Drug-Related Enteropathy

Abstract

Over 700 drugs have been implicated as cause of chronic diarrhea and potential enteral damage. Pathophysiologic mechanisms include intrinsic malabsorption as their main mode of action (i.e., acarbose or orlistat), increased risk of microscopic colitis/enteritis (proton-pump inhibitors (PPI), non-steroidal anti-inflammatory drugs (NSAID), selective serotonin reuptake inhibitors (SSRI)), dysbiosis (antibiotics, metformin, PPI), and microscopic or overt enteropathy (angiotensin inhibitors, antineoplastic agents, targeted therapy and check-point inhibitors). According to type, diarrhea can be malabsorptive, inflammatory or mixed, and may affect different portions of small intestine, colon, or both. Drug-induced enteropathy ranges from asymptomatic histological changes to macroscopic damage similar to that seen in inflammatory bowel disease. Treatment may include discontinuation of drug, correction of dysbiosis, and in severe cases, directed therapy towards intestinal wall inflammatory states, in similar mode as in other inflammatory bowel diseases.

1. Introduction

Diarrhea is one of the most common symptoms in the gastroenterologist clinical practice. It is defined as an increase in the average number of bowel movements, stool output and/or weight, or a reduced stool consistency, and according to duration, can be acute if it lasts less than 7 days, persistent acute (>7 days and < 14 days), sub-acute (>14 days and < 28 days), or chronic (>4 weeks) [1, 2, 3, 4, 5, 6]. Most episodes of acute diarrhea occur as a result of infectious agents or dietary transgression. Acute persistent and subacute diarrhea may be caused by unidentified microorganisms or might be secondary to medications [1]. Chronic diarrhea is one of those conditions with the broadest differential diagnosis, that includes anatomical and/or physiologic abnormalities of the gastrointestinal (GI) tract, inflammatory or neoplastic conditions, malabsorptive disorders, drug side effects, dysbiosis, functional as well as post-infectious syndromes such as small intestine bowel overgrowth (SIBO), functional diarrhea or post-infectious irritable bowel syndrome (Pi-IBS) [2, 3, 4, 5, 6]. One of the most common, albeit rarely unconsidered causes, is drug-side effect [7, 8]. A large number of at least 700 drugs have been implicated as cause of chronic diarrhea through a number of different, and sometimes overlapped pathophysiologic mechanisms [9]. Although initial therapy is drug withdrawal, in several cases treatment directed at pathophysiologic mechanism is needed to revert damage and improve symptoms.

2. Mechanisms of enteral damage

Enteral damage and consequent symptoms such as diarrhea, bloating, flatulence and pain may be mediated through different mechanisms falling into two main categories: (1) Functional damage: it can be caused by abnormalities in any of the mechanisms involving digestion (maldigestion) and/or absorption (malabsorption), GI motility disturbances, alterations in the water and electrolyte absorption and/or secretion mechanisms, and altered microbiota and/or microbiome (dysbiosis), and (2) Microscopic or overt mucosal damage: this can be caused by direct contact of the drug, ischemic-related damage, systemic inflammatory or autoimmune mechanisms, and may affect different portions of the small intestine, colon, or both (Figure 1, [9]). According to the involved mechanism, main symptoms may predominate diarrhea, malabsorptive complaints such as steatorrhea, weight loss and anemia, or abdominal pain, and in severe cases, occult or overt bleeding.

Figure 1.

Pathophysiologic mechanisms of enteropathy according to drug type.

3. Maldigestion and malabsorption

Small intestine is involved in both digestive and absorptive processes of all major nutrients, fatty acids and multiple ions, occurring across the entire intestinal wall at different levels. Normal functional anatomy includes a full bowel length, normal intestinal villi and absorptive capacity, conserved neuroendocrine regulatory systems, and a normal motility activity, particularly the major motor complex (MMC) [10]. Several drugs may interfere with one or multiple mechanisms associated with either digestion processes or mechanisms associated with intestinal absorption. Alpha-glucosidase inhibitors such as acarbose decrease carbohydrate digestion, lipase-inhibitors such as orlistat and cetilistat affect fat absorption, bile acid binding resins such as cholestyramine or colestipol affects not only bile acid absorption but also that of vitamin B12 and lipid-soluble vitamins, but as they are used in bile-acid diarrhea as main therapeutic indication, they can be associated with constipation instead of diarrhea. Different drugs may induce calcium precipitation, such as aluminum or tetracycline, with further changes in bowel habit. Structural damage leading to villous inflammation and/or atrophy is described in the mucosal damage section [11].

3.1 Drugs associated with interference in digestion and/or malabsorption processes

A number of drugs used to treat metabolic conditions such as diabetes mellitus and obesity have intrinsic malabsorptive mechanisms as their main mode of action, and may lead to diarrhea and other related symptoms due to those mechanisms.

Acarbose is a pseudo-tetrasaccharide that selectively inhibits alpha-glucosidase activity in the brush border membrane of the small intestine, an essential enzyme for digestion of starch, maltose and sucrose, delaying glucose absorption from carbohydrate food and thus improving glycemic control among patients with either glucose intolerance or diabetes mellitus [12]. Among common side effects, mainly intrinsic to its mode of action, include flatulence, bloating and diarrhea [13].

Orlistat is a reversible inhibitor of gastric and pancreatic lipoprotein lipases, resulting in inhibition of up to 30% of dietary fat absorption, decreasing fat mass, as well as levels of the regulatory hormone leptin as patients lose weight [14]. Most common adverse events, also intrinsic to its mechanism of action, are diarrhea, steatorrhea, flatulence, bloating and abdominal pain [15]. Recently a second lipase inhibitor, cetilistat, has shown similar efficacy with fewer side effects when compared to orlistat, however prevalence of diarrhea may be as high as 25% of users [16].

Metformin, a dimethyl-biguanide, is an oral glucose-lowering agent absorbed in the small intestine, that has several modes of action: it reduces hepatic glucose production by inhibition of hepatic gluconeogenesis, it increases insulin sensitization by increasing plasma glucagon-like-protein (GLP) type 1 concentrations, with a smaller effect on dipeptidyl-peptidase 4 (DPP-4), resulting in increased glucose uptake in the small intestine [17]. It may also induce alterations in enteral microbiome, particularly increased abundance of Akkermansia muciniphila, a bacterium reported to improve glucose tolerance by increasing endocannabinoids, reducing inflammation, and increasing gut mucous barrier thickness [18]. Despite these beneficial effects, metformin is frequently associated with GI side effects such as flatulence, bloating, dyspepsia, and diarrhea. A number of potential mechanisms of GI intolerance have been described, including altered transport of serotonin, histamine or both, increased enterocyte lactate concentration, dysbiosis, increased bile acid pool in the distal ileum, bile acid receptor activation, and increased conversion from primary to secondary bile acids, which are pro-secretory, leading to increased water and electrolyte luminal secretion. Most of these side effects are dose-related and decrease with time, or after probiotic use, but may persist or even develop after withdrawal [19].

4. Alterations in motility and water absorption/secretion

As previously mentioned, small intestine is both an absorptive and secretory organ, and most of the water and electrolyte handling in the GI tract is regulated at this level by autonomic nerve system as well as by neuromuscular signal pathways [10]. A number of drugs may alter one or several of the mechanisms associated with normal GI motility and/or water and electrolyte secretion including laxatives, motilin analog antibiotics, enterokinetic drugs, secretagogues, colchicine, and prostaglandin analogs.

4.1 Drugs associated with diarrhea due to dysmotility and/or alterations in water absorption and/or secretion

Several antibiotics, particularly the macrolides (e.g., azithromycin, clarithromycin, erythromycin), act as motilin analogues. Motilin is a hormone that induces MMC activity though four distinct phases: first one is a period of near quiescence, second is characterized by irregular small-amplitude waves, phase III induces high-amplitude propulsive contractions all along the small intestine, and during phase IV, motor activity declines to basal values [20]. Although macrolides have a predominant gastroduodenal site-of-action, they may also induce diarrhea by similar MMC-related mechanisms in the small bowel, and are fully reversible after stopping the drug [21].

Laxatives are drugs used to treat different types of constipation, and may cause diarrhea through a number of mechanisms according to pharmacologic type. Osmotic agents extract through osmosis fluid into the intestinal lumen to soften stools an accelerate colon transit time, examples are non-absorbable carbohydrates (e.g., lactulose), polyethylene glycol, as well as citrate, sodium or phosphate-based products. Stimulant agents induce high-amplitude propagated contractions (HAPC) and alter intestinal and colonic absorption as well as secretion mechanisms, examples include the anthraquinones senna and cascara sagrada, bisacodyl and sodium picosulfate. Newer enterokinetic drugs such as tegaserod and prucalopride are agonists of serotonin 5-HT₄ receptors throughout the GI tract, they also induce increased MMC and HAPC activity and accelerate enteric transit time. Secretagogue agents such as linaclotide, plecanatide, lubiprostone and tenapanor increase intestinal secretion by one of three different mechanisms: activation of intestinal guanylate cyclase C receptors, increasing intraluminal fluid secretion (e.g., linaclotide, plecanatide), type 2 chloride channel activation in the apical membrane of epithelial cells resulting in increased fluid and chloride secretion (e.g., lubiprostone), and inhibition of gastrointestinal sodium-hydrogen exchanger-3 (e.g., tenapanor). All these drugs are used for treating chronic constipation, and IBS with predominant constipation, and diarrhea is the most common side effect. Colchicine is a cytotoxin used to treat acute attacks of gout, and is frequently associated with diarrhea as enhances intestinal water secretion. Misoprostol, a prostaglandin analogue used in the past for drug-associated peptic ulcer disease or in the obstetric practice, is associated frequently with diarrhea induced by an increased smooth-muscle GI activity [22].

5. Dysbiosis

Dysbiosis is a term used to describe any quantitative and/or qualitative imbalance, dysfunction or disturbance of the gut microbiota and microbiome as an indicator of disease or poor health status [23], and may be caused by a number of risk factors, including medications. Drugs and microbiota have a two-way relationship: drugs exert a significant impact on organs and tissues through their effect on gut microbiota, but in the other hand, microbiota metabolic capacity may affect stability, metabolite production, availability, absorption and thus, increase or decrease efficacy and/or toxicity of different medications [24, 25, 26]. A number of drugs have been described to alter the composition 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, 28, 29, 30, 31, 32, 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, 35, 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, 28, 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, 41, 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.

6. Mucosal damage

Drug-associated gastrointestinal damage may affect any part of the GI tract, and small intestine and colon enteropathy accounts for 20–40% of all GI side effects [10]. Mechanisms include direct cytotoxic damage on the intestinal mucosa resulting in several degrees of inflammation, including mucositis, erosions and/or ulcers, hemorrhagic enteritis, alterations in permeability, protein-loss associated enteropathy, and ischemic damage, either caused by long-standing vasoconstriction and/or thrombosis [11]. In some cases, as with chemotherapeutic agents, bone marrow damage and neutropenia may lead to intestinal bacterial translocation, secondary infections with pathogens such as Pseudomonas and fungi, resulting in neutropenic enteritis [49]. Another group of inflammatory conditions characterized by microscopic changes only, without endoscopic abnormalities, may affect any part of the GI tract. When small intestine is the affected organ, the condition is called microscopic enteritis, it is manifested usually by chronic diarrhea, anemia and micronutrient deficiencies, and may present with a variety of histological findings with different inflammatory infiltrates –eosinophilic, lymphocytic, or both, collagen deposits, and in some cases, mucosal atrophy. A number of drugs can be associated with this type of microscopic inflammation, affecting small intestine (i.e., angiotensin inhibitors), colon (PPI, selective serotonin release inhibitor antidepressants (SSRI)), or both (aspirin, NSAID) [50, 51].

6.1 Drugs associated with diarrhea due to macroscopic enteral mucosal damage

Non-steroidal anti-inflammatory drugs (NSAID) are prescribed for a variety of pain and inflammation-associated conditions such as rheumatologic and orthopedic disorders, migraine as well as post-surgical states, and exert their effects through cyclooxygenase (COX) inhibition with resultant decrease of prostaglandin synthesis. NSAID are associated both with upper and lower GI symptoms, as well as mucosal injury at any part of the GI tract, and symptoms vary widely from dyspepsia and heartburn to diarrhea, bloating and overt GI bleeding [7, 8, 11, 52, 53, 54, 55]. Despite gastroduodenal damage is the most common clinical presentation in most NSAID long-term users, up to 70% may develop different degrees of mucosal breaks, including erosions, ulcerations, mucosal hemorrhage or even stenosis in distal portions of the small intestine such as jejunum or ileum, as determined by studies using video capsule endoscopy [56, 57]. Pathophysiology of NSAID-induced enteropathy is a complex one, and includes different mechanisms such as COX inhibition and topical effect, interactions with bacteria and bile acids, as well as overexpression of pro-inflammatory cytokines. Inhibition of COX-1 is associated with decreased mucosal blood flow, mucus production, and intestinal motility, which are predominant, but not critical factors for damage. Topical effect, a COX-independent action requiring mucosal contact of the drug from the luminal side, is considered the triggering event in most cases [53, 54]. Once NSAID is absorbed into the cell, induces mitochondrial injury by producing vacuolation and swelling, and alters oxidative phosphorylation and electron transport, considered one of the earliest intracellular changes after NSAID administration. As a result, intestinal permeability is increased, allowing luminal factors to disrupt the intestinal barrier function [54]. A second mechanism is associated with interactions between microbiota, bile acids and further activation of innate immunity after being exposed to NSAID. Animal models have shown that germ-free rats treated with NSAID do not develop intestinal ulcers unless bacteria are introduced. NSAID induce an increase in Gram-negative bacterial abundance, Clostridium spp. and Enterobacterococci. It is well known that Gram-negative bacterial lipopolysaccharides either activate or inhibit toll-like receptors (TLR), leading to inflammatory cascade activation. It has been suggested that antibiotics against Gram-negative bacteria may be effective in reducing NSAID-induced enteral damage [58]. Some bile acids have shown to induce a pro-inflammatory state associated with interleukin-8 (IL-8) and nuclear factor-kβ activation (NF-κβ) activation [54]. Degree of enteral damage varies according to NSAID type and their effect over COX isoforms: non-selective NSAID such as diclofenac, naproxen, meloxicam, or indomethacin inhibits both COX-1 (a constitutive enzyme involved in mucosal integrity), and COX-2 (an isoform primarily inducible related to inflammation), and therefore exert effects through several mechanisms, including topical and systemic effect, as well as dysbiosis. Naproxen have been associated with increased enteral permeability, while indomethacin induces overexpression of the pro-inflammatory tumor necrosis factor-α (TNF-α). NSAID enterohepatic circulation also plays a role in enteral damage, as many are carboxylic acids conjugated in the liver and excreted to bile, cleaved by beta-glucoronidases in the small bowel lumen, and lately reabsorbed. Acetylsalicylic acid (e.g., aspirin), even at low doses, may induce small bowel mucosal breaks after 2 weeks of therapy, mainly due to direct contact damage. On the other part, selective COX-2 inhibitors (ICOX-2) such as celecoxib and etoricoxib have their effect only over the inflammatory isoform, sparing COX-2 and thus, reducing significantly the risk of mucosal damage, unless they are given for prolonged periods of time, after which may have similar risk to that seen with conventional NSAID [7, 11, 53, 54, 58, 59]. Several approaches may diminish the risk of NSAID-induced enteropathy, including withdrawal of drugs, use of selective ICOX-2, or NSAID at the lower therapeutic dose and for short periods of time, or combination with probiotics such as Lactobacillus casei, VSL#3, and S. boulardii, as well as misoprostol, a prostaglandin analog. PPI are not indicated for either prophylaxis nor therapy, and may indeed increase the risk of intestinal injury, apparently associated with changes in microbiota composition [60]. Novel intestinal-sparing NSAID known as co-drugs, consist of two portions: the “NSAID portion” and a gaseous mediator portion (based on nitric oxide or hydrogen sulfide) that exerts mucosal protective effect while sparing therapeutic effect [53]. Further studies are needed to prove their long-term safety in the GI tract.

In addition to NSAID, several drugs may induce small intestine mucosal disease secondary to vasoconstriction and ischemia, including potassium supplements, oral contraceptive pills, and a number of cytotoxic drugs such as methotrexate and chemotherapeutic agents that are associated with different degrees of mucositis [11], and are discussed below.

Among patients receiving oncologic therapy, those treated with cytotoxic drugs, radiotherapy, targeted therapy, and immunotherapy, particularly with the so-called check-point inhibitors have increased risk of developing various degrees of enteropathy and diarrhea. Between 40 and 100% of cancer patients treated with chemotherapeutic agents develop gut toxicity at some point during their treatment, a term called “chemotherapy-induced intestinal mucositis” (CIM). Prevalence and severity depend on drug and dosing regimen, intensity, route of delivery, and patient predisposing conditions. CIM pathophysiology involves mainly mechanisms related to cell growth inhibition, immunological reactions, and dysbiosis [61]. Cytotoxic agents such as methotrexate, doxorubicin, 5-fluorouracil, capecitabin and irinotecan target enteral tissue by interrupting DNA synthesis by direct injury or by generation of reactive oxygen species, leading to release of active signaling factors (i.e., caspases, β-catenin, and NF-κβ), and eventually to mucosal damage and apoptosis, most of which wipe out the intestinal crypt stem cell pool [61, 62]. A five-stage model for CIM has been proposed, that includes: 1) initiation, 2) signal activation and primary damage response, 3) pathway amplification, 4) tissue inflammation (e.g., erosions, ulcerations, apoptosis), and 5) healing. Clinical picture varies widely, and ranges from short periods of diarrhea and abdominal pain, to severe degrees of enterocolitis. When bone marrow-targeted chemotherapeutic agents are also given, increased risk of neutropenic enterocolitis, abdominal sepsis, and even death may occur. Treatment options, beside adjusting dose or even withdrawal of the drug may include antibiotics and probiotics in order to restore normal gut microbiota and reduce pathogenic intestinal bacteria, octreotide to decrease peptide-associated intestinal secretions, antioxidants such as amifostine, a drug that detoxifies reactive metabolites and scavenges free radicals, steroid anti-inflammatory agents to reduce inflammatory response, and possibly incretins and anti-apoptotic agents, most of which are under investigation [11, 61, 62].

Radiation therapy plays an important role as sole curative therapy for 25% of all cancers, and as adjuvant with chemotherapy in many other cases. During radiotherapy of abdominal and/or pelvic tumors, either the small intestine, colon or both are included in the treatment field and may be prone to toxicity. Risk factors for gut damage include those related to therapy itself such as radiation dose, time-dose-fractionation parameters, volume, and concomitant chemotherapy, and patient-related factors such as advanced age, previous abdominal surgeries, as well as vascular and metabolic comorbidities. Radiation enteropathy is classified as early or delayed when occurs prior or after 3 months after treatment. Early symptoms are nausea and abdominal pain, while diarrhea occurs usually after 2 or 3 weeks of treatment onset, and may persist for longer periods of time. Mechanisms of damage are multifactorial and include increased production of reactive oxygen species, mitotic cell death, mucosal atrophy, endothelitis, microvascular sclerosis, as well as fibrosis of the entire bowel wall. As radiation affects predominantly rapidly proliferating intestinal cells, villus epithelium turnover is insufficient to keep normal absorptive mechanisms. Long-term side-effects may include nutrient malabsorption, anemia, stenosis, and in most severe cases, intestinal obstruction. Management is largely symptomatic, with anti-diarrheal agents. As one of the early mechanisms of damage is production of reactive oxygen species, free radical scavengers such as amifostine can be used for reduction of radiotherapy side effects, but it has a narrow therapeutic time window and potential life-threathening side effects. Several candidate mitigator drugs are under investigation [63].

The immune system has an important role in recognizing and eliminating some tumors. Activation of T cells require a signal between T-cell receptors and the major histocompatibility complex along with a stimulatory checkpoint expressed on T cells called CD-28, and the antigen-presenting cells [64]. Tumors may use immune-checkpoint pathways as a mechanism of immune resistance. Two well-known immune-checkpoint receptors are CTLA-4 (CD152), a negative regulator of T-cell-mediated anti-tumor response, and the programmed cell death protein 1 (PD-1 or CD279), expressed on the surface of activated T cells that interacts with programmed death ligand (PD-L1 and L2), leading to T-cell inactivation [64, 65]. The immune check-point inhibitors (ICI) are monoclonal antibodies that block these pathways, including inhibitors of PD-1, PD-L1, and CTLA-4. Immunomodulating therapy, or immunotherapy act to enhance anti-tumor immune responses by blocking negative regulators of immunity, and has revolutionized cancer therapy by improving survival outcomes and is now the standard treatment of different types of cancer, including several metastatic tumors. Currently approved ICI are the anti-PD-1 pembrolizumab and nivolumab, used for treating melanoma and metastatic non-small-cell lung cancer, the anti-CTLA-4 ipilimumab, a fully humanized monoclonal antibody approved for metastatic melanoma, as well as the anti-PDL-L1 atezolizumab and durvalumab, also for non-small cell lung cancer. Ipilimumab, for instance, competitively binds to CTLA-4, blocking tolerance to self-antigens, without blocking CD28 (a stimulatory checkpoint), increasing T-cell proliferation and activation leading to autoimmune damage to a number of organs, including the entire GI tract. In a similar way, anti-PD1/PDL-1 agents such as nivolumab and pembrolizumab increase T-cell response while reducing self-tolerance, and the result is similar to that seen with ipiliumumab [64, 65, 66, 67]. This kind of damage behaves similarly to that seen on inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis, as well as their clinical presentation, with various degrees of enteral and/or colonic damage ranging from erosions and ulcerations to obstruction, and wall necrosis, and presenting as chronic diarrhea, abdominal pain, GI bleeding and progressive anemia [68]. Histologic findings range from combined acute (e.g., neutrophils) and chronic (i.e., lymphocytes and plasma cells) inflammatory infiltrates, eosinophilia, atrophy, granulomatous reaction, crypt abscesses, and bullous pemphigoid, and in most severe cases an increased apoptotic activity within the crypt epithelium may be seen, affecting small intestine, colon or both [69, 70]. Treatment is similar to that given for IBD and may include mesalazine, systemic corticosteroids, and in refractory cases, biologic therapy with infliximab [71, 72].

Another category of oncologic treatment is the called targeted therapy, which acts by identifying and attacking certain types of cancer cells, and by inhibiting oncogenes driving aberrant growth, and may include monoclonal antibodies and small molecule inhibitors. A number of targeted therapies are approved for different types of cancer. Many of them may be associated with different degrees of oral and GI mucositis, particularly cetuximab, erlotinib, gefitinib, lapatinib, sorafenib, and sunitinib, with odds ratio for diarrhea and enteritis ranging from 1.5 to 4.5 [73]. More recently, the HER-2-targeted monoclonal antibody trastuzumab, used for HER-2-overexpressing breast cancer, has been associated with a number of GI manifestations associated to toxicity, including diarrhea, abdominal pain, and ulcerative enterocolitis similar to that seen with ICI. Mechanism underlying GI toxicity remains under investigation, but it seems to be associated with HER-2 receptors in gut epithelial cells [74]. Treatment is empiric, following the same principles as for ICI.

6.2 Drugs associated with diarrhea due to microscopic enteral mucosal damage

A number of drugs are associated with an increased risk of microscopic enteritis and/or colitis, in some cases eosinophilic enteritis, or even may resemble microscopic enteral damage of other diseases, such as celiac disease. Microscopic enteritis encompasses a group of disorders characterized by microscopic mucosal and/or mucosal inflammatory infiltrates by a number of different inflammatory cells, including lymphocytes (i.e., lymphocytic enteritis/colitis), eosinophils (e.g., eosinophilic enteritis/colitis), and lymphocytes along with collagen deposits (i.e., collagenous sprue/collagenous colitis), in absence of significant macroscopic mucosal damage, leading to watery diarrhea [50, 75, 76, 77]. In the small bowel, microscopic enteritis may also be associated with mucosal atrophy in some cases, and the clinical picture may be that of malabsorptive diarrhea, with foul-smelling feces, steatorrhea, and anemia [76]. In most cases an autoimmune predisposition has been proposed, but when disease develops during or shortly after a specific drug use, causality for drug-induced disease can be proposed according to a World Health Organization system based on temporal sequence, prior information of the drug, dose–response relationship, exclusion of other etiologies, and re-challenge [78]. Pathophysiology mechanisms are not clear, and may involve activation of the immune system in response to exposure to luminal antigenic factors, including drug-itself, metabolites, bile-acids, or may be associated with changes in microbiota linked to long-term drug use, such as in PPI.

A number of drugs have been linked to microscopic colitis, including aspirin, NSAID, PPI, SSRI, particularly sertraline, clozapine, ticlopidine, flavonoids and acarbose [51]. A recent case–control study found a significant increased risk for microscopic colitis with current use of NSAID, PPI, and SSRI with adjusted odd ratios of 1.86, 3.37 and 2.03 respectively. Current PPI use was associated also with increased risk of both lymphocytic (OR 2.06) and collagenous colitis (OR 5.3), whereas current NSAID use was associated with increased risk of collagenous colitis (OR 2.32), and current SSRI use increased risk of lymphocytic colitis (OR 2.28). Long-term PPI and/or NSAID use had the highest odds ratio (4.6 and 4.8 respectively) for developing microscopic colitis [79]. As previously mentioned, NSAID may affect any part of the GI tract, by a number of different pathophysiologic mechanisms. In the small intestine NSAID-associated damage ranges from microscopic enteritis to severe mucosal affection with erosions and/or ulcers. Histologic manifestations of NSAID may resemble those of celiac disease, with villous blunting and intraepithelial lymphocytosis, and can be found in any part of the small intestine [80].

Eosinophilic enteritis and colitis are included in the group of eosinophilic gastrointestinal disorders, and are characterized by a high eosinophilic infiltrate in the gut wall, without evidence of other causes. Pathophysiology involves a combination of genetic predisposition, dysbiosis, and a triggering factor, usually an allergen, that may include drugs, followed by recruitment and activation of eosinophils to sites of inflammation regulated by pro-inflammatory cytokines [81]. Drugs such as clozapine, naproxen, carbamazepine, and rifampicin have been associated with increased eosinophilic infiltrate in the distal ileum and colon [77]. More recently the anti-CTLA-4 check-point inhibitor ipilimumab and the anti-PD1 nivolumab have been link to eosinophilic enteritis [70]. Other immunosuppressant drugs such as mycophenolate mofetil, a drug used to prevent acute allograft rejection may affect both small bowel and colon, causing an eosinophilic-associated damage, with features similar to those of acute graft-versus-host disease [82].

Angiotensin II receptor inhibitors (AT-II RI) are one of the most common drugs for treating high blood pressure, with a generally safe side-effect profile. In 2012 a case series of 22 patients developing chronic diarrhea and weight loss while taking olmesartan was published. None had positive celiac serology, and a combination of villous atrophy and variable degrees of inflammation including collagen deposits was observed in small intestine biopsies, with clinical and histologic recovery after discontinuation of the drug [83]. More recently, other AT-II RI have been also associated with different degrees of enteropathy. A systematic review included 248 cases, most of which were associated with olmesartan (94%), however telmisartan, irbesartan, valsartan, losartan and eprosartan also were reported to be associated with various degrees of enteropathy. Interestingly, despite negative serology in most cases, 71% had a positive HLA-DQ2 or DQ-8, haplotypes associated with celiac disease [84].

7. Conclusion

Drugs are a common cause of chronic diarrhea and enteropathy by a number of mechanisms including intrinsic mode of action, malabsorption, dysbiosis, increased GI motility, alterations in water and electrolyte absorption and secretion mechanisms, autoimmune macroscopic or microscopic damage, and cytotoxic effect. Site of damage may include either part of the small intestine, colon, or both, and can be manifested by malabsorptive, inflammatory or watery diarrhea. In most cases diarrhea subsides after drug withdrawal, but in some cases a number of inflammatory conditions requiring other forms of therapy may be needed.