| Scientist - News - 18-12-2007: Gut microbiota and ulcerative colitis Rajiliæ-Stojanoviæ, Mirjana Ulcerative colitis (UC) is an intestinal disease with unknown origin. Among several factors that are involved in its development, the intestinal (gut) microbiota is suspected to be a relevant one. However, the direct links between the gut microbiota composition and/or activity on one side, and UC on the other side have not yet been found. The major obstacle for defining such links is that the vast majority of intestinal inhabitants are uncultured bacteria with unknown physiological properties. This hampers a rational definition of microbial “suspects” that are possibly involved in disease development. Moreover, studying the intestinal microbiota is challenging because of its mere complexity and variability among individuals. These features of the gut microbiota call for a comprehensive analysis of large amounts of intestinal samples, for which classical microbiological techniques are too laborious, costly, and more importantly – insufficient. In contrast, molecular techniques, particularly those based on the small subunit ribosomal RNA sequence, enable rapid microbiota profiling or quantification analysis. Recently, a methodology that combines the power of fingerprinting, phylogenetic and quantitative community analysis was developed in the Laboratory of Microbiology at Wageningen University. The Human Intestinal Tract Chip (HITChip) targets over 1,000 intestinal microbial inhabitants, and its application on the analysis of intestinal samples of patients suffering from intestinal diseases and corresponding controls, provided novel insights into the relation between the gut microbiota and health/disease. Before it was possible to comprehensively study the gut microbiota composition, a global metabolic activity of intestinal contents of UC patients was assessed. In these studies it was found that fresh faecal material of UC patients produces large amounts (four fold greater than in the case of healthy subjects) of hydrogen sulphide. Hydrogen sulphide is highly toxic for humans as its lethal concentration is similar to that of a well known poison – cyanide. Furthermore, hydrogen sulphide impairs butyrate oxidation – a process in which gut epithelial cells harvest their energy, and it influences gut-nerve signalling. Because of these features, an excessive presence of hydrogen sulphide in intestinal contents of UC patients is considered to be highly relevant for the development and/or occurrence of this disease, but it can also be considered an important factor in the development of the colon cancer. There are two major pathways for hydrogen-sulphide production: (i) by the oxidation of sulphides, which are present in some foods and intestinal mucins, and (ii) by the utilisation of sulphur-containing amino acids. Sulphated compounds are available only in small amounts in the intestinal contents. The microbial subpopulation which can utilise sulphate, the so-called sulphate-reducing bacteria, is scarce in the human gut, as it represents, not more than 0.01% of the total microbial community. Despite its low abundance, sulphate reducing bacteria were suspected to play an important role in UC, and initial experiments that employed traditional microbiological culturing suggested that there might be a link between UC and some specific sulphate-reducing bacteria. Nevertheless, the application of novel molecular techniques, such as quantitative PCR and the HITChip, could not confirm such link. In contrast to sulphated compounds, proteins are present at high concentrations in the human intestine, specifically in the distal colon where proteins are the major energy source for gut microbes. Previous studies have shown that increased protein intake is directly proportional to the levels of hydrogen sulphide in faeces of healthy subjects, while the protein (and alcohol) intake was significantly correlated with UC relapse incidence. This data suggests that an excessive activity or quantity of microbes that can produce sulphide from protein might be relevant for UC. Comprehensive analysis of the gut microbiota of UC patients and healthy subjects using the HITChip identified a significantly higher proportion of Peptostreptococcus species in some of the UC patients. Peptostreptococci are members of the normal human gut and oral microbiota, which were previously identified as major oral hydrogen sulphide producers. Based on the presented facts, it is likely that an increased incidence and abundance of the intestinal peptostreptococci is a consequence of high dietary protein intake (typical for the western diet), which causes increased hydrogen sulphide production in the lower intestine of UC patients and subsequent strong immune reaction on the subset of the commensal gut inhabitants. The HITChip analysis could identify another, this time a well-known human pathogen – Clostridium difficile – in the faeces of some of UC patients. The increased incidence of this bacterium in stools of UC patients in relapse is a known fact. It is fascinating that the HITChip analysis of the UC patients gut microbiota showed an almost exclusive presence of either C. difficile or members of the Peptostreptococcus genus. This finding provides the first biological basis for previously suggested heterogeneous nature of UC. It, furthermore, clearly shows the advantages of comprehensive and high throughput analysis of the human gut microbiota. Such analysis, when applied full scale, is expected to provide information which is essential for an adequate understanding of the gut microbiota and its relation to UC. Recommended literature [1-9].
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