Butyric Acid-Producing Anaerobic Bacteria As a Novel Probiotic Treatment Approach for Inflammatory Bowel Disease
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JMMEditorial Butyric acid-producing anaerobic bacteria as a novel probiotic treatment approach for inflammatory bowel disease Inflammatory bowel disease (IBD), of (Gueimonde et al., 2007; Hedin et al., increase in butyrate production which Crohn’s disease (CD) and ulcerative 2007). The only well-documented may result from a direct colitis (UC) are the most common indication for the use of probiotics in IBD stimulation of butyrate producers manifestations, is characterized by chronic is in the treatment of pouchitis, or indirect effects such as inflammation of the lining of the particularly using a mixed lactobacilli– metabolic cross-feeding of gastrointestinal tract, which causes severe bifidobacteria product (Mimura et al., fermentation products from other watery and bloody diarrhoea, and 2004). Many trials using probiotics either bacterial groups (Flint et al., 2007). abdominal pain. IBD is often debilitating as maintenance therapy in UC, to treat (b) The use of butyric acid-coated and is characterized by onset at a young active UC, to maintain remission in CD, or tablets is a possible delivery age and extra-intestinal manifestations. to treat active CD, have yielded mixed method, but the tablets may not Whereas CD can affect any part of the results, concluding that their use cannot be always release their content at the gastrointestinal tract, UC is usually recommended based on the available intended location because of inter- confined to the colon and rectum. IBD is evidence (Hedin et al., 2007). individual differences in gut lumen an emerging disease and the incidence pH and transit time. Moreover the Butyric acid, produced within the intestinal amounts to 20/100 000 in Europe and taste is very unpleasant. Alternative lumen by bacterial fermentation of dietary North America. There is a link with the approaches are the consumption of carbohydrates, exerts a wide variety of social and economic development of the butyrylated starch and the use of effects on intestinal function (Hamer et al., countries: the increase in IBD was first butyryl-L-carnitine as a potential 2008). First of all, butyric acid is the seen in northern Europe and North prodrug (Srinivas et al., 2007; preferred source of energy for colonocytes. America, followed by the rest of Europe, Bajka et al., 2008). It affects cellular proliferation, Japan, South America and certain parts of (c) Rectal butyric acid enemas hold differentiation and apoptosis. Moreover, Asia (Cohen, 2000; Ouyang et al., 2005). promise but the use of enemas is butyric acid has well documented anti- Although the exact aetiopathogenesis of often hampered by a low inflammatory effects. Inhibition of histone IBD are not clear, it is widely accepted that compliance rate, and a short and deacetylase activity, resulting in the disease derives from an inappropriate discontinuous exposure of the hyperacetylation of histones, and as a immune response in genetically susceptible colon mucosa to the butyrate consequence suppression of nuclear factor- individuals as the result of a complex (Breuer et al., 1997). kappa B activation, is a likely explanation. interaction between environmental factors, (d) A final possibility is the Secondly, it has been proposed that butyric the microbiota and the intestinal immune administration of colonizing acid reinforces the colonic defence barrier system (Danese & Fiocchi, 2006). butyric acid-producing bacteria, by increasing production of mucins and enabling in situ production of In IBD, the response to conventional drug antimicrobial peptides. Thirdly, it has been butyric acid. therapy is suboptimal. This therapy is shown that butyric acid decreases intestinal associated with a number of disadvantages, epithelial permeability by increasing the Several studies have shown that, including a considerable burden of side expression of tight junction proteins. Anti- numerically, the majority of butyrate- effects, and surgery is still required in a inflammatory activities, combined with a producing bacteria found in human faeces subgroup of patients. Because IBD strengthening of the mucosal barrier are highly oxygen-sensitive anaerobes represents a distortion of the relationship integrity, are ideal properties for therapeutic belonging to the clostridial clusters IV and between the gut microbiota and the host compounds against IBD-like syndromes. XIVa (Louis & Flint, 2009). Decreases in response, probiotics and prebiotics have Indeed it has been shown that butyrate members of the butyrate-producing been proposed as possible therapeutic enemas can yield positive results in the clostridial clusters IV and XIVa have been products. The probiotics that are being treatment of active UC (Breuer et al.,1997). reproducibly reported in the gut of IBD tested for treatment of IBD are mainly patients (Sokol et al., 2008; Takaishi et al., Butyric acid thus has a potential therapeutic lactic acid bacteria, i.e. lactobacilli and 2008). These species are thus probiotic value against IBD, but the actual delivery bifidobacteria. Although a decrease in the candidates for the treatment of IBD. into the gut is still problematic. Several number of lactic acid bacteria has been Recently, considerable progress has been mechanisms are possible. shown in IBD, administration of lactic acid made in the isolation of these strictly bacteria has yielded inconsistent results (a) Fermentation of dietary fibre leads anaerobic butyric acid-producing bacteria with respect to the treatment of IBD to butyrate production. An from the human gut. It has been shown DOI 10.1099/jmm.0.017541-0 G 2010 SGM Printed in Great Britain 141 Editorial that lactic acid, produced in vitro by lactic (Sokol et al., 2008). This clearly suggests Research Centre (LFoRCe), University acid bacteria, is used by some strictly that F. prausnitzii secretes certain molecules Hospital, Leuven, Belgium anaerobic butyrate-producing bacteria of that have the potential to be used as 5Centre of Excellence Food2Know, clostridial cluster XIVa for the production therapeutics. In fact it has not been resolved Ghent University, Ghent, Belgium of high concentrations of butyric acid whether butyrate is the key molecule in the 6 (Louis & Flint, 2009). This mechanism is anti-colitis effects of F. prausnitzii or Microbial Ecology Group, Gut Health called cross-feeding and could explain why whether these depend on a combination of Programme, Rowett Institute of Nutrition and Health, University of Aberdeen, administration of lactic acid bacteria to IBD secreted compounds yet-to-be identified Aberdeen, UK patients can in certain cases be an that might act independently or together advantage, i.e. through stimulation of with butyrate. Notably, however, F. Correspondence: Filip Van Immerseel butyric acid production. However, other prausnitzii administration led to a shift in ([email protected]) possible mechanisms of action, including the microbiota composition that could also immunoregulatory effects, also have been have complex effects on colitis (Sokol et al., Bajka, B. H., Clarke, J. M., Cobiac, L. & Topping, suggested (Geier et al., 2007). An ideal 2008). It has been shown that the inflamed D. L. (2008). Butyrylated starch protects probiotic would thus be a colonizing intestinal mucosa of IBD patients has a colonocyte DNA against dietary protein- induced damage in rats. Carcinogenesis 29, bacterium that combines systemic anti- defective butyrate metabolism, leading to 2169–2174. inflammatory and immunoregulatory reduced efficiency of butyrate, again Breuer, R. I., Soergel, K. H., Lashner, B. A., Christ, effects with delivery of high butyrate levels suggesting that other compounds in M. L., Hanauer, S. B., Vanagunas, A., Harig, J. M., at the site of action and that can be ingested addition to butyrate may be involved in the Keshavarzian, A., Robinson, M. & other authors in a stable form, such as spores. One beneficial effects of the butyrate-producing (1997). Short-chain fatty acid rectal irrigation for potential problem is that bowel conditions microbiota (Thibault et al., 2010). left-sided ulcerative colitis: a randomized, in IBD patients may not be optimal to Nevertheless, it is clear that the pool of placebo-controlled trial. Gut 40, 485–491. support growth of these bacterial species. butyrate-producing bacteria from clostridial Cohen, M. L. (2000). Changing patterns of However, butyrate producers present in the cluster IV and XIVa harbours very infectious disease. Nature 406, 762–767. colon are phylogenetically diverse and it has promising preventive and therapeutic Danese, S. & Fiocchi, C. (2006). not been investigated in detail yet which probiotic strains. In a comparative study Etiopathogenesis of inflammatory bowel species are decreased in IBD. Therefore, it is using four strains, it was shown that a diseases. World J Gastroenterol 12, 4807–4812. likely that strains can be identified that are particular strain from clostridium cluster IV, Eeckhaut, V., Flahou, B., Romero, C., Van Der good colonizers. Furthermore, a synbiotic Butyricicoccus pullicaecorum,wassuperiorin Heyden, S., Pasmans, F., Haesebrouck, F., approach, using a prebiotic in combination decreasing lesions in a rat IBD model Ducatelle, R. & Van Immerseel, F. (2009). The anaerobic butyrate-producing strain with a butyrate producer, may help to re- compared to F. prausnitzii (Eeckhaut et al., Butyricicoccus pullicaecorum decreases colonic establish such bacteria in the individual in 2009). It is therefore suggested that research inflammation and ulceration in a TNBS-induced