The Effect of Deoxycholic Acid on Secretion and Motility in the Rat and Guinea Pig Large Intestine

Kim, Nam Hee; Park, Jung Ho; Park, Jaesoon; Joung, Yeun-Ho

doi:10.5056/jnm16201

Cited by 10 publications

(6 citation statements)

References 28 publications

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“…Bile acid malabsorption (BAM) has been widely implicated in the development of diarrhea, including diarrhea caused by the tyrosine kinase inhibitor neratinib [49] and in patients with GI-GvHD [50], increasing colonic secretion of water and electrolytes and the induction of propagated contractions [51]. We identified changes in plasma bile acids and ileal gene expression following melphalan, indicative of BAM.…”

Section: Discussionmentioning

confidence: 97%

Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever

Wardill

Mooij

Ferreira

et al. 2021

Cancer Chemother Pharmacol

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Purpose Conditioning therapy with high-dose melphalan (HDM) is associated with a high risk of gut toxicity, fever and infections in haematopoietic stem cell transplant (HSCT) recipients. However, validated preclinical models that adequately reflect clinical features of melphalan-induced toxicity are not available. We therefore aimed to develop a novel preclinical model of melphalan-induced toxicity that reflected well-defined clinical dynamics, as well as to identify targetable mechanisms that drive intestinal injury. Methods Male Wistar rats were treated with 4–8 mg/kg melphalan intravenously. The primary endpoint was plasma citrulline. Secondary endpoints included survival, weight loss, diarrhea, food/water intake, histopathology, body temperature, microbiota composition (16S sequencing) and bacterial translocation. Results Melphalan 5 mg/kg caused self-limiting intestinal injury, severe neutropenia and fever while impairing the microbial metabolome, prompting expansion of enteric pathogens. Intestinal inflammation was characterized by infiltration of polymorphic nuclear cells in the acute phases of mucosal injury, driving derangement of intestinal architecture. Ileal atrophy prevented bile acid reabsorption, exacerbating colonic injury via microbiota-dependent mechanisms. Conclusion We developed a novel translational model of melphalan-induced toxicity, which has excellent homology with the well-known clinical features of HDM transplantation. Application of this model will accelerate fundamental and translational study of melphalan-induced toxicity, with the clinical parallels of this model ensuring a greater likelihood of clinical success. Graphic abstract

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Section: Discussionmentioning

confidence: 97%

Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever

Wardill

Mooij

Ferreira

et al. 2021

Cancer Chemother Pharmacol

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“…Clinical studies have shown that the increase in total fecal BAs is significantly correlated with abdominal pain and accelerated colonic transit in patients (15, 16). Animal studies also showed that BAs directly induce accelerated colonic motility and visceral hypersensitivity (17, 18). Conversely, attenuation of BA excretion with sequestering agents partially alleviated the symptoms of IBS-D patients (19, 20).…”

Section: Introductionmentioning

confidence: 99%

A Clostridia-rich microbiota enhances bile acid excretion in diarrhea-predominant irritable bowel syndrome

Zhao

Yang

Chen

et al. 2019

Journal of Clinical Investigation

135

114

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An excess of fecal bile acids (BAs) is thought to be one of the mechanisms for diarrhea-predominant irritable bowel syndrome (IBS-D). However, the factors causing excessive BA excretion remain incompletely studied. Given the importance of gut microbiota in BA metabolism, we hypothesized that gut dysbiosis might contribute to excessive BA excretion in IBS-D. By performing BA-related metabolic and metagenomic analyses in 290 IBS-D patients and 89 healthy volunteers, we found that 24.5% of IBS-D patients exhibited excessive excretion of total BAs and alteration of BA-transforming bacteria in feces. Notably, the increase in Clostridia bacteria (e.g., C. scindens) was positively associated with the levels of fecal BAs and serum 7α-hydroxy-4-cholesten-3-one (C4), but negatively correlated with serum fibroblast growth factor 19 (FGF19) concentration. Furthermore, colonization with Clostridia-rich IBS-D fecal microbiota or C. scindens individually enhanced serum C4 and hepatic conjugated BAs but reduced ileal FGF19 expression in mice. Inhibition of Clostridium species with vancomycin yielded opposite results. Clostridia-derived BAs suppressed the intestinal FGF19 expression in vitro and in vivo. In conclusion, this study demonstrates that the Clostridia-rich microbiota contributes to excessive BA excretion in IBS-D patients, which provides a mechanistic hypothesis with testable clinical implications.

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“…Our findings provide an explanation for the fact that the most effective therapeutic agents for diarrhea and constipation are known to alter both chloride secretion and motility. These includes 5-hydroxytryptamine receptor 4 agonists and other prokinetic agents [ 64 , 65 ], prosecretory drugs, such as lubiprostone [ 66 , 67 , 68 , 69 ], and high concentrations of bile acids, such as deoxycholic acid [ 70 ]. The relationship between gut motility and fluid secretion provides insights into how prokinetic drugs can contribute to increasing stool moisture content and volume, address the constipation caused by CF, and have the potential to cause diarrhea and fluid loss.…”

Section: Discussionmentioning

confidence: 99%

Paracellular Filtration Secretion Driven by Mechanical Force Contributes to Small Intestinal Fluid Dynamics

2021

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Studies of fluid secretion by the small intestine are dominated by the coupling with ATP-dependent generation of ion gradients, whereas the contribution of filtration secretion has been overlooked, possibly by the lack of a known mechanistic basis. We measured apical fluid flow and generation of hydrostatic pressure gradients by epithelia of cultured mouse enterocytes, Caco-2 and T-84 cells, and fibroblasts exposed to mechanical force provided by vigorous aeration and in response to ion gradients, inhibitors of ion channels and transporters and in vitro using intact mouse and rat small intestine. We describe herein a paracellular pathway for unidirectional filtration secretion that is driven by mechanical force, requires tight junctions, is independent of ionic and osmotic gradients, generates persistent hydrostatic pressure gradients, and would contribute to the fluid shifts that occur during digestion and diarrhea. Zinc inhibits the flow of fluid and the paracellular marker fluorescein isothyocyanate conjugated dextran (MW = 4 kD) across epithelia of cultured enterocytes (>95%; p < 0.001) and intact small intestine (>40%; p = 0.03). We propose that mechanical force drives fluid secretion through the tight junction complex via a “one-way check valve” that can be regulated. This pathway of filtration secretion complements chloride-coupled fluid secretion during high-volume fluid flow. The role of filtration secretion in the genesis of diarrhea in intact animals needs further study. Our findings may explain a potential linkage between intestinal motility and intestinal fluid dynamics.

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The Effect of Deoxycholic Acid on Secretion and Motility in the Rat and Guinea Pig Large Intestine

Cited by 10 publications

References 28 publications

Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever

Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever

A Clostridia-rich microbiota enhances bile acid excretion in diarrhea-predominant irritable bowel syndrome

Paracellular Filtration Secretion Driven by Mechanical Force Contributes to Small Intestinal Fluid Dynamics

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