The Two Faces of Col­ibactin

Note­wor­thy

Two decades ago, col­ibactin – a geno­toxic nat­ural prod­uct – broke into the scene with bad news. Its abil­ity to break apart DNA from eu­kary­otic cells, cou­pled to its pro­duc­tion by strains of the in­testi­nal res­i­dent E. coli raised the specter of a pos­si­ble in­volve­ment in colon can­cer.

Then, in 2022, came a find­ing that seemed to re­deem the mol­e­cule. Its geno­toxic ac­tiv­ity in­duced the SOS re­sponse in nu­mer­ous bac­te­ria. Con­se­quently, col­ibactin pro­duc­ers play an im­por­tant role in shap­ing the com­po­si­tion of the mi­cro­bial com­mu­ni­ties where they re­side. There­fore, view­ing col­ibactin in the hu­man gut pri­mar­ily as a car­cino­gen is not the whole story. As Roberto wrote in a post de­scrib­ing the chem­i­cal ecol­ogy of col­ibactin, think­ing of this nat­ural prod­uct as hav­ing evolved to at­tack eu­kary­otic hosts is "bark­ing up the wrong ecological/evolutionary tree."

But the bad news on col­ibactin re-emerged just last year. Re­sults from a large study pointed to an as­so­ci­a­tion be­tween the type of mu­ta­tions caused by col­ibactin and early-on­set colon can­cer. It seems that the wor­ri­some in­crease of the dis­ease over the last twenty years among those un­der fifty may be linked to ex­po­sure to col­ibactin dur­ing the first few years of life. 

How­ever, there may still be a good side to this mol­e­cule. A re­cent and note­wor­thy study of col­ibactin pro­duc­tion shows con­vinc­ingly that the mol­e­cule has a ben­e­fi­cial role; it de­fends a host against a pathogen. At least in hon­ey­bees.

The hon­ey­bee Apis mel­lif­era. ©Roberto Kolter

The hon­ey­bee gut mi­cro­biome is much less com­plex than that of hu­mans, mak­ing it a great model to de­fine the eco­log­i­cal roles of in­di­vid­ual bac­te­r­ial strains or even mol­e­cules. The hon­ey­bee has a rel­a­tively sim­ple gut mi­cro­biota dom­i­nated by five bac­te­r­ial taxa: Snod­gras­sella, Gilliamella, Bom­bi­lac­to­bacil­lus, Lac­to­bacil­lus and Bi­fi­dobac­terium. With mem­bers of these taxa present in their gut, hon­ey­bees do well. Un­til they be­come in­fected by Ser­ra­tia marcescens. How­ever, if they also har­bor a strain of Frischella per­rara that makes col­ibactin, hon­ey­bees re­sist the pathogen. The eco­log­i­cal con­text clearly mat­ters; ax­enic bees col­o­nized with only the col­ibactin pro­ducer lose fit­ness. But when the col­ibactin pro­duc­ers are part of the com­plete mi­cro­biota (whose mem­bers are col­ibactin re­sis­tant), col­ibactin pro­tects from the pathogen.

Now, back to col­ibactin-pro­duc­ing strains in the hu­man gut and some spec­u­la­tion. It is pos­si­ble that hu­mans har­bored such strains for mil­len­nia and that they con­tributed to colon can­cer all along but at a low fre­quency. But, per­haps, these strains also of­fered some pro­tec­tion from pathogens. Then, some ma­jor change in the nat­ural his­tory of our species changed about sev­enty years ago that led to changes in the com­po­si­tion of early-life gut mi­cro­biota. Think: an­tibi­otic overuse and abuse. This change could have led to an in­crease in abun­dance of col­ibactin pro­duc­ers in the guts of count­less chil­dren from then on­wards. And then, start­ing two decades ago, the neg­a­tive con­se­quences be­gin to emerge... Just some thoughts to con­sider.