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    • In addition to the type of food consumed also the

    2022-05-27

    In addition to the type of food consumed, also the effect of calorie restriction (CR), i.e. an intermittent fasting and re-feeding cycles with concomitant fluctuations in the level of glucose and insulin, can affect the course of IBS through the modulation of the BA homeostasis. This type of nutrition focuses on reducing daily calorie intake, without causing malnutrition. In vivo, CR increased the expression of CYP7A1 and conjugating enzymes such as BAL, and regulated the expression of FXR in the liver and BA transporters e.g. IBABP in the colon [7]. This correlates with changes in BA pool observed as disproportion between the primary vs. secondary BAs (DCA, LCA or ωMCA). In effect, not only the synthesis of BAs were higher but also its resorption in the mouse ileum. Augmentation in secondary BAs can suggest that intestinal microbiome could aid in achieving the BA composition during CR, particularly in the gut lumen. Furthermore, the increase in BA concentration contributed to the activation of the TGR5 receptor [7].
    BA pool in constipated patients It is known that diarrhea is caused by increased secretion of water as a result of influx of primary biliary Quercitrin sale CDCA and the secondary bile acid DCA to the intestinal lumen. However, the effect of the change in the amount of these acids was not examined as a factor in the development of CC. However, the sulfation of CDCA and DCA inhibits water secretion in the ileal enterocytes [73]. This may indicate a new potential function of secondary BAs and their biochemical modifications in disorders with distorted motility and intestinal secretion. Recent studies in children with functional constipation determined the role of BAs in CC. Although the fecal BA profile in most participants did not differ from control subject, the observable changes were seen in the formation of 3-sulfate of CDCA, which might occur due to variation in microbiota composition [74]. So far, similar abnormality in BA metabolism has not been reported in adults with constipation. A subset of constipated patients have reduced total fecal BAs and lower percentage of fecal secretory BAs e.g. DCA [75]. Moreover, a direct correlation has been reported between fecal BAs excretion, C4 and colonic transit, and an inverse link between FGF19 and colonic transit [55]. The C4 is the intermediate in BAs synthesis; its reduced level lowers the BA synthesis in the liver [75]. Finally, recent studies demonstrated that the inhibition of ileal BA transporter reduces BA reabsorption and stimulates colonic motility in patients with CC and therefore constitutes a promising novel approach in the treatment of the disease [76].
    BA pool in patients with diarrhea BAM is a disorder characterized by a change in the proportion of various BAs in feces and is associated with the occurrence of diarrhea; BAM is observed in 10–33% of patients with IBS-D which correlates with the occurrence and the severity of the disease symptoms such as abdominal pain, increased intestinal permeability and accelerated colonic transit [75]. It has been observed that IBS-D patients with increased fecal BA excretion have a significantly elevated proportion of the secondary BAs, e.g. CDCA, nonsecretory lithocholic and CA, when compared to control group [57]. Moreover, the correlation between the overall intestinal motility and fecal BA excretion or serum C4 suggests that colonic BA content affects colonic transit. Of note, the ileocolonic delivery of CDCA increased colonic transit in patients with IBS-C and healthy individuals [77]. Many studies found a negative correlation between serum C4 and FGF19 in patients with IBS-D which suggests that both C4 and FGF19 can be considered as biomarkers for the occurrence of BA diarrhea [21], [78]. Camilleri et al. showed that around 25% of IBS-D patients incorporated in the study had increased C4 level, which was correlated with substantial increase in colonic permeability [79]. It has been shown that hydrophobic BAs augmented small intestinal permeability either through nicotinic cholinergic mechanisms or changes within the small intestinal brush border membrane (changes in fragility and fluidity of the membrane) and caused higher influx of fluid and electrolytes to the intestinal lumen that contributed to the loose stool consistency. Genetic variations in the regulation of endogenous BA synthesis play a role in the etiology of IBS-D. Two genes, klotho B and FGFR4, were identified to modulate BA pool and contribute to worsening of symptoms in patients with accelerated colonic transit and IBS-D patients [80]. More specifically, differences in protein stability were detected between two alleles within klotho B (rs17618244) which provide a biologically plausible mechanism by which the single nucleotide polymorphisms may affect intestinal motility [80]. The use of widely available methods of genotyping assays for analyzing multiple loci in distinct genes responsible for BA regulation may uncover potential derangements in BA pool and enable identification of patients having a predisposition for accelerated colonic transit.