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Biomedical subjects

W E Roediger

Publications and source records attributed to W E Roediger.

At least 19 recordsLinked to original sources
PubMed1997

Colonic sulfide in pathogenesis and treatment of ulcerative colitis.

A role for colonic sulfide in the pathogenesis and treatment of ulcerative colitis (UC) has emerged based on biochemical, microbiological, nutritional, toxicological, epidemiological, and therapeutic evidence. Metabolism of isolated colonic epithelial cells has indicated that the bacterial short-chain fatty acid n-butyrate maintains the epithelial barrier and that sulfides can inhibit oxidation of n-butyrate analogous to that observed in active UC. Sulfur for fermentation in the colon is essential for n-butyrate formation and sulfidogenesis aids disposal of colonic hydrogen produced by bacteria. The numbers of sulfate-reducing bacteria and sulfidogenesis is greater in UC than control cases. Sulfide is mainly detoxified by methylation in colonic epithelial cells and circulating red blood cells. The enzyme activity of sulfide methylation is higher in red blood cells of UC patients than control cases. Patients with UC ingest more protein and thereby sulfur amino acids than control subjects. Removing foods rich in sulfur amino acids (milk, eggs, cheese) has proven therapeutic benefits in UC. 5-Amino salicylic acid reduces fermentative production of hydrogen sulfide by colonic bacteria, and aminoglycosides, which inhibit sulfate-reducing bacteria, are of therapeutic benefit in active UC. Methyl-donating agents are a category of drugs of potential therapeutic use in UC. A correlation between sulfide production and mucosal immune responses in UC needs to be undertaken. Control of sulfidogenesis and sulfide detoxification may be important in the disease process of UC, although whether their roles is in an initiating or promoting capacity has yet to be determined.

Bacteria↗
PubMed1997

Thiolmethyltransferase activity in the human colonic mucosa: implications for ulcerative colitis.

Ulcerative colitis is associated with a selective reduction of n-butyrate oxidation by the colonic epithelial cells although the reason for this has been unclear. Colonic epithelial cell n-butyrate oxidation can be inhibited in vitro by incubation with sulphide but the role of mucosal detoxification of sulphide in the metabolic welfare of the colonic mucosa has not been examined. This study aimed to assess the role mucosal detoxification of sulphide by thiolmethyltransferase (TMT)-mediated methylation may play in protecting the healthy colonic mucosa from the adverse effects of luminal sulphide. Colonic epithelial cell suspensions from healthy human proximal (n = 9) and distal colon (n = 10) were incubated in the presence of 14C-labelled n-butyrate (5 mmol/L) alone, butyrate plus sodium hydrogen sulphide (NaHS) (1.5 mmol/L), or butyrate plus NaHS plus S-adenosyl-methionine 1,4 butane disulphonate (SAMe) (5 mmol/L). Study end points were metabolic performance (14CO2 production) and mucosal TMT activity. Incubation with NaHS induced a significant inhibition of 14CO2 production compared with control incubations (P < 0.001) which was similar for proximal and distal colonic cell suspensions. S-adenosyl-methionine 1,4 butane disulphonate reversed this effect completely in proximal but not in distal cell incubations, suggesting a greater susceptibility of the distal colon to the sulphide effect. Although median whole mucosal TMT values did not differ between proximal and distal colonic mucosa, a non-normal distribution of distal TMT values was observed. However, neither the degree of sulphide inhibition of control 14CO2 production nor the degree to which SAMe reversed this inhibition correlated with whole mucosal TMT activity. The study concluded that regional variation exists in TMT activity in the human colon but whilst methylation appears to protect colonic epithelial cells against sulphide-induced inhibition of n-butyrate oxidation, this cannot be directly correlated with mucosal TMT activity.

Aged↗
PubMed1997

Hydrogen sulphide produces diminished fatty acid oxidation in the rat colon in vivo: implications for ulcerative colitis.

BACKGROUND: Several lines of evidence suggest a possible role for reduced forms of sulphur (including sulphide) in ulcerative colitis. The aims of this study were to assess the metabolic profile of colonic epithelial cells after treatment in vivo with hydrogen sulphide and correlate this with mucosal histological appearances. METHODS: Adult Sprague-Dawley rats had antegrade Roux-en-Y colostomies fashioned to allow access to the 'in-flow' bowel. Animals were treated with 2 mL sodium hydrosulphide (10, 20, 30 mmol/L) or saline control twice daily via the stoma for four (acute experiments) and 90 (chronic experiments) days. Isolated colonic epithelial cell suspensions prepared from such animals were incubated in the presence of [1-14C]-labelled n-butyrate (5 mmol/L) or [6-14C]glucose (5 mmol/L). Metabolic performance was measured radiometrically (14CO2 production) and enzymatically (ketone body production and lactogenesis). The histological appearances of treated mucosa were scored for acute inflammatory changes. RESULTS: There was a highly significant reduction in 14CO2 production from both n-butyrate and glucose in all groups compared to the control in both acute and chronic experiments. There was no difference between groups with respect to histological appearance and no evidence of acute inflammation in any specimen. CONCLUSIONS: Sodium hydrosulphide impairs rat colonic epithelial metabolic performance in vivo, but does not produce mucosal inflammation.

Animals↗
PubMed1997

Effect of sulphide on short chain acyl-CoA metabolism in rat colonocytes.

BACKGROUND: It has been proposed that the diminished n-butyrate oxidation observed in ulcerative colitis may be the result of sulphide induced inhibition of short chain acyl-coenzyme A (acyl-CoA) dehydrogenase activity. AIM: To examine the acyl-CoA ester profiles in isolated rat colonic epithelial cells treated in vitro with sodium hydrogen sulphide (NaHS). METHODS: Isolated rat colonic epithelial cell suspensions were incubated for 10 minutes in the presence of [1-14C] n-butyrate (5 mM), with and without NaHS (1.5 mM). Incubations were carried out both in the presence and the absence of exogenous CoA and ATP. Metabolic performance was assessed by 14CO2 production and by acyl-CoA ester production measured by HPLC with ultraviolet detection. RESULTS: Results are given as mean (SEM). For colonocytes incubated in the presence of exogenous CoA and ATP, treatment with NaHS significantly diminished 14CO2 production (control 0.97 (0.06) mumol/g dry weight cells/min, treated 0.26 (0.09) mumol/g dry weight cells/min, p = 0.0019), was associated with an increase in butyryl-CoA concentrations in the final reaction mixture at 10 minutes (control 2.55 (0.28) mumol/g dry weight cells, treated 3.32 (0.32) mumol/g dry weight cells, p = 0.002), and a reduction in crotonyl-CoA concentrations (control 0.274 (0.02) mumol/g dry weight cells, treated 0.120 (0.04) mumol/g dry weight cells, p = 0.008). The mean concentration of acetyl-CoA in the reaction mixture at 10 minutes was not significantly different between control and sulphide treated incubations. There were no significant differences in acyl-CoA ester profiles observed when cells were incubated in the absence of exogenous CoA and ATP. CONCLUSIONS: These results support the view that sulphides inhibit n-butyrate oxidation in colonic epithelial cells by inhibiting short chain acyl dehydrogenation of activated fatty acids.

Acyl Coenzyme A↗
PubMed1997

Stump appendicitis--a potential problem after laparoscopic appendicectomy.

Appendicitis is now commonly diagnosed and treated using laparoscopic techniques. Laparoscopic appendicectomy has the potential to result in incomplete removal of the appendix stump and subsequent risk of stump appendicitis. This article reports such a case, requiring laparotomy 5 months after the original appendectomy.

Aged↗
PubMed1996

Methionine derivatives diminish sulphide damage to colonocytes--implications for ulcerative colitis.

BACKGROUND: Bacterial production of anionic sulphide is increased in the colon of ulcerative colitis and sulphides can cause metabolic damage to colonocytes. AIMS: To assess the reversal of the damaging effect of sulphide to isolated colonocytes by methionine and methionine derivatives. METHODS AND SUBJECTS: Isolated colonocytes were prepared from rat colons and 12 human colectomy specimens. In cell suspensions 14CO2/acetoacetate generation was measured from [1-14C]-butyrate (5.0 mmol/l) in the presence of 0-2.0 mmol/l sodium hydrogen sulphide. The effect of 5.0 mmol/l L-methionine, S-adenosylmethionine 1,4 butane disulphonate and DL-methionine-S-methylsulphonium chloride on sulphide inhibited oxidation was observed. RESULTS: In rat colonocytes sodium hydrogen sulphide dose dependently reduced oxidative metabolite formation from n-butyrate, an action reversed in order of efficacy by S-adenosylmethionine 1,4 butane disulphonate > DLmethionine-S-methyl-sulphonium chloride > L-methionine. In human colonocytes S-adenosylmethionine 1,4 butane disulphonate most significantly improved 14CO2 production (p = < 0.005) suppressed by sodium hydrogen sulphide. CONCLUSION: Sulphide toxicity in colonocytes is reversible by methyl donors. The efficiency of sulphide detoxification may be an important factor in the pathogenesis and treatment of ulcerative colitis for which S-adenosylmethionine 1,4 butane disulphonate may be of therapeutic value.

Acetamides↗
PubMed1995

Selective inhibition of fatty acid oxidation in colonocytes by ibuprofen: a cause of colitis?

Ibuprofen is associated with initiation or exacerbation of ulcerative colitis. As ibuprofen selectively inhibited fatty acid oxidation in the liver or caused mitochondrial damage in intestinal cells, its effect on substrate oxidation by isolated colonocytes of man and rat was examined. Ibuprofen dose dependently (2.0-7.5 mmol/l) and selectively inhibited 14CO2 production from labelled n-butyrate in colonocytes from the proximal and distal human colon (n = 12, p = < 0.001). Glucose oxidation was either unaltered or increased. Because short chain fatty acid oxidation is the main source of acetyl-CoA for long chain fatty acid synthesis, the inhibition of prostaglandin synthesis by ibuprofen in the colonic mucosa could also occur at this level. Because the concentrations of ibuprofen that can be attained in the human colon are not known, conclusions drawn from current dosages are tentative. The inhibition of fatty acid oxidation by ibuprofen may be biochemically implicated in the initiation and exacerbation of ulcerative colitis, manifestation of which would depend on the ibuprofen concentrations reached in the colon.

Aminosalicylic Acids↗
PubMed1995

Thiol methyltransferase activity in colonocytes and erythrocyte membranes.

AIMS: To verify the improved thiol methyltransferase (TMT) assay and measure activity in isolated colonocytes and erythrocyte membranes of the same subjects. METHODS: High performance liquid chromatography with radioactivity detection was used to measure 14C-methylmercaptoethanol formation, the reaction product of cell extracts incubated with mercaptoethanol and 14C-S-adenosylmethionine. RESULTS: Verification of radiolabelled 14C-methylmercaptoethanol was by exogenous addition of methylmercaptoethanol and simultaneous ultraviolet detection at 214 nm. Using a substrate concentration of 10 mM mercaptoethanol, the Km for S-adenosylmethionine was 25 microM. The sensitivity of the radioactive method was 2 pmol, with coefficients of variation of 7% within assay and 6.4% between assay. TMT activities (mean +/- SE; n = 17) were 471 +/- 64 pmol/hour/mg protein for colonocytes and 73 +/- 7 pmol/hour/mg protein for erythrocyte membranes. CONCLUSIONS: The direct assay of TMT activity is sensitive, specific and eliminates concern over non-enzymatic methylation of thiol compounds. High activities in colonic epithelial cells deserve evaluation in disease states.

Biomarkers↗
PubMed1994

Endocrine and cytokine changes during elective surgery.

Elective surgery was used as a model of severe non-thyroidal illness (SNTI) to study the inter-relation between changes in serum thyroid hormones, thyroid stimulating hormone (TSH), cortisol, and interleukin 6 concentrations. The study was designed to determine whether the expected interleukin 6 increases after surgery are the cause of decreased serum tri-iodothyronine (T3) concentration normally observed following severe trauma. Blood was sampled for 24 hours before, during, and for 48 hours after abdominal surgery under general anaesthesia in 11 patients. Total T3 decreased 30 minutes after induction and continued to decrease at 24 hours. After a transient increase at 30 minutes, free T3 also decreased, and free thyroxine (T4) concentrations, other than a similar transient increase, did not change. TSH concentrations were increased at four hours and the nocturnal surge was suppressed. The increase in the serum interleukin 6 concentration was not observed until four hours. Cortisol concentrations were increased at 30 minutes and peaked at four hours. Therefore, the early changes in thyroid hormones and TSH accompanying surgery do not seem to be caused by changes in interleukin 6 concentrations.

Elective Surgical Procedures↗
PubMed1993

Reducing sulfur compounds of the colon impair colonocyte nutrition: implications for ulcerative colitis.

BACKGROUND: Mercaptides (sodium hydrogen sulfide and sodium methanethiol) and mercapto-fatty acid (sodium mercaptoacetate) are reducing agents that help to maintain anaerobic conditions in the colonic lumen. The metabolic effect of these agents on n-butyrate and glucose oxidation in human colonocytes is unknown. METHODS: Isolated human colonocytes were prepared from 31 colectomy specimens, and generation of oxidative metabolites from [1-14C]n-butyrate and [6-14C]glucose was measured in the presence and absence of reducing agents. Injury to cells was judged by diminished production of metabolites. RESULTS: The injurious action of mercaptides at all sites of the colon was of the order of sodium hydrogen sulfide > methanethiol > mercaptoacetate. Significant inhibition of n-butyrate (< 0.005) but not glucose oxidation was observed with sodium hydrogen sulfide in the ascending colon, splenic flexure, and rectosigmoid region. Hydrogen sulfide more significantly inhibited fatty acid oxidation in the rectosigmoid than in the ascending colon (P < 0.02). CONCLUSIONS: Metabolic effects of sodium hydrogen sulfide on butyrate oxidation along the length of the colon closely mirror metabolic abnormalities observed in active ulcerative colitis, and the increased production of sulfide in ulcerative colitis suggests that the action of mercaptides may be involved in the genesis of ulcerative colitis.

Colitis, Ulcerative↗
PubMed1993

Sulphide impairment of substrate oxidation in rat colonocytes: a biochemical basis for ulcerative colitis?

1. Isolated colonic epithelial cells of the rat were incubated for 40 min with [6-14C]glucose and n-[1-14C]butyrate in the presence of 0.1-2.0 mmol/l NaHS, a concentration range found in the human colon. Metabolic products, 14CO2, acetoacetate, beta-hydroxybutyrate and lactate, were measured and injury to cells was judged by diminished production of metabolites. 2. Oxidation of n-butyrate to CO2 and acetoacetate was reduced at 0.1 and 0.5 mmol/l NaHS, whereas glucose oxidation remained unimpaired. At 1.0-2.0 mmol/l NaHS, n-butyrate and glucose oxidation were dose-dependently reduced at the same rate. 3. To bypass short-chain acyl-CoA dehydrogenase activity necessary for butyrate oxidation, ketogenesis from crotonate was measured in the presence of 1.0 mmol/l NaHS. Suppression by sulphide of ketogenesis from crotonate (-10.5 +/- 6.1%) compared with control conditions was not significant, whereas suppression of ketogenesis from n-butyrate (-36.00 +/- 5.14%) was significant (P = < 0.01). Inhibition of FAD-linked oxidation was more affected by NaHS than was NAD-linked oxidation. 4. L-Methionine (5.0 mmol/l) significantly redressed the impaired beta-oxidation induced by NaHS. Methionine equally improved CO2 and ketone body production, suggesting a global reversal of the action of sulphide. 5. Sulphide-induced oxidative changes closely mirror the impairment of beta-oxidation observed in colonocytes of patients with ulcerative colitis. A hypothesis for the disease process of ulcerative colitis is that sulphides may form persulphides with butyryl-CoA, which would inhibit cellular short-chain acyl-CoA deHydrogenase and beta-oxidation to induce an energy-deficiency state in colonocytes and mucosal inflammation.

Animals↗
PubMed1993

Does exclusion of enteral lipid assist remission in Crohn's disease?

Based on the improvement of Crohn's disease (CD) with elemental diets, we treated a patient with recurrent stenosing disease using prednisolone and drastic reduction of oral lipid intake. Complete symptomatic and good radiological improvement took place. A newly proposed hypothesis for CD suggests that enteral lipids together with certain luminal bacterial fragments become strongly antigenic to produce an inflammatory reaction analogous to the adjuvant response. Because of the apparent success of dietary lipid exclusion in this patient, we suggest that it be considered as a future option for management of acute CD.

Adult↗
PubMed1992

Lipogenesis from n-butyrate in colonocytes. Action of reducing agent and 5-aminosalicylic acid with relevance to ulcerative colitis.

Cell membranes of colonic epithelial cells (CEC) in ulcerative colitis show structural abnormalities which are specific to the disease and which suggest impaired lipogenesis in CECs. Lipogenesis from [1-14C]-n-butyrate, the chief oxidative fuel of colonic epithelial cells, was measured in isolated CECs under control conditions, with or without glucose and in the presence of mercaptoacetate, a major reducing agent in the colonic lumen. Glucose significantly (p < 0.01) stimulated lipogenesis from [1-14C]-butyrate which was reversed by 5 mM mercaptoacetate. Mercaptoacetate significantly diminished CEC thiolase activity (EC 2.3.1.9). 5-Aminosalicylic acid reversed the adverse effects of mercaptoacetate in the saponifiable fraction of extracted lipids. Changes in lipogenesis due to colonic luminal reducing agents would affect the barrier function of CECs a feature relevant to the disease process of ulcerative colitis.

Aminosalicylic Acids↗