Antibiotics and probiotics in inammatory bowel disease: why, when, and how

Cosimo Prantera and Maria Lia Scribano

Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy Correspondence to Cosimo Prantera, MD, Azienda Ospedaliera San Camillo-Forlanini, Circonvallazione Gianicolense 87, 00152 Rome, Italy Tel: +39 06 3200626 Current Opinion in Gastroenterology 2009, 25:329333

Purpose of review To summarize recent evidence on the role of intestinal bacteria in inammatory bowel diseases, and of antibiotics and probiotics in their treatment. The implications connected with the use of antibiotics are also examined. Recent ndings The hypothesis that Mycobacterium paratuberculosis could be a causative agent of Crohns disease has not been conrmed by a large trial on symptomatic patients treated by a combination of antibiotics active against this bacterium. An increased number of adherent-invasive Escherichia coli have been found in the intestinal tissue of patients with Crohns disease, but their role in the pathogenesis of this condition remains to be dened. The combination of metronidazole and azathioprine, associating the effects of a reduced bacterial load with immunosuppression, appears to be a therapeutic option to decrease the recurrence of postoperative Crohns disease in high-risk patients. However, concerns are raised by the possibility that antibiotics may induce disease relapse due to Clostridium difcile infection. Summary Recent literature provides increasing support for the use of antibiotics in Crohns disease, although the side effects limit their long-term use. The efcacy of antibiotics in ulcerative colitis is not conrmed by the available literature, except in severe colitis. More trials are needed to support the use of probiotics as therapy in inammatory bowel disease. Keywords antibiotics, Crohns disease, inammatory bowel disease, intestinal bacteria, probiotics, ulcerative colitis
Curr Opin Gastroenterol 25:329333 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0267-1379

Introduction
The most widely accepted hypothesis on the cause of inammatory bowel disease (IBD) is that it is caused by an excessively aggressive immune response to antigens in the gut of genetically susceptible individuals [1]. Intestinal bacteria are dominant antigens present in the gut and their role in IBD is supported by many experimental and clinical data. Nevertheless, whereas antibiotics are widely used in clinical practice for treating IBDs septic complications [2], only few clinicians consider these drugs useful in the active noncomplicated stages of IBD to reduce a possible antigenic overload [3]. A number of randomized studies on antibiotic therapy have been carried out with varied results, mainly in Crohns disease, but also in ulcerative colitis and pouchitis. The antibiotics used were those with antimycobacterial activity, metronidazole (Metro) active against anaerobic bacteria, ciprooxacine (Cipro) active against
0267-1379 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

Escherichia coli and, most recently, the nonabsorbable rifaximin.

Antimycobacterial therapy and Crohns disease

The pathological aspects of IBD lesions are similar to those of an infectious disease, and many studies have been directed towards the identication of a specic causative agent. During the 1980s and 1990s some investigators reported the presence of atypical Mycobacteria in Crohns disease intestine, with limited supporting immunological evidence [4,5]. With the hope of curing Crohns disease, antibiotics active against atypical Mycobacteria have been tested with conicting outcomes [6]. The most important study, published at the end of 2007, employed the antibiotic clofazimine together with clarithromycin and
DOI:10.1097/MOG.0b013e32832b20bf

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330 Inflammatory bowel disease

rifabutin, against placebo, for up to 2 years, in addition to a 16-week tapering course of prednisolone [7]. This antibiotic combination was chosen because of its activity against Mycobacterium paratuberculosis (MAP), the agent of Johnes disease in animals, considered a potential cause of Crohns disease. Two hundred and thirteen Australian patients were enrolled and randomized. The only signicant benet was observed at 16 weeks, when antibiotics were combined with steroid. A modest nonsignicant advantage of antibiotics over placebo in reducing Crohns disease relapse was registered at every observation time point during the 2-year period. In conclusion (and in line with a previous meta-analysis), this trial has shown that antimycobacterial treatment is not effective in inducing remission without a course of corticosteroids, and that the advantage of adding antimycobacterials to steroids is minimal. Some comments supported the conclusions of this trial, whereas others disputed it, afrming that the causality of MAP in Crohns disease cannot still be completely refuted [8,912]. The main objections were: the well known antibiotic resistance of MAP, the relatively low doses of antimycobacterials employed, and the use in the placebo arm of mesalamine and/or azathioprine which have a potential anti-MAP effect. Such arguments, however, are unconvincing in view of the fact that current antitumour necrosis factor (TNF) treatments induce remission of active Crohns disease and heal colonic and ileal lesions. TNF plays a key role in the host reaction against mycobacteria, namely granuloma formation and control of inammatory disease. Over 70 cases of tuberculosis in close temporal association with the initiation of treatment with anti-TNF agents have been reported in Crohns disease. However, anti-TNF therapy has never been associated with disseminated MAP in Crohns disease, a strong argument against the role of MAP as infectious agent of Crohns disease. Consequently, it would seem that the small clinical advantage observed with antimycobacterials, as shown in some studies, is ascribable to a generic effect directed towards those commensal enteric bacteria which may have a pathogenic potential without being typical infectious agents [13].

can penetrate into macrophages and can be effective in eradicating the bacteria. The only trial performed last year in active Crohns disease has compared clarithromycin 1g against placebo, administered for 3 months to 41 patients with Crohns disease with CDAI over 200 points and high concentration of C-reactive protein (CRP) [17]. There was no difference in the remission or response rate at 3 months between the antibiotic and placebo and the study was stopped. It is possible that clarithromycin, given its mediocre activity against E. coli, is not the best antibiotic to treat Crohns disease ares, assuming that AIEC is really implicated. Maintenance of Crohns disease remission induced by surgery or by drugs is a key goal for a gastroenterologist. His/her job is to increase the time until reappearance of lesions and to reduce their severity without inducing signicant side effects. A patients compliance with the prescribed drug is crucial. It is well established that surgery in Crohns disease is followed by a high 1-year endoscopic recurrence and that bacteria are strongly suspected to be implicated in the recurrence of the lesions. Antianaerobic bacterial drugs, such as metro and ornidazole, have been shown to reduce the severity of endoscopic recurrence after Crohns disease surgery, but their long-term use is burdened by a low compliance because of an elevated number of side effects. A randomized, placebo-controlled study employed a 3-month course of metro in combination with a 1-year of azathioprine to reduce the 1-year endoscopic recurrence in 81 operated patients with high risk of recurrence [18]. This strategy reduces the period of metro use utilizing it as bridge therapy, given the slow action of azathioprine. Four patients were withdrawn because of side effects; in three of them side effects probably due to metro occurred in the rst 3 months. The difference in recurrence rates between metro and azathioprine and metro and placebo was statistically signicant, 55 vs. 78%, respectively, thus offering the prospect of a biologically plausible therapy with limited side effects. This strategy combines the approach of reducing the anaerobic bacteria with the down-regulation of immune response. In fact, a recent study on Crohns disease paediatric patients reported that a subset of such patients with antibodies against microbial antigens was more susceptible to complications [19]. The most signicant reason for antibiotic treatment failure is the emergence of side effects, particularly important in long-term treatment. The interest of clinicians has been recently moved towards the nonabsorbable antibiotic rifaximin which, due to its high safety prole, is suitable for long-term treatment. Rifaximin, active against anaerobic bacteria and E. coli, has been approved for the treatment of travellers diarrhoea. In 2008 two case reports described the response to rifaximin

Antibiotics and Crohns disease

In the last years several groups have reported the presence of E. coli in Crohns disease ileal and colonic tissue [14,15]. E. coli with adherent-invasive properties (AIEC) found in these specimens is able to colonize the intestinal mucosa and to invade and replicate within macrophages, inducing the secretion of a large quantity of TNF [16]. Clarithromycin, a macrolide wide-spectrum antibiotic,

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Antibiotics and probiotics in IBD Prantera and Scribano 331

in six patients with Crohns disease [20,21]. In one of these articles the clinical remission obtained in three newly diagnosed ileal Crohns disease patients was conrmed also by a capsule endoscopy mucosal improvement [20]. The doses employed varied from 600 to 800 mg daily for a period of 3 weeks to over 6 months. A previous rifaximin-controlled trial had shown that 800 mg given twice daily for 3 months in patients with elevated CRP provided the best result [22].

NOD2/CARD15 and resistance to antibiotics

One important question concerning antibiotics and Crohns disease is their ineffectiveness in about 40 50% of patients. An interesting light on this problem has been shed by a study on the relationship between antibiotic response and NOD2/CARD15 gene variants. Cipro was dispensed to 49 and metro to 3 patients with perianal disease [23]. A complete stula response was recorded in 33.3% of patients with NOD2/CARD15 wild type compared with none of those with NOD2/CARD15 variants. This result could indicate that more than one reason is at the origin of the failure of antibiotics, apart from the bacteria resistance and low patient compliance. Unfortunately, neither Bacteroides nor Enterobacteriaceae group was permanently suppressed by metrocipro therapy and they tended to reappear when the treatment was stopped [24].

difcile-associated disease (CDAD). In recent years uoroquinolones have emerged as prominently implicated in this infection and their generalized employment in Crohns disease and pouchitis has alerted the gastroenterological community. In 2007 two retrospective studies analysed the connection between IBD and CDAD [27,28]. The rst reported the admission, between 1998 and 2004, of all cases of CDAD in the IBD and non-IBD population [27]. CDAD incidence was higher in IBD than non-IBD patients. Moreover there was an overall increased incidence during the 7 years under examination. The second study, assessing the impact of CDAD on IBD patients followed in a US referral centre during the years 20042005, registered an increase of the infection in the IBD cohort from 1.8% in 2004 to 4.6% in 2005 [28]. Colonic involvement and immunosuppressors were signicantly associated with the development of CDAD. This study also reported that more than half the infections required hospitalization and in 20% of cases colectomy was needed. A further US study analysed the morbidity and mortality of CDAD on IBD patients, utilizing the data from Nationwide Inpatients Sample [29]. The study reported that in patients with associated IBD and CDAD there was a four times greater mortality and longer hospitalization than in patients with IBD or CDAD alone. An editorial comment pinpointed the studys limitations, that is lack of information on severity of the cases, particularly on its relationship with surgery and mortality [30]. In conclusion, clinicians in charge of IBD patients must be aware of this risky complication, which can present the symptoms characteristics of IBD ares. Some symptoms, however, must alert to the possibility of CDAD, especially if they are more severe than those reported in the patients previous clinical history, and if the white blood cell count exceeds 20 000 with increased number of neutrophils. We must consider that 2040% of all hospitalized patients are colonized with C. difcile and that only in a few of them is there a conversion from spore to vegetative forms with replication and toxin production [31]. IBD patients are frequently on immunosuppressors, are often hospitalized and can be taking antibiotics, such as cipro and metro. Most strains of C. difcile are resistant to uoroquinolones and an increasing resistance to metro has recently been registered. This resistance could be more pronounced in strains harboured in IBD patients, due to their occasional use of metro.

Antibiotics and ulcerative colitis

In the last year no relevant paper has been published on the use of antibiotics and probiotics in ulcerative colitis. A recent consensus by the European Crohns and Colitis Organization (ECCO) concluded that antibiotics were not useful in ulcerative colitis treatment except metro, which is used on empirical grounds in cases of severe colitis [25]. Nevertheless, a meta-analysis published in 2007 seems to contradict this conclusion [26]. Ten placebo-controlled trials were included in this systematic review, and 530 patients were analysed. Different single antibiotics or combinations of the same were utilized. Remission was obtained in 72% of patients on antibiotics in comparison to 55% treated with placebo [odds ratio (OR) of 2.14, 95% condence interval (CI) 1.483.09, P < 0.0001]. However, the studies were not homogeneous, because various antibiotics were administered for a different period of time and some patients received concomitant drugs. These discrepancies could have altered the nal results.

Clostridium difcile infection and inammatory bowel disease

The ip side of the coin in which antibiotics are concerned is that they can induce IBD relapse by Clostridium

Probiotics
Probiotics are dened as a living microbial food ingredient with a benecial effect on human health [32]. However, it is wise to treat with scientic scepticism

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332 Inflammatory bowel disease

the claim that they are useful in many pathological conditions as a long elixir of life. Like other natural remedies considered free of side effects, probiotics have attracted the consumers favour, possibly biasing medical criticism. However, to do them justice, they have been successfully employed for the treatment of acute diarrhoeal illnesses and in prevention of antibiotic-related diarrhoea [33,34]. A previous Cochrane review on the efcacy of probiotics in maintenance of Crohns disease remission failed to show any benecial effect [35]. The authors concluded that, on account of the small number of the patients enrolled in these trials, the analysis could not have the statistical power to eventually detect a difference. A recent meta-analysis conrmed that probiotics do not seem to be a therapeutic option for maintenance of Crohns disease remission [36]. Last year a Cochrane systematic review of randomized controlled trials comparing probiotics against placebo or any other intervention for induction of remission in Crohns disease included only one study with only 11 patients [37]. Another Cochrane study reviewed the role of probiotics in inducing remission in ulcerative colitis [38]. Four studies were analysed for a total of 244 patients. The conclusion was that adding probiotics to conventional treatment did not improve the overall remission rates in mild to moderate ulcerative colitis, but it was possible to obtain a slight benet in decreasing the disease activity. The only advantage of probiotics in IBD has been registered with VSL#3, a combination of four Lactobacillus species, three Bidobacterium species, and 1 Streptococcus salivarius species, for treatment and prevention of pouchitis, as shown in two small trials published between 2000 and 2003 [39]. ECCO consensus suggests that E. coli Nissle 1917 could be useful as alternative therapy to mesalazine in ulcerative colitis [25]. Another meta-analysis concluded that, despite many methodological differences and a signicant heterogeneity of studies, probiotics do not differ signicantly from antiinammatory drugs for efcacy and safety in achieving ulcerative colitis remission [40]. In spite of this optimistic conclusion our point of view is that the use of probiotics in IBD cannot be recommended [41]. The published trials have employed diverse bacterial strains with various bacterial contents in different clinical situations and, more critically still, few patients have been enrolled in these studies. More randomized trials with strict enrolment criteria are needed before accepting probiotics in the therapeutic armamentarium of IBD.

ease [7,18]. The Australian trial has overcome two criticisms previously made regarding other antimycobacterial studies, that is the exceedingly brief time of treatment and the type of antibiotics not specically active against atypical mycobacteria employed in previous studies [7]. The trial failed, mainly because the healing of lesions (an effect to be expected from a drug claimed to exert a therapeutic effect on the causative agent of Crohns disease) was not obtained. To sum up, the trial does not conrm the hypothesis of mycobacterial cause in Crohns disease, even if this possibility is not completely ruled out. In fact, a hypothetical infectious agent that commenced the inammatory process may no longer be detectable, having long since left the initial crime scene. The second study gives us important information on prevention of recurrent lesions of Crohns disease [18]. The combination of antibiotic and azathioprine seems an acceptable choice for providing patients with high risk of recurrence after surgery a chance of reduction of disease reappearance. Antibiotics alternative to metro, which is burdened by side effects that in turn affect patients compliance, could improve the performance of this strategy. In our opinion antibiotics are extremely useful for treating Crohns disease complications, especially when the use of immunosuppressors may be counter-indicated because of abscesses and septic complications. In the active phases, when the colon is involved, they are a possible rst-step therapy; however, there are serious doubts about their efcacy in Crohns disease ileitis. The combination of antibiotics with steroids needs to be reassessed. There is no proof of antibiotic usefulness in ulcerative colitis; however, it is advisable to use them in case of severe colitis. Finally, the value of probiotics deserves to be further investigated. We believe that a key research goal should be to discover new antibiotics with fewer side effects, a wide spectrum of activity, and low bacterial resistance. Another future assignment should be to test the efcacy of various combinations of antibiotics and the corresponding response of mucosal adherent bacteria.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:  of special interest  of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 383). 1 2 Podolsky DK. Inammatory bowel disease. N Engl J Med 2002; 347:417 429. Sartour RB. Therapeutic manipulation of the enteric microora in inammatory bowel disease: antibiotics, probiotics, and prebiotics. Gastroenterology 2004; 126:16201633.

Conclusion
The past year has not seen any major update to the topic antibiotic/probiotic in IBD. However, two noteworthy studies have addressed major questions in Crohns dis-

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Antibiotics and probiotics in IBD Prantera and Scribano 333

3 4 Prantera C. What role do antibiotics have in the treatment of IBD? Nat Clin Pract Gastroenterol Hepatol 2008; 5:670671. Chiodini RJ, Van Kruiningen HJ, Thajer WR, et al. Possible role of mycobacteria in inammatory bowel disease. I. An unclassied Mycobacterium species isolated from patients with Crohns disease. Dig Dis Sci 1984; 29:1073 1079. Graham DY, Markesich DC, Yoshimura HH. Mycobacteria as the cause of Crohns disease. Gastroenterology 1989; 97:13541356. Borgaonkar MR, MacIntosh DG, Fardy JM. A meta-analysis of antimycobacterial therapy for Crohns disease. Am J Gastroenterol 2000; 95:725 729. Selby W, Pavli P, Crotty B, et al. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohns disease. Gastroenterology 2007; 132:23132319. Peyrin-Biroulet L, Neut C, Colombel J-F. Antimycobacterial therapy in Crohns disease: game over? Gastroenterology 2007; 132:25942598. Lipton JE, Barash DP. Flawed Australian CD study does not end MAP controversy. Gastroenterology 2007; 133:1742. 23 Angelberger S, Reinisch W, Dejaco C, et al. NOD2/CARD15 gene variants  are linked to failure of antibiotic treatment in perianal stulating Crohns disease. Am J Gastroenterol 2008; 103:11971202. Perianal disease responds better to ciprooxacin in patients with NOD2/CARD15 wild type compared with those with NOD2/CARD15 variants. 24 Swidsinski A, Loening-Baucke V, Bengmark S, et al. Bacterial biolm sup pression with antibiotics for ulcerative and indeterminate colitis: consequences of aggressive treatment. Arch Med Res 2008; 39:198204. This important article describes the rebound effect of the suppression of mucosal ora induced after stopping the antibiotics. 25 Travis SPL, Stange EF, Lemann M, et al. European evidence-based con sensus on the management of ulcerative colitis: current management. J Crohns Colitis 2008; 2:2462. The article reports the consensus of a group of European experts on the management of ulcerative colitis. 26 Rahimi R, Nikfar S, Rezaie A, Abdollahi M. A meta-analysis of antibiotic therapy for active ulcerative colitis. Dig Dis Sci 2007; 52:29202925. 27 Rodemann JF, Dubberke ER, Reske KA, et al. Incidence of Clostridium difcile infection in inammatory bowel disease. Clin Gastroenterol Hepatol 2007; 5:339344. 28 Issa M, Vijayapal A, Graham MB, et al. Impact of Clostridium difcile on inammatory bowel disease. Clin Gastroenterol Hepatol 2007; 5:345351. 29 Ananthakrishan AN, McGinley EL, Binion DG. Excess hospitalisation burden  associated with Clostridium difcile in patients with inammatory bowel disease. Gut 2008; 57:205210. Patients with both IBD and Clostridium difcile infection carry a higher mortality than patients with infection without IBD. 30 Stone CD. Prognosis in Clostridium difcile infection complicating inam matory bowel disease. Gut 2008; 57:150152. The editorial comment highlights the growing problem of Clostridium difcile infection in general population and, in particular, in IBD patients. 31 Bartlett JG, Perl TM. The new Clostridium difcile: what does it mean? N Engl J Med 2005; 353:25032505. 32 Gorbach SL. Probiotics and gastrointestinal health. Am J Gastroenterol 2000; 95:S2S4. 33 Saavedra JM, Bauman NA, Oung I, et al. Feeding of Bidobacterium bidum and Streptococcus thermophilus to infants in hospital for prevention of diarrhoea and shedding of rotavirus. Lancet 1994; 344:10461049. 34 Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospective study. Gastroenterology 1989; 96:981988. 35 Rolfe VE, Fortun PJ, Hawkey CJ, Bath-Hextall F. Probiotics for maintenance of remission in Crohns disease. Cochrane Database Syst Rev 2006; 18:CD:004826. 36 Rahimi R, Nikfar S, Rahimi F, et al. A meta-analysis on the efcacy of probiotics for maintenance of remission and prevention of clinical and endoscopic relapse in Crohns disease. Dig Dis Sci 2008; 53:25242531. 37 Butterworth AD, Thomas AG, Akobeng AK. Probiotics for induction of remission in Crohns disease. Cochrane Database Syst Rev 2008; 16:CD:006634. 38 Mallon P, McKay D, Kirk S, Gardiner K. Probiotics for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2007; 17:CD:005573. 39 Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology 2000; 119:305309. 40 Zigra PI, Maipa VE, Alamanos YP. Probiotics and remission of ulcerative colitis: a systematic review. Neth J Med 2007; 65:411418. 41 Prantera C. Probiotics for Crohns disease: what have we learned? Gut 2006; 55:757759.

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