In­ac­tive In­gre­di­ents Meet Gut Mi­crobes

by Janie

Among all the hu­man microbiome's kalei­do­scopic ef­fects on hu­man health, one likely less fre­quently thought about by pre­scrib­ing med­ical pro­fes­sion­als is the abil­ity to chem­i­cally al­ter the med­ica­tions we take. It's well-es­tab­lished that our gut res­i­dents are teem­ing with en­zymes that can me­tab­o­lize drugs: plenty of ac­tive in­gre­di­ents are tweaked by mi­cro­scopic gut-dwellers, some of which have been pin­pointed to spe­cific mi­crobes. Digoxin, a fa­mous ex­am­ple, is a car­diac drug that is re­duced into an in­ac­tive form by gly­co­side re­duc­tases in some strains of Eg­gerthella lenta. Still so many other drugs re­main who­dunits or com­plete un­knowns when it comes to me­tab­o­lism by mi­crobes. When a mol­e­cule reaches the gut and en­ters the purview of the count­less mi­cro­bial en­zymes present, the en­zy­matic free-for-all that en­sues – re­duc­tion, deam­i­na­tion, demethy­la­tion, de­car­boxy­la­tion, acety­la­tion, de­halo­gena­tion, the whole she­bang – is a topic of study dubbed "phar­ma­comi­cro­bio­mics."

In­side any med­ica­tion ad­min­is­tered to a per­son is not just the ac­tive in­gre­di­ent. A pill taken orally, for ex­am­ple, is com­posed of the ac­tive in­gre­di­ent and a hodge­podge of other stuff that ben­e­fits qual­i­ties of the drug like ap­pear­ance, bioavail­abil­ity, and taste. This "other stuff" com­prises the ex­cip­i­ents, which are rather vaguely de­fined as any­thing else in the med­ica­tion that is in­ert, is not it­self an ac­tive in­gre­di­ent, and has no ef­fect on the ac­tual ac­tive ingredient(s). The va­lid­ity of this de­lin­eation is per­haps de­bat­able be­cause pre­sum­ably, any­thing you put in your mouth that goes to your gut will have some ac­tive ef­fect ei­ther on you or on the tril­lions of mi­cro­scopic com­pan­ions within you, or both.

So, what are these "fillers," and what do they do, and might they also be sub­ject to tin­ker­ing by the mi­cro­bial en­zyme ar­se­nal in­side us?

Lac­tose, for one, is the most com­mon ex­cip­i­ent. This is worth keep­ing in mind, con­sid­er­ing that 70% of the world's pop­u­la­tion is lac­tose-in­tol­er­ant. (This is rem­i­nis­cent of the sit­u­a­tion with vac­cines and peo­ple with egg al­ler­gies: many viruses used for vac­ci­na­tion are pro­duced in chicken eggs be­fore be­ing in­ac­ti­vated, and those with se­vere egg al­ler­gies must be cau­tious about the po­ten­tial for trace amounts of egg pro­tein car­ried along in some vac­cines.) Lac­tose that isn't bro­ken down in the small in­testines by lac­tase-phlo­rizin hy­dro­lase – the en­zyme com­monly lack­ing or in­ac­tive in lac­tose-in­tol­er­ant in­di­vid­u­als – moves into the purview of gut bac­te­ria, which then me­tab­o­lize the sugar them­selves into gasses and other byprod­ucts that cause cramp­ing, bloat­ing, di­ar­rhea, headaches, and re­lated un­pleas­antries.

Fig. 1. List of in­ac­tive in­gre­di­ents that can act as al­ler­gens or are po­ten­tially con­t­a­m­i­nated with al­ler­gens. Per­cent­age oc­cur­rence refers to frac­tion of all for­mu­la­tions of med­ica­tions (solid oral dosage forms) that con­tain the crit­i­cal in­gre­di­ent. Source. Fron­tispiece: Pills. Source

Other com­mon ex­cip­i­ents in­clude cel­lu­lose, starches, gelatin, sugar al­co­hols, in­or­ganic salts, su­crose, poly­eth­yl­ene gly­col, and shel­lac. Many of these are known al­ler­gens (Fig. 1), and sev­eral oth­ers are known to af­fect the GI sys­tem in many in­di­vid­u­als. Mal­todex­trin, xyl­i­tol, and iso­malt are of no­to­ri­ety, caus­ing dis­com­fort when fer­mented by gut bac­te­ria. In­ulin may also be a fa­mil­iar name in a more pos­i­tive con­text, as a pre­bi­otic fer­mented by gut bac­te­ria and in­ten­tion­ally taken by some for pur­ported ben­e­fits such as in­creased short-chain fatty acid pro­duc­tion. The re­cur­ring theme? Many "in­ac­tive in­gre­di­ents" may not be so in­ac­tive if they are present in amounts enough to trig­ger a re­ac­tion in a per­son. Lac­tose, as one ex­am­ple, is cer­tainly present in nu­mer­ous oral med­ica­tions in lev­els suf­fi­cient to cause dis­com­fort in lac­tose-in­tol­er­ant in­di­vid­u­als (>200 mg). How these ex­cip­i­ents are re­ceived by en­zymes en­coded in your genome and in your mi­crobes' genomes could con­ceiv­ably af­fect the phar­ma­co­ki­net­ics of the ac­tual drug.

But in re­al­ity, is any com­pound in­ert to bac­te­ria and their panoply of en­zymes for very long? The sce­nario with sea­weed poly­sac­cha­ride di­ges­tion by gut bac­te­ria in Japan­ese pop­u­la­tions comes to mind – en­zymes re­quired to di­gest com­plex poly­sac­cha­rides in sea­weed are not present in gut bac­te­ria of North Amer­i­can in­di­vid­u­als, but are en­coded in gut bac­te­ria of Japan­ese in­di­vid­u­als, pre­sum­ably hor­i­zon­tally ac­quired from fre­quent ex­po­sure to sea­weed and the mi­crobes that live on it and feed off it. In the con­text of a drug, too, a sim­i­lar sce­nario seems rea­son­able: the like­li­hood of gut bac­te­ria find­ing a way to tin­ker with both the ac­tive in­gre­di­ent and ex­cip­i­ent com­pounds in­creases the longer that drug is taken. Ex­pose a con­sor­tium of mi­crobes to some mol­e­cule for long enough, and chances are, you end up with a group that's divvied up the meta­bolic steps and found a way to to­gether munch through that mol­e­cule.

Could there be com­mer­cial tests to give clues as to how your body and its mi­crobes might re­act not only to iso­lated ac­tive drug in­gre­di­ents, but also to com­bi­na­tions of ac­tive and in­ac­tive in­gre­di­ents? There are com­pa­nies of­fer­ing to peek at your genome to iden­tify how cer­tain classes of drugs will in­ter­act with your body's unique ar­ray of drug-me­tab­o­liz­ing en­zymes. Whether Gen­e­Sight or 23andMe, these phar­ma­co­ge­net­ics ser­vices are well-in­tend­ing, but by sur­vey­ing only your cells' genome and not those of your mi­crobes', they are surely miss­ing a part of the pic­ture – all those strands and strands of ge­netic ma­te­r­ial con­tained within the count­less other be­ings that share your body and are in­te­grated into your life. But then again, this mi­cro­bial part of the pic­ture is prone to flux in­duced by lifestyle changes, in­clud­ing med­ica­tion reg­i­mens, and any one-time mi­cro­bial phar­ma­co­ge­netic analy­sis would be at best a fleet­ing snap­shot of the mi­cro­bial land­scape within you.

 

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