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

IBD-ulcerative colitis and Crohn's disease-is emerging as a worldwide epidemic. An association between the increased incidence of IBD and environmental factors linked to socioeconomic development has been persistently detected in different parts of the world. The lifestyle in developed countries might impair the natural patterns of microbial colonization of the human gut. The interaction of microbes with mucosal immune compartments in the gut seems to have a major role in priming and regulating immunity. In IBD, mucosal lesions are generated by an excessive or dysregulated immune response against commensal microbes in the gut. In individuals with a genetic susceptibility to IBD, abnormal microbial colonization of the gastrointestinal tract might be the origin of such dysregulation. Developments in gene-sequencing technologies, as well as increased availability of powerful bioinformatic tools, have enabled novel insights into the microbial composition of the human gut microbiota and the effect of microbial communities on human physiology and disease. Studies that used these technologies indicate that dysbiosis (that is, abnormal microbiota composition) and decreased complexity of the gut microbial ecosystem are common features in patients with Crohn's disease or ulcerative colitis. Whether such changes are a cause or a consequence of the disease remains to be elucidated.

/pdf/the-gut-microbiota-in-ibd-18vtgm4g15.pdf

The gut microbiota in IBD.

Summary
The microbiota of the human intestinal tract play an important role in health, in particular by mediating many of the effects of diet upon gut health. Surveys of 16S rRNA sequence diversity in the human colon have emphasized the low proportion of sequences that match cultured bacterial species. This may reflect limited recent effort on cultivation rather than inherent unculturability, however, as anaerobic isolation methods can apparently recover a wide range of the diversity found. A combination of information from representative cultures, molecular tools for enumeration and tracking of bacterial metabolites offers the most powerful route to understanding the roles played by different groups of bacteria in the gut ecosystem. Progress is being made for example in defining key functional groups including primary colonizers of insoluble dietary substrates, and major contributors to metabolites such as butyrate that influence the health of the gut mucosa. There is increasing evidence that bacterial populations in the large intestine respond to changes in diet, in particular to the type and quantity of dietary carbohydrate. A general consequence of increased carbohydrate consumption is to reduce the pH of the gut lumen, which is likely to play a major role in determining bacterial metabolism and competition. Oligosaccharides used as dietary prebiotics must inevitably have complex effects upon the bacterial community that include non-target organisms and the consequences of metabolic cross-feeding and changes in the gut environment.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1462-2920.2007.01281.x

Interactions and competition within the microbial community of the human colon: links between diet and health

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

It has been proposed that the reduction in n-butyrate oxidation by colonic epithelial cells observed in ulcerative colitis may be related to exposure to reduced forms of sulfur derived from dissimilatory sulfate reduction by luminal microflora. This study aims to compare stool sulfide concentrations in control and colitic subjects. Control subjects had significant colorectal disease excluded by virtue of their selection. Patients with ulcerative colitis were stratified by disease extent and activity, and by salicylate drug use. Stool sulfide was measured using a direct spectrophotometric method on NaOH (free sulfide) and zinc acetate (total sulfide) stool slurries. Fifteen control and 19 colitic subjects were studied. There was no significant difference in stool sulfide between control and colitic patients (free sulfide, control = 0.52 (0.17), colitic = 0.45 (0.10), t = 0.36, P = 0.71, total sulfide, control = 1.33 (0.21), colitic = 0.96 (0.15), t = 1.44, P = 0.16). Disease extent or activity did not significantly influence stool sulfide. These results do not support a primary etiologic role for luminal sulfide in ulcerative colitis.

W. Babidge

Papers

Colonic Sulfide in Pathogenesis and Treatment of Ulcerative Colitis

Colonic luminal hydrogen sulfide is not elevated in ulcerative colitis.