There have been several studies assessing the efficacy of probiotics in pouchitis. Pouchitis occurs in up to 45 % of patients after proctocolectomy and is thought to be secondary to alterations of the luminal flora in the pouch [64]. This hypothesized pathophysiology has made pouchitis an attractive candidate for probiotic therapy. In 2000, Gionchetti et al. published a randomized, double-blind, placebo-controlled trial assessing VSL#3 at 900 billion CFUs twice daily in the maintenance of remission of pouchitis in UC [30]. Forty patients in clinical and endoscopic remission were enrolled in the trial and followed for 9 months. Fifteen percent of patients (3 of 20) in the VSL#3 arm and 100 % (20/20) of the placebo arm relapsed. Gionchetti also demonstrated that the same dose of VSL#3 was capable of preventing onset of pouchitis after surgery in 2003 [65]. In 2004, Mimura et al. were able to demonstrate that a once daily dose of 600 billion CFUs of VSL#3 maintained remission in 85 % of pouchitis patients, compared to 5 % in the placebo arm [66]. A meta-analysis published in 2007 assessed 5 randomized controlled trials of probiotics in pouchitis. This study demonstrated an overall OR of 0.04 (95 % CI 0.0–0.14, p < 0.0001). There was significant heterogeneity between trials and variability in probiotics used, with one trial using Lactobacillus rhamnosus GG, while the other four used VSL#3 [67].

The term “prebiotic” was coined by Glenn R. Gibson and Marcel B. Roberfroid in 1995 as “nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacterial species already resident in the colon, and thus attempt to improve host health” [68, 69]. This definition was refined in 2007 by Roberfroid to “a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora that confers benefits upon host well-being and health” [70]. Combining a prebiotic and probiotic in the same preparation is considered a “synbiotic” [69]. Such combinations are thought to enhance colonization, survival, and function of the probiotic species.

Prebiotics typically consist of oligosaccharides and polysaccharides that cannot be digested by the human host but can be digested by specific bacteria in the gut, providing them with a selective advantage. To be considered a prebiotic, a compound must be completely resistant to the host digestive tract, including gastric acid, host hydrolytic enzymes, and direct absorption. The compound must then be fermentable by host bacteria, resulting in stimulation of specific commensal bacteria. Two compounds that have been extensively researched and meet these criteria are inulin and trans-galactooligosaccharides (TOS) [70]. The bacterial “targets” of these agents are typically the same bacteria delivered in common probiotic formulation. When added to both pure strains of colonic flora and cultured human feces, inulin has been shown to selectively promote the growth of Bifidobacterium and may even inhibit the growth of other species such as C. perfringens and E. coli in mixed culture [71]. Furthermore, the end products of fermentation of these sugars include short chain fatty acids (SCFAs), which are an energy source of colonic enterocytes [69].

Research into the effects of both prebiotics and synbiotics in human disease, particularly with regard to disorders of the gastrointestinal tract, has begun. Inulin, oligofructose, and TOS have been assessed in the management of constipation, which is thought to be secondary to dysbiosis. A review by Macfarlane published in 2007 assessed 7 trials of various types and doses of prebiotics, with only two demonstrating a statistically significant improvement in stool output [72]. Further research has demonstrated a potential role for fructooligosaccharides (FOS) in a placebo-controlled, randomized trial, though results did not reach statistical significance [73]. Additional research demonstrated potential improvement in some symptoms in IBS with administration of TOS as well, though further research is required [74].

With regard to ulcerative colitis, there have been several animal models suggesting efficacy, but there is limited human data. The effects of a wide range of agents, including FOS, inulin, lactulose, or combinations thereof, have demonstrated efficacy in increasing the quantity of Bifidobacterium and Lactobacillus species in several animal models of colitis, as well as modulating inflammatory markers [72, 75–79]. Controlled trials in humans are limited, however. Furrie et al. conducted a small randomized, placebo-controlled trial in 18 patients of a 1-month course of a synbiotic containing Bifidobacterium longum and a combination of inulin and oligofructose [54]. Patients were assessed before and after therapy via clinical index, endoscopic score, and several immunologic markers such as defensin excretion, TNF-α, IL-1α, and IL-10. After therapy with the synbiotic, all patients had a significant reduction in defensins, TNF-α, and IL-1α. There was also a 42-fold increase in concentration of Bifidobacterium on mucosal biopsies, determined via rRNA, after therapy. Histologically, there was also reduced inflammation in those in the treatment arm as well as reduced clinical symptoms. Statistical significance was not reported for these outcomes, however. Fujimori et al. conducted a 3-armed trial of a synbiotic (Bifidobacterium and psyllium) versus probiotic alone versus prebiotic alone in 120 patients with mild UC or in remission for 4 weeks [80]. Only the synbiotic group appreciated an improvement in IBDQ, a validated questionnaire of IBD symptoms and quality of life.

In summary, prebiotics and synbiotics represent a new method of modifying the microbiome, promoting the growth of potentially beneficial commensal and probiotic strains. There is a small but growing body of literature of the effect of these oligosaccharides on microbiome composition and their ability to modulate inflammation. There are also several small, randomized controlled trials, but much more research is needed to assess the efficacy of these agents.

As previously noted, the first publications of antibacterial agents being used to treat IBD were published in the 1940s [1–3]. However, the role of antibiotics in the pathogenesis and treatment of IBD has become considerably more complex since these early studies. Recent research has demonstrated that antibiotic exposure has been shown to have a significant and long-lasting effect on microbiome composition in neonates and infants [81, 82]. Amoxicillin can markedly reduce Lactobacillus species in the gut after administration, and this has been shown to have a significant effect on developmental gene expression in enterocytes [83]. Antibiotic-related dysbiosis has also been shown to create a permissive environment for several invasive, pathogenic strains of bacteria, including Clostridium difficile, Clostridium perfringens, Salmonella species, and E. coli O157:H7 [84–86]. Promotion of these species may exacerbate IBD-related inflammation.

There is intriguing new data that suggests antibiotic exposure may increase the risk of later developing IBD. Margolis et al. performed a retrospective study in The Health Improvement Network database in the UK, assessing 94,487 patients with acne for exposure to tetracycline antibiotics. Tetracyclines are frequently used in the treatment of acne, and this class includes drugs such as minocycline, tetracycline, oxytetracycline, and doxycycline. The authors detected an increased risk of developing IBD with exposure to any of these antibiotics, with a hazard ratio (HR) of 1.39 (95 % CI 1.02–1.90). When stratified by IBD subtype and antibiotic, tetracycline/oxytetracycline remained associated with an increased risk of CD, while no antibiotics maintained significance for UC [87]. Further epidemiologic and animal-based research is needed to explore this potential relationship between antibiotic exposure and risk for developing IBD.

Once IBD has developed, antibiotic exposure may actually have a protective effect. A recent population-based cohort study using the General Practice Research Database (GPRD) in the UK assessed this effect [88]. The authors studied 1,205 patients with CD and 2,230 patients with UC, with a median of approximately 4 years’ follow-up time for each group. In this cohort, exposure to antibiotics was associated with an overall reduced risk of disease flare for CD, with an OR of 0.78 (95 % CI 0.64–0.96), but this association was not present for UC. This protective effect was strongest with more recent exposure, suggesting that the acute changes in the microbiome may be responsible.

There have been a multitude of studies looking at the role of antibiotics in the treatment of IBD. The two most commonly used classes of antibiotics are the fluoroquinolones, such as ciprofloxacin and levofloxacin, and the nitroimidazoles, including metronidazole. The combination of these two classes of antibiotics provides broad-spectrum coverage against most enteric bacteria, with the fluoroquinolone providing coverage against gram-negative and gram-positive aerobes and metronidazole covering gram-negative and gram-positive anaerobes [4]. Both classes are typically well tolerated, although fluoroquinolones can cause nausea, vomiting, abdominal pain, diarrhea, lightheadedness, photosensitivity, and an increased risk of tendon rupture. Side effects due to metronidazole include dysgeusia, resulting in a metallic taste. It has also been associated with nausea, vomiting, diarrhea, abdominal cramping, and a disulfiram-like reaction when combined with alcohol. Another common, though more serious, complication of metronidazole is peripheral neuropathy. The risk of this side effect appears to increase with prolonged exposure and increasing dose. It typically resolves upon cessation of the drug but may persist. A newer agent that has been assessed in several recent trials is rifaximin. This nonabsorbable rifamycin derivative is a nonabsorbable antibiotic with broad-spectrum coverage against gram-positive and gram-negative aerobes and anaerobes and is also well tolerated.

There appears to be an established role for antibiotic therapy in pouchitis. A small, randomized controlled trial by Madden et al. examined the benefit of metronidazole versus placebo in pouchitis in 1994. The authors appreciated a statistically significant decrease in the number of bowel movements, but no significant endoscopic or histological changes [89]. Another study compared metronidazole and budesonide enemas for a total of 6 weeks in active pouchitis, and a clinical improvement was appreciated in both groups, but there was no difference between the two groups [90]. Shen et al. performed a randomized trial in 2001 comparing ciprofloxacin to metronidazole, demonstrating a greater reduction in Pouchitis Disease Activity Index (PDAI) in the ciprofloxacin group. Ciprofloxacin was also better tolerated, with 33 % of patients experiencing adverse effects in the metronidazole group [91]. Another study looking at flora changes related to pouchitis suggested that more complete eradication of pathogenic C. perfringens and E. coli strains with ciprofloxacin may be responsible for the observed improvement in efficacy compared to metronidazole [92]. Mimura et al. also performed an open-label trial assessing the efficacy of combining both metronidazole and ciprofloxacin for refractory pouchitis [93]. Eighty-two percent (44 of 36) of their patients entered remission, with a significant decrease in median PDAI from 12 to 3 after therapy. The therapy was well tolerated. Rifaximin has also been assessed in open-label trials, either alone or in combination with other antibiotics [4, 94]. A recent case series demonstrated a reduction in PCDAI in 16 of 18 patients, with 6 patients entering remission. However, in a recent small, randomized, double-blind, placebo-controlled trial by Isaacs et al., rifaximin provided no benefit over placebo [95]. Based on this evidence, the American College of Gastroenterology currently recommends either metronidazole or ciprofloxacin for the treatment of pouchitis [96].

The data are less clear regarding the potential benefit of antibiotics in inducing remission in UC. As is the case with pouchitis, multiple antibiotics and combinations of antibiotics have been assessed for efficacy in active UC, with most studies focusing on ciprofloxacin or combination therapy. A number of other agents, such as tobramycin, oral vancomycin, or rifaximin, have been assessed, with mixed results. With regard to ciprofloxacin, there have been several placebo-controlled trials. In 1997, Mantzaris et al. performed a randomized, placebo-controlled trial of a 2-week course of oral ciprofloxacin versus placebo in 70 patients with mild to moderately active UC in addition to 5-ASA and prednisolone [97]. No significant difference in response was appreciated between groups. Mantzaris also conducted a study in 55 patients with severe UC, examining the effects of IV ciprofloxacin versus placebo in addition to IV steroids and parenteral nutrition. IV ciprofloxacin provided no additional benefit [98]. In one of the few positive studies, Turunen et al. assessed 6 months of ciprofloxacin versus placebo in conjunction with 5-ASA and steroids for maintenance of remission of subjects with moderate to severe active UC. At 6 months, 79 % of patients in the ciprofloxacin group had maintained an initial response, compared to 56 % in the placebo group (p = 0.02) [99].

Several other antibiotic-based therapies have been assessed in randomized controlled trials of induction of remission in UC. Burke et al. performed a randomized controlled trial of oral tobramycin versus placebo in mild to severely active UC, in conjunction with steroid therapy, with 31 of 42 (74 %) patients achieving complete symptomatic remission compared to 18 of 42 (43 %) in the placebo arm (p = 0.008) [100]. Several combinations of antibiotics have been assessed as well. Mantzaris et al. assessed the combination of IV metronidazole and tobramycin versus placebo, along with parenteral nutrition and steroids, in 39 patients with acute severe UC. Sixty-three percent in the treatment arm and 65 % in the placebo arm noted significant improvement [101]. Rifaximin was assessed by Gionchetti et al. in a small placebo-controlled trial. Rifaximin 400 mg twice daily demonstrated significant decreases in clinical activity, with 9 of 14 patients receiving rifaximin demonstrating benefit compared to 5 of 12 receiving placebo [102].

Recent studies of antibiotic therapy have considered targeting specific organisms. In 2005, Okhusa et al. published a randomized controlled trial of a regimen specifically targeting Fusobacterium varium, containing amoxicillin, tetracycline, and metronidazole (ATM) versus placebo for 2 weeks in 20 patients with mild to moderately active UC [103]. At 3–5 months, the authors appreciated a statistically significant reduction in endoscopic score, but not histology or symptom index, in the treatment group. At 12–14 months after therapy, there were significant reductions in endoscopic score, symptom index, and histological grading. The same group performed a placebo-controlled, randomized trial of 2 weeks of oral ATM in 206 patients with mild to severe chronic relapsing UC [104]. The authors appreciated a greater clinical and endoscopic response at 3 months in the treatment group compared to placebo, though remission rates were not significantly different. Interestingly, this 2-week course of antibiotics improved clinical, endoscopic, and remission rates at 12 months in the treatment arm compared to placebo. While such targeted approaches are compelling, further research is required to ascertain the exact effects such broad-spectrum therapies are having on the microbiome and clinical outcomes of UC patients.

There have also been several meta-analyses of the efficacy of antibiotics in UC. Rahimi et al. published a meta-analysis including ten randomized, placebo-controlled trials of antibiotics in addition to steroids for induction of remission in active UC [105]. Disease severity was not reported. Antibiotics assessed included vancomycin, metronidazole, tobramycin, ciprofloxacin, rifaximin. Two studies of the studies in the meta-analysis evaluated combinations of antibiotics for treatment of UC. Overall, there did appear to be a statistically significant benefit for antibiotic use in active UC, with an OR of 2.14 (95 % CI 1.48–3.09), without significant heterogeneity or detected publication bias. Khan et al. performed another meta-analysis in 2011, examining 9 trials including 662 patients for induction of remission of active UC. Of note, 7 of these trials were also included in the meta-analysis conducted by Rahimi et al. Those studies that commented on UC disease severity were typically moderate to severe. In this study, an overall benefit for antibiotic therapy was appreciated as well, with an Odds RatioR of not being in remission of 0.64 (95 % CI 0.43–0.96). They did detect moderate heterogeneity as well as possible publication bias. Of note, the authors rigorously reviewed the quality of these studies as well and found that only one of the 7 trials included for UC had a low risk of bias [106].

There is currently limited data regarding the role of antibiotics in the maintenance of remission in UC. Lobo et al. performed a long-term follow-up of active UC patients who had received tobramycin and entered remission. In this trial, antibiotics were only given for a single 1-week period during the induction of the remission phase [107]. When examining those who were in remission, there was no significant difference between groups regarding relapse rates at 1 and 2 years. The previously mentioned trial by Turunen et al. which examined the benefits of ciprofloxacin for 6 months in active UC also reported the rates of relapse in those that responded from 6 months to 1 year after cessation of study medication, demonstrating similar failure rates in the treatment arm (9 of 30, 30 %) as in the placebo arm (7 of 25, 28 %) [99]. Both of these trials demonstrate failure rates after antibiotic cessation, however; a paucity of data regarding continued therapy may represent wariness in using long-term antibiotic therapy.

In summary, there is ample evidence demonstrating that antibiotic therapy has a significant impact on the microbiome of the intestinal track. Furthermore, there is a growing body of literature suggesting that antibiotic exposure may have an effect on the risk of developing IBD, and once diagnosed with IBD, antibiotic exposure may significantly impact the course of disease. It also appears that there is benefit to antibiotic therapy for treatment of IBD-related complications and for pouchitis. However, there is currently mixed evidence with regard to the efficacy of antibiotic therapy for the treatment of UC. There is considerable variation in efficacy in treatment based on the specific antibiotic, number of antibiotics used, and duration of treatment. Based on these data, more research is required before antibiotic therapy can be formally recommended for the management of ulcerative colitis in the absence of peritonitis, abscess, or toxic megacolon. Table 18.2 shows antibiotic clinical trials for induction and maintenance of remission in UC.