Product Details: Butyrate Enema (Discontinued)

Butyrate Enema  This product is discontinued!

Control IBD and inflammation

• Provide colonocytes the energy they require
• Decrease colon cancer risk
• Accelerate healing in the large intestine

Ulcerative colitis (UC) and Crohn's disease (CD) are the most common forms of inflammatory bowel disease (IBD) in humans. As many as 250,000 Canadians suffer from IBD. UC is characterized by damage to the colonic epithelial cells that results in impaired cell metabolism and compromise of the protective barrier function of the large bowel. IBD affects the patient's well being and quality of life due to severe pain, malabsorption, weight loss, rectal bleeding and diarrhea. IBD sufferers are also at a higher risk of colorectal cancer than the general population due to the presence of chronic inflammation in the gastrointestinal tract. The goal of treatment is to achieve remission and relief of symptoms, but occasionally IBD sufferers have 'flare-ups'.
Butyrate enema
AOR's butyrate enema can be used for acute flare-ups and as an IBD treatment. This product can be combined with AOR's Alimentin, for a multiple-mechanism approach to the treatment of IBD. Multi-echanism treatment strategies provide the best possible treatment for chronic conditions like IBD.

Serving Size 1 Application Source: Country of Origin
Sodium Butyrate 1320mg Chemical Synthesis China

Non-medicinal ingredients: distilled water, hydrochloric acid.

120ml Single Application

Suggested Use: One application daily, or as directed by a qualified health care professional. Do not use if pregnant or nursing.

Key Feature: Promotes healing of the colonic epithelium.

Possible irritation from enema tip.

Pregnancy/Nursing: Not tested. Do not use.


Butyrate and SCFAs
Dietary fiber and digestive-resistant starches undergo bacterial fermentation by colonic microflora. This process produces short-chain fatty acids (SCFAs), such as acetate, propionate, and the most abundant SCFA - butyrate. Butyrate has been shown to have considerable effects on colonic epithelial cells. Butyrate is the primary energy source for normal colonic epithelium and stimulates the growth of the colonic mucosa. Butyrate also inhibits the growth and induces apoptosis in colonic tumor cells. In patients with UC, there is an impaired butyrate utilization compared to the normal population and it has been suggested that UC may be an energy deficiency disease of the colonic mucosa. SCFAs and butyrate prevent the development of colitis in animal models. Research has also shown that the absence of SCFAs and their derivatives inevitably leads to the development of colitis.

Colon inflammation and butyrate
Inflammation is a major element in the etiology of UC. Heat-shock proteins (HSPs) activate the immune system in numerous ways that propagate inflammation and colonic tissue damage. HSP70 is an HSP that is produced in response to an array of cellular stresses and is increased in inflammatory bowel diseases, such as UC. In UC, colonocytes produce a marked increase in HSP70, oxygen-free radicals and other cytokines that continuously induce HSP expression, creating a cycle of inflammation. Research has shown that treatment with butyrate results in an inhibition of HSP70, HSPs and inflammatory cytokine synthesis, resulting in decreased pro-inflammatory stimulus.

Butyrate and Nuclear Factor - κB
NF- κB regulates a variety of genes related to immune function and inflammatory responses, including cancer. NF- κB activation has been shown to be increased in inflammatory bowel diseases. On the other hand, butyrate inhibits the activation of NF- κB when administered as an enema. This inhibition leads to decreased colon inflammation by inhibiting not only HSPs, but decreasing inflammation related to immune cells such as neutrophils and macrophages which infiltrate the colon mucosa.

Butyrate and colon cancer
Colon cancer is a leading cause of cancer-related deaths in many industrialized countries. The transition to malignancy is caused by gene alterations which lead to increased cellular proliferation and decreased cell death. Research shows that dietary factors alter the expression of genes that directly influence the progression of colon cancer. Butyrate is of importance, because it is the primary energy source of the colon epithelium and plays a major role in the protection of the colonic cells by regulating the genes that are involved in the proliferation, differentiation and apoptosis of colon cells. Butyrate is essential to the health of the colon and the disruption of its production and supply are associated with several colonic disorders.

Butyrate and cancer genes
Butyrate is transported across the colonic membrane by the transporter MCT1. MCT1 has been shown to be significantly down-regulated in colon cancer. This down-regulation reduces the availability and can lead to a deficiency of intracellular butyrate for the colonocytes. This decreased availability of butyrate is thought to disrupt the expression of genes that are associated with the maintenance of a healthy and cancer-free colonic mucosa. The MCT1 gene is not the only gene shown to be down-regulated in colon cancer. Tumor suppressor genes, pro-apoptotic genes and cell-cycle regulator genes have all been shown to be down-regulated in colon cancer. Treatment with butyrate has been shown to up-regulate more than 59 genes that colon cancer cells down-regulate to increase their blood supply, survival and proliferation.

Butyrate research
Alarge clinical trial was done with UC patients receiving butyrate enemas twice a day. The results of the trial found that butyrate encouraged mucosal repair processes, reduced mucosal permeability and facilitated electrolyte and water absorption. Participants treated with sodium butyrate had less diarrhea, improved histological scores, decreased disease activity index (DAI), increased mucin secretion and in some participants the disease went into remission. UC participants experiencing a flare-up of less than 6 months duration had the best results with the butyrate treatment. No significant side effects were noted on examination or laboratory results, the only reaction being minor irritation caused by the enema tip. It is believed that butyrate treatment may contribute to reduced bleeding, enhanced healing, reduced bacterial and/or food antigens crossing the colonic mucosa, and diminish diarrhea. Butyrate was also found to stimulate the proliferation of normal cells, increase colon mucosal oxygen and blood flow by decreasing arteriole resistance, and improve the differentiation of colon cells.

IBD and Butyrate
UC and Crohn's disease are the most prevalent forms of inflammatory bowel diseases. Impaired cell metabolism and a degradation of the colon's protective barrier due to colonic epithelial cells are key to UC. Butyrate is formed through the bacterial fermentation of unabsorbed carbohydrates by the large intestine's epithelium. Butyrate acts as the primary food source for colonic epithelium cells, improving the colon's protective barrier, health and function. Research has shown butyrate to be an encouraging choice in the treatment of inflammatory bowel diseases.

Breuer, R., Soergel, K., Lashner, B. Short chain fatty acid rectal irrigation for left-sided ulcerative colitis: a randomized, placebo controlled trial. Gut 1997:40:485-491

Daly, K., Shirazi-Beechy, S. Microarray analysis of butyrate regulated genes in colonic epithelial cells. DNA and cell biology. 2006, Vol 25, No1, pp49-62

Venkatraman, A., Ramakrishna, B., Shaji, R. Amelioration of dextran sulfate colitis by butyrate: role of heat shock protein 70 and NF- B. Am J Physiol Gastrointest Liver Physiol. 285: G177-184, 2003.

Inatomi, O., Andoh, A., Kitamura, KI. Butyrate blocks interferon- -inducible protein-10 release in human intestinal subepithelial myofibroblasts. J Gastroenterol 2005:40:483-489

Luhrs, H., Gerke, T., Muller J. Butyrate inhibits NK- B activation in lamina propria macrophages of patients with ulcerative colitis. Scand J Gastroenterol. 2002 Apr:37(40):458-66

Mechanism of Action
Mechanism Of Action

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Amelioration of dextran sulfate colitis by butyrate: role of heat shock protein 70 and NF-κB
Venkatraman A, Ramakrishna BS, Shaji RV, Nanda Kumar NS, Pulimood A, Patra S. Am J Physiol Gastrointest Liver Physiol; 2003, 285: G177-G184

Butyrate enemas have been demonstrated to ameliorate inflammation in ulcerative colitis. The mechanism of this protective effect of butyrate is not known, and this study examines the effect of butyrate on epithelial function, inducible heat shock protein 70 (HSP70) expression, and NF-κB activation in experimental colitis. Colitis was induced in rats by oral dextran sulfate sodium (DSS) and by butyrate or saline enemas. Mucosal barrier function was assessed by electrical resistance and [14C]mannitol permeability. HSP70 production was determined by [35S]methionine labeling, Western blot analysis, and immunohistochemistry. Activation of heat shock factors (HSFs) and NF-κB was evaluated by EMSA. Butyrate showed a significant protection against the decrease in cell viability, increase in mucosal permeability, and polymorphonuclear neutrophil infiltration seen in DSS colitis. Butyrate inhibited HSP70 expression in DSS colitis and also inhibited the activation of HSF and NF-κB. Thus butyrate enema was found to be cytoprotective in DSS colitis, an effect partly mediated by suppressing activation of HSP70 and NF-κB.

Microarray Analysis of Butyrate Regulated Genes in Colonic Epithelial Cells
Daly K, Shirazi-Beechey SP. DNA and Cell Biology; 2006, 25(1): 49-62.

Butyrate is a naturally occurring product of colonic microbial fermentation of dietary carbohydrates that escape hydrolysis in the small intestine. Butyrate plays a significant role in the maintenance of colonic tissue homeostasis by regulating the expression of genes associated with the processes of proliferation, differentiation, and apoptosis. Using microarray analysis, we assessed changes in the expression of 19,400 genes in response to butyrate in a human colonic epithelial cell line. Among these, we have identified 221 potentially butyrate-responsive genes specifically associated with the processes of proliferation, differentiation, and apoptosis. Of these genes, 59 are upregulated and 162 downregulated, in accordance with the known modes of action of butyrate. The changes in the expression levels (up- or downregulation) of many of these genes were found to be opposite to that reported in colon cancer tissue, where the intracellular concentration of butyrate would be reduced due to the decline in expression of the colonic butyrate transporter, MCT1.

Short chain fatty acid rectal irrigation for left-sided ulcerative colitis: a randomised, placebo controlled trial
Breuer RI, Soergel KH, Lashner BA, Christ ML, Hanauer SB, Vanagunas A, Harig JM, Keshavarzian A, Robinson M, Sellin JH, Weinberg D, Vidican DE, Flemal KL, Rademaker AW. Gut; 1997, 40: 485-491.

Short chain fatty acid (SCFA) deficiency is associated with colitis in animals and humans, and the mucosal metabolism of these compounds is decreased in ulcerative colitis.

Aims: To assess the efficacy of topical SCFA treatment in ulcerative colitis.

Patients and Methods: 103 patients with distal ulcerative colitis were entered into a six week, double-blind, placebo controlled trial of rectal SCFA twice daily; patients who were unchanged on placebo were offered SCFA in an open-label extension trial.

Results: Of the 91 patients completing the trial, more patients in the SCFA treated than in the placebo treated group improved (33% v 20%, p=0 14, NS). Those on SCFA also had larger, but statistically non-significant, reductions in every component of their clinical and histological activity scores. In patients with a relatively short current episode of colitis (<6 months, n=42), more responded to SCFA than to placebo (48% v 18%, p=003). These patients also had larger, but statistically non-significant, decreases in their clinical activity index (p=0.08 v placebo). Every patient who improved used at least five of six of the prescribed rectal SCFA irrigations, whereas only 37% who did not improve were as compliant. In the open-label extension trial, 65% improved on SCFA; these patients also had significant reductions (p<0.02) in their clinical and histological activity scores.

Conclusions: Although SCFA enemas were not of therapeutic value in this controlled trial, the results suggest efficacy in subsets of patients with distal ulcerative colitis including those with short active episodes. Prolonged contact with rectal mucosa seems to be necessary for therapeutic benefit.

Butyrate blocks interferon-γ-inducible protein-10 release in human intestinal subepithelial myofibroblasts
Inatomi O, Andoh A, Kitamura K, Yasui H, Zhang Z, Fujiyama Y. J Gastroenterol 2005; 40:483-489

Background: Interferon (IFN)-γ-inducible protein (IP)- 10 is a chemoattractant for CXCR 3-expressing T lymphocytes and monocytes. IP-10 has been reported to mediate chronic inflammation such as that in inflammatory bowel disease (IBD). However, the local secretion of IP-10 in the intestine remains unclear. In this study, we investigated IP-10 secretion in human colonic subepithelial myofibroblasts (SEMFs).

Methods: IP-10 secretion was determined by enzyme linked immunosorbent assay (ELISA), and IP-10 mRNA expression was evaluated by Northern blotting.

Results: Interleukin (IL)-10 mRNA was not detected in unstimulated SEMFs. Interferon (IFN)-γ strongly induced IP-10 mRNA expression. Tumor necrosis factor (TNF)-α also stimulated IP-10 mRNA expression, but this was much weaker than that induced by IFN-γ. The effects of IFN-γ and TNF-α were detected in a doseand time-dependent manner. These responses were also observed at the protein levels. The IFN-γ-induced IP-10 secretion was not affected by acetate or propionate, but was significantly reduced by butyrate. Trichostatin A, a specific inhibitor of histone deacetylase, also blocked the IFN-γ- and TNF-α-induced IP-10 mRNA expression, but the effects of trichostatin A were weaker than those of butyrate. The inhibitory effect of butyrate on IFN-γ-induced IP-10 release was not associated with STAT (signaling transducer and activator of transcription)- 1α activation.

Conclusions: We demonstrated that human colonic SEMFs are the local site for the secretion IP-10. The regulation of IP-10 release by IFN-γ and butyrate may play an important role in controlling chronic mucosal inflammation in pathological entities such as IBD.

Short Chain Fatty Acids are Effective in Short-Term Treatment of Chronic Radiation Proctitis: Randomized, Double-Blind, Controlled Trial

Pinto A, Fidalgo P, Cravo M, Midoes J, Chaves P, Rosa J, dos Anjos Brito M, Leitao CN. Dis Colon Rectum; 1999, 42(6): 788-795

Short chain fatty acids are the main energy source of coloncytes and their use may be impaired in chronic radiation proctitis. The aim of the present study was to evaluate the therapeutic effect of short chain fatty acid enemas in patients with chronic radiation proctitis.

METHODS: A prospective, randomized, double-blind trial comparing short chain fatty acid enemas with placebo was conducted in 19 patients with chronic radiation proctitis. Short chain fatty acid enemas contained 60 mM sodium acetate, 30 mM sodium propionate, and 40 mM sodium butyrate. The treatment period lasted five weeks and patients were followed up for six months.

RESULTS: On admission, both groups were similar regarding all parameters evaluated. After five weeks short chain fatty acid-treated patients showed a significant decrease in the number of days with rectal bleeding from the previous week (4.4±1.8 to 1.4±2.2;P=0.001) and an improvement of endoscopic score (4.8±1.4 to 2.2±1.2;P=0.001). Hemoglobin values were also significantly higher in short chain fatty acid-treated patients (13.1±0.9 g/dlvs. 10.7±2.1 g/dl;P=0.02). Mucosal DNA and protein concentrations decreased in both groups but significantly so only in placebotreated patients (P=0.05). Changes in histologic parameters were not significant in either group. Although short chain fatty acid-treated patients did not get worse in the next six months, placebo-treated ones gradually improved, and at the end of six months, differences between the two groups were no longer observed.

CONCLUSIONS: Short chain fatty acid enemas can accelerate the process of healing in chronic radiation proctitis, but treatment has to be continuous if a complete and sustained clinical, endoscopic, and histologic response is to be obtained.

Fecal Short-Chain Fatty Acids in Patients with Diarrhea-Predominant Irritable Bowel Syndrome: In Vitro Studies of Carbohydrate Fermentation.
Treem W, Ahsan N, Kastoff G, Hyams J. Journal of Pediatric Gastroenterology & Nutrition; 1996, 23(3): 280-286

Summary: Colonic bacterial production of short-chain fatty acids (SCFA) plays an important role in the salvage of unabsorbed carbohydrate and in colonic absorption of electrolytes and water. The objective of this study was to determine whether patients with diarrhea-predominant irritable bowel syndrome (DP-IBS) have a different pattern and rate of fermentation of carbohydrate and fiber to SCFA compared with controls. Fecal homogenates from 10 patients with DP-IBS and 10 age-matched controls were studied. SCFA were measured by gas chromatography in baseline fecal samples and in fecal homogenates in an in vitro anaerobic fermentation system after incubation with no additional substrate, lactulose, potato starch, citrus pectin, and hemicellulose over a 24-hour period. Net SCFA production rates were calculated for the first 6 h of the incubation period. Patients with DP-IBS had a consistently different pattern of less total SCFA, a lower percentage of acetate (p < 0.05), and a higher proportion of n-butyrate (p < 0.05) than controls. In stool homogenates from both controls and DP-IBS patients, lactulose fermentation resulted in the highest rate of SCFA production followed by pectin, starch, and hemicellulose. However, at all time points, the fecal homogenates from controls generated a higher concentration of total SCFA, acetate, and propionate with all substrates tested. SCFA production rates were higher in controls incubated with lactulose, starch, and hemicellulose. The fecal SCFA profile of patients with DP-IBS is characterized by lower concentrations of total SCFA, acetate, and propionate and a higher concentration and percentage of n-butyrate. Fecal flora from these patients produced less SCFA in an in vitro fermentation system in response to incubations with various carbohydrates and fibers. Differences in SCFA production by colonic bacterial flora in patients with DP-IBS may be related to the development of gastrointestinal symptoms.

Preventive efficacy of butyrate enemas and oral administration of Clostridium butyricum M588 in dextran sodium sulfate-induced colitis in rats.
Okamoto T, Sasaki M, Tsujikawa T, Fujiyama Y, Bamba T, Kusunoki M, Journal of Gastroenterology; 2000, 35: 341-346.

Butyrate enemas have been reported to be effective in ulcerative colitis. However, long-term use is difficult because of the troublesome procedure and the unpleasant smell. We therefore investigated the effects of the oral administration of Clostridium butyricum M588 (CBM588), an enterobacterium producing butyrate, in dextran sodium sulfate (DSS)-induced colitis in rats. First, we confirmed the effects of pre-treatment with a butyrate enema on DSS colitis. We then studied the efficacy of oral administration of CBM588 which was started 1 week prior to the induction of DSS colitis. In the CBM588 group, the ulcer index and myeloperoxidase (MPO) activity in the distal colon were significantly lower than in the control group. Proliferating cell nuclear antigen (PCNA) immuno-positive cells were increased around the ulcer in the CBM588 group. In regard to the contents of the cecum and colon, the proportions of Lactobacillus and Eubacterium were increased in the cecum in the CBM588 group. Further, there were significant increases of n-butyrate, propionate, and acetate concentrations in the cecum in the CBM588 group. These results indicated that the oral administration of CBM588 alleviated DSS-induced colitis, and may be useful instead of butyrate enema.

Effect of Sodium Butyrate on Reactive Oxygen Species Generation by Human Neutrophils.
Liu Q, Shimoyama T, Suzuki K, Umeda T, Nakaji S, Sugawara K. Scand J Gastroenterol; 2001, 36(7): 744-750.

Background: Short-chain fatty acids enema has been shown to be effective in the treatment of ulcerative colitis (UC). However, the mechanisms that lead to this response have not been well characterized. The aims of this study were to investigate the effect sodium butyrate has on reactive oxygen species (ROS) generation by human neutrophils, which are responsible for mucosal injury.

Methods: Human neutrophils incubated with or without sodium butyrate were stimulated with opsonized zymosan (OZ) or phorbol myristate acetate (PMA). ROS generation was largely differentiated with ow cytometry assays of hydroethidine oxidation and dichloro uorescein oxidation for superoxide anion and hydrogen peroxide respectively, and luminol-dependent chemiluminescence for myeloperoxidase-mediated oxidants.

Results: Sodium butyrate (up to 50 mM) did not alter hydroethidine oxidation upon stimulation of the OZ or PMA. However, sodium butyrate at a concentration of 25 mM elevated dichlorofluorescein oxidation to 125 § 8% (P = 0.028) of control upon stimulation of OZ and to 191 § 30% (P = 0.0016) upon stimulation of PMA. Contrary to these results, sodium butyrate greatly inhibited chemiluminescence responses in a dose-dependent manner. The inhibition by 50 mM sodium butyrate was 61 § 6% upon OZ and 71 § 9% upon PMA, respectively.

Conclusions: These data indicate that sodium butyrate up-regulates hydrogen peroxide generation but down-regulates generation of myeloperoxidase-mediated oxidants, the latter being more potent in killing microorganisms and in inducing tissue injury. A possible mechanism is suggested whereby sodium butyrate may inhibit myeloperoxidase activity and hence attenuate the destructive activities of neutrophils in UC.

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