Butyrate Enemas Research Articles

Chronic radiation proctitis refractory to steroid enema was successfully treated by metformin and sodium butyrate: a case report

BackgroundRadiation proctitis (RP) is a significant complication of pelvic radiation. Effective treatments for chronic RP are currently lacking. We report a case where chronic RP was successfully managed by metformin and butyrate (M-B) enema and suppository therapy.Case presentationA 70-year-old Asian male was diagnosed with prostate cancer of bilateral lobes, underwent definitive radiotherapy to the prostate of 76 Gy in 38 fractions and six months of androgen deprivation therapy. Despite a stable PSA nadir of 0.2 ng/mL for 10 months post-radiotherapy, he developed intermittent rectal bleeding, and was diagnosed as chronic RP. Symptoms persisted despite two months of oral mesalamine, mesalamine enema and hydrocortisone enema treatment. Transition to daily 2% metformin and butyrate (M-B) enema for one week led to significant improvement, followed by maintenance therapy with daily 2.0% M-B suppository for three weeks, resulting in continued reduction of rectal bleeding. Endoscopic examination and biopsy demonstrated a good therapeutic effect.ConclusionsM-B enema and suppository may be an effective treatment for chronic RP.

Gut Microbial Metabolite Butyrate and Its Therapeutic Role in Inflammatory Bowel Disease: A Literature Review.

Background and objective: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder characterized by aberrant immune responses and compromised barrier function in the gastrointestinal tract. IBD is associated with altered gut microbiota and their metabolites in the colon. Butyrate, a gut microbial metabolite, plays a crucial role in regulating immune function, epithelial barrier function, and intestinal homeostasis. In this review, we aim to present an overview of butyrate synthesis and metabolism and the mechanism of action of butyrate in maintaining intestinal homeostasis and to discuss the therapeutic implications of butyrate in IBD. Methods: We searched the literature up to March 2023 through PubMed, Web of Science, and other sources using search terms such as butyrate, inflammation, IBD, Crohn's disease, and ulcerative colitis. Clinical studies in patients and preclinical studies in rodent models of IBD were included in the summary of the therapeutic implications of butyrate. Results: Research in the last two decades has shown the beneficial effects of butyrate on gut immune function and epithelial barrier function. Most of the preclinical and clinical studies have shown the positive effect of butyrate oral supplements in reducing inflammation and maintaining remission in colitis animal models and IBD patients. However, butyrate enema showed mixed effects. Butyrogenic diets, including germinated barley foodstuff and oat bran, are found to increase fecal butyrate concentrations and reduce the disease activity index in both animal models and IBD patients. Conclusions: The current literature suggests that butyrate is a potential add-on therapy to reduce inflammation and maintain IBD remission. Further clinical studies are needed to determine if butyrate administration alone is an effective therapeutic treatment for IBD.

Intravaginal Mesalamine Administration: A Novel Technique for Neovaginal Diversion Colitis

Background: Vaginoplasty utilizing sigmoid colon has the advantage of spontaneous mucus production similar to a native vagina and appropriate vaginal length. Neovaginal diverting colitis, a potential side effect of sigmoid vaginoplasty, is an inflammatory process that affects the colonic tissue. Patients may present with vaginal pain, postcoital bleeding, vaginal spotting, and dyspareunia. Treatment for neovaginal diversion colitis includes a combination of intravaginal application mesalamine foam and sodium butyrate enemas.

A264 HELMINTH-INFECTION MOBILIZES HOST AND MICROBIAL FACTORS THAT CO-OPERATE TO SUPPRESS CHEMICAL-INDUCED COLITIS IN MICE

Abstract Background Infection with helminth parasites suppresses inflammation in murine model systems; for example, IL-10 is important in Hymenolepis diminuta-inhibition of DNBS-induced colitis. Bacteria-derived products can have anti-inflammatory effects. Given that infection with H. diminuta, or other parasitic worms, results in perturbation of the gut microbiota, the present study tested a role for bacteria in helminth-suppression of colitis by assessing reciprocity between IL-10 and butyrate signaling in the amelioration of colitis. Aims To determine if a functional relationship exists between IL-10 and butyrate in the inhibition of colitis observed following infection with the lumen-dwelling tapeworm, Hymenolepis diminuta. Methods Colitis was induced in male BALB/c mice by intra-rectal dinitrobenzene sulphonic acid (DNBS) (3 mg/~22g mouse), with necropsy and assessment 3 days later. Mice received either infection with five H. diminuta cysticercoids by gavage or daily butyrate enemas or acetate in their drinking water. Immunostaining assessed IL-10R protein expression on formalin-fixed sections of colon. The murine IEC4.1 epithelial cell line and epithelial organoids were treated with butyrate and mRNA for the IL10Rα chain assessed, as was colonic tissue from mice. Results Mice infected with H. diminuta or receiving butyrate enemas (n=8–12) were protected from DNBS-induced colitis as gauged by colon length, and macroscopic disease and histopathology scores. Addition of acetate to the drinking water resulted in a more modest anti-colitic effect. Suppression of colitis was accompanied by increased epithelial expression of IL-10 in butyrate- and H. diminuta-treated mice, with the later also showing upregulation of the IL-10R on lamina propria cells; an effect negated by co-treating the mice with broad spectrum antibiotics. In vitro analyses revealed increased IL10Rα mRNA in butyrate-treated epithelia (n=4). Conclusions This study begins to tease apart the host (i.e. IL-10) and bacterial (i.e. butyrate) molecules that mediate H. diminuta-evoked suppression of colitis in a murine model. These proof-of-principle data suggest that knowledge of the individual patient (i.e. immunological basis of their disease and their microbiota) may be a critical determinant of the success or failure of helminth therapy. Funding Agencies CAG, CCCNSERC

The role of the gut microbiome in chronic liver disease: the clinical evidence revised.

SummaryRecent research has suggested a role for the intestinal microbiota in the pathogenesis and potential treatment of a wide range of liver diseases. The intestinal microbiota and bacterial products may contribute to the development of liver diseases through multiple mechanisms including increased intestinal permeability, chronic systemic inflammation, production of short-chain fatty acids and changes in metabolism. This suggests a potential role for pre-, pro- and synbiotic products in the prevention or treatment of some liver diseases. In addition, there is emerging evidence on the effects of faecal microbial transplant. Herein, we discuss the relationship between the intestinal microbiota and liver diseases, as well as reviewing intestinal microbiota-based treatment options that are currently being investigated.

Butyrate promotes visceral hypersensitivity in an IBS-like model via enteric glial cell-derived nerve growth factor.

Altered visceral sensation is common in irritable bowel syndrome (IBS) and nerve growth factor (NGF) participates in visceral pain development. Sodium butyrate (NaB) could induce colonic hypersensitivity via peripheral up-regulation of NGF in animals. Enteric glial cells (EGCs) appear to be an important source of NGF. Whether butyrate could induce visceral hypersensitivity via increased EGC-derived NGF is still unknown. CRL-2690 cells were used for transcriptome analyses after butyrate treatment. Rats received butyrate enemas to induce colonic hypersensitivity. Colorectal distention test was performed to assess visceral sensitivity. Immunofluorescence studies were used to evaluate the co-expression of glial fibrillary acidic protein (GFAP) and NGF or growth associated protein 43 in animal model. NGF expression in rat colon was also investigated. In vitro, CRL-2690 cells were stimulated with NaB or trichostatin A (TSA). NGF or GFAP expression was also examined. Transcriptome analyses showed that butyrate induced marked changes of genes expression related to neurotrophic signaling pathways. NaB-treated rats showed increased visceral sensitivity. An improved NGF expression level was observed in NaB-treated rats. Meanwhile, a 2.1-fold increase in co-expression of GFAP and NGF was also determined in rats received NaB enemas. In cultured cells, both NaB and TSA treatment could cause obvious NGF expression. Thus, butyrate might regulate EGC function via histone deacetylase inhibition. Butyrate-EGC interplay may play a pivotal role in regulation of NGF expression and the development of colonic hypersensitivity in IBS-like animal model.

Comparison of three different application routes of butyrate to improve colonic anastomotic strength in rats

IntroductionDespite extensive research, anastomotic leakage (AL) remains one of the most dreaded complications after colorectal surgery. Since butyrate enemas are known to enhance anastomotic healing, several administration routes have been explored in this study.MethodsThree intraluminal approaches involving butyrate were investigated: (1) butyrin-elucidating patch, (2) a single injection of hyaluronan-butyrate (HA-But) prior to construction of the proximal anastomosis and (3) rectal hyaluronan-butyrate (HA-But) enemas designed for distal anastomoses. The main outcome was AL and secondary outcomes were bursting pressure, histological analysis of the anastomosis, zymography to detect MMP activity and qPCR for gene expression of MMP2, MMP9, MUC2 and TFF3.ResultsNeither the patches nor the injections led to a reduction of AL in experiments 1 and 2. In experiment 3, a significant reduction of AL was accomplished with the (HA-But) enema compared to the control group together with a higher bursting pressure. Histological analysis detected only an increased inflammation in experiment 2 in the hyaluronan injection group compared to the control group. No other differences were found regarding wound healing. Zymography identified a decreased proenzyme of MMP9 when HA-But was administered as a rectal enema. qPCR did not show any significant differences between groups in any experiment.ConclusionButyrate enemas are effective in the enhancement of colonic anastomosis. Enhanced butyrate-based approaches designed to reduce AL in animal models for both proximal and distal anastomoses were not more effective than were butyrate enemas alone. Further research should focus on how exogenous butyrate can improve anastomotic healing after gastrointestinal surgery.

Effect of estrogen on visceral sensory function in a non-inflammatory colonic hypersensitivity rat model.

Increased prevalence of functional gastrointestinal disorders in women and perimenstrually accentuated symptoms imply that sexual hormones play a crucial role in the pathogenesis of such syndromes. The aim of this study was to analyze the selective effect of estrogen on visceral sensitivity in gonadectomized female and male Lewis rats with or without prior treatment with butyrate enemas. Following ovariectomy (OVX) or orchiectomy (ORX) estradiol pellets (E2-P) or sham pellets (Sham-P) were implanted. After treatment with butyrate (BUT) or saline (NaCl) enemas, colorectal distensions (CRD) were performed and the visceromotor reflex (VMR) to CRD was measured by electromyography. Gender did not influence VMR to CRD in gonadectomized animals. VMR in E2-P animals compared to Sham-P animals was increased (635 ± 32 μVs vs 470 ± 39 μVs; p = 0.002). Overall, instillation of butyrate enemas did not influence VMR to CRD. A comparison of CRD clusters showed that butyrate enemas in the E2-P animals resulted in a significant sensitization in both OVX and ORX animals. In female rats, sensitization was also caused by estrogen substitution alone. In our animal model, estrogen is a strong factor for an increase in visceral sensory function. Surprisingly, the treatment with butyrate alone did not evoke a general rise in VMR to CRD. Rats treated with butyrate enemas and under selective estrogen substitution developed visceral sensitization during the series of CRDs.

Effect of butyrate enemas on gene expression profiles and endoscopic/histopathological scores of diverted colorectal mucosa: A randomized trial

BackgroundA temporary stoma is often created to protect a distal anastomosis in colorectal surgery. Short-chain fatty acids, mainly butyrate, are the major fuel source for the epithelium and their absence in the diverted tract may produce mucosal atrophy and inflammation. AimsTo investigate whether the administration of sodium butyrate enemas (Naburen©, Promefarm, Italy) could prevent mucosal inflammation and atrophy and affect gene expression profiles after ileo/colostomy. MethodsWe performed a randomized, double-blind, placebo-controlled clinical trial, in patients with enterostomy performed for inflammatory bowel disease, colorectal cancer or diverticulitis. Twenty patients were randomly allocated to receive 30ml of sodium butyrate 600mmol/L (group A) or saline (group B), b.i.d. for 30 days. ResultsIn group A endoscopic scores were significantly improved (p<0.01) while mucosal atrophy was reduced or unchanged; in group B mucosal atrophy was increased in 42.8% of patients. Despite the high dose of butyrate used, no short-chain fatty acids were detectable by gas chromatography–mass spectrometry in colorectal biopsies. Group A patients showed up-regulation of genes associated with mucosal repair such as Wnt signalling, cytoskeleton regulation and bone morphogenetic protein-antagonists. ConclusionButyrate enemas may prevent the atrophy of the diverted colon/rectum, thus improving the recovery of tissue integrity.

Hepatic Uptake of Rectally Administered Butyrate Prevents an Increase in Systemic Butyrate Concentrations in Humans1–3

Background: Short-chain fatty acids (SCFAs), fermentation products of undigested fibers, are considered beneficial for colonic health. High plasma concentrations are potentially harmful; therefore, information about systemic SCFA clearance is needed before therapeutic use of prebiotics or colonic SCFA administration.Objective: The aim of this study was to investigate the effect of rectal butyrate administration on SCFA interorgan exchangeMethods: Twelve patients (7 men; age: 66.4 ± 2.0 y; BMI 24.5 ± 1.4 kg/m2) undergoing upper abdominal surgery participated in this randomized placebo-controlled trial. During surgery, 1 group received a butyrate enema (100 mmol sodium butyrate/L; 60 mL; n = 7), and the other group a placebo (140 mmol 0.9% NaCl/L; 60 mL; n = 5). Before and 5, 15, and 30 min after administration, blood samples were taken from the radial artery, hepatic vein, and portal vein. Plasma SCFA concentrations were analyzed, and fluxes from portal-drained viscera, liver, and splanchnic area were calculated and used for the calculation of the incremental area under the curve (iAUC) over a 30-min period.Results: Rectal butyrate administration led to higher portal butyrate concentrations at 5 min compared with placebo (92.2 ± 27.0 μmol/L vs. 14.3 ± 3.4 μmol/L, respectively; P < 0.01). In the butyrate-treated group, iAUCs of gut release (282.8 ± 133.8 μmol/kg BW · 0.5 h) and liver uptake (−293.7 ± 136.0 μmol/kg BW · 0.5 h) of butyrate were greater than in the placebo group [−16.6 ± 13.4 μmol/kg BW · 0.5 h (gut release) and 16.0 ± 13.8 μmol/kg BW · 0.5 h (liver uptake); P = 0.01 and P < 0.05, respectively]. As a result, splanchnic butyrate release did not differ between groups.Conclusion: After colonic butyrate administration, splanchnic butyrate release was prevented in patients undergoing upper abdominal surgery. These observations imply that therapeutic colonic SCFA administration at this dose is safe. The trial was registered at clinicaltrials.gov as NCT02271802.

Butyrate and Mucosal Inflammation: New Scientific Evidence Supports Clinical Observation

Butyrate and Mucosal Inflammation: New Scientific Evidence Supports Clinical Observation

Su1871 Effects of DA-9701, a Prokinetic Agent on Gastric Motor Function in Guinea Pig; In Vivo and In Vitro Study

ity was induced in twenty adult male Sprague-Dawley rats by butyrate enemas in the distal colon, and 10 control rats served as vehicle only. After butyrate enema, the rats were divided into 2 groups and were given respectively DA 9701 3mg/kg or vehicle. The rats were sacrificed at 1 and 2 days after treatment, and colonic damage score and tissue myeloperoxidase activity were evaluated. In lumbosacral L1 and L2 DRG, expression level of BDNF, ASIC 1a, ASIC 2b, IL-1β, and TNF-α were assessed using quantitative real-time PCR, ELISA, and western blot. Results: In L1 DRG, the levels of BDNF protein were increased at both 1 and 2 days of colitis (2.2to 3.2-fold, p < 0.05). There were no significant changes in the BDNF protein level in L2 DRG at both days of colitis. In addition, level of ASIC 1a (2.5to 4.3fold, p < 0.05) and 2b (2.7to 3.6-fold, p < 0.05) protein expression in L2 DRG significantly higher after administration. RT PCR results showed significant increases in the level of BDNF mRNA in L1 DRG (2.1to 2.3-fold, p < 0.05) at 1 and 2 days of colitis. ASIC 1a and 2b mRNA expression was significantly increased in L1 level. There was no change in IL-1β and TNF-α expression in colitis group. In butyrate-treated colitis model, administration of DA 9701 led to significantly decreased level of BDNF, ASIC 1a, and ASIC 2b protein and mRNA expression in both L1 and L2 DRG levels compared with control groups. Conclusion: Our data suggest that peripheral BDNF and ASIC1a/2b concomitantly contribute to the development of butyrate-induced colon hypersensitivity. In addition, DA 9701 can negatively modulate the activity of ASICs and BDNF in lumbosacral DRG.

Su1870 Entacapone, A Peripherally Restricted COMT Inhibitor, Regulates Gastrointestinal Motility and Pain Sensitivity in Mice

ity was induced in twenty adult male Sprague-Dawley rats by butyrate enemas in the distal colon, and 10 control rats served as vehicle only. After butyrate enema, the rats were divided into 2 groups and were given respectively DA 9701 3mg/kg or vehicle. The rats were sacrificed at 1 and 2 days after treatment, and colonic damage score and tissue myeloperoxidase activity were evaluated. In lumbosacral L1 and L2 DRG, expression level of BDNF, ASIC 1a, ASIC 2b, IL-1β, and TNF-α were assessed using quantitative real-time PCR, ELISA, and western blot. Results: In L1 DRG, the levels of BDNF protein were increased at both 1 and 2 days of colitis (2.2to 3.2-fold, p < 0.05). There were no significant changes in the BDNF protein level in L2 DRG at both days of colitis. In addition, level of ASIC 1a (2.5to 4.3fold, p < 0.05) and 2b (2.7to 3.6-fold, p < 0.05) protein expression in L2 DRG significantly higher after administration. RT PCR results showed significant increases in the level of BDNF mRNA in L1 DRG (2.1to 2.3-fold, p < 0.05) at 1 and 2 days of colitis. ASIC 1a and 2b mRNA expression was significantly increased in L1 level. There was no change in IL-1β and TNF-α expression in colitis group. In butyrate-treated colitis model, administration of DA 9701 led to significantly decreased level of BDNF, ASIC 1a, and ASIC 2b protein and mRNA expression in both L1 and L2 DRG levels compared with control groups. Conclusion: Our data suggest that peripheral BDNF and ASIC1a/2b concomitantly contribute to the development of butyrate-induced colon hypersensitivity. In addition, DA 9701 can negatively modulate the activity of ASICs and BDNF in lumbosacral DRG.

Daily Sodium Butyrate Enema for the Prevention of Radiation Proctitis in Prostate Cancer Patients Undergoing Radical Radiation Therapy: Results of a Multicenter Randomized Placebo-Controlled Dose-Finding Phase 2 Study

To evaluate the efficacy of sodium butyrate enemas (NABUREN) in prostate cancer radiation therapy (RT) in reducing the incidence, severity, and duration of acute RT-induced proctitis. 166 patients, randomly allocated to 1 of 4 groups (rectal sodium butyrate 1 g, 2 g, or 4 g daily or placebo), were treated with NABUREN during and 2 weeks after RT. The grade of proctitis was registered in a daily diary. The correlation between NABUREN and proctitis was investigated through χ(2) statistics. The toxicity endpoints considered were as follows: total number of days with grade ≥1 proctitis (≥G1); total number of days with grade ≥2 proctitis (≥G2); ≥G1 and ≥G2 proctitis lasting at least 3 and 5 consecutive days starting from week 4 (≥G1+3d, ≥G2+3d); damaging effects of RT on rectal mucosa as measured by endoscopy. The relationship between endpoints and pretreatment morbidities, hormonal therapy, presence of diabetes or hypertension, abdominal surgery, or hemorrhoids was investigated by univariate analysis. The patients were randomly allocated to the 4 arms. No difference in the distribution of comorbidities among the arms was observed (P>.09). The mean ≥G1 and ≥G2 proctitis were 7.8 and 4.9 for placebo and 8.9 and 4.7 for the NABUREN group, respectively. No favorable trend in reduction of incidence, severity, and duration of ≥G1 and ≥G2 proctitis was observed with NABUREN use. In univariate analysis, ≥G1+3d toxicity was found to be related to hemorrhoids (P=.008), and a slight correlation was found between ≥G2 proctitis and hormonal therapy (P=.06). The RT effects on rectal mucosa as based on endoscopic assessment were mainly related to diabetes (P<.01). Endoscopy data at 6 week showed no significant difference between the placebo and butyrate arms. The other investigated endpoints were not correlated with any of the clinical risk factors analyzed. There was no evidence of efficacy of NABUREN in reducing the incidence, severity, and duration of acute radiation proctitis. There was a correlation between some endpoints and clinical risk factors.

Peripheral contribution of NGF and ASIC1a to colonic hypersensitivity in a rat model of irritable bowel syndrome

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with idiopathic colonic hypersensitivity (CHS). However, recent studies suggest that low-grade inflammation could underlie CHS in IBS. The pro-inflammatory mediator nerve growth factor (NGF) plays a key role in the sensitization of peripheral pain pathways and several studies have reported its contribution to visceral pain development. NGF modulates the expression of Acid-Sensing Ion Channels (ASICs), which are proton sensors involved in sensory neurons sensitization. This study examined the peripheral contribution of NGF and ASICs to IBS-like CHS induced by butyrate enemas in the rat colon. Colorectal distension and immunohistochemical staining of sensory neurons were used to evaluate NGF and ASICs contribution to the development of butyrate-induced CHS. Systemic injection of anti-NGF antibodies or the ASICs inhibitor amiloride prevented the development of butyrate-induced CHS. A significant increase in NGF and ASIC1a protein expression levels was observed in sensory neurons of rats displaying butyrate-induced CHS. This increase was specific of small- and medium-diameter L1+S1 sensory neurons, where ASIC1a was co-expressed with NGF or trkA in CGRP-immunoreactive somas. ASIC1a was also overexpressed in retrogradely labeled colon sensory neurons. Interestingly, anti-NGF antibody administration prevented ASIC1a overexpression in sensory neurons of butyrate-treated rats. Our data suggest that peripheral NGF and ASIC1a concomitantly contribute to the development of butyrate-induced CHS NGF-ASIC1a interplay may have a pivotal role in the sensitization of colonic sensory neurons and as such, could be considered as a potential new therapeutic target for IBS treatment.

PMO-047 Diversion colitis treatment with rapidly fermentable fibre-suppositories

IntroductionDiversion colitis, a nutritional deficiency disease of short chain fatty acids (SCFAs) in the defunctioned rectum, responds to butyrate enemas but these are impracticable due to unpleasant malodour. Treatment with...

Mo2034 Card-024, a Vitamin D Analog, Attenuates the PRO-Fibrotic Response to TGFβ or Substrate Stiffness in Colonic Myofibroblasts

Background and aims: Diversion colitis is a relatively common complication of colostomy involving the excluded colon's segment. Although the pathogenesis of the chronic inflammatory process remains unclear, the lack of luminal nutrients is believed to play a major role in the development of the disease. Therefore, we tested whether essential colonocyte nutrients, such as butyrate or glutamine could attenuate the inflammation in a model of diversion colitis. Methods: Forty eight male Wistar SPF rats were randomly distributed in 4 groups of 12 rats each. Animals were submitted to a Hartmann's end colostomy, and treated with enemas containing glutamine, butyrate, or saline. Enemas were administered twice a week in the excluded segment of the colon from the 4th to the 12th week after the surgical procedure. Follow-up video-colonoscopy was performed every 4 weeks, during 12 weeks. Afterwards, animals of all groups, including a normal control group were sacrificed either on the 8th week or the 12th week. The effects of treatment were evaluated using videoendoscopic and histologic scores, Picrosirius, Periodic Acid of Schiff and TUNEL staining, and also measuring the production of IL-1β, TNF-α and TGF-β in organ cultures, by ELISA. Results: Colonoscopies of the diverted segment, on 8th and 12th weeks, showed mucosa with hyperemia, increased number of vessels, spontaneous bleeding and mucus discharge, with the peak of the inflammatory activity in the 8th week. Treatment with either glutamine or butyrate prevented a significant increase in both colonoscopic (P < 0.01) and histological (P < 0.01) inflammatory scores, and stabilized the densities of collagen fibers in tissue (P < 0.02), the number of goblet cells (P <0.04), and the rate of apoptosis within the epithelium (P < 0.04) to normal low values, compared to the high values of the untreated inflamed tissues. Butyrate and glutamine enemas significantly abrogated the increased production of IL-1β and TGF-β (butyrate), and also of TNF-α (butyrate and glutamine) from tissue explants of surgically diverted colon, and levels were kept within the normal ranges following treatment. Conclusion: Topical administration of either glutamine or butyrate provides mucosal protection against the development of inflammation in the diverted colonic segment after colostomy. These results strongly suggest that the lack of specific luminal nutrients can induce inflammation, and support the potential utilization of glutamine or butyrate enemas for the treatment and possibly the prevention of human diversion colitis.

Mo2033 Butyrate or Glutamine Enemas Prevent Inflammation and Fibrosis in Experimental Diversion Colitis

Background and aims: Diversion colitis is a relatively common complication of colostomy involving the excluded colon's segment. Although the pathogenesis of the chronic inflammatory process remains unclear, the lack of luminal nutrients is believed to play a major role in the development of the disease. Therefore, we tested whether essential colonocyte nutrients, such as butyrate or glutamine could attenuate the inflammation in a model of diversion colitis. Methods: Forty eight male Wistar SPF rats were randomly distributed in 4 groups of 12 rats each. Animals were submitted to a Hartmann's end colostomy, and treated with enemas containing glutamine, butyrate, or saline. Enemas were administered twice a week in the excluded segment of the colon from the 4th to the 12th week after the surgical procedure. Follow-up video-colonoscopy was performed every 4 weeks, during 12 weeks. Afterwards, animals of all groups, including a normal control group were sacrificed either on the 8th week or the 12th week. The effects of treatment were evaluated using videoendoscopic and histologic scores, Picrosirius, Periodic Acid of Schiff and TUNEL staining, and also measuring the production of IL-1β, TNF-α and TGF-β in organ cultures, by ELISA. Results: Colonoscopies of the diverted segment, on 8th and 12th weeks, showed mucosa with hyperemia, increased number of vessels, spontaneous bleeding and mucus discharge, with the peak of the inflammatory activity in the 8th week. Treatment with either glutamine or butyrate prevented a significant increase in both colonoscopic (P < 0.01) and histological (P < 0.01) inflammatory scores, and stabilized the densities of collagen fibers in tissue (P < 0.02), the number of goblet cells (P <0.04), and the rate of apoptosis within the epithelium (P < 0.04) to normal low values, compared to the high values of the untreated inflamed tissues. Butyrate and glutamine enemas significantly abrogated the increased production of IL-1β and TGF-β (butyrate), and also of TNF-α (butyrate and glutamine) from tissue explants of surgically diverted colon, and levels were kept within the normal ranges following treatment. Conclusion: Topical administration of either glutamine or butyrate provides mucosal protection against the development of inflammation in the diverted colonic segment after colostomy. These results strongly suggest that the lack of specific luminal nutrients can induce inflammation, and support the potential utilization of glutamine or butyrate enemas for the treatment and possibly the prevention of human diversion colitis.

Butyrate enemas enhance both cholinergic and nitrergic phenotype of myenteric neurons and neuromuscular transmission in newborn rat colon

Postnatal changes in the enteric nervous system (ENS) are involved in the establishment of colonic motility. In adult rats, butyrate induced neuroplastic changes in the ENS, leading to enhanced colonic motility. Whether butyrate can induce similar changes during the postnatal period remains unknown. Enemas (Na-butyrate) were performed daily in rat pups between postnatal day (PND) 7 and PND 17. Effects of butyrate were evaluated on morphological and histological parameters in the distal colon at PND 21. The neurochemical phenotype of colonic submucosal and myenteric neurons was analyzed using antibodies against Hu, choline acetyltransferase (ChAT), and neuronal nitric oxide synthase (nNOS). Colonic motility and neuromuscular transmission was assessed in vivo and ex vivo. Butyrate (2.5 mM) enemas had no impact on pup growth and histological parameters compared with control. Butyrate did not modify the number of Hu-immunoreactive (IR) neurons per ganglia. A significant increase in the proportion (per Hu-IR neurons) of nNOS-IR myenteric and submucosal neurons and ChAT-IR myenteric neurons was observed in the distal colon after butyrate enemas compared with control. In addition, butyrate induced a significant increase in both nitrergic and cholinergic components of the neuromuscular transmission compared with control. Finally, butyrate increased distal colonic transit time compared with control. We concluded that butyrate enemas induced neuroplastic changes in myenteric and submucosal neurons, leading to changes in gastrointestinal functions. Our results support exploration of butyrate as potential therapy for motility disorders in preterm infants with delayed maturation of the ENS.

Use of butyrate or glutamine in enema solution reduces inflammation and fibrosis in experimental diversion colitis

To investigate whether butyrate or glutamine enemas could diminish inflammation in experimental diversion colitis. Wistar specific pathogen-free rats were submitted to a Hartmann's end colostomy and treated with enemas containing glutamine, butyrate, or saline. Enemas were administered twice a week in the excluded segment of the colon from 4 to 12 wk after the surgical procedure. Follow-up colonoscopy was performed every 4 wk for 12 wk. The effect of treatment was evaluated using video-endoscopic and histologic scores and measuring interleukin-1β, tumor necrosis factor-alpha, and transforming growth factor beta production in organ cultures by enzyme linked immunosorbent assay. Colonoscopies of the diverted segment showed mucosa with hyperemia, increased number of vessels, bleeding and mucus discharge. Treatment with either glutamine or butyrate induced significant reductions in both colonoscopic (P < 0.02) and histological scores (P < 0.01) and restored the densities of collagen fibers in tissue (P = 0.015; P = 0.001), the number of goblet cells (P = 0.021; P = 0.029), and the rate of apoptosis within the epithelium (P = 0.043; P = 0.011) to normal values. The high levels of cytokines in colon explants from rats with diversion colitis significantly decreased to normal values after treatment with butyrate or glutamine. The improvement of experimental diversion colitis following glutamine or butyrate enemas highlights the importance of specific luminal nutrients in the homeostasis of the colonic mucosa and supports their utilization for the treatment of human diversion colitis.