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 the diseased state. First attempts have been efforts should be increased to test the colitis rat model. In 5th Probiotics, Prebiotics and made in animal models of IBD to apply therapeutic value of these next generation New Foods Congress, Rome, Italy. http:// butyrate-producing bacteria (Sokol et al., probiotic strains, and to identify further www.probiotics-prebiotics-newfood.org/pdf/ 2008; Eeckhaut et al., 2009). Strains of strains that are able to colonize the gut of 5th_Probiotics_Prebiotics_Newfood.pdf clostridium cluster IV and XIVa were found IBD patients without being outcompeted. Flint, H. J., Duncan, S. H., Scott, K. P. & Louis, P. to be highly successful in decreasing (2007). Interactions and competition within the microbial community of the human colon: links inflammation and necrosis in rodent IBD 1 Filip Van Immerseel, between diet and health. Environ Microbiol 9, models. Indeed, Faecalibacterium Richard Ducatelle,1 Martine De Vos,2 1101–1111. prausnitzii, a species belonging to cluster IV, 3 3 Nico Boon, Tom Van De Wiele, Geier, M. S., Butler, R. N. & Howarth, G. S. has been shown to be much less prevalent in 4 4 Kristin Verbeke, Paul Rutgeerts, (2007). Inflammatory bowel disease: current the gut microbiota of IBD patients. This Benedikt Sas,5 Petra Louis6 insights into pathogenesis and new therapeutic species showed great promise in and Harry J. Flint6 options; probiotics, prebiotics and synbiotics. counterbalancing dysbiosis in a mouse IBD Int J Food Microbiol 115, 1–11. 1 model (Sokol et al., 2008, 2009). Department of Pathology, Bacteriology Gueimonde, M., Ouwehand, A., Huhtinen, H., Interestingly, components of the culture and Avian Diseases, Faculty of Salminen, E. & Salminen, S. (2007). Qualitative supernatant of this bacterium had the Veterinary Medicine, Ghent University, and quantitative analyses of the bifidobacterial capacity to decrease production of the Ghent, Belgium microbiota in the colonic mucosa of patients with colorectal cancer, diverticulitis and inflammatory cytokines interleukin 12 and 2 Department of Gastroenterology, Ghent inflammatory bowel disease. World J gamma interferon, and to increase University Hospital, Ghent, Belgium Gastroenterol 13, 3985–3989. production of the anti-inflammatory 3 Hamer, H. M., Jonkers, D., Venema, K., cytokine interleukin 10, in peripheral blood Laboratory of Microbial Ecology and Technology (LabMET), Faculty of Vanhoutvin, S., Troost, F. J. & Brummer, R. J. mononuclear cells in a way independent of (2008). Bioscience Engineering, Ghent Review article: the role of butyrate on butyrate (Sokol et al., 2008). Oral and colonic function. Aliment Pharmacol Ther 27, University, Ghent, Belgium intraperitoneal administration of the 104–119. 4 culture supernatant in a mouse IBD model Department of Gastroenterology and Hedin, C., Whelan, K. & Lindsay, J. O. (2007). reduced colitis and mortality, respectively Leuven Food Science and Nutrition Evidence for the use of probiotics and prebiotics

142 Journal of Medical Microbiology 59 Editorial

in inflammatory bowel disease: a review of Pacific region. Curr Opin Gastroenterol 21, Transport of butyryl-L-carnitine, a potential clinical trials. Proc Nutr Soc 66, 307–315. 408–413. prodrug, via the carnitine transporter OCT2 and 0,+ Louis, P. & Flint, H. J. (2009). Diversity, Sokol,H.,Pigneur,B.,Watterlot,L.,Lakhdari,O., the amino acid transporter ATB . Am J Physiol metabolism and microbial ecology of butyrate- Bermudez-Humaran, L. G., Gratadoux, J. J., Gastrointest Liver Physiol 293, G1046–G1053. producing bacteria from the human large Blugeon, S., Bridonneau, C., Furet, J. P. & other Takaishi, H., Matsuki, T., Nakazawa, A., intestine. FEMS Microbiol Lett 294, 1–8. authors (2008). Faecalibacterium prausnitzii is an Takada, T., Kado, S., Asahara, T., Kamada, N., Mimura, T., Rizzello, F., Helwig, U., Poggioli, G., anti-inflammatory commensal bacterium identified Sakuraba, A., Yajima, T. & other authors Schreiber, S., Talbot, I. C., Nicholls, R. J., by gut microbiota analysis of Crohn disease patients. (2008). Imbalance in intestinal microflora Gionchetti, P., Campieri, M. & Kamm, M. A. Proc Natl Acad Sci U S A 105, 16731–16736. constitution could be involved in the (2004). Once daily high dose probiotic therapy Sokol, H., Seksik, P., Furet, J. P., Firmesee, O., pathogenesis of inflammatory bowel disease. Int (VSL#3) for maintaining remission in Nion-Larmurier, I., Beaugerie, L., Cosnes, J., J Med Microbiol 298, 463–472. recurrent or refractory pouchitis. Gut 53, Corthier, G., Marteau, P. & Dore´ , J. (2009). Low Thibault, R., Blachier, F., Darcy-Vrillon, B., De 108–114. counts of Faecalibacterium prausnitzii in colitis Coppet, P., Bourreille, A. & Segain, J. P. (2010). Ouyang, Q., Tandon, R., Goh, K. L., Ooi, C. J., microbiota. Inflamm Bowel Dis 15, 1183–1189. Butyrate utilization by the colonic mucosa in Ogata, H. & Fiocchi, C. (2005). The emergence Srinivas, S. R., Prasad, P. D., Umapathy, N. S., inflammatory bowel diseases: a transport of inflammatory bowel disease in the Asian Ganapathy, V. & Shekhawat, P. S. (2007). deficiency. Inflamm Bowel Dis 16 (in press).

http://jmm.sgmjournals.org 143