Interest has been recently rekindled in short chain fatty acids (SCFAs) with the emergence of prebiotics and probiotics aimed at improving colonic and systemic health Dietary carbohydrates, specifically resistant starches and dietary fiber, are substrates for fermentation that produce SCFAs, primarily acetate, propionate, and butyrate, as end products The rate and amount of SCFA production depends on the species and amounts of microflora present in the colon, the substrate source and gut transit time SCFAs are readily absorbed Butyrate is the major energy source for colonocytes Propionate is largely taken up by the liver Acetate enters the peripheral circulation to be metabolized by peripheral tissues Specific SCFA may reduce the risk of developing gastrointestinal disorders, cancer, and cardiovascular disease Acetate is the principal SCFA in the colon, and after absorption it has been shown to increase cholesterol synthesis However, propionate, a gluconeogenerator, has been shown to inhibit cholesterol synthesis Therefore, substrates that can decrease the acetate: propionate ratio may reduce serum lipids and possibly cardiovascular disease risk Butyrate has been studied for its role in nourishing the colonic mucosa and in the prevention of cancer of the colon, by promoting cell differentiation, cell-cycle arrest and apoptosis of transformed colonocytes; inhibiting the enzyme histone deacetylase and decreasing the transformation of primary to secondary bile acids as a result of colonic acidification Therefore, a greater increase in SCFA production and potentially a greater delivery of SCFA, specifically butyrate, to the distal colon may result in a protective effect Butyrate irrigation (enema) has also been suggested in the treatment of colitis More human studies are now needed, especially, given the diverse nature of carbohydrate substrates and the SCFA patterns resulting from their fermentation Short-term and long-term human studies are particularly required on SCFAs in relation to markers of cancer risk These studies will be key to the success of dietary recommendations to maximize colonic disease prevention

Colonic health: fermentation and short chain fatty acids.

Background: The inflammatory bowel diseases (IBD) Crohn’s disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically-related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status. Results: Firmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohn’s disease was notable for increases in virulence and secretion pathways.

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Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment

BACKGROUND: Butyrate, a short-chain fatty acid, is a main end-product of intestinal microbial fermentation of mainly dietary fibre. Butyrate is an important energy source for intestinal epithelial cells and plays a role in the maintenance of colonic homeostasis. AIM: To provide an overview on the present knowledge of the bioactivity of butyrate, emphasizing effects and possible mechanisms of action in relation to human colonic function. METHODS: A PubMed search was performed to select relevant publications using the search terms: 'butyrate, short-chain fatty acid, fibre, colon, inflammation, carcinogenesis, barrier, oxidative stress, permeability and satiety'. RESULTS: Butyrate exerts potent effects on a variety of colonic mucosal functions such as inhibition of inflammation and carcinogenesis, reinforcing various components of the colonic defence barrier and decreasing oxidative stress. In addition, butyrate may promote satiety. Two important mechanisms include the inhibition of nuclear factor kappa B activation and histone deacetylation. However, the observed effects of butyrate largely depend on concentrations and models used and human data are still limited. CONCLUSION: Although most studies point towards beneficial effects of butyrate, more human in vivo studies are needed to contribute to our current understanding of butyrate-mediated effects on colonic function in health and disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2036.2007.03562.x

Review article: the role of butyrate on colonic function

Accumulating evidence suggests that the human intestinal microbiota contributes to the aetiology of colorectal cancer (CRC), not only via the pro-carcinogenic activities of specific pathogens but also via the influence of the wider microbial community, particularly its metabolome. Recent data have shown that the short-chain fatty acids acetate, propionate and butyrate function in the suppression of inflammation and cancer, whereas other microbial metabolites, such as secondary bile acids, promote carcinogenesis. In this Review, we discuss the relationship between diet, microbial metabolism and CRC and argue that the cumulative effects of microbial metabolites should be considered in order to better predict and prevent cancer progression.

The gut microbiota, bacterial metabolites and colorectal cancer

Microbial Influences in Inflammatory Bowel Diseases

https://www.gastrojournal.org/article/0016-5085(93)91016-B/pdf

Reducing sulfur compounds of the colon impair colonocyte nutrition: Implications for 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.

Colonic Sulfide in Pathogenesis and Treatment of 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.

Sulphide Impairment of Substrate Oxidation in Rat Colonocytes: A Biochemical Basis for Ulcerative Colitis?

The disease process of ulcerative colitis (UC) is associated with a block in β-oxidation of short chain fatty acid in colonic epithelial cells which can be reproduced by exposure of cells to sulfides. The aim of the current work was to assess the level in the β-oxidation pathway at which sulfides might be inhibitory in human colonocytes. Isolated human colonocytes from cases without colitis (n = 12) were exposed to sulfide (1.5 mM) in the presence or absence of exogenous CoA and ATP. Short chain acyl-CoA esters were measured by a high performance liquid chromatographic assay. 14CO2 generation was measured from [1-14C]butyrate and [6-14C]glucose. 14CO2 from butyrate was significantly reduced (p < 0.001) by sulfide. When colonocytes were incubated with hydrogen sulfide in the presence of CoA and ATP, butyryl-CoA concentration was increased (p < 0.01), while crotonyl-CoA (p < 0.01) and acetyl-CoA (p < 0.01) concentrations were decreased. These results show that sulfides inhibit short chain acyl-CoA dehydrogenase. As oxidation of n-butyrate governs the epithelial barrier function of colonocytes the functional activity of short chain acyl-CoA dehydrogenase may be critical in maintaining colonic mucosal integrity. Maintaining the functional activity of dehydrogenases could be an important determinant in the expression of ulcerative colitis.

Sulfides impair short chain fatty acid beta-oxidation at acyl-CoA dehydrogenase level in colonocytes: implications for ulcerative colitis.

In the healthy colon, sodium nitrite stimulates mucosal metabolism of short-chain fatty acids and absorption of ions, both functions that are impaired in the mucosa of patients with ulcerative colitis

W.E.W. Roediger

Papers

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

Colonic Sulfide in Pathogenesis and Treatment of Ulcerative Colitis

Sulphide Impairment of Substrate Oxidation in Rat Colonocytes: A Biochemical Basis for Ulcerative Colitis?

Sulfides impair short chain fatty acid beta-oxidation at acyl-CoA dehydrogenase level in colonocytes: implications for ulcerative colitis.

Detectable Colonic Nitrite Levels in Inflammatory Bowel Disease – Mucosal or Bacterial Malfunction?