Aspirin reduces the development of colorectal tumours in mouse models, an effect that is dependent on the gut microbiota. Moreover, the gut microbiota altered the bioavailability and chemopreventive effects of aspirin in mice, according to new research.

Evidence indicates that aspirin has chemopreventive benefit in human colorectal cancer (CRC), but the reported overall efficacy has varied. As the gut microbiota seems to have a role in CRC development and in drug metabolism, Jun Yu and colleagues wanted to explore this relationship in mouse models of CRC. “As accumulating evidence suggest that drugs shift the composition of gut microbiota, [and] conversely, gut microbiota affects the drug’s metabolism, we aimed to elucidate the specific role of the gut microbiota in aspirin-based CRC chemoprevention in various mouse models,” Yu explains.

The researchers examined the effects of gut microbiota depletion (via antibiotics) on the preventive efficacy of aspirin in two different mouse models of CRC (mimicking human CRC associated with either familial adenomatous polyposis or inflammatory bowel disease). Crucially, aspirin administration reduced colorectal tumour burden in both models of CRC, but only in mice with a depleted gut microbiota and not in mice with an intact microbiota. The same trend for fewer colorectal tumours was observed in germ-free mice given aspirin versus conventionalized germ-free mice given aspirin.

Notably, plasma levels of aspirin were higher in microbiota-depleted mice than in mice with an intact gut microbiota; a concomitant decrease in cyclooxygenase 2 and prostaglandin 2 (factors thought to be involved in the chemopreventive effects of aspirin) was observed in microbiota-depleted mice. Interestingly, analysis of the luminal contents from the mice demonstrated that aerobic gut microorganisms degraded aspirin, with Lysinibacillus sphaericus identified as one such microorganism that degraded aspirin in vitro and in vivo. Finally, monocolonization of germ-free mice with L. sphaericus decreased plasma levels of aspirin and, in CRC mouse models, L. sphaericus impaired the chemopreventive efficacy of aspirin.

the gut microbiota altered the bioavailability and chemopreventive effects of aspirin in mice

“The specific mechanism through which L. sphaericus degrades aspirin is still unknown,” explains Yu, who plans further work to determine the enzymes generated from L. sphaericus that catalyse aspirin degradation. “Human study is essential to evaluate the impact of L. sphaericus on aspirin-based CRC chemoprevention,” she adds.