To Your Health: The Growing Importance of Clinically Relevant Drug-Nutrient Interactions
Population growth trends and an increased emphasis on chronic disease management have resulted in a rising incidence of drug-nutrient and drug-microbiome interactions. The challenge remains for researchers and clinicians to advance both basic and applied clinical research in this field to help bridge the gap between science and practice.
A Growing Public Health Concern
Significant increases in global medication utilization have resulted in myriad unintended consequences, among which is a dramatic rise in drug-nutrient interactions (DNIs). DNIs are defined as physical, chemical, physiologic or pathophysiologic relationships between a drug and a nutrient present in a food or a supplement. It is estimated that 70% of Americans take at least one prescription drug (more than 50% take two), of which over 40% are concurrently taking supplements. High-risk patient subgroups (i.e. patients over the age of 65 with multiple comorbidities, malnourished individuals, pregnant women and/or children) represent a disproportionate share of overall drug and nutrient utilization, further compounding the risk of complications in individuals engaging in polypharmacy for chronic disease treatment and management. In the Western world, adverse drug events are the third most common cause of mortality – third only to cardiovascular disease and cancer. Yet, DNIs remain meaningfully underreported; recent studies have estimated that 94% of potential drug reactions remain unreported by healthcare professionals (HCPs) internationally.[4,5] Meanwhile, emerging research has highlighted the measurable impact of prescription drugs on gut microbiome composition, a critical component of human metabolism, nutrition, physiology and immune function.[6,7]
The Clinical Relevance of Drug-Nutrient Interactions
A DNI is considered clinically relevant when the pharmacokinetic response of a drug (i.e. its absorption, volume of distribution, metabolism or excretion) is altered, impacting drug and/or nutrient availability at various sites of action or altering its physiological action at the cellular level. This may result in a variety of therapeutic drug and/or nutrient responses leading to loss of therapeutic efficacy or disease control, compromised nutritional status, drug toxicity, or mortality.[9,10]
While there are a variety of well-documented DNI’s, three are increasingly encountered in clinical practice:
Metformin & Vitamin B12
Biguanides such as metformin precipitate dose and treatment duration-dependent vitamin B12 deficiency in approximately 30% of patients with type 2 diabetes mellitus. Left untreated, vitamin B12 deficiency can lead to dementia, neurologic damage and anemia.
Proton Pump Inhibitors (PPIs) & Vitamins C and B12
The primary mechanism of action of PPIs is to inhibit gastric acid production. Thus, decreased absorption of micronutrients that depend on low pH environments for intestinal and cellular uptake may occur with chronic use. Recent case–control and prospective cohort studies measuring serum B12 in older adults demonstrated that the use of PPIs for at least 12 months was associated with an increased risk of B12 deficiency. This relationship persisted even when adjusting for multivitamin use or supplementation with B12 alone [13,14]. In addition, given the dependence of biologically-active vitamin C on gastric acid, recent research has demonstrated that PPI use may also be linked to the reduction of serum/plasma vitamin C levels. Finally, there is evidence to suggest that PPIs directly influence gut microbiome composition through alterations in overall gastric pH.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Vitamin C
A recent prospective, randomized, double-blind, parallel-arm study in healthy men and women found that 2400 mg aspirin for six days reduced vitamin C concentrations in urine, plasma, and particularly gastric mucosa. Decreased vitamin C in gastric mucosa may be due to increased antioxidant defenses in response to aspirin-induced mucosal damage, rather than impaired intestinal absorption.[Ibid] This hypothesis is supported by several in vivo and in vitro studies in which the co-administration of vitamin C and aspirin decreased the number of aspirin-induced gastric lesions and increased gastric tolerability. Rogers et al. recently assessed the impact of NSAIDs on the gut microbiome, ultimately concluding that gut bacterial composition varied among patients according to which specific NSAID was utilized (and which drugs were being taken concomitantly), thereby substantiating the impact of this medication class on gut health.
A Unique Opportunity
Although the clinical impacts of DNIs are becoming increasingly clear, the solutions to the problems they create are decidedly less so. Primarily, the HCP educational gap regarding DNIs needs to be addressed through a systematic overhaul of medical, pharmacy, and nursing education programs. Stringent DNI-specific patient-centered clinical guidelines must also be developed, thus improving awareness and accountability for all practitioners. Finally, given the increasing consumption of dietary supplements and the subsequent growth of DNI utilization and risk, it is essential that the existing regulatory framework is reviewed and optimized to facilitate greater supplement oversight and resourcing, ultimately helping bridge the gap between science and practice.
As DNIs and drug-microbiome interactions begin to take center stage, future therapeutic modalities will emerge. Probiotic + vitamin combination treatments have the potential to address clinical manifestations of drug-nutrient and drug-microbiome interactions. Ultimately, personalized array testing and pharmacogenomic applications will allow patients and HCPs to identify and treat clinical outcomes in a precise and patient-specific manner, thereby minimizing adverse events and improving overall clinical outcomes.
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 Mayo Clinic: Nearly 7 in 10 Americans take prescription drugs, April 2018 (https://newsnetwork.mayoclinic.org/discussion/nearly-7-in-10-americanstake-prescription-drugs-mayo-clinic-olmstedmedical-center-find).
 J. Boullata et al. Handbook of drug-nutrient interactions. Humana Press 2010.
 M. Raats et al. Food for the ageing population. Woodhead Publishing Limited 2009.
 A. Jemal et al. Trends in the leading causes of death in the United States in years 1970–2002. JAMA 2005;294(10):1255–1259.
 L. Hazell et al. Under-reporting of adverse drug reactions: a systematic review. Drug Saf 2006;29(5):385-371.
 L. Maier et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 2018;555:623-628.
 M. Bull et al. The Human Gut Microbiome in Health and Disease. Integr Med 2014;13(6):17-22.
 J. Boullata et al. Drug and nutrition interactions: not just food for thought. J Clin Pharm Ther 2013;38(4):269-271.
 U. Grober et al. Interactions between drugs and micronutrients. Med Monatsschr Pharm 2006;29(1):26–35.
 Op. cit. (J. Boullata 2013).
 G. Tomkin et al. Vitamin-B12 status of patients on long-term metformin therapy. Br Med J 1971;19(2):685-7.
 DSM. Understanding drug-nutrient interactions and their clinical relevance. Pharmaceutical Solutions Monograph 2018.
 Op. cit. (L. Hazell 2006).
 P. Mason et al. Symposium 8: Drugs and nutrition Important drug-nutrient interactions. Proceedings of the Nutrition Society 2010;69(4):551-557.
 Op. cit. (DSM 2018).
 M. Rogers et al. The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. Clin Microbiol Infect 2016;22:171-179.
 W. Caspary et al. Alteration of bile acid metabolism and vitamin-B12 absorption in diabetes on biguanides. Diabetologia 1977;13(3):187-93.
 Op. cit. (DSM 2018).
 Op. cit. (M. Rogers 2016).
 Op. cit. (DSM 2018).