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The intestinal reclamation of bile acids is crucial for the maintenance of their enterohepatic circulation. The majority of bile acids are actively absorbed via specific transport proteins that are highly expressed in the distal ileum. The uptake of bile acids by intestinal epithelial cells modulates the activation of cytosolic and membrane receptors such as the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1), which has a profound effect on hepatic synthesis of bile acids as well as glucose and lipid metabolism. Extensive research has focused on delineating the processes of bile acid absorption and determining the contribution of dysregulated ileal signaling in the development of intestinal and hepatic disorders. For example, a decrease in the levels of the bile acid-induced ileal hormone FGF15/19 is implicated in bile acid-induced diarrhea (BAD). Conversely, the increase in bile acid absorption with subsequent overload of bile acids could be involved in the pathophysiology of liver and metabolic disorders such as fatty liver diseases and type 2 diabetes mellitus. This review article will attempt to provide a comprehensive overview of the mechanisms involved in the intestinal handling of bile acids, the pathological implications of disrupted intestinal bile acid homeostasis, and the potential therapeutic targets for the treatment of bile acid-related disorders. Published 2020. Compr Physiol10:21-56, 2020. A. L. Ticho, P. Malhotra, P. K. Dudeja, R. K. Gill, W. A. Alrefai.Intestinal Absorption of Bile Acids in Health and Disease. Compr Physiol10: 2020, 21-56. The enterohepatic circulation of bile acids entails synthesis and secretion from the liver, reabsorption from the intestine, recirculation back to liver via the portal blood, and resecretion from the liver.Bile acids are efficiently reabsorbed in the intestine with only 5% lost in the feces.Bile acid absorption is critical for the negative feedback inhibition of their synthesis in the liver via the secretion of ileal fibroblast growth factor FGF19/15 hormone.Bile acids are crucial for lipid digestion and absorption due to their roles as fat solubilizers. Bile acids also activate specific receptors and signaling pathways to modulate a number of hepatic and intestinal functions and exert systemic effects such as increasing energy expenditure and improving insulin sensitivity.Disturbances in the enterohepatic circulation of bile acids contribute to the pathophysiology of hepatic and intestinal disorders such as cholestatic liver diseases and inflammatory bowel disorders. The following legends to the figures that appear throughout the article are written to be useful for teaching. Figure 1 Teaching points: The structure of different types of bile acids can be depicted by a schematic representation of these molecules demonstrating the location and orientation of the hydroxyl groups relevant to the plain of the steroid ring. The primary bile acids in mice and humans are directly synthesized in the liver. The secondary bile acids are the products of dehydroxylation and/or OH-epimerization of primary bile acids mediated by bacterial enzymes from gut microbiota. Figure 2 Teaching points: Bile acids are conserved in the enterohepatic circulation, and only 5% of total bile acids is lost in the feces. The efficiency of bile acid absorption influences the hepatic synthesis of those molecules via inducing the secretion of the ileal hormone FGF19 (FGF15 in rodents) that circulates to the liver to inhibit CYP7A1-mediated bile acid synthesis. Blocking bile acid absorption decreases FGF19-mediated negative feedback and, hence, promotes bile acid synthesis from cholesterol. Therefore, blockers of bile acid absorption could be used for the treatment of hypercholesterolemia. Figure 3 Teaching points: The increase in the amounts of bile acids in the colonic lumen stimulates the secretion of electrolytes and water, leading to diarrhea. Bile acid diarrhea may occur due to bile acid malabsorption as a result of a decrease in the expression and/or function of the ileal apical sodium-dependent bile acid transporter (ASBT). A decrease in FGF19 expression also leads to an increase in the hepatic production of bile acids and subsequent overload in the intestine causing diarrhea. Figure 4 Teaching points: The ileal bile acid transporter ASBT is subject to posttranslational modifications including N-glycosylation on the first extracellular loop and serine-threonine phosphorylation on the intracellular c-terminal of the protein. These posttranslational modifications modulate the function of ASBT. Also, certain mutations have been identified that cause impaired ASBT function. Figure 5 Teaching points: ASBT function is crucial for the intestinal reclamation of bile acids. ASBT is rapidly regulated by different mechanisms. The disruption of lipid rafts of plasma membrane by dietary compounds such as the green tea catechin EGCG decreases ASBT function. ASBT membrane expression is decreased by endocytosis in response to activation of protein kinase c-zeta. The activation of protein tyrosine phosphatases in response to infection with enteric microbes such as EPEC decreases ASBT function and expression on the plasma membrane.

Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the intestine, with increasing incidence worldwide. At present, the management of IBD is an unmet medical need due to the ineffectiveness of currently available drugs in treating all patients, and there is strong demand for novel therapeutics. In this regard, vasoactive intestinal peptide, a potent anti-inflammatory endogenous hormone, has shown promise in managing multiple immune disorders in animal models. However, when administered in the free form, VIP undergoes rapid degradation in vivo, and with continuous infusion, it causes severe dose limiting side effects. To overcome these barriers, we have developed a superior mode to deliver VIP in its native form, using sterically stabilized micelles (VIP-SSM). Our previous studies demonstrated that, VIP, when administered in SSM, prevented joint damage and inflammation in a mouse model of rheumatoid arthritis at a significantly lower dose than the free peptide, completely abrogating the serious side effect of hypotension associated with VIP. In the current study, we demonstrate the therapeutic benefit of VIP-SSM over free peptide in reversing severe colitis associated with IBD. First, we conducted preliminary studies with dextran sulfate sodium (DSS) induced colitis in mice, to determine the effectiveness of VIP administered on alternate days in reducing disease severity. Thereafter, a single intra peritoneal injection of VIP-SSM or the free peptide was used to determine its therapeutic effect on the reversal of colitis and associated diarrhea. The results demonstrated that when administered on alternate days, both VIP-SSM and VIP were capable of alleviating DSS colitis in mice. However, when administered as a single dose, in a therapeutic setting, VIP-SSM showed superior benefits compared to the free peptide in ameliorating colitis phenotype. Namely, the loss of solid fecal pellets and increased fluid accumulation in colon resulting from DSS insult was abrogated in VIP-SSM treated mice and not with free VIP. Furthermore, reduced protein and mRNA levels of the major chloride bicarbonate exchanger, down regulated in adenoma (DRA), seen with DSS was reversed with VIP-SSM, but not with the free peptide. Similarly, VIP-SSM treatment significantly reduced the elevated mRNA levels of pro-inflammatory cytokines and showed significant histologic recovery when compared to mice treated with free VIP. Therefore, these results demonstrated that as a single dose, the anti-inflammatory and antidiarrheal effects of VIP can be achieved effectively when administered as a nanomedicine. Therefore, we propose VIP-SSM to be developed as a potential therapeutic tool for treating ulcerative colitis, a type of IBD.

ABSTRACTBackground & AimClostridioides difficileinfection (CDI) is the leading cause of hospital-acquired diarrhea and pseudomembranous colitis. Two protein toxins, TcdA and TcdB, produced by C. difficileare the major determinants of disease. However, the pathophysiological causes of diarrhea during CDI are not well understood. Here, we investigated the effects of C. difficiletoxins on paracellular permeability and apical ion transporters in the context of an acute physiological infection.MethodsWe studied intestinal permeability and apical membrane transporters in female C57BL/6J mice. Üssing chambers were used to measure paracellular permeability and ion transporter function across the intestinal tract. Infected intestinal tissues were analyzed by immunofluorescence microscopy and RNA-sequencing to uncover mechanisms of transporter dysregulation.ResultsIntestinal permeability was increased through the size-selective leak pathway in vivoduring acute CDI in a 2-day-post infection model. Chloride secretory activity was reduced in the cecum and distal colon during infection by decreased CaCC and CFTR function, respectively. SGLT1 activity was significantly reduced in the cecum and colon, accompanied by ablated SGLT1 expression in colonocytes and increased luminal glucose concentrations. SGLT1 and DRA expression was ablated by either TcdA or TcdB during acute infection, but NHE3 was decreased in a TcdB-dependent manner. The localization of key proteins that link filamentous actin to the ion transporters in the apical plasma membrane was unchanged. However, Sglt1, Nhe3, and Drawere drastically reduced at the transcript level, implicating downregulation of ion transporters in the mechanism of diarrhea during CDI.ConclusionsCDI increases intestinal permeability and decreases apical abundance of NHE3, SGLT1, and DRA. This combination likely leads to dysfunctional water and solute absorption in the large bowel, causing osmotic diarrhea. These findings provide insights into the pathophysiological mechanisms underlying diarrhea and may open novel avenues for attenuating CDI-associated diarrhea.

ABSTRACTSalmonellaand Citrobacterare gram negative, members of Enterobacteriaceaefamily that are important causative agents of diarrhea and intestinal inflammation. TGF-β1 is a pleiotropic multifunctional cytokine that has been implicated in modulating the severity of microbial infections. How these pathogens alter the TGF-β1 signaling pathways in the intestine is largely unknown. Streptomycin-pretreated C57BL/6J mouse model colonized with S. typhimuriumfor 8 hours (acute) and 4 days (chronic) infection and FVB/N mice infected with C. rodentiumfor 6 days were utilized. Results demonstrated an increase in TGF-β1 receptor I expression (p<0.05) in S. typhimuriuminfected mouse ileum at both acute and chronic post-infection vs control. This was associated with activation of Smad pathways as evidenced by increased phosphorylated (p)-Smad2 and p-Smad3 levels in the nucleus. The inhibitory Smad7 mRNA levels showed a significant up regulation during acute phase of Salmonellainfection but no change at 4d post-infection. In contrast to Salmonella, infection with Citrobacter caused drastic downregulation of TGF receptor I and II concomitant with a decrease in levels of Smad 2, 3, 4 and 7 expression in the mouse colon. We speculate that increased TGF-β1 signaling in response to Salmonellamay be a host compensatory response to promote mucosal healing; while C. rodentiumdecreases TGF-β1 signaling pathways to promote inflammation and contribute to disease pathogenesis. These findings increase our understanding of how enteric pathogens subvert specific aspects of the host-cellular pathways to cause disease.