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A study by Vanessa Eeckhaut et al1 shows that subjects with inflammatory bowel disease (IBD) have lower faecal counts of Butyricicoccus pullicaecorum, that this bacterium attenuates trinitrobenzenesulfonic acid-induced colitis in rats and that the supernatant of its culture strengthens the epithelial barrier of Caco-2 cells. More generally, it is now established that some of the bacteria that dominate the intestinal mucosal and luminal ecosystems of healthy subjects are under-represented in IBD.1 ,2 It is possible that these findings are partly due to confounding factors such as IBD treatments (including low residue diet), and smoking, and this requires attention. This raises the question whether those microbes might be used as diagnostic or theragnostic markers. Developing new (bacterial) diagnostic markers of IBD is a long way off, which requires establishing their specificity, sensitivity, and predictive positive and negative values to answer relevant clinical questions, especially in differentiating subtypes of IBD with close phenotypes and in predicting relapse risks.2 Candidates include Faecalibacterium prausnitzii, Butyricicoccus, Roseburia and the so called ‘enterotypes’, that is, complex ecosystems with co-occurring bacteria.1–3
Several species among the bacteria under-represented in IBD have protecting properties against some experimental models of colitis, and therefore the second question is whether they could be used as treatments. Interestingly, many of them are butyrate-producing bacteria. Butyrate itself sometimes has protective value in experimental colitis,1 but this is not always the case.2 Learning the microbial ecology of these species and how to maintain or increase butyrate levels or butyrate-producing bacteria thus seems a rational and promising step to improve treatments of IBD.
Intestinal and colonic bacteria gain energy from dietary substrates that escape digestion and host secretions including mucins. Owing to the proximal fermentation of some alimentary substrates, the respective part of host-derived substrates is higher in the distal colon. Butyrate can be synthesised by two metabolic pathways: butyrate kinase and butyryl-CoA:acetate CoA-transferase,4 the latter being the dominant one in the human colonic ecosystem.4 Certain dietary substrates lead to a higher intracolonic production of butyrate than others and are thus referred to as ‘butyrogenic’. They include inulin, fructo-oligosaccharides, resistant starch and ispaghula. They may stimulate butyrate production directly by certain groups of fibrolytic and amylolytic bacteria, or indirectly, for example, by cross-feeding some butyrate producers with lactate which is generated by lactobacilli and bifidobacteria during fermentation. Noticeably, several of the butyrogenic substrates are also ‘bifidogenic’ and ‘prebiotic’ (in other words, they increase colonic concentrations of bifidobacteria). Eubacterium hallii, Anaerostipes caccae and Escherichia coli are some of the endogenous butyrate-producing bacteria that use lactate as a substrate5; thus they can be cross-fed by lactic acid bacteria which tend to co-occur with them.6 This may explain the pharmabiotic properties of some bifidobacteria and lactobacilli.6 By contrast, F prausnitzii and Roseburia spp. (the major endogenous bacteria that produce butyrate) are unable to use lactate.7 The two phylogroups of F prausnitzii8 can ferment several sugars, uronic acids and the host-derived N-acetylglucosamine. Despite being extremely oxygen sensitive, they can survive close to the gut mucosa owing to an extracellular electron shuttle of flavins and thiols (which are present in the healthy human gut but might lack in IBD).9 Butyrate itself may be butyrogenic; for example, Li et al10 showed that experimental infusion of butyrate in the rumen had a stimulating effect on butyrate-producing bacteria.
Is one of those bacteria likely to be clinically useful as a pharmabiotic for IBD in the future? Bifidobacteria and lactobacilli are easy to grow, but the therapeutic efficacy of the few strains tested in IBD seems limited despite some hope with the VSL 3 product.11 The justification to study F prausnitzii in this setting is high,2 but this anaerobic bacterium is difficult to grow, because of which it has not been possible to test its therapeutic value in humans until now. Active products secreted in its supernatant are currently being scrutinised. Butyricicoccus is also in the early stages of evaluation.1 Therefore, there is no new diagnostic or therapeutic tool available for the clinician in this field, but it is hoped that current efforts in the modern and holistic approach to study intestinal ecology will soon lead to such progress.
Competing interests PM has received lecture fees and does expert consulting for Danone, Biocodex Merck Médication Familiale, Pharmabiotic Research Institute.
Provenance and peer review Commissioned; internally peer reviewed.
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