deoxycholic-acid and Colitis

The etiology of inflammatory bowel disease (IBD) remains unclear. However, intestinal metabolism is known to be critical in the pathogenesis of IBD. Bile acid is one of the main intestinal metabolites, and its role in the pathogenesis of IBD is worthy of investigation. This study investigated the role of deoxycholic acid (DCA), a bile acid, in the pathogenesis of IBD.. Peripheral serum metabolomics, fecal metabolomics, and microbiome analyses were performed on patients with IBD and healthy controls. Flow cytometry, real-time quantitative polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay, immunohistochemical staining, and immunofluorescence analysis were used to evaluate cytokines in the inflamed colonic mucosa and immune cells and tuft cells in the intestine of mice with dextran sulfate sodium (DSS)-induced colitis.. In total, 156 patients with IBD and 58 healthy controls were enrolled. DCA levels in the serum and feces of patients with IBD were significantly decreased compared to the controls. This decrease was associated with a decrease in the abundance of intestinal flora, including Firmicutes, Clostridia, Ruminnococcaceae, and Lachnospiraceae. Additionally, interleukin (IL)-1. In IBD patients, the decreased DCA levels in serum and fecal samples are associated with disturbances in gut microflora diversity and abundance. Possible mechanisms by which DCA affects immunity in DSS-induced murine colitis include increasing IL-1

Topics: Animals; Colitis; Deoxycholic Acid; Dextran Sulfate; Inflammation; Inflammatory Bowel Diseases; Interleukin-1beta; Mice

The Western dietary pattern, characterized by high consumption of fats and sugars, has been strongly associated with an increased risk of developing Crohn's disease (CD). However, the potential impact of maternal obesity or prenatal exposure to a Western diet on offspring's susceptibility to CD remains unclear. Herein, we investigated the effects and underlying mechanisms of a maternal high-fat/high-sugar Western-style diet (WD) on offspring's susceptibility to 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced Crohn's-like colitis.. Maternal dams were fed either a WD or a normal control diet (ND) for eight weeks prior to mating and continued throughout gestation and lactation. Post-weaning, the offspring were subjected to WD and ND to create four groups: ND-born offspring fed a normal diet (N-N) or Western diet (N-W), and WD-born offspring fed a normal (W-N) or Western diet (W-W). At eight weeks of age, they were administered TNBS to induce a CD model.. Our findings revealed that the W-N group exhibited more severe intestinal inflammation than the N-N group, as demonstrated by a lower survival rate, increased weight loss, and a shorter colon length. The W-N group displayed a significant increase in Bacteroidetes, which was accompanied by an accumulation of deoxycholic acid (DCA). Further experimentation confirmed an increased generation of DCA in mice colonized with gut microbes from the W-N group. Moreover, DCA administration aggravated TNBS-induced colitis by promoting Gasdermin D (GSDMD)-mediated pyroptosis and IL-1beta (IL-1β) production in macrophages. Importantly, the deletion of GSDMD effectively restrains the effect of DCA on TNBS-induced colitis.. Our study demonstrates that a maternal Western-style diet can alter gut microbiota composition and bile acid metabolism in mouse offspring, leading to an increased susceptibility to CD-like colitis. These findings highlight the importance of understanding the long-term consequences of maternal diet on offspring health and may have implications for the prevention and management of Crohn's disease. Video Abstract.

Topics: Animals; Colitis; Crohn Disease; Deoxycholic Acid; Diet, High-Fat; Diet, Western; Female; Humans; Mice; Mice, Inbred C57BL; Pregnancy; Prenatal Exposure Delayed Effects

Cholecystectomy (XGB) is widely recognized as a risk factor for colon cancer (CC). Continuous exposure of the colonic epithelium to deoxycholic acid (DCA) post-XGB may exert cytotoxic effects and be involved in the progression of CC. However, the functions of the XGB-induced DCA increase and the underlying mechanism remain unclear.. Colitis-associated CC (CAC) mouse models constructed by AOM-DSS inducement were used to confirm the effect of XGB on the CC progression. Hematoxylin & eosin staining was performed to assess the tumor morphology of CAC mouse models tissues. Various cell biological assays including EdU, live-cell imaging, wound-healing assays, and flow cytometry for cell cycle and apoptosis were used to evaluate the effect of DCA on CC progression. The correlation among XGB, DCA, and CC and their underlying mechanisms were detected with immunohistochemistry, mass spectrometry, transcriptome sequencing, qRT-PCR, and western blotting.. Here we proved that XGB increased the plasma DCA level and promoted colon carcinogenesis in a colitis-associated CC mouse model. Additionally, we revealed that DCA promoted the proliferation and migration of CC cells. Further RNA sequencing showed that 120 mRNAs were upregulated, and 118 downregulated in DCA-treated CC cells versus control cells. The upregulated mRNAs were positively correlated with Wnt signaling and cell cycle-associated pathways. Moreover, DCA treatment could reduced the expression of the farnesoid X receptor (FXR) and subsequently increased the levels of β-Catenin and c-Myc in vitro and in vivo. Moreover, the FXR agonist GW4064 decreased the proliferation of CC cells by repressing the expression of β-catenin.. We concluded that XGB-induced DCA exposure could promote the progression of CC by inhibiting FXR expression and enhancing the Wnt-β-catenin pathway. Video Abstract.

Topics: Animals; beta Catenin; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Cholecystectomy; Colitis; Colonic Neoplasms; Deoxycholic Acid; Gene Expression Regulation, Neoplastic; Mice; Wnt Signaling Pathway

Secondary bile acids (SBAs) with high hydrophobicity are abundant in the colonic lumen. However, both aggravating and protective roles of SBAs have been proposed in the pathogenesis of inflammatory bowel diseases (IBDs). We observed that oral administration of hyodeoxycholic acid (HDCA), a hydrophilic bile acid, prevented the development of dextran sulfate sodium (DSS)-induced colitis in mice. We then examined the individual effects of DSS and HDCA as well as their combined effects on fecal bile acid profile in mice. HDCA treatment increased the levels of most of fecal bile acids, whereas DSS treatment had limited effects on the levels of fecal bile acids. The combined treatment with DSS and HDCA synergistically increased the levels of fecal chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) in feces, which are potent activators of the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5). The overall hydrophobicity of fecal bile acids was not modified by any treatments. Our data suggest that the preventive effect of HDCA on DSS-induced colitis in mice is due to the synergism between DSS and HDCA in increasing the levels of the fecal bile acids with potencies to activate FXR and TGR5.

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Colitis; Deoxycholic Acid; Dextran Sulfate; Mice; Receptors, G-Protein-Coupled

We treated Campylobacter jejuni-infected mice with fecal microbiota transplantation (FMT), oral butyric acid and deoxycholic acid in a controlled trial and analyzed the possible mechanisms of treatment by a combination of chromatography, immunohistochemistry, fluorescence in situ hybridization, 16s rRNA gene, proteomics and western blot techniques.. We first investigated the therapeutic effect of FMT on. This is the first time that Akkermansia has been found to be effective in fighting pathogens, which provides new ideas and insights into the use of FMT to alleviate colitis caused by

Topics: Akkermansia; Animals; Butyrates; Campylobacter Infections; Colitis; Deoxycholic Acid; Gastroenteritis; In Situ Hybridization, Fluorescence; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases; Proteomics; RNA, Ribosomal, 16S

Topics: Animals; Anti-Bacterial Agents; Colitis; Colon; Cytokines; Deoxycholic Acid; Diet, High-Fat; Feces; Gastrointestinal Microbiome; Gram-Positive Bacteria; Macrophage Activation; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; NF-kappa B; Phosphorylation; Receptor, Muscarinic M2; Toll-Like Receptor 2; Tyrosine; Vancomycin

Pyruvate is a normal constituent of the body that participates in carbohydrate metabolism and functions as a scavenger of free radicals. Calcium pyruvate monohydrate (CPM) is a more stable derivative that has proved its anti-inflammatory effect in experimental colitis, among other disorders, and that could also be considered a source of calcium. Thus, it would be useful for the treatment of diseases with an inflammatory component and a high prevalence of osteoporosis like the irritable bowel syndrome (IBS). The aim of the present study is to evaluate the effects of CPM in a rat model of chronic post-inflammatory visceral pain induced by deoxycholic acid (DCA) that resembles IBS. Rats were administered DCA for three days intracolonically and then treated daily with CPM (40 and 100 mg/kg) or gabapentin (70 mg/kg) (positive control) by oral gavage for 17 days. The treatments reduced the visceral hypersensitivity measured by response to colorectal distension and referred pain. DCA induced changes in the colonic immune response characterized by increased expression of the cytokine

Topics: Animals; Calcium; Calcium Compounds; Colitis; Colon; Cyclooxygenase 2; Deoxycholic Acid; Disease Models, Animal; Inflammation; Inflammation Mediators; Interleukin-1beta; Intestinal Mucosa; Irritable Bowel Syndrome; Male; Mucin-2; Mucin-3; Pain; Pain Threshold; Pyruvates; Rats, Sprague-Dawley; Toll-Like Receptor 3

Inflammatory bowel disease (IBD) is characterized by pain, bleeding, cramping and altered gastrointestinal (GI) function. Changes in mucosal 5-HT (serotonin) signalling occur in animal models of colitis and in humans suffering from IBD. Melatonin is co-released with 5-HT from the mucosa and has a wide variety of actions in the GI tract. Here, we examined how melatonin signalling is affected by colitis and determined how this relates to 5-HT signalling.. Using electroanalytical approaches, we investigated how 5-HT release, reuptake and availability as well as melatonin availability are altered in dextran sodium sulfate (DSS)-induced colitis in mice. Studies were conducted to explore if melatonin treatment during active colitis could reduce the severity of colitis.. We observed an increase in 5-HT and a decrease in melatonin availability in DSS-induced colitis. A significant reduction in 5-HT reuptake was observed in DSS-induced colitis animals. A reduction in the content of 5-HT was observed, but no difference in tryptophan levels were observed. A reduction in deoxycholic acid-stimulated 5-HT availability and a significant reduction in mechanically-stimulated 5-HT and melatonin availability were observed in DSS-induced colitis. Orally or rectally administered melatonin once colitis was established did not significantly suppress inflammation.. Our data suggest that DSS-induced colitis results in a reduction in melatonin availability and an increase in 5-HT availability, due to a reduction/loss of tryptophan hydroxylase 1 enzyme, 5-HT content and 5-HT transporters. Mechanosensory release was more susceptible to inflammation when compared with chemosensory release.

Topics: Administration, Oral; Administration, Rectal; Animals; Colitis; Colon; Deoxycholic Acid; Dextran Sulfate; Electrochemical Techniques; Intestinal Mucosa; Male; Melatonin; Mice; Serotonin; Signal Transduction; Tryptophan

Topics: Alarmins; Animals; Cathepsin B; Cell Line; Colitis; Deoxycholic Acid; Dextran Sulfate; Disease Models, Animal; Female; Humans; Inflammasomes; Inflammatory Bowel Diseases; Macrophages; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine-1-Phosphate Receptors

To assess whether deoxycholic acid (DOC) and lithocholic acid (LCA) administered in a period of six months in a concentration of 0.25% may have a carcinogenic role in mice colon.. The study used C57BL6 female mice divided into four groups. The control group received a balanced diet and the others received diets supplemented with 0.25% DOC, 0.25% LCA and 0.125% DOC+0.125% LCA, respectively. After euthanasia, the lesions found in the resected gastrointestinal tracts were stained with hematoxylin-eosin and examined microscopically.. No gastrointestinal tract changes were observed in the control group, while hyperplastic Peyer's patches in the small intestine, flat adenomas with mild dysplasia and chronic colitis at the level of the colon were found in all three test groups. The colonic lesions prevailed in the proximal colon. The highest number of flat adenoma lesions (8), hyperplasia of Peyer's patches (25) and chronic colitis (2) were found in mice fed with diet and LCA.. Precancerous or cancerous pathological lesions could not be identified. Instead, adenomatous colonic injuries occurred in a shorter period of time (six months), compared to the reported data.

Topics: Adenoma; Animals; Bile Acids and Salts; Carcinogenicity Tests; Carcinogens; Cholagogues and Choleretics; Colitis; Colon; Colonic Neoplasms; Deoxycholic Acid; Disease Models, Animal; Feces; Female; Lithocholic Acid; Mice, Inbred C57BL; Peyer's Patches; Time Factors

The proinflammatory effect of high-fat diet has been observed beyond the cardiovascular system, but there is little evidence to support its role in triggering inflammatory bowel disease. GPx1/2-double-knockout (DKO) mice deficient in 2 intracellular glutathione peroxidases, GPx1 and GPx2, on a C57BL/6 (B6) background, have mild ileocolitis on a conventional chow.. We fed B6 DKO mice 2 atherogenic diets to test the dietary effect on atherosclerosis and ileocolitis. Both atherogenic diets have high cholesterol-the Chol+/CA diet has cholic acid (CA), and the Chol+ diet has no CA.. The Chol+/CA diet induced severe colitis, but not ileitis, in the DKO mice compared with the Chol+ and the Chol- control diet. On the Chol+/CA diet, the wild-type (WT) mice had levels of aortic lesions and hypercholesterolemia similar to those of DKO mice but had no intestinal pathology. The diet-associated inflammatory responses in the DKO mice included increased colonic proinflammatory serum amyloid A3 expression, plasma lipopolysaccharide, and TNF-α levels. The Chol+/CA diet lowered the expression of the unfolded protein response genes ATF6, CHOP, unspliced Xbp(U) , and Grp78/Bip, in WT and DKO mice compared with mice on the Chol- diet.. We concluded that a cholesterol diet weakens the colon unfolded protein response, which can aggravate spontaneous colitis, leading to gut barrier breakdown. GPx has no impact on atherosclerosis without ultrahypercholesterolemia.

Topics: Animals; Atherosclerosis; Blotting, Western; Cholesterol; Colitis; Crohn Disease; Deoxycholic Acid; Diet, Atherogenic; Endoplasmic Reticulum Chaperone BiP; Fatty Liver; Feces; Female; Gas Chromatography-Mass Spectrometry; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Inflammation; Inflammation Mediators; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Survival Rate; Tumor Necrosis Factor-alpha

Chronic visceral hyperalgesia is considered an important pathophysiologic symptom in irritable bowel syndrome (IBS); previous gastrointestinal inflammation is a potent etiologic factor for developing IBS. Although there are several animal models of adult visceral hypersensitivity after neonatal perturbation or acute colonic irritation/inflammation, current models of postinflammatory chronic visceral hyperalgesia are unsatisfactory. The aim of this study was to establish a model of chronic visceral hyperalgesia after colonic inflammation in the rat.. Deoxycholic acid (DCA) was instilled into the rat colon daily for 3 days and animals were tested for up to 4 weeks.. DCA induced mild, transient colonic inflammation within 3 days that resolved within 3 weeks. An exaggerated visceromotor response, referred pain to mechanical stimulation, increased spinal Fos expression, and colonic afferent and dorsal horn neuron activity were apparent by 1 week and persisted for at least 4 weeks, indicating chronic dorsal horn hyperexcitability and visceral hyperalgesia. There was no spontaneous pain, based on open field behavior. There was a significant increase in opioid-receptor activity.. DCA induces mild, transient colitis, resulting in persistent visceral hyperalgesia and referred pain in rats, modeling some aspects of postinflammatory IBS.

Topics: Abdominal Pain; Animals; Chronic Disease; Colitis; Colon; Deoxycholic Acid; Disease Models, Animal; Electrophysiology; Follow-Up Studies; Ganglia, Sensory; Immunohistochemistry; Male; Pain Measurement; Rats; Rats, Sprague-Dawley

Nos2 knockout mice were compared to wild-type mice for susceptibility to colitis in response to a diet supplemented with deoxycholate, a bile acid increased in the colon of individuals on a high-fat diet. Wild-type mice fed a fat-related diet, supplemented with 0.2% DOC, develop colonic inflammation associated with increases in nitrosative stress, proliferation, oxidative DNA/RNA damage, and angiogenesis, as well as altered expression of numerous genes. However, Nos2 knockout mice fed a diet supplemented with deoxycholate were resistant to these alterations. In particular, 35 genes were identified whose expression was significantly altered at the mRNA level in deoxycholate-fed Nos2(+/+) mice but not in deoxycholate-fed Nos2(-/-) mice. Some of these alterations in NOS2-dependent gene expression correspond to those reported in human inflammatory bowel disease. Overall, our results indicate that NOS2 expression is necessary for the development of deoxycholate-induced colitis in mice, a unique dietary-related model of colitis.

Topics: Animals; Colitis; Deoxycholic Acid; Detergents; Dietary Supplements; Disease Models, Animal; Disease Progression; DNA Damage; Gene Expression Profiling; Immunohistochemistry; Intestinal Mucosa; Membrane Proteins; Mice; Mice, Inbred Strains; Nitric Oxide Synthase; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Tight Junctions

A potential adverse effect of cyclo-oxygenase (COX) inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs]) in horses is colitis. In addition, we have previously shown an important role for COX-produced prostanoids in recovery of ischaemic-injured equine jejunum. It was hypothesised that the nonselective COX inhibitor flunixin would retard repair of bile-injured colon by preventing production of reparative prostaglandins, whereas the selective COX-2 inhibitor, etodolac would not inhibit repair as a result of continued COX-1 activity. Segments of the pelvic flexure were exposed to 1.5 mmol/l deoxycholate for 30 min, after which they were recovered for 4 h in Ussing chambers. Contrary to the proposed hypothesis, recovery of bile-injured colonic mucosa was not affected by flunixin or etodolac, despite significantly depressed prostanoid production. However, treatment of control tissue with flunixin led to increases in mucosal permeability, whereas treatment with etodolac had no significant effect. Therefore, although recovery from bile-induced colonic injury maybe independent of COX-elaborated prostanoids, treatment of control tissues with nonselective COX inhibitors may lead to marked increases in permeability. Alternatively, selective inhibition of COX-2 may reduce the incidence of adverse effects in horses requiring NSAID therapy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Clonixin; Colitis; Colon; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Deoxycholic Acid; Etodolac; Horse Diseases; Horses; Intestinal Mucosa; Isoenzymes; Permeability; Prostaglandin Antagonists; Prostaglandin-Endoperoxide Synthases; Prostaglandins

Rats and guinea-pigs were treated with degraded carrageenan (50 g/litre in the drinking-water) and their intestinal permeability was studied at weekly intervals over the last 4 wk of the test period by determining the recovery of orally administered tracer doses of [3H]polyethylene glycol (PEG-900) or D-[3H]mannitol in 16-hr urine collections. A freely diffusible dye, Azure A, was administered simultaneously to compensate for non-intestinal factors that could modify renal excretion. Animals were killed after a total treatment period of 5 months for rats and 6 wk for guinea-pigs. After 3 wk of carrageenan treatment, excretion of PEG-900 (expressed as a ratio of the Azure A excretion) in guinea-pigs showed a statistically significant increase over that in the control group. At autopsy, the caeca showed numerous macroscopically visible erosions of the entire mucosal surface and histological examination showed ulcerations largely in the mucosa with abscesses in the crypts. Although no such histological changes were seen in the intestines of the treated rats, even after 5 months, a statistically significant increase in PEG-900 excretion was again found compared with the control group. This increase did not occur when deoxycholate was administered with the carrageenan solution. No effect of carrageenan treatment on mucosal permeability to D-[3H]mannitol was demonstrated in either species. The results suggest that degraded carrageenan-induced colitis could be a result of increased intestinal permeability, since ingestion of this polysaccharide by rats increased PEG-900 absorption without causing mucosal damage.

Topics: Animals; Azure Stains; Carrageenan; Colitis; Deoxycholic Acid; Guinea Pigs; Intestinal Mucosa; Male; Mannitol; Permeability; Polyethylenes; Rats; Rats, Inbred Strains; Species Specificity

Bile acid studies were performed in patients with Crohn's disease, radiologically confined to the colon. The bile acid pool size of 10 patients with isolated Crohn's colitis was significantly lower than that of 10 normal control subjects (P less than 0.001) and of 10 ulcerative colitis patients (P less than 0.005). Measurements of 14C-excretion in breath and in 24 hours stool collections after the administration of 5 muCi 14C-glycocholate showed a normal 14C-excretion in breath and usually a markedly increased loss of 14C in the stool (greater than 7% of the dose). The simultaneous administration of 5 muCi 3H-polyethylene glycol MW 4000 (3H-PEG) as a marker indicated that the 14C/3H ratio in the patients with Crohn's colitis was significantly greater than in a control series of patients with diarrhoea not due to bile acid malabsorption. Studies on the composition of duodenal bile showed a significantly decreased concentration of deoxycholic acid in duodenal bile. These observations suggest bile acid malabsorption in patients with Crohn's disease apparently confined to the colon.

Topics: Adolescent; Adult; Bile Acids and Salts; Breath Tests; Colitis; Colitis, Ulcerative; Crohn Disease; Deoxycholic Acid; Feces; Female; Glycocholic Acid; Humans; Intestinal Absorption; Male; Middle Aged; Vitamin B 12