Gut Microbiome Interactions with Drug Metabolism, Efficacy and Toxicity, excerpt:
Given the interplay between host and gut microbiota permanent changes in the composition of the latter resulting from drug treatment may have important long term consequences for the host. So, in considering the effects of the microbiota on drug metabolism there is also the need to consider the potential for the administration of drugs to radically alter its composition either directly on the microorganisms themselves, or as a result of toxic or pharmacological effects on the gut. Clearly the most obvious category of drugs to impinge on the microbiota are antibiotics and, whilst it is not possible here to fully review the topic, many studies have shown antibiotic administration to have both short and long term effects on its composition in animals and humans. In particular, incomplete recovery of the microflora in response to repeated exposure to ciprofloxacin has been shown for the distal gut microbiota of humans124. Whilst these observations were based on a relatively small sample (3 volunteers) the effect of antibiotic administration on the gut microbiota was “profound” with a rapid decrease in diversity and changes in community composition taking place within a few days of beginning administration. Although, following cessation of dosing, the microbiota recovered somewhat, this recovery was often incomplete. And, whilst the changes observed in bacterial communities in response to ciprofloxacin was noted as being broadly similar it differed between both subjects and between the two courses of antibiotic treatment and, at the end of the experiment the composition of the gut microbiota was different from what it had been at the start. As the authors noted, “Antibiotic perturbation may cause a shift to an alternative stable state, the full consequences of which remain unknown124.” One obvious consequence is of course the selection and persistence of antibiotic resistance in the gut and studies have revealed both ecological disturbances in the human gut microbiota after antibiotic administration and the long-term persistence of antibiotic resistance genes125.
As discussed above the presence or absence of the gut microbiota appears to have effects on CYP expression related to the lithocholic acid exposure to the host113. In a study on the effects of ciprofloxacin126 Cyp3a expression was suppressed in mouse liver by reducing lithocholic acid-producing intestinal flora. The authors noted that hepatic Cyp3a11 expression and triazolam metabolism were significantly reduced by treating SPF mice with the antibiotic, but that such changes were not seen when germ-free mice were dosed. In addition there was a reduction in both lithocholic acid-producing bacteria in the feces and the amount of its taurine conjugate in the livers of the SPF mice administered ciprofloxacin. Further support for the hypothesis that these effects were driven by the production of lithocholic acid, which is known to activate both the farnesoid X and PXR receptors, was provided by the response of germ free mice that, when treated with this bile acid, showed increased expression of Cyp3a11.
Whilst the effects of antibiotics on the gut microbiota, if unwanted, are hardly unexpected the increasing evidence that the very widely used proton pump inhibitors (PPI) cause changes in the microbiota (apart from those that can be anticipated for H. pylori), including reducing diversity, perhaps represents a less obvious consequence of therapy. However, numerous studies (of which a selection is given here) have associated PPI use and C. difficile incidence as well as changes in the ecology of the gut microbiota128–131. In a small scale study128 the use of these drugs resulted in decreases to observed operational taxonomic unit (OTU) counts after both 1 week and 1 month of dosing. These effects were partly reversible after a 1 month recovery period, supporting the hypothesis that PPIs disrupt the healthy human gut microbiome, and were suggested as a potential explanation for the association between prolonged PPI usage and the incidence of C. difficile. A much larger study, that examined fecal samples obtained from 1827 healthy twins, also revealed effects of PPIs on the gut microbiota129 showing significantly lower abundance and microbial diversity in those treated with such drugs. Concomitantly, there was a significant increase in the abundance of oral and upper GI tract species in fecal samples. These observations were confirmed by an independent interventional study and a paired analysis between 70 monozygotic twin pairs discordant for PPI use. These findings indicated a significant impact of PPIs on the gut microbiome and led the authors to caution against their over-use129.
In a further large scale in humans the effect of PPI use on the gut microbiota was undertaken on some 1815 individuals, in three cohorts, with 211 of the subjects using PPIs at the time of stool sampling130. PPI use was found to be associated with a significant decline in diversity, with changes in 20% of the bacterial taxa. As with the other large scale study described above129 species of oral bacteria were seen to be over-represented in the faecal microbiome of PPI-users. The authors suggested that the differences resulting from PPI use were “consistently associated with changes towards a less healthy gut microbiome” and in line with changes predisposing users to infection with C. difficile. On a population level, the effects of PPI were considered to be more prominent than the effects of antibiotics or other commonly used drugs.
A comparison of the faecal microbiomes of 32 of subjects with ≥5 years of continuous PPI use, compared with 29 non-users, found that changes in bacterial populations had occurred at the both species and phylum level with, in the case of the latter, decreased Bacteroidetes and increased Firmicutes131. The authors suggested that this alteration in the Firmicutes: Bacteroidetes ratio might pre-dispose PPI-treated subjects to C. difficile infection.
Another class of widely used compounds with a clear ability to affect gut physiology via toxicity, as described above, is composed of the NSAIDS. Various effects of exposure to NSAIDs on the composition of the gut microbiota have been described some of which are considered below132–134. An examination of the effects of age and administration of NSAIDs on the intestinal microbiota in a group of subjects aged between 70 and 85 years compared to that of much younger individuals (mean age 28yr) found “remarkable changes” 132 in composition. In terms of age-related differences it was found that the overall number of microbes was reduced in elderly compared to younger subjects but, interestingly, was higher in the elderly NSAID users compared to non-users of the same age group. Whilst many changes seemed to be associated with age the authors noted that the Actinobacteria group showed a reduction in Collinsella spp. in elderly subjects using NSAIDs in comparison to both the non-users and young adults. Similarly, the numbers of Lactobacilli seen the elderly NSAIDs users was reduced compared to non-users, leading the authors to suggest “that the use of NSAID along with age may also influence the composition of intestinal microbiota”. In a separate study133 the effect on the gut microbiota of exposure to NSAIDs was examined in a group of over 150 subjects. It was noted that the type of NSAID being used by these individuals had a significant influence on the composition of the gut microbiota with individual NSAIDs associated with distinct microbial populations. Thus the investigators found that aspirin users could be discriminated from those taking no medication via four OTUs namely Prevotella sp., Bacteroides sp., family Ruminococcaceae, and Barnesiella sp.), whilst the bacterial profiles seen for celecoxib and ibuprofen users both showed enrichment in the Acidaminococcaceae and Enterobacteriaceae. In the case of ibuprofen users the families Propionibacteriaceae, Pseudomonadaceae, Puniceicoccaceae and Rikenellaceae also showed greater abundance compared to either non-users or those taking naproxen. Individuals taking a combination of NSAIDs and proton-pump inhibitors differed from those taking only NSAIDs in species of Bacteroides and Erysipelotrichaceae. Further, Bacteroides species and a bacterium of family Ruminococcaceae differed between those only taking NSAIDs and those combining them with antidepressants and laxatives from those using NSAIDs alone. The authors concluded from this investigation, not unreasonably, that “bacteria in the gastrointestinal tract reflect the combinations of medications that people ingest”132.
An investigation of the interactions between the microbiota and the NSAID indomethacin at “clinically relevant doses” in mice, using both acute and chronic exposures, resulted in damage to the intestine described as “reminiscent of the upper and lower GI complications induced by NSAIDs in humans”134. Dosing with indomethacin was also associated with alterations in the intestinal microbiota in these mice, particularly expansion of pro-inflammatory bacteria. When treated with antibiotics changes, in both the pharmacokinetics and pharmacodynamics of the drug, were noted that were ascribed to the prevention of glucuronide hydrolysis by bacterial ß-glucuronidases (as would be anticipated based on the results of the inhibition of this enzyme described earlier91,92). Given that both PPI’s and NSAID’s have been shown to alter the composition of the gut microbiota it is hardly surprising that the use of these drugs on combination has been the subject of increasing interest.
A recent review135 on the topic of combined PPI and NSAID use concluded that, whilst PPIs were effective as a means of reducing damage to the stomach resulting from NSAID use they were “without proven benefit in preventing NSAID-related damage in the rest of the GI tract” and that the “frequent use of PPIs can exacerbate NSAID-induced small intestinal injury by altering intestinal microbiota”. Positive benefit has been seen from the use of probiotics in the prevention of NSAID-induced damage in patients receiving PPI and NSAIDs136.
Clearly, the use of therapeutic drugs that are designed to directly act on bacteria such as antibiotics, or those that the affect gut physiology via intended pharmacology, e.g., PPI’s, or accidentally through unintended toxicity, thereby causing intestinal damage, including the NSAID’s, have an obvious potential to result in changes to the environment that lead to compositional changes in the gut microbiota. It is however, less clear what the effects of other drugs might be on the biochemistry of the gut microbiota. Recent studies in mice137 have shown significant changes to the physiology, structure, and gene expression of the active gut microbiome following short-term exposure to a panel of xenobiotics (which included antibiotics). A range of bacterial genes were found to respond to drug exposure across, with changes seen in e.g., those responsible for antibiotic resistance, drug metabolism and response to stress. These effects were seen across a range of phyla. The authors suggested that the “results demonstrate the power of moving beyond surveys of microbial diversity to better understand metabolic activity, highlight the unintended consequences of xenobiotics, and suggest that attempts at personalized medicine should consider interindividual variations in the active human gut microbiome”137. Certainly, in e.g., the light of the differential responses of the microbiome seen for the various NSAIDs described above132, it would be of great interest to see this type of study expanded to cover a larger number of compounds and therapeutic classes.
