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    • CC is a widespread disorder affecting up to of

    2022-02-14

    CC is a widespread disorder affecting up to 20% of people worldwide, which also deteriorates the quality of life of patients and causes a substantial economic burden to society. There are 3 categories of CC: normal-transit constipation, slow-transit constipation and defecatory or rectal evacuation disorders [37]. CC is observed if symptoms occur for longer than 3 months and are usually described as a difficult, infrequent or incomplete defecation [38]. More and more studies show that intestinal bacteria can contribute to the development of CC [38].
    Regulation of BAs in IBS patients The mechanism by which gut bacteria contribute to local and extraintestinal IBS symptoms has been reviewed thoroughly elsewhere [39], [40] (Table 2[2], [37], [41], [42], [43], [44], [45], [46], [47], [48]). Studies shed light on changes in the intestinal bacteria that trigger defects in the integrity of the gut barrier and their well-established role in the initiation of the host innate and adoptive immune responses [18]. In vitro, in vivo and clinical studies proved that the imbalance in the composition of gut bacteria causes bacterial infection of epithelial galunisertib receptor which usually correlates with the induction of diarrhea and subsequently tissue inflammation. Studies showed that mice lacking FXR have increased levels of bacteria in the ileum and exhibit disturbed integrity of the epithelial barrier owing to higher infiltration of macrophages and exaggerated production of pro-inflammatory cytokines [18]. These outcomes were confirmed in pharmacological studies with a synthetic FXR ligand, INT-747, which exhibited a protective role against the development of inflammation in chemically-induced intestinal inflammation in mice. The exposure to FXR ligand attenuated the release of several cytokines including IL-1β, IL-4, IL-5 or IL-6 and improved colonic condition [49]. It should be mentioned that during the ongoing intestinal inflammatory process, the continuous release of inflammatory mediators can sensitize the peripheral afferent nerves leading to the onset of visceral hypersensitivity, the most frequently reported symptom among IBS patients. Modulation of the intestinal bacteria through antibiotics, diet or the use of probiotics are thereby beneficial strategies to reduce visceral pain and ease the suffering of patients [47]. In vivo studies showed that oral administration of Lactobacillus farciminis releases nitric oxide in the colon what strengthens the intestinal barrier, by stabilizing tight junctions, and prevents the increase in paracellular permeability and subsequent colonic hypersensitivity in response to bacterial translocation [48], [50]. Moreover, as demonstrated in a rat model of chemically-induced inflammation, this strain can adhere to the mucosa of the colon where it decreases the number of pro-inflammatory interleukins in the colonic mucosa and diminishes inflammation-induced macroscopic damages [52]. Of note, various genera of bacteria, including Lactobacillus, can produce BSHs, which facilitate deconjugation of the amino acid and remove the BA from enterohepatic circulation. Lactobacillus strains are relevant mediators of metabolism of BAs through their interaction with the potent murine FXR antagonist TβMCA [29]. Taking into consideration the underlying cause of IBS development, it can be suggested that probiotics containing the strains of L. firciminis can be used to diminish symptoms in a subset of IBS patients. Diet plays an important role in the functioning of the digestive system. Patients with IBS very often notice a reduction in pain symptoms and normalization of intestinal motility after the elimination of some nutrients or the inclusion of fiber in their diet [18]. High-fat (HF) diet is the factor that modulates the composition of gut microbiota by decreasing the number of Bacteroidetes and simultaneously increasing Proteobacteria and Firmicutes. These changes in bacteria strains in turn, modify colonic permeability and deteriorate intestinal barrier function by a mechanism related to BAs [53], [54]. In line, Shen et al. showed that mice galunisertib receptor fed with HF diet for 20 weeks had a greater abundance of a specific type of sulfate-reducing bacteria (SRB), and proved the correlation between SRB with distorted epithelial integrity, increased epithelial permeability and higher expression of ileal pro-inflammatory markers, including Mcp1, Tlr4 and F4/80 [55]. SRB are hydrogen consuming microorganisms able to generate H2S which slows intestinal transit by suppressing smooth muscle contractions and inhibiting cholinergic pathways by potentiating fast excitatory postsynaptic potentials evoked by splanchnic nerves [56], [57]. More than 90% of IBS patients suffer from visceral hypersensitivity which may be caused by the intake of a diet rich in inorganic sulfate that stimulates H2S production in the colon [48], [58]. It has been suggested that FXR ligands can directly or indirectly promote the generation of H2S through the regulation of the expression and activity of the cystathionine-γ-lyase enzyme [59].