**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, 75–77]. 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
