Atovaquone-Proguanil and Reduced Digestive Cancer Risk: A Toxoplasma gondii Connection
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Background
Cancers of the digestive tract, notably colorectal cancer (CRC) and pancreatic malignancies, represent a major global health burden, with microbial risk factors remaining poorly understood. Atovaquone-proguanil (A-P), an antimalarial agent, has been associated with reduced CRC incidence. We hypothesized that A-P may lower the risk of digestive cancers by eliminating Toxoplasma gondii , a protozoan capable of colonizing the digestive mucosa.
Methods
Using the TriNetX US Collaborative Network, we conducted propensity score-matched cohort analyses of patients aged 40-49 (mean age, 45.2 years), 50-59 (mean, 54.8), and 60-69 (mean, 64.6) who had received A-P versus any other medication. We assessed incident digestive cancers and calculated hazard ratios (HRs). Independently, we reanalyzed metagenomic data from 1,044 fecal microbiota samples (PRJEB6070; 156 individuals), quantifying T. gondii sequence reads among 8,425 microbial species and evaluating associations with CRC using the Mann-Whitney U test.
Results
A-P use was associated with a 49-54% lower risk of digestive cancers, with HRs of 0.51, 0.46, and 0.46 across the three age groups, respectively (P<0.0001). Protective associations extended to pancreatic malignancies (HRs, 0.55, 0.71, and 0.69; P<0.05). The reduced risk persisted more than a decade after treatment. In metagenomic analyses, T. gondii most strongly differentiated CRC from non-cancer samples (P=1.8×10 -16 ); its presence (≥50 reads) was associated with an odds ratio of 18.2 for CRC (P=2.3×10 -22 ).
Conclusions
T. gondii may represent a major, underrecognized microbial risk factor for digestive cancers. The long-term protective association with A-P use may reflect eradication of this parasite, suggesting a novel target for cancer prevention.
