Oral antibiotic use and risk of colorectal cancer in the United Kingdom, 1989–2012: a matched case–control study

Abstract

BackgroundMicrobiome dysbiosis predisposes to colorectal cancer (CRC), but a population-based study of oral antibiotic exposure and risk patterns is lacking.ObjectiveTo assess the association between oral antibiotic use and CRC risk.DesignA matched case–control study (incident CRC cases and up to five matched controls) was performed using the Clinical Practice Research Datalink from 1989 to 2012.Results28 980 CRC cases and 137 077 controls were identified. Oral antibiotic use was associated with CRC risk, but effects differed by anatomical location. Antibiotic use increased the risk of colon cancer in a dose-dependent fashion (ptrend <0.001). The risk was observed after minimal use, and was greatest in the proximal colon and with antibiotics with anti-anaerobic activity. In contrast, an inverse association was detected between antibiotic use and rectal cancers (ptrend=0.003), particularly with length of antibiotic exposure >60 days (adjusted OR (aOR), 0.85, 95% CI 0.79 to 0.93) as compared with no antibiotic exposure. Penicillins, particularly ampicillin/amoxicillin increased the risk of colon cancer (aOR=1.09 (1.05 to 1.13)), whereas tetracyclines reduced the risk of rectal cancer (aOR=0.90 (0.84 to 0.97)). Significant interactions were detected between antibiotic use and tumour location (colon vs rectum, pinteraction<0.001; proximal colon versus distal colon, pinteraction=0.019). The antibiotic–cancer association was found for antibiotic exposure occurring >10 years before diagnosis (aOR=1.17 (1.06 to 1.31)).ConclusionOral antibiotic use is associated with an increased risk of colon cancer but a reduced risk of rectal cancer. This effect heterogeneity may suggest differences in gut microbiota and carcinogenesis mechanisms along the lower intestinal tract.

The Role of the Gut Microbiome in Colorectal Cancer Development and Therapy Response

“…On the other hand, the use of antibiotics in early childhood has been associated with increased colonic adenoma formation (a precursor lesion to CRC) in later life, suggesting that a dysbiotic microbiota is acquired and hold over a longer period of time [83][84][85]. In a recent study based on the Clinical Practice Research Datalink (CPRD), the use of oral antibiotics with anti-anaerobic activity has been associated with increased CRC risk in a dose-dependent fashion in the UK population, although the effects differed depending on the anatomical location, being greatest in the proximal colon [86]. In this regard, a systematic review and meta-analysis of observational studies was performed to assess whether the use of antibiotics was associated with the development of pre-cancerous or cancerous lesions in adults [87].…”

Are antibacterial effects of non-antibiotic drugs random or purposeful because of a common evolutionary origin of bacterial and mammalian targets?

“…Thus, almost all of the nonantibiotics mentioned above affect mitochondrial functions being either part of their modes of action or potential toxicities. Many antibiotics cause mitochondrial dysfunction, too, thus explaining their anti-neoplastic activities [30], or possibly promoting tumorigenesis [265][266][267][268], obesity [269], and psychiatric disorders [270,271]. Thus, antibiotics as well as non-antibiotics exert beneficial or detrimental antimitochondrial activities.…”

Selective toxicity of antibacterial agents—still a valid concept or do we miss chances and ignore risks?

“…Moreover, antibiotic-resistance was not always, but usually, associated with a significant economic burden resulting from (re-)admission to hospital, need for i.v.-administration, or even use of a less well tolerated antibiotic [390][391][392][393][394][395][396]. Antibiotics causing mitochondrial dysfunction may promote tumorigenesis [397][398][399][400], obesity [401], and psychiatric disorders [402,403]. Furthermore, this review has demonstrated that antibiotics may have an unpredictable impact on cell culture metabolism, gene expression and signalling cascades thus supporting a previous study entitled "are cell culture data skewed?"…”