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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