pellet gavage drives healing of cisplatin-induced intestinal damage. Bacterial translocation to the blood stream is correspondingly abrogated, resulting in a significant reduction in systemic inflammation, as evidenced by decreased serum IL-6 and reduced mobilization of granulocytes. Mechanistically, reversal of dysbiosis in response to fecal gavage results in the production of protective mucins and mobilization of CD11b myeloid cells to the intestinal mucosa, which promotes angiogenesis. Administration of Ruminococcus gnavus, a bacterial strain selectively depleted by cisplatin treatment, could only partially restore the integrity of the intestinal mucosa and reduce systemic inflammation, without measurable increases in the accumulation of mucin proteins. Together, our results indicate that reconstitution of the full repertoire of intestinal bacteria altered by cisplatin treatment accelerates healing of the intestinal epithelium and ameliorates systemic inflammation. Therefore, fecal microbiota transplant could paradoxically prevent life-threatening bacteremia in cancer patients treated with chemotherapy.

Editorial: Cancer, drugs, and bugs—Bacteriotherapy on the rise?

“…In more detail, they showed that the microbial gavage enhanced intestinal mucus production and the mobilization of CD11b+ myeloid cells into the mucosa. This in turn enhanced angiogenesis and healing of the cisplatin‐damaged intestinal tissues . With these findings, Perales‐Puchalt et al.…”

“…discovered that cisplatin therapy causes enhanced translocation of bacteria into the bloodstream which resulted in enhanced systemic inflammation (bacteremia). At the same time, alterations in the gastrointestinal microbial composition (dysbiosis) were induced in cisplatin treated tumor‐bearing mice . These results suggested that restoration of the pre‐cisplatin microbiome might reverse the therapy‐induced adverse effects.…”

“…Likewise, the microbiota might also impact the responsiveness to anticancer therapeutics and its adverse effects . In this issue of Journal of Leucocyte Biology, Perales‐Puchalt et al . examined how the administration of fecal microbiota paradoxically prevents cisplatin‐induced bacteremia and intestinal damage.…”

“…Therefore, it is commonly used as an antitumoral agent in many types of cancer. Due to its cytotoxic activity, cisplatin administration has also effects on rapidly dividing intestinal epithelial cells with extensive damage of the intestinal integrity . Using a mouse model for ovarian cancer, Perales‐Puchalt et al.…”

“…At least partially, Perales‐Puchalt et al. circumvent this potential problem, as they did not use “foreign” feces but used pretherapeutic feces . Therefore, the patient's wellbeing during chemotherapy might be improved by individual usage of feces.…”