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Torres-Carrillo, N.; Martínez-López, E.; Torres-Carrillo, N.M.; López-Quintero, A.; Moreno-Ortiz, J.M.; González-Mercado, A.; Gutiérrez-Hurtado, I.A. Pharmacomicrobiomics and Drug–Infection Interactions. Encyclopedia. Available online: https://encyclopedia.pub/entry/52637 (accessed on 01 July 2024).
Torres-Carrillo N, Martínez-López E, Torres-Carrillo NM, López-Quintero A, Moreno-Ortiz JM, González-Mercado A, et al. Pharmacomicrobiomics and Drug–Infection Interactions. Encyclopedia. Available at: https://encyclopedia.pub/entry/52637. Accessed July 01, 2024.
Torres-Carrillo, Norma, Erika Martínez-López, Nora Magdalena Torres-Carrillo, Andres López-Quintero, José Miguel Moreno-Ortiz, Anahí González-Mercado, Itzae Adonai Gutiérrez-Hurtado. "Pharmacomicrobiomics and Drug–Infection Interactions" Encyclopedia, https://encyclopedia.pub/entry/52637 (accessed July 01, 2024).
Torres-Carrillo, N., Martínez-López, E., Torres-Carrillo, N.M., López-Quintero, A., Moreno-Ortiz, J.M., González-Mercado, A., & Gutiérrez-Hurtado, I.A. (2023, December 13). Pharmacomicrobiomics and Drug–Infection Interactions. In Encyclopedia. https://encyclopedia.pub/entry/52637
Torres-Carrillo, Norma, et al. "Pharmacomicrobiomics and Drug–Infection Interactions." Encyclopedia. Web. 13 December, 2023.
Pharmacomicrobiomics and Drug–Infection Interactions
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This entry is adapted from the peer-reviewed paper 10.3390/ijms242317100

Microorganisms have a close relationship with humans, whether it is commensal, symbiotic, or pathogenic. It has been documented that microorganisms may influence the response to drug therapy. Pharmacomicrobiomics is an emerging field that focuses on the study of how variations in the microbiome affect the disposition, action, and toxicity of drugs. Two additional sciences have been added to complement pharmacomicrobiomics, namely toxicomicrobiomics, which explores how the microbiome influences drug metabolism and toxicity, and pharmacoecology, which refers to modifications in the microbiome as a result of drug administration. Additionally, the concept of "drug-infection interaction" is included to describe the influence of pathogenic microorganisms on drug response. This entry analyzes in detail each of these concepts.

pharmacomicrobiomics toxicomicrobiomics pharmacoecology drug–infection interaction microbiome

1. Introduction

A pharmacological interaction is a situation in which the activity of a medication is affected because it is administered simultaneously with another drug, with certain food, or due to extrinsic or intrinsic factors. Pharmacological interactions can lead to the development of medical complications, mainly because they can reduce therapeutic effectiveness or increase the toxicity of pharmacological treatment. According to the World Health Organization, at least 60% of adverse drug reactions could be avoided. In this context, drug interactions stand out as the primary cause of these adverse reactions [1][2].
There are several ways to classify drug interactions; however, the most common approach is to classify them according to their mechanism of action: into pharmacokinetic or pharmacodynamic interactions. The former refers to those that affect how a drug is absorbed, distributed, metabolized, or eliminated in the body, while the latter refers to how drugs interact directly with biological systems to produce therapeutic or side effects [1][2][3][4].
A pharmacological interaction is considered clinically relevant when it significantly affects the therapeutic efficacy or safety of a medication to the extent that a dose adjustment or a complete treatment change is required. Different regulatory agencies, such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Japan Pharmaceutical and Medical Device Agency (PMDA), have developed guidelines for determining the clinical relevance of pharmacological interactions.
In addition to the mentioned interactions, it has recently been proposed that the microorganisms comprising the microbiome could also modify the response to drugs. As a result, the concept of pharmacomicrobiomics emerges to describe the effects of the microbiome on the absorption, activity, and toxicity of medications. Within pharmacomicrobiomics, terms like toxicomicrobiomics and pharmacoecology have been included. The former refers to the study of how variations in the microbiome affect the metabolism and modify the toxicity of xenobiotics, including drugs, while the latter is used to conceptualize modifications in microbial taxa or specific functions of the microbiome as a result of administering a drug with either microbicidal or promicrobial activity [5][6][7].
In general, pharmacomicrobiomics focuses on interactions between drugs and the “microbiome”. The microbiome, and even dysbiosis, specifically refer to symbiotic or commensal microorganisms. It is worth mentioning that, in this context, pharmacomicrobiomics does not provide a specific definition for interactions between drugs and pathogenic microorganisms, because an infection is characterized by the invasion and proliferation of pathogenic microorganisms in body tissues [8][9][10]. In Figure 1, the distinction between pharmacomicrobiomics, pharmacoecology, toxicomicrobiomics, and drug–infection interaction is made clear.
Figure 1. Effect of microorganisms on the host response to drugs. This depiction illustrates the distinction between four key concepts: pharmacomicrobiomics, toxicomicrobiomics, pharmacoecology, and drug–infection interaction. Pharmacomicrobiomics focuses on how variations in the microbiome affect drug disposition, action, and toxicity. Toxicomicrobiomics, meanwhile, explores the influence of the microbiome on drug metabolism and toxicity. Meanwhile, pharmacoecology focuses on the modifications in the microbiome that result from drug administration. Finally, drug–infection interaction investigates the impact of pathogenic microorganisms on drug response.

2. Effect of the Microbiome on Drug Response: “Pharmacomicrobiomics”

To easily grasp the term “pharmacomicrobiomics”, it is essential to begin by defining and clearly distinguishing between the concepts of microbiota and microbiome. Although they are sometimes used interchangeably, they have significant differences. Microbiota refers to the organisms that maintain a symbiotic relationship with humans, while the microbiome encompasses both these organisms and their genetic composition, as well as their interaction with the host’s genome [9][11].
Pharmacomicrobiomics is defined as the study of the effect of variations in the microbiome on the disposition, action, and toxicity of drugs. Although most of the research related to pharmacomicrobiomics is centered on the intestinal microbiota, it is important to note that there are five specific regions in the human body that host a resident microbiota: the skin, oral cavity, respiratory tract, intestines, and urogenital tract [11]. In general, there are two main reasons for why a significant portion of the research in the field of pharmacomicrobiomics focuses on the intestinal microbiota. First, approximately 90% of drugs consumed globally are administered orally. Second, the intestinal microbiota is the most diverse of all, consisting of between 30 to 400 trillion microorganisms, and its composition varies based on factors such as ethnicity, dietary intake, and environmental influences [12][13].
Today, especially concerning the intestinal microbiota, it has been demonstrated to play a highly relevant role in how pharmacological treatments are absorbed, distributed, metabolized, excreted, and in their potential toxicity. This mainly occurs through two key mechanisms: drug bioaccumulation and drug metabolism by the microbiota [14].
In the context of pharmacomicrobiomics, the term “drug bioaccumulation” is used to describe the ability of bacteria to store a drug intracellularly without chemically modifying it. This has two consequences: the first is a reduction in drug availability, and the second is due to changes in the composition of the microbial community [15].
Currently, the mechanisms regulating bioaccumulation by intestinal bacteria are not fully understood. Regarding the accumulation process, some studies have found that drugs such as duloxetine and hydrochlorothiazide have the ability to bind to proteins present in the intestinal microbiota bacteria. Therefore, the binding of drugs to bacterial proteins could be a plausible explanation for accumulation [15][16]. Information about drug transport into bacteria remains limited. However, based on the results of some research, hypotheses can be formulated. For instance, it has been observed that metformin increases the presence of Akkermansia muciniphila, a bacterium classified as Gram-negative. These microorganisms possess transport proteins in their outer membrane, such as porins. Among these, the Outer Membrane Protein A (OmpA), due to its nonspecific nature, facilitates the passive transport of many small chemical substances, generally with a molecular weight less than 600 Da, such as metformin [17][18].
Regarding drug metabolism, the metabolic potential and influence of the microbiota on drug metabolism have been known since 1968 [19]. Intestinal microorganisms can metabolize drugs through processes such as oxidation, reduction, acetylation, deamination, and hydrolysis, among others [20]. One of the most intriguing mechanisms through which gut bacteria metabolize drugs is via CYP enzymes [21][22]. While the human body has a total of 57 identified CYP, bacteria have been found to possess 2979. However, not all bacteria possess these enzymes; for instance, bacteria like E. coli lack CYP [23]. Bacterial and archaeal CYP enzymes are soluble and lack membrane-anchoring regions, unlike human enzymes, which are membrane-bound via a transmembrane N-terminal alpha-helical segment. Research on the role of bacterial CYP enzymes extends beyond their involvement in phase I drug metabolism reactions. Experiments have been conducted to modify specific enzymes, such as CYP102A1 (P450 BM3), aiming to alter their structure and potentially affect drug activity. Hence, the study of bacterial CYP enzymes represents a promising research field [24][25]. The differences between drug metabolism and microbial metabolism are illustrated in Figure 2.
Figure 2. 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.
Table 1. Experimental studies in pharmacomicrobiomics across various models. The table presents the most recent studies in pharmacomicrobiomics, encompassing investigations in humans, mice, and in vitro. These studies examine the impact of the microbiome on drugs, either in terms of drug bioaccumulation, metabolism, or both.

Drug Involved

Affected Process

Associated Microorganisms

Clinical Effect

Condition for Which Studied

Organism in Which the Study Was Conducted

Chemotherapy and/or immunotherapy

Not described

L. mucosae and L. salivarius

Favorable response

Metastatic/unresectable HER2-negative gastric/gastroesophageal junction adenocarcinoma

Humans [26]

FOLFOX regimen

Drug metabolism

Akkermansia muciniphila

Better therapeutic effect

Colon Cancer

Mice [27]

Hydrochlorothiazide

Bioaccumulation

Gram-negative enterobacteriaceae

Impair glucose tolerance

Metabolic control

Mice [16]

Mycophenolate mofetil

Drug metabolism

Bacteroides vulgatus, Bacteroides stercoris and Bacteroides thetaiotaomicron

Graft-versus-host disease risk reduction

Transplantation

Humans [28]

Simvastatin

Drug metabolism and bioaccumulation

Probiotic bacteria

Alteration of simvastatin bioavailability and therapeutic effect

Metabolic control

in vitro [29]

Statins

Drug metabolism

Bacteroides

Intense statin responses

Metabolic control

Humans [30]
The table above illustrates the breadth of applications of pharmacomicrobiomics, covering both in vivo and in vitro studies, in animal models and in humans. These studies cover a wide range of conditions, from metabolic disorders to organ transplantation. Advances in next-generation sequencing, metabolomics, transcriptomics, and proteomics suggest that, in the near future, healthcare is likely to experience significant benefits through improved clinical practices, thanks to a better understanding and manipulation of the microbiome for the benefit of the patient [31].

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 [13][32][33].
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 [33].
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 [14][34][35].

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 [36]. 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 [37]. 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 [34][38][39].
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 [34][40].
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 [39]. 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 [41].
Regardless of the physiological cause, infections impact CYP enzyme activity due to the inflammatory process they trigger [36][42][43]. 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 [44].
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 [42][45][46]. 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 [47][48][49].
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 [50][51].
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 [52][53]. 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 [54][55].
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 [34][54].
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 [56][57]. 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 [58].
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 [59]. 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 [60]. 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 [61][62][63]. 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 [64]. 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 [65]. 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 [66]. However, the elimination of HP has been reported to improve tremor, although it does not change the bioavailability of the drug [67]. 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.

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Subjects: Pharmacology & Pharmacy
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Norma Torres-Carrillo
,
Erika Martínez-López
,
Nora Magdalena Torres-Carrillo
,
Andres López-Quintero
,
José Miguel Moreno-Ortiz
,
Anahí González-Mercado
,
Itzae Adonai Gutiérrez-Hurtado
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Revisions: 3 times (View History)
Update Date: 05 Jan 2024
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