*Drug-Related Enteropathy DOI: http://dx.doi.org/10.5772/intechopen.103734*

of the gut microbiota, including antibiotics, proton-pump inhibitors (PPI), nonsteroidal anti-inflammatory drugs (NSAID), opioids, metformin, statins, psychotropics, particularly atypical anti-psychotics, levothyroxine, anticoagulants, antiarrhythmics, and several oncologic medications including chemotherapeutic agents, and targeted therapy [18, 27–33]. A recent study evaluated more than 1000 marketed drugs and found that 24% of them induced significant microbiota composition [30].

## **5.1 Drugs associated with diarrhea due to dysbiosis**

Between 5 and 49% of antibiotic users develop diarrhea during or after treatment. Prevalence is highly variable and can be influenced by reporting country, age, and hospital setting. For instance, antibiotic-associated diarrhea (AAD) represent between 3.2–29% of all causes of diarrhea, with a mean prevalence of 9.6%, in the emergency department this figure raises to 18.6%, and in the intensive care units range from 13.9 to 21.5% [34–36]. Risk factors for AAD are: increasing age, therapy with more than 1 antibiotic, clindamycin use, long-term antibiotic use, and concomitant PPI use. In most cases, withdrawal of antibiotic may stop diarrhea. However, longer use may predispose to enteral and colonic damage, dysbiosis, and increases risk of developing infections by patobionts (microorganisms that usually interact with host in a symbiotic way, but have the potential of acting as pathogens under certain circumstances). Most common microorganisms associated with DAA are *Clostridioides difficile* (formerly known as *Clostridium difficile*), *Klebsiella pneumoniae*, *Clostridium perfringens*, and *Staphylococcus aureus* [37]. Mechanisms associated with DAA can be divided into two main categories: alteration of microbiota/microbiome, and direct effect over intestinal mucosa and motility. Current vision of DAA pathophysiology suggests that antibiotics induce bacterial diversity depletion by at least 30%, with selection of intrinsically resistant micro-organisms, they also may generate gen transfer and de novo mutations conferring resistance to antibiotics. On the other hand, they alter genetic expression, protein activity and cell metabolism, induce under-expression of immunoglobulins, decrease neutrophil and natural killer cell activity, and alter T-cell balance by increasing cytotoxic cells, causing an increased inflammatory tone, that may have a deleterious effect over intestinal permeability [27–29]. *Clostridioides difficile* infection (CDI) is a severe form of DAA with a mixed pathophysiologic model including altered host immune factors, bacterial virulence factors, altered intestinal microbiome and metabolic environment [38]. It has been described a decreased microbial diversity, a direct effect over intestinal permeability, a positive effect on toll-like receptor expression and activation, immune system dysregulation, an altered short-chain fatty acid synthesis, as well as an effect on biliary salts increasing bacterial sporulation/germination capacity [25]. Multiple antibiotics have been linked to ICD, particularly clindamycin, which increase odds ratio almost up to 47 times, but different groups of antibiotics such as amoxicillin/clavulanic acid, aztreonam, cefalosporins, ampicillin, fluoroquinolones, macrolides and even tetracycline may increase risk of ICD [39]. During the last 2 years since the beginning of the SARS-COV-2 pandemics, an increasing incidence of ICD has been reported as widespread antibiotic use and abuse [40–42]. Infection with SARS-COV-2 is associated with two patterns of diarrhea: an early stage, mainly associated to infection itself, apparently caused by direct functional damage of columnar epithelium, and mediated by angiotensin-converting enzyme 2 (ACE-2) receptor interference [40, 42], and a mid to late stage, occurring weeks thereafter, mainly associated with antibiotic use and is related to secondary dysbiosis. A cohort of infected patients that developed

diarrhea during the weeks and months following the infection were evaluated, and an AAD prevalence of 16.7% was reported during the follow-up time, with 70% of those developing ICD. In that study, medications associated with increased risk of CDI were amoxicillin (OR 2.2), clarithromycin (OR 3.7), as well as prolonged systemic steroid use (OR 4.4), a drug known for decreasing systemic inflammatory response and immunity [41].

Proton pump inhibitors (PPI) inhibit gastric acid secretion through irreversible blockage of the hydrogen-potassium pump in the parietal cell, and are used for a number of conditions associated with acid exposure such as gastroesophageal reflux disease, peptic-ulcer disease and associated bleeding, and certain types of dyspepsia, and are one of the most common used drugs worldwide [43]. Chronic associated hypochloridria may induce significant changes in microbiota composition throughout the whole gastrointestinal tract. At small intestine long-term PPI use is associated with increasing abundance of *Streptococcaceae*, *Staphylococcaceae, Enterobacteriaceae*, *Clostridiaceae*, and decreased abundance of *Bifidobacteriaceae*, and an increased risk for small intestine bacterial overgrowth (SIBO), a condition defined by the presence of more than 10 [5] bacteria per ml of duodenal aspirate and characterized by chronic malabsorptive diarrhea has been reported [31, 44, 45]. In the large bowel, prolonged PPI use also reduces microbial diversity, increasing abundance of *Proteobacteria*, and may also increase risk of CDI (OR 2.3), apparently as a result of a combined pro-inflammatory environment and altered bile-acid homeostasis [45, 46].

A number of different drugs such as atypical anti-psychotics, antidepressants and other mood stabilizers, statins, antiarrhythmics, and anticoagulants are associated with changes in microbiome composition, but its role as a cause of diarrhea is unclear [30, 47, 48]. In several cases, in statins for instance, microbiome changes may be associated with improved outcomes, such as better lipid control [47], in others, as with psychotropics, resulting dysbiosis is associated with anti-commensal activity and drug metabolism alterations, resulting in minor GI symptomatology [30, 48]. Finally, NSAID and immunotherapy are drugs involved in enteropathy by different mechanisms, including dysbiosis, but as mucosal damage is their main pathophysiologic mechanism, are discussed below.
