**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].
