Effects of the microbiome on drug response. In this figure, the processes of drug bioaccumulation and metabolism are depicted. Bioaccumulation refers to the ability of bacteria to store certain drugs intracellularly. Drug metabolism, on the other hand, indicates how the microbiome participates in the metabolization of drugs. The arrow in the box corresponding to ‘drug biotransformation’ indicates that bacteria interact with the drug to metabolize it.
Currently, the scientific community is showing great interest in the relationship between drug response and the microbiome or microbiota. This growing attention is reflected in the abundance of publications on this topic. As an example, some of the most recent experimental studies in the field of pharmacomicrobiomics are presented in Table 1.
3. Effect of an Infection on Drug Response
3.1. Difference between Pharmacomicrobiomics and Drug–Infection Interaction
There are two fundamental differences between pharmacomicrobiomics and drug–infection interaction. The first one lies in the type of microorganism that influences the drug response. In pharmacomicrobiomics, the microbiome is the protagonist, whereas in drug–infection interaction, it involves a pathogenic microorganism
[1013][2932][3033].
Pathogenic microorganisms are those capable of causing diseases, as they are transmissible and, in some cases, have developed the ability to evade cellular defenses. Only a small percentage of microbes are inherently pathogenic. Pathogenic microorganisms include some viruses, bacteria, prions, fungi, protozoa, and parasites
[3033].
The second difference is that, unlike pharmacomicrobiomics, which modifies the drug response through bioaccumulation or metabolism, infections can alter the drug response mainly through inflammation and the regulation of CYP enzymes
[1114][3134][3235].
3.2. Inflammation as a Result of Infection Modifies Drug Response
Inflammation is a response to aggression, whether of endogenous or exogenous origin, and can manifest acutely or chronically. It plays a prominent role in numerous diseases, including infections
[3336]. While inflammation is a complex and highly coordinated process involving multiple cell types and molecules operating in a cascading network, cytokines play a particularly relevant role in this process
[3437]. For several years, it has been proven that inflammation has a significant impact on drug metabolism. This is partly because elevated levels of proinflammatory cytokines lead to a negative regulation of CYP enzymes, which play a fundamental role in drug metabolism
[3134][3538][3639].
CYP enzymes are polymorphic proteins associated with a heme molecule and are capable of absorbing light at a wavelength of approximately 450 nm when exposed to carbon monoxide. These enzymes play an essential role in the biosynthesis of compounds such as steroids, prostacyclin, and thromboxane A2. While CYP enzymes are found in a wide variety of tissues, their expression is most prominent in the liver and small intestine. Regarding drug metabolism, a specific group of CYP enzymes, including CYP 1A2, 2B6, 2D6, 2C8, 2C9, 2C19, and 3A4, are responsible for metabolizing most drugs
[3134][3740].
CYP enzymes during inflammation can be repressed by different mechanisms. These include the transcriptional downregulation of transcription factors, interference with nuclear transcription factor dimerization and translocation, alteration of C/EBP-enriched signaling in the liver, direct regulation by NF-κB, and various post-transcriptional mechanisms
[3639]. It has recently been proposed that the reduction in CYP enzyme activity during inflammation, in the context of an infection, is due to a physiological response. This response involves a shift from a metabolic mode to a defensive mode, allowing the cell to concentrate its resources on fighting the infection
[3841].
Regardless of the physiological cause, infections impact CYP enzyme activity due to the inflammatory process they trigger
[3336][3942][4043]. A prominent example of this is the disease caused by SARS-CoV-2, known as COVID-19. This disease follows a progression divided into three stages: the viral invasion phase, the pulmonary immunoinflammatory phase, and the hyperinflammatory phase. Inflammation is its distinguishing feature, marked by increased NF-κB signaling, which in turn induces the production of proinflammatory cytokines such as IL-6, IL-2, TNF-α, and IFN-γ
[4144].
In this context, it has been documented that the increased proinflammatory cytokines induced by COVID-19 impact drug metabolism as they interfere with the regulation of CYP enzymes and drug transporter expression
[3942][4245][4346]. In humans, it has been observed that inflammation caused by COVID-19 reduces CYP3A activity, which, in turn, affects the metabolism of midazolam. Furthermore, two independent studies consistently reported abnormally elevated levels of lopinavir and ritonavir in COVID-19 patients, suggesting that this could be due to the negative regulation of CYP3A
[4447][4548][4649].
Regarding COVID-19, the response to treatment is not solely related to the disease itself. In 2021 and 2022, two cases were reported, in which increased levels and adverse effects of clozapine were observed in patients who had been vaccinated against COVID-19. These specific vaccines were Moderna’s Spikevax and Pfizer-BioNTech’s vaccine. In both cases, the adverse reaction was associated with inflammation and CYP1A2 activity. It is important to note that this adverse reaction was short lived
[4750][4851].
In the case of the human immunodeficiency virus (HIV), it has been described to affect CYP enzyme levels. People infected with HIV have shown a reduction in hepatic CYP3A4 and CYP2D6 enzyme activity compared to uninfected individuals
[4952][5053]. However, the interpretation of these findings is not entirely conclusive, as other research has not found changes in drug metabolism in HIV patients, and, in other studies, an increase in CYP3A4 expression has even been observed in HIV patients receiving antiretroviral therapy
[5154][5255].
For HIV patients, future research aimed at determining the impact of infection-generated cytokines on the pharmacokinetics of antiretroviral drugs should address various variables. This includes individual gene expression, the possible co-infection of HIV with hepatitis B, the presence of liver disease, the anti-inflammatory effects of drug therapy, and study design, among other factors. A consideration of these elements is crucial for obtaining clearer and more accurate results in this area of research
[3134][5154].
As evidence continues to accumulate, it is likely that closer medical monitoring may be needed in the future for patients with an infection who are also being treated with drugs metabolized by CYP enzymes to prevent possible overdoses and toxicity.
3.3. Other Mechanisms by Which Infections May Affect Drug Response
3.3.1. Alterations in Gastrointestinal Motility and Drug Absorption
It has been proposed that gastrointestinal infections may affect the availability of certain drugs due to various factors, such as changes in intestinal transit speed or the pH of gastrointestinal fluids; however, information is limited
[5356][5457]. In the context of alterations in intestinal transit caused by an infection, it is important to consider infectious diarrhea. While this condition can influence the absorption of a medication, its specific impact can vary considerably, depending on several factors, including the severity of the diarrhea, its duration, the overall health of the individual, and the underlying infectious agent, as infectious diarrhea can be caused by viral, bacterial, or parasitic infections
[5558].
Overall, the evidence supporting the impact of an infection that causes diarrhea on drug absorption is limited. As a result of this research, very few studies directly addressed the impact of infectious diarrhea on drug absorption.
The lack of research directly addressing the mechanisms by which infectious diarrhea affects drug absorption is largely due to the fact that most patients with acute diarrhea typically present mild and transient symptoms. Additionally, in severe cases of diarrhea, the priority is to immediately address the clinical condition rather than evaluating whether diarrhea might modify the absorption of a prescribed medication
[5659]. Further research is needed to fully understand the impact of infectious diarrhea on drug absorption and its implications in clinical practice.
3.3.2. Pharmacological Effect Mimicry
A poorly described mechanism by which an infection might modify the response to a drug is through mimicry of the drug effect. An example of this is human adenovirus 36 (HAdV-36), which has been associated with obesity and changes in glucose and lipid metabolism, with long-term effects, such as the irreversible expansion of adipose tissue, even after the resolution of the acute phase of infection
[5760]. HAdV-36 increases peroxisome proliferator-activated receptor-γ (PPAR-γ) expression in the same way as thiazolidinediones, which are used to increase insulin sensitization in patients with type 2 diabetes mellitus
[5861][5962][6063]. This virus could potentially influence the response to drugs used in lipid or glucose control, although there is no evidence so far that HAdV-36 modifies the response to drugs such as metformin
[6164]. To the researchers' knowledge, there is no other virus that can mimic the effect of a drug.
3.3.3. Unknown Mechanisms: The Case of Helicobacter pylori and Levodopa
Helicobacter pylori (HP) has been documented to cause inflammation at the intestinal level, delay gastric emptying, and possibly affect the absorption of drugs, such as Levodopa
[6265]. In this context, it has been observed that people with Parkinson’s disease who have HP infection show a poor response to Levodopa and experience increased severity of motor symptoms
[6366]. However, the elimination of HP has been reported to improve tremor, although it does not change the bioavailability of the drug
[6467]. All this information underscores the need for further research to understand how HP influences drug interactions with drugs, such as Levodopa, and other potential drugs.