An evolutionary explanation for antibiotics' association with increased colon cancer risk

Abstract

 : More than 10 studies have confirmed the association of antibiotic overuse with colorectal cancer. The exact cause is unknown, but most authors hypothesize that disturbance of colon microbiota is the main culprit. In this commentary, an evolutionary explanation is proposed. It is well known that antibiotics can induce antibiotic resistance in bacteria through selection of mutators-DNA mismatch repair deficient (dMMR) strains. Mutators have an increased survival potential due to their high mutagenesis rate. Antibiotics can also cause stress in human cells. Selection of dMMR colon cells may be advantageous under this stress, mimicking selection of bacterial mutators. Concomitantly, mismatch repair deficiency is a common cause of cancer, this may explain the increased cancer risk after multiple cycles of oral antibiotics. This proposed rationale is described in detail, along with supporting evidence from the peer-reviewed literature and suggestions for testing hypothesis validity. Treatment schemes could be re-evaluated, considering toxicity and somatic selection mechanisms.

Lay summary: The association of antibiotics with colon cancer is well established but of unknown cause. Under an evolutionary framework, antibiotics may select for stress-resistant cancerous cells that lack mechanisms for DNA mismatch repair (MMR). This mimics the selection of antibiotic resistant 'mutators'-MMR-deficient micro-organisms-highly adaptive due to their increased mutagenesis rate.

Keywords: DNA repair; MLH1; MSH2; adaptation; cancer evolution; natural selection.

Figure 1.

MLH1 gene tree. MLH1 orthologues exist in all five life kingdoms. Protein sequences were derived from Ensembl. Maximum-likelihood phylogeny method was used for the gene tree construction (CLC Main Workbench 21).

Figure 2.

Possible ways that inflammation or antibiotic use can predispose to cancer. ECM, extracellular matrix.