Ulcerative colitis, microbiota and prebiotics
Ulcerative colitis, microbiota and prebiotics
Pavel Nesmiyanov, MD, PhD
Inflammatory bowel diseases are characterized by complex interactions of the immune system and gut microbiota. With the recent technological advances, it became possible to provide new insights into disease pathogenesis. Accumulating evidence suggests the utility of microbiota in diagnostics, prognostics, and therapeutics in inflammatory bowel diseases. In this review we focus on alterations of microbiota and immune system in ulcerative colitis and issues on the use of prebiotics and novel prebiotic formulations.
Keywords: ulcerative colitis, microbiota, prebiotics
Figure 1. Pathogenetic networks in ulcerative colitis
Ulcerative colitis (UC) is a chronic and relapsing inflammatory bowel disease (IBD) restricted to the large intestine, in contrast to Crohn’s disease (CD) which may involve any part of the gut. Despite of unknown etiology of UC, many factors are described to contribute to the disease: genetic background, immune system reactions, environmental factors, NSAIDs use, low levels of antioxidants, psychological stress factors, and dairy products consumption[1–3]. Among all these factors, immune reactions (both genetically and environmentally defined), play a major role, to our opinion.
Immune dysregulation has long been suspected to play a role in the course of inflammatory bowel disease with earliest research that dates back to 1970s[4, 5]. UC is characterized by a plethora of immunological changes, including accumulation of neutrophils and activated cytotoxic T cells in the lamina propria of the affected colonic region, increased B cell count with corresponding IgG and IgE elevation, some of which are specific to colonic antigens . The presence of antineutrophil cytoplasmic antibodies and anti-Saccharomyces cerevisae antibiodies is a common feature in UC[6–10]. Interestingly, appendectomy leads to a lower incidence of UC[11, 12]: one hypothesis is that alterations in mucosal immune responses leading to appendicitis or resulting from appendectomy may negatively affect the pathogenetic mechanisms of UC. Abnormal function of immunoregulatory cytokines, such as IFN-γ, TNF-α in animal models of UC is well documented. Microscopic changes include signs of chronic inflammation, crypt branching and villous atrophy as well as formation of inflammatory polyps. Sufficient evidence have been provided recently on the involvement of gut microbiota in the pathophysiology of UC. Dysregulation of the immune system, it’s inappropriate immune responses to intestinal microorganisms and their products, continuous inflammation have profound effects on gut microbiota. Vice versa, changes in microbiota play a role in development of inflammatory bowel disease, as discussed below.
Ulcerative colitis and microbiota
New insights into the composition of gut microbiota in health and disease have been provided with the development of next-generation sequencing techniques. Generally, gut microorganisms are seen as a system of two phylums: Firmicutes (49-76%) and Bacteroidetes (16-23%) although members of at least 10 different phyla (Proteobacteria, Actinobacteria etc.) are functionally important.
Mucosa-associated microorganisms are increased in IBD, and are highly coated in sIgA and probably are more relevant in UC than that found in fecal samples[15, 16]; an imaging study using approaches that carefully preserve the structure of faeces also identified discrete patches; individual groups of bacteria were found to spatially vary in abundance from undetectable to saturating levels.
Changes of microbiota in UC are summarized in Table 1. Usually, healthy state is characterized by a relative temporal stability of microbiota, while UC patients have reduced diversity of gut microorganisms [1, 18], largely due to a decrease in the diversity of Firmicutes and an increase of Proteobacteria. Though the ratio of Firmicutes:Bacterioidetes is not the same even in healthy individuals, even a single species depletion, such as Faecalibacterium prausnitzii (Firmicutes phylum) can be associated with IBD [19, 20]. Discrepant results are found in the studies on E.coli, Bifidobacteria species, Lactobacillus species, Enterobacteriaceae and Bacteroides [16, 21, 22]. The common feature in UC patients is that the composition of gut microbiota differs between active and remission stages and even unstable in quiescent stage . Exacerbations of UC is preceded by decrease in so-called “anti-inflammatory” anaerobes, e.g Bacteroides, Escherichia, Eubacterium, Lactobacillus, and Ruminococcus and diminution in the diversity of the gut microbiota .
In other reports a localized dysbiosis found. For example, inflamed and non-inflamed sites of the mucosa are substantially different in the prevalence of Lactobacilli and the Clostridium leptum subgroup and that this may be related to UC [25, 26]. Proteobacteria and Firmicutes were more frequently observed in the inflamed UC mucosa . However, recent research has found no correlation between regional inflammation and a breakdown in this spatial differentiation or bacterial diversity . Dysbiosis not only affects bacterial species. It has been shown that disturbances in microbiota promote specific Candida and Cladosporium fungi  as well as virome components .
To summarize, bacterial dysbiosis has been proven to play an important role in UC pathogenesis. Mucosal dysbiosis may have diagnostic, prognostic, and therapeutic implications. Whether modification of microbiota is a cause or a consequence of intestinal inflammation in UC is still a matter of debate. Data on specific microbiota shifts also vary. More well-designed trials are required to show UC-specific changes. Studies should focus on mucosa-associated microbiota. The findings can be viewed in the context of microbiota-associated pathogenic network in UC comprising two perspectives: how UC affects gut microbiota and how microbiota affects UC.
|Table 1. Summary of microbiota major changes in UC compared to healthy subjects
Escherichia coli 
Campylobacter urealyticus [52,159]
Campylobacter concisus 
Sulfate-reducing bacteria [74,125]
Firmicutes (Faecalibacterium prausnitzii (Clostridium subcluster IV) and Roseburia (Clostridium subcluster XIVa) [33,137,141,164, 167] – controversial, increased in [31,53]
Lactobacillus spp. – controversial, increased in 
Microbiota-associated pathogenic networks in ulcerative colitis
Ulcerative colitis and associated immune changes induce gut dysbiosis
Though UC is a complex disease leading to many perturbations that may affects gut microbiota, the main focus can be put on two pathogenic pathways that influence the bacterial composition: first, morphological changes (tissue impairment), and second, immune dysregulation. Sufficient evidence also found on the on the selection of intestinal flora by dietary habits .
Tissue impairment as a factor of microbiota disbalance
Tremendous quantity of anaerobic bacteria in the distal small intestine and large intestine is a factor that predisposes to an inflammatory response in the case of any epithelial damage. Epithelium defects (spontaneous or post-NSAID) allow bacterial antigens to stimulate immune cells in the mucosa and to induce inflammation, as it was shown on mouse models . In IBD, quantity of mucosal bacteria is increasing, which is correspondent with the finding that many of the UC susceptibility genes are involved in mucosal barrier consistency . DSS-induced colitis in mice is also characterized by overall increase of mucosa-associated bacteria (consistent with the findings in human UC ) and suppression of mucosal Lactobacillus species at the same time , as well as reduced microbial diversity . Another example is an increase in auxotrophic bacteria functions, including a decrease in amino acid biosynthesis, and an increase in amino acid transfer. These bacteria benefit from conditions where nutrients are released during inflamed tissue destruction and are easily accessible in the environment . Furthermore, mucin-degrading bacteria are increased in IBD, for example Ruminococcus gnavus and Ruminococcus torques, which utilize mucin as an energy source and provide degraded mucins as nutrients for other bacteria . However, mucin production in IBD is impaired due to Goblet cell defects. This allows us to propose that failure in immune inhibition of the bacteria, described below, rather than the increased source of digestible endogenous mucin, enhances the presence of mucosa-associated bacteria in IBD.
Immune dysregulation as a factor of microbiota disbalance
Aberrant immune response in UC is of great significance. For example, targeted knockout (KO) of IL-2 and IL-10 in rodents as well as HLA-B27 knockin leads to the development of IBD in the presence of a normal microflora but not in a germ-free animals . Numerous murine strains develop IBD as a result of genetic manipulation or targeted knock out (KO) of genes that affect the mucosal immune system (T-bet, IL-2-KO, IL-2R-KO, IL-10-KO, TCR-KO, TGF-β-KO, SMAD 3-KO, MHC class II, WASP, A20, COX-1 and COX-2) or epithelial function (Gαi2-KO, XBP1) [37–47] which in turn modulate microbiota composition. Overexpression of genes, responsible for immune interaction with microbial antigens (eg, HLA-B27, N-cadherin, CD3e) or deficiency of regulatory cell types (eg, CD4+ CD45RBlo, CD25+ T-cells) that are involved in either lymphoid or epithelial cell homeostasis also leads to IBD-like condition [32, 47–51]. An interesting discover, connecting gut microbiota composition and immune function (T-cell dependent/independent IgA secretion, regulated by ILC-produced lymphotoxins), has been made recently by Nedospasov team .
Gut dysbiosis is a risk factor for the UC: pathogens and commensals
Gut dysbiosis can be directly responsible for initiating or promoting UC. Indirect confirmation of this statement is the fact that broad-spectrum antibiotics have been shown to reduce clinical signs of inflammation in UC [53–55]. At the same time antibiotic exposure during the first year of life has been identified as independent risk factors for IBD [56–58]. Altered microbiota precedes the onset of colitis mouse models . Not to mention, recent studies have confirmed the immunoregulatory role of some gut bacteria, with certain species favoring the growth of protective or inflammatory T-cell subsets, such as Bacteroides fragilis (↑Treg), Clostridia and segmented filamentous bacteria (SFB) (↑Th17) [60–62]. Moreover, pathiological changes of the gut microbiota are associated with certain genotype (NOD2 and ATG18L alleles, which are two major CD susceptibility genes) in humans , which is consistent with the theory that genetic and environmental factors, rather than inflammation, induce dysbiotic changes.
Unfortunately, no research to date has either confirmed or denied the precise role of any particular organisms in IBD. However, several specific bacteria have been identified to be associated with UC. Documented Salmonella or Campylobacter gastroenteritis increased risk of developing IBD compared to a control group during the 15-year follow-up period [64, 65]. This finding is of great significance taking into account the prevalence of Salmonella carriage among asymptomatic children . These bacteria induce inflammation by invading into intestinal epithelium, increasing permeability and causing cell damage and microvillus degradation . It was also observed that Fusobacterium varium invades the inflamed mucosa in UC, inducing corresponding humoral response; its role in colitis induction has been confirmed in animal models [68–70]. In other studies, clostridial-specific T cells are present in mice with experimental colitis, and these T cells induce colitis when adoptively transferred into immunodeficient mice .
Commensal bacteria are thought to be the primary trigger of intestinal inflammation in those who may be susceptible to UC; however, the relationship between UC pathogenesis and commensal bacteria is not completely understood. It is widely accepted that the increased exposure of mucosal T cells to bacteria results in chronic inflammation . “Proinflammatory” bacteria — Campylobacter spp , E. coli [15, 74, 75], Enterohepatic Helicobacter , and Bacteroides ovatus  have been shown to induce the intestinal inflammation. In contrast, “anti-inflammatory” Pediococcus acidilactici and Lactobacillus spp are increased during remission of UC, probably stimulating Tregs and maintaining gut gomeostasis [77, 78]. A recent study reported that mucosal bacteria of UC patients failed to induce colitis in human microbiota‑associated mice but the same bacteria increased the susceptibility to DSS-induced colitis , thus supporting the multifactorial nature of UC. Analogues of SFB were observed to be prevalent in UC patients , in contrast to healthy controls.
A study, in which a single strain of bacteria was transferred into germ-free IL-10-KO mice, demonstrated that E. coli induced mild cecal inflammation and Enterococcus faecalis induced distal colitis . These results show that alteration of the composition of the gut microbiota can cause distinct intestinal immune responses even in a genetically same host. Garrett et al.  reported that immunodeficient mice with both T-bet (Th1 signature transcription factor), and RAG (enzyme essential to the generation of mature B and T lymphocytes) knockout developed spontaneous UC-like colitis. Treatment with the broad spectrum antibiotics combination cured the mice of their colitis, as wells as selective treatment with metronidazole alone. What is more intriguing, co-housing wild-type mice with colitic Tbet/Rag double knockout animals led to development colitis in wild-type mice, raising the possibility that colitic gut microbiota is communicable.
The mechanisms of UC triggering by microbiota involve metabolic alterations. Gut microbiota products control functions of epithelium and energy balance. Analysis of gut microbiota metagenome showed a decrease in genes responsible for carbohydrate and amino acid metabolism and an increase in those in the oxidative stress pathway , suggesting that bacterial oxidative stress causes intestinal inflammation. Also, gut bacteria synthesize short-chain fatty acids (SCFA), such as butyrate and propionate. These SCFAs control the immune system by inducing the differentiation of colonic regulatory T cells [83–87]. Clostridia— and Bacteroides-derived butyrate is used by epithelium as an energy source for the production of mucin and AMPs . Therefore, decreased concentrations of Clostridium groups IV and XIVa  could explain the observed decreased SCFA concentrations in fecal extracts of IBD patients . Inflammatory processes in the intestine are promoted by decline in butyrate production. Consistently, one of the butyrate producers, F. prausnitzii, is decreased in IBD . Overgrowth of sulfate-reducing bacteria (SRB) in UC has also been reported [91, 92]. SRB produce hydrogen sulfide, which blocks butyrate utilization by colonocytes  and can cause mucosal inflammation.
Thus, it seems that dysbalance of the gut commensal composition is involved in the pathophysiology of UC. However, studies in twins show inconsistent results when comparing healthy individuals and individuals with UC [94, 95]. Moreover, a decrease in F. prausnitzii was reported to be observed in both UC patients and their first-grade relatives . Hence, we can’t exactly define the microbial profile associated with UC; the situation gets more complicated because many studies come from animal models – however, most mouse models (currently about 60 different models) of colitis do not fully recapitulate the pathophysiology of human UC . For example, Akkermansia was found to be reduced in abundance in a human UC study , but was increased in the DSS-induced mouse model .
Treatment regimens affect gut microbiota in UC
There are many treatment options for the UC patients with emerging novel therapies such as fecal microbiota transplantation and Microbial Ecosystem Therapeutics. Approved medications for UC management are:
- Topical (suppositories) or oral 5-aminosalicylic Acid Derivatives (5-ASA) (Sulfasalazine, Balsalazide, Mesalazine)
- Topical/oral corticosteroids (Methylprednisolone, Prednisone, Hydrocortisone, Budesonide)
In severe UC:
- Antimicrobials (in severe UC in patients with signs of systemic toxicity) (Ciprofloxacin, Metronidazole)
- TNF inhibitors (Infliximab, Adalimumab, Golimumab)
- Immunosuppressant agents (Azathioprine, Cyclosporine, 6-Mercaptopurine, Tacrolimus)
- Alpha 4 integrin inhibitors (Vedolizumab)
- Antidiarrheal (Diphenoxylate hydrochloride/Atropine Sulfate, Loperamide)
Any medication may affect the composition of gut microbiota. 5-ASA, for example, noticeably reduces the gut bacteria quantity . However, there were no dramatic differences in fecal microbiota pattern between newly diagnosed, untreated patients with IBD and previously reported long-term (treated) patients . Antibiotic treatment in IBD is associated with an increased risk of Clostridium dificille infection (CDI) which has worse outcomes in this patients [102, 103]. On the other hand, a study of patients with IBD found that antibiotics, after cessation of therapy, increase concentration of mucosal bacteria to 25-fold numbers compared to patients without antibiotic treatment .
Anti-TNF therapeutics dampens inflammation in IBD, at least in part, by modulating the gut microbiota toward eubiosis. The microbiome of treated individuals was characterized by reduced Enterobacteriaceae (specifically E. coli) and Ruminococcus, and increased proportions of Bacteroidetes and Firmicutes, restoring the microbiome to a composition more reflective of healthy individuals .
Important application of the microbiome in UC involves the reduction of conventional treatment pressure (especially, antibiotics [106–108]) on microbiota and growth promotion of “anti-inflammatory” bacteria. This approach could be further expanded to the preclinical drug approval process to ensure that our drugs in development have the lowest possible impact on the status of our normal commensals . Not only will this aid in improving the outcomes of individual patients, but will also help with infection control efforts to prevent and/or shorten the duration of resistant bacteria colonization. One of the possibilities in this field is use of combined formulations, containing the conventional drug and prebiotic, as discussed below.
Gut microbiota markers for UC
Several specific bacteria that are associated with UC are described above in the section Gut dysbiosis is a risk factor for the UC. Analytic strategies to identify microbiota relevant to disease risk or disease activity in individual UC patients were described recently . A study of colonic crypt mucus in patients with UC found the positive correlation between crypt bacterial load and subacute disease activity in UC, whereas bacterial load was reduced in acute UC . Kolho et al demonstrated that in children with IBD intensity of intestinal inflammation was positively associated with reduced microbial diversity, abundance of butyrate producers, and relative abundance of Clostridium clusters IV and XIVa . Quantitative variations in different species of Lactobacillus have been found between active UC and remission . A consistent decrease of F. prausnitzii have been demonstrated in UC remission ; most prominent decrease in the concentration of F. prausnitzii was associated with a four-fold increase in the risk of relapse. However, inter-individual variations of microbiota are larger than inter-disease differences [63, 112], which makes the latter difficult to use as a diagnostic or prognostic tool. Moreover, biopsy locations less than 1 cm apart are different in composition of microbiota, thus limiting the diagnostic power of microbiota assessment .
Some attempts have been made to use microbiota as a biomarker. Firmicutes have been reported to be increased in UC patients who responded to mesalazine . During the induction therapy with anti–TNF-α, the microbial diversity and similarity to the microbiota of healthy controls increased in the responder group by week 6 but not in the non-responders . The abundance of 6 groups of bacteria, including those related to Eubacterium rectale and Bifidobacterium spp., predicted the response to anti–TNF-α medication . Firmicutes:Bacteroidetes ratio shift has been proposed as a predictor of clinical outcome in IBD . Microbiota metabolism, namely SCFA levels have been reported to monitor the response to prebiotic treatment .
Targeting microbiota: role of prebiotics
Increasing data on the human microbiota involvement in intestinal inflammation has led to investigation of the potentially therapeutic effect of prebiotics in IBD. Prebiotics are generally regarded as non-digestible food ingredients that are fermented by intestinal bacteria in a selective manner which promote changes in the gut ecosystem that benefit the host . No formal definition of prebiotics is established, though [117, 118]. It is required, however, that to be characterised as a prebiotic, a substance should meet the following criteria: 1. The fermentability should be demonstrated in in vitro tests that simulate, for example, physiological conditions found in the gut. Promising substrates should be evaluated in randomised and placebo-controlled clinical studies, in order to confirm the positive outcomes obtained by in vitro studies; 2. The main trait of a prebiotic is to be a selective substrate for one or more beneficial gut commensal bacteria, which are stimulated to multiply and/or are metabolically activated, beneficially altering the colonic microbiota composition of the host. To confirm the selectivity of a prebiotic, it is of great importance to monitor the changes in the faecal microbiota during supplementation studies with the prebiotic through in vitro and in vivo tests. Moreover, selectivity consists of a key attribute that distinguishes prebiotics from other dietary fibres .
Prebiotics include oligosaccharides, which further divide into fructo-oligosaccharides (FOS) (oligofructose and inulin which have been shown to increase commensal anti-inflammatory faecal and mucosal Bifidobacteria and Faecalibacterium prausnitzii in healthy humans ), galacto-oligosaccharides (lactulose), and gluco- and xylo-oligosaccharides, psyllium (Plantago ovata seeds); and germinated barley foodstuff (GBF). Prebiotic fermentation results in the production of SCFA and gas (CO2 + H2) . The subsequent drop in pH favors an increase in Bifidobacteria, Lactobacilli and non-pathogenic E. coli, while decreasing Bacteroidaceae and inhibition of some strains of pathogenic bacteria, e.g., Clostridium spp . This fermentation of carbohydrates also leads to the production of butyrate acids, which has been proven to exert anti-inflammatory action. One of the proposed mechanisms of beneficial prebiotic action on the mucosa is a decreased activity of the endocannabinoid system (ECS) in the gut and an increased level of glucagon-like peptide-2, which stimulates tight junctions formation .
Only a small number of clinical trials have assessed the use of prebiotics in UC. Despite convincing and reproducible results from animal studies showing multiple benefits in IBD (e.g. [123–126], the data in humans remain scarce and not so encouraging. There is an issue with the dosage regimens of prebiotics. Typical efficacious dose in animal studies is 10% w/w of the diet, which in humans equates to about 50 g/day . Lactulose, for example, provides positive effects starting from 10 g/day, which is considered as a low dose; usual regimens fall into the range of 30-60 g/day, producing laxative effect [127–132] and lowering the dose is considered to avoid this while preserving the beneficial prebiotic properties . In one small non-controlled study, lactulose use provided no clinical or endoscopic improvement in UC . However, UC patients showed an improvement in the quality of life.
The high water-holding capacity of the prebiotic germinated barley foodstuff (GBF) has been found to help modulate stool water content, leading to amelioration of symptoms in IBD . In induction of remission, GBF had a significant decrease in clinical ± endoscopic activity in 3 open-label trials of the same team [134–137]. Kanauchi et al. found that 4 weeks of GBF in UC patients results in both clinical and endoscopic improvement. Exacerbation of disease with completion of GBF suggests that long-term or chronic treatment might be required for this therapy to be permanently effective. With regards to its effect on the human microbiome, GBF administration has led to an increased abundance of luminal Bifidobacterium and Eubacterium, as well as increased butyrate levels, resulting in attenuation of colitis.
In a small RCT (n=19), FOS+inulin vs placebo, added in both groups to mesalamine, had a significant decrease in fecal calprotectin level, but not in disease activity, possibly due to short-term study period of 2 weeks . Another prebiotic, bifidogenic growth stimulator led, in an open-label trial (n=12), to a significant decrease in clinical and endoscopic activity in UC patients .
For maintenance of remission, the largest RCT (n=102) was conducted where prebiotic was found to be non-inferior to mesalamine . GBF added to medication in an open-label trial was significantly superior to medication only in reducing the recurrence rate .
A head-to-head trial comparing the efficacy of probiotic, prebiotic, and synbiotic in UC  showed a superior benefit in quality of life with the use of symbiotic compared to probiotic or prebiotic alone. Another study showed no difference between synbiotic (Bifidobacterium longum+inulin/oligofructose 6 g/d) and placebo in terms of clinical disease activity. However, a significant decrease in colonic endoscopic signs was observed in the synbiotic group compared to placebo. Inflammation markers in the mucosa (TNFα, IL-1, β‐defensins decreased in the group receiving synbiotic .
Two studies have examined the use of pre- and synbotics in pouchitis (a common complication in patients undergoing restorative proctocolectomy for UC). In an open-label study , 10 patients with antibiotic-refractory or antibiotic-dependent pouchitis were treated with combination of Lactobacillus GG and FOS. Complete clinical and endoscopic remission have been achieved one month after the treatment start. In a double-blind crossover trial by Welters et al. , 20 UC and FAP patients with subclinical chronic pouchitis were randomized to receive dietary inulin 24 g/d or placebo for two 3-week study phases interconnected by 4-week washout period. Although patients with pouchitis were not specifically excluded, none of the enrolled patients had overtly clinical pouchitis. No change in clinical activity scores was detected during the inulin period, although there was an endoscopic and histological reversal of mucosal inflammation, reflected by a significant reduction of pouchitis disease activity index. This drives us to the nest section, where combination of known drugs and prebiotics are discussed.
While these findings are overall promising, there is currently no substantial evidence arguing for or against prebiotics in the treatment of IBD, and they continue to be used as a supplement to conventional IBD therapy rather than as a replacement. Furthermore, data on the effect they have on the microflora remain limited.
Possible combinations of prebiotics and traditional anti-colitis drugs
There are anecdotal studies on the use of prebiotics in combination with anti-colitis treatments. Schulz et al  tested the efficacy of a prebiotic/probiotic formulation (Lactobacillus acidophilus, Bifidobacterium lactis + inulin) in combination with metronidazole in rat model of colitis. Probiotic/prebiotic combination alone reduced inflammation while no added benefit has been found in combination with metronidazole. Interestingly, the authors make a note that anti-inflammatory effect has been persuaded by prebiotic.
Clearly, studies on combination of prebiotics and traditional drugs used in UC treatment are lacking. However, we can speculate that possible combinations not investigated yet in treament of UC may include:
- Oral 5-ASA + prebiotic
- Oral antimicrobials + prebiotic
- Oral GCS + prebiotic
One of the studies demonstrated that antibiotics suppress anti-inflammatory effects of lactulose and authors declare that combined antibiotic/lactulose administration is not indicated . However, lactulose still prevented the colon from shortening; furthermore, in a small study combined lactulose+antibiotics dosage forms have proved to be effective in terms of preservation of normal microbiota during antibiotic treatment . Combined formulations of 5-ASA and prebiotics seem to be a reasonable option since concurrent lactulose administration doesn’t seem to affect oral 5-ASA pharmacokinetics despite luminal content acidification . Moreover, lactulose-containing formulations can be used for colon-targeted drug delivery which is crucial in the case of both 5-ASA and topical GCSs . Powder for oral suspension containing drug-loaded microspheres is a convenient formulation, easily transportable and allowing accurate dosage as well as use in persons with swallowing difficulties. Granules also can mask an unpleasant taste, thus increasing compliance.
In conclusion, use of prebiotics is an encouraging treatment modality for UC; design of novel drug formulations, containing both prebiotic and traditional drug is a promising strategy. More well-designed trials are needed to confirm the early results and to accelerate the development of treatment regimens using the prebiotics.
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The authors declare that they have no competing interests.
PN developed and wrote the manuscript.
- Matsuoka K, Kanai T: The gut microbiota and inflammatory bowel disease. Semin Immunopathol 2015, 37:47–55.
- Missaghi B, Barkema H, Madsen K, Ghosh S: Perturbation of the Human Microbiome as a Contributor to Inflammatory Bowel Disease. Pathogens 2014, 3:510–527.
- Schulberg J, De Cruz P: Characterisation and therapeutic manipulation of the gut microbiome in inflammatory bowel disease. Intern Med J 2016, 46:266–273.
- Matsuura T, West G, Youngman K, Klein J, Fiocchi C: Immune activation genes in inflammatory bowel disease. Gastroenterology 1993, 104:448.
- Fiocchi C, Battisto JR, Farmer RG: Studies on isolated gut mucosal lymphocytes in inflammatory bowel disease. Detection of activated T cells and enhanced proliferation to Staphylococcus aureus and lipopolysaccharides. Dig Dis Sci 1981, 26:728–36.
- Dubinsky MC, Ofman JJ, Urman M, Targan SR, Seidman EG: Clinical utility of serodiagnostic testing in suspected pediatric inflammatory bowel disease. Am J Gastroenterol 2001, 96:758–765.
- Duggan a E, Usmani I, Neal KR, Logan RF: Appendicectomy, childhood hygiene, Helicobacter pylori status, and risk of inflammatory bowel disease: a case control study. Gut 1998, 43:494–498.
- Hoffenberg EJ, Fidanza S, Sauaia a: Serologic testing for inflammatory bowel disease. J Pediatr 1999, 134:447–452.
- Kaditis AG, Perrault J, Sandborn WJ, Landers CJ, Zinsmeister AR, Targan SR: Antineutrophil cytoplasmic antibody subtypes in children and adolescents after ileal pouch-anal anastomosis for ulcerative colitis. J Pediatr Gastroenterol Nutr 1998, 26:386–92.
- Peeters M, Joossens S, Vermeire S, Vlietinck R, Bossuyt X, Rutgeerts P: Diagnostic value of anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease. Am J Gastroenterol 2001, 96:730–734.
- Andersson RE, Olaisson G, Tysk C EA: Appendectomy and protection against ulcerative colitis. N Engl J Med 2001, 344:808–814.
- Hallas J, Gaist D, Sørensen HT: Does appendectomy reduce the risk of ulcerative colitis? Epidemiology 2004, 15:173–8.
- Marchesi JR, Adams DH, Fava F, Hermes GD a, Hirschfield GM, Hold G, Quraishi MN, Kinross J, Smidt H, Tuohy KM, Thomas L V, Zoetendal EG, Hart A: The gut microbiota and host health: a new clinical frontier. Gut 2016, 65:330–339.
- Palm NW, De Zoete MR, Cullen TW, Barry NA, Stefanowski J, Hao L, Degnan PH, Hu J, Peter I, Zhang W, Ruggiero E, Cho JH, Goodman AL, Flavell RA: Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 2014, 158:1000–1010.
- Schultsz C, Van den Berg FM, Kate FWT, Tytgat GNJ, Dankert J: The intestinal mucus layer from patients with inflammatory bowel disease harbors high numbers of bacteria compared with controls. Gastroenterology 1999, 117:1089–1097.
- Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening-Baucke V, Ortner M, Weber J, Hoffmann U, Schreiber S, Dietel M, Lochs H: Mucosal flora in inflammatory bowel disease. Gastroenterology 2002, 122:44–54.
- Swidsinski A, Loening-Baucke V, Verstraelen H, Osowska S, Doerffel Y: Biostructure of Fecal Microbiota in Healthy Subjects and Patients With Chronic Idiopathic Diarrhea. Gastroenterology 2008, 135:568–579.
- Nemoto H, Kataoka K, Ishikawa H, Ikata K, Arimochi H, Iwasaki T, Ohnishi Y, Kuwahara T, Yasutomo K: Reduced diversity and imbalance of fecal microbiota in patients with ulcerative colitis. Dig Dis Sci 2012, 57:2955–2964.
- Sokol H, Seksik P, Furet JP, Firmesse O, Nion-Larmurier I, Beaugerie L, Cosnes J, Corthier G, Marteau P, Doraé J: Low counts of faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis 2009, 15:1183–1189.
- Wang W, Chen L, Zhou R, Wang X, Song L, Huang S, Wang G, Xia B: Increased proportions of Bifidobacterium and the Lactobacillus group and loss of butyrate-producing bacteria in inflammatory bowel disease. J Clin Microbiol 2014, 52:398–406.
- Andoh A, Imaeda H, Aomatsu T, Inatomi O, Bamba S, Sasaki M, Saito Y, Tsujikawa T, Fujiyama Y: Comparison of the fecal microbiota profiles between ulcerative colitis and Crohn’s disease using terminal restriction fragment length polymorphism analysis. J Gastroenterol 2011, 46:479–486.
- Duboc H, Rajca S, Rainteau D, Benarous D, Maubert M-A, Quervain E, Thomas G, Barbu V, Humbert L, Despras G, Bridonneau C, Dumetz F, Grill J-P, Masliah J, Beaugerie L, Cosnes J, Chazouillères O, Poupon R, Wolf C, Mallet J-M, Langella P, Trugnan G, Sokol H, Seksik P: Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut 2013, 62:531–9.
- Martinez C, Antolin M, Santos J, Torrejon A, Casellas F, Borruel N, Guarner F, Malagelada JR: Unstable composition of the fecal microbiota in ulcerative colitis during clinical remission. Am J Gastroenterol 2008, 103:643–648.
- Ott SJ, Plamondon S, Hart A, Begun A, Rehman A, Kamm MA, Schreiber S: Dynamics of the mucosa-associated flora in ulcerative colitis patients during remission and clinical relapse. J Clin Microbiol 2008, 46:3510–3513.
- Walker AW, Sanderson JD, Churcher C, Parkes GC, Hudspith BN, Rayment N, Brostoff J, Parkhill J, Dougan G, Petrovska L: High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol 2011, 11:7.
- Zhang M, Liu B, Zhang Y, Wei H, Lei Y, Zhao L: Structural shifts of mucosa-associated lactobacilli and Clostridium leptum subgroup in patients with ulcerative colitis. J Clin Microbiol 2007, 45:496–500.
- Forbes JD, Van Domselaar G, Bernstein CN: Microbiome Survey of the Inflamed and Noninflamed Gut at Different Compartments Within the Gastrointestinal Tract of Inflammatory Bowel Disease Patients. Inflamm Bowel Dis 2016, 22:817–25.
- Lavelle A, Lennon G, O’Sullivan O, Docherty N, Balfe A, Maguire A, Mulcahy HE, Doherty G, O’Donoghue D, Hyland J, Ross RP, Coffey JC, Sheahan K, Cotter PD, Shanahan F, Winter DC, O’Connell PR: Spatial variation of the colonic microbiota in patients with ulcerative colitis and control volunteers. Gut 2015, 64:1553–61.
- Chehoud C, Albenberg LG, Judge C, Hoffmann C, Grunberg S, Bittinger K, Baldassano RN, Lewis JD, Bushman FD, Wu GD: Fungal signature in the gut microbiota of pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2015, 21:1948–1956.
- Norman JM, Handley SA, Baldridge MT, Droit L, Liu CY, Keller BC, Kambal A, Monaco CL, Zhao G, Fleshner P, Stappenbeck TS, McGovern DPB, Keshavarzian A, Mutlu EA, Sauk J, Gevers D, Xavier RJ, Wang D, Parkes M, Virgin HW: Disease-Specific Alterations in the Enteric Virome in Inflammatory Bowel Disease. Cell 2015, 160:447–460.
- Ananthakrishnan AN: Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol 2015, 12:205–217.
- Hermiston ML, Gordon JI: Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science 1995, 270:1203–7.
- Bibiloni R, Mangold M, Madsen KL, Fedorak RN, Tannock GW: The bacteriology of biopsies differs between newly diagnosed, untreated, Crohn’s disease and ulcerative colitis patients. J Med Microbiol 2006, 55:1141–1149.
- Håkansson Å, Tormo-Badia N, Baridi A, Xu J, Molin G, Hagslätt M-L, Karlsson C, Jeppsson B, Cilio CM, Ahrné S: Immunological alteration and changes of gut microbiota after dextran sulfate sodium (DSS) administration in mice. Clin Exp Med 2015, 15:107–120.
- Munyaka PM, Rabbi MF, Khafipour E, Ghia J-E: Acute dextran sulfate sodium (DSS)-induced colitis promotes gut microbial dysbiosis in mice. J Basic Microbiol 2016.
- Png CW, Linden SK, Gilshenan KS, Zoetendal EG, McSweeney CS, Sly LI, McGuckin MA, Florin TH: Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol 2010, 105:2420–2428.
- Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M, Fernández-Sueiro JL, Balish E, Hammer RE: The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 1994, 180:2359–64.
- Garrett WS, Lord GM, Punit S, Lugo-Villarino G, Mazmanian SK, Ito S, Glickman JN, Glimcher LH: Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 2007, 131:33–45.
- Goyette P, Lefebvre C, Ng A, Brant SR, Cho JH, Duerr RH, Silverberg MS, Taylor KD, Latiano A, Aumais G, Deslandres C, Jobin G, Annese V, Daly MJ, Xavier RJ, Rioux JD: Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis. Mucosal Immunol 2008, 1:131–8.
- Kaser A, Lee A-H, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EES, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS: XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 2008, 134:743–56.
- Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W: Interleukin-10-deficient mice develop chronic enterocolitis. Cell 1993, 75:263–74.
- Mombaerts P, Mizoguchi E, Grusby MJ, Glimcher LH, Bhan AK, Tonegawa S: Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell 1993, 75:274–82.
- Morteau O, Morham SG, Sellon R, Dieleman LA, Langenbach R, Smithies O, Sartor RB: Impaired mucosal defense to acute colonic injury in mice lacking cyclooxygenase-1 or cyclooxygenase-2. J Clin Invest 2000, 105:469–78.
- Nguyen DD, Maillard MH, Cotta-de-Almeida V, Mizoguchi E, Klein C, Fuss I, Nagler C, Mizoguchi A, Bhan AK, Snapper SB: Lymphocyte-Dependent and Th2 Cytokine-Associated Colitis in Mice Deficient in Wiskott-Aldrich Syndrome Protein. Gastroenterology 2007, 133:1188–1197.
- Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I: Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 1993, 75:253–261.
- Sartor RB: Microbial Influences in Inflammatory Bowel Diseases. Gastroenterology 2008, 134:577–594.
- Xavier RJ, Podolsky DK: Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007, 448:427–434.
- Holländer GA, Simpson SJ, Mizoguchi E, Nichogiannopoulou A, She J, Gutierrez-Ramos JC, Bhan AK, Burakoff SJ, Wang B, Terhorst C: Severe colitis in mice with aberrant thymic selection. Immunity 1995, 3:27–38.
- Hammer RE, Maika SD, Richardson JA, Tang JP, Taurog JD: Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human β2m: An animal model of HLA-B27-associated human disorders. Cell 1990, 63:1099–1112.
- Morrissey PJ, Charrier K, Braddy S, Liggitt D, Watson JD: CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells. J Exp Med 1993, 178:237–44.
- Powrie F, Leach MW, Mauze S, Caddie LB, Coffman RL: Phenotypically distinct subsets of cd4+t cells induce or protect from chronic intestinal inflammation in c. B-17 scid mice. Int Immunol 1993, 5:1461–1471.
- Kruglov A a, Grivennikov SI, Kuprash D V, Winsauer C, Prepens S, Seleznik GM, Eberl G, Littman DR, Heikenwalder M, Tumanov A V, Nedospasov S a: Nonredundant function of soluble LTα3 produced by innate lymphoid cells in intestinal homeostasis. Science (80- ) 2013, 342:1243–6.
- Khan KJ, Ullman T a, Ford AC, Abreu MT, Abadir A, Marshall JK, Talley NJ, Moayyedi P: Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 2011, 106:661–673.
- Turner D, Levine A, Kolho KL, Shaoul R, Ledder O: Combination of oral antibiotics may be effective in severe pediatric ulcerative colitis: A preliminary report. J Crohn’s Colitis 2014, 8:1464–1470.
- Yang C-Q: Meta-analysis of broad-spectrum antibiotic therapy in patients with active inflammatory bowel disease. Exp Ther Med 2012, 4:1051–1056.
- Hviid A, Svanström H, Frisch M: Antibiotic use and inflammatory bowel diseases in childhood. Gut 2011, 60:49–54.
- Neuman MG, Nanau RM: Inflammatory bowel disease: Role of diet, microbiota, life style. Transl Res 2012, 160:29–44.
- Shaw SY, Blanchard JF, Bernstein CN: Association Between the Use of Antibiotics in the First Year of Life and Pediatric Inflammatory Bowel Disease. Am J Gastroenterol 2010, 105:2687–2692.
- De Cruz P, Prideaux L, Wagner J, Ng SC, McSweeney C, Kirkwood C, Morrison M, Kamm MA: Characterization of the gastrointestinal microbiota in health and inflammatory bowel disease. Inflamm Bowel Dis 2012, 18:372–390.
- Goto Y, Panea C, Nakato G, Cebula A, Lee C, Diez MG, Laufer TM, Ignatowicz L, Ivanov II: Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 2014, 40:594–607.
- Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch S V, Tanoue T, Imaoka A, Itoh K, Takeda K, Umesaki Y, Honda K, Littman DR: Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009, 139:485–98.
- Hooper L V, Littman DR, Macpherson AJ: Interactions between the microbiota and the immune system. Science 2012, 336:1268–73.
- Frank DN, Robertson CE, Hamm CM, Kpadeh Z, Zhang T, Chen H, Zhu W, Sartor RB, Boedeker EC, Harpaz N, Pace NR, Li E: Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases. Inflamm Bowel Dis 2011, 17:179–84.
- Gradel KO, Nielsen HL, Schønheyder HC, Ejlertsen T, Kristensen B, Nielsen H: Increased Short- and Long-Term Risk of Inflammatory Bowel Disease After Salmonella or Campylobacter Gastroenteritis. Gastroenterology 2009, 137:495–501.
- García Rodríguez LA, Ruigómez A, Panés J: Acute gastroenteritis is followed by an increased risk of inflammatory bowel disease. Gastroenterology 2006, 130:1588–94.
- Zaidi MB, Calva JJ, Estrada-Garcia MT, Leon V, Vazquez G, Figueroa G, Lopez E, Contreras J, Abbott J, Zhao S, McDermott P, Tollefson L: Integrated food chain surveillance system for Salmonella spp. in Mexico. Emerg Infect Dis 2008, 14:429–435.
- Serban DE: Microbiota in Inflammatory Bowel Disease Pathogenesis and Therapy: Is It All About Diet? Nutr Clin Pract 2015, 30:760–79.
- Ohkusa T, Okayasu I, Tokoi S, Ozaki Y: Bacterial invasion into the colonic mucosa in ulcerative colitis. J Gastroenterol Hepatol 1993, 8:116–118.
- Ohkusa T, Sato N, Ogihara T, Morita K, Ogawa M, Okayasu I: Fusobacterium varium localized in the colonic mucosa of patients with ulcerative colitis stimulates species-specific antibody. J Gastroenterol Hepatol 2002, 17:849–853.
- Ohkusa T, Okayasu I, Ogihara T, Morita K, Ogawa M, Sato N: Induction of experimental ulcerative colitis by Fusobacterium varium isolated from colonic mucosa of patients with ulcerative colitis. Gut 2003, 52:79–83.
- Lodes MJ, Cong Y, Elson CO, Mohamath R, Landers CJ, Targan SR, Fort M, Hershberg RM: Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest 2004, 113:1296–306.
- Sartor RB, Mazmanian SK: Intestinal Microbes in Inflammatory Bowel Diseases. Am J Gastroenterol Suppl 2012, 1:15–21.
- Mukhopadhya I, Thomson JM, Hansen R, Berry SH, El-Omar EM, Hold GL: Detection of Campylobacter concisus and Other Campylobacter Species in Colonic Biopsies from Adults with Ulcerative Colitis. PLoS One 2011, 6:e21490.
- Kalischuk LD, Inglis GD, Buret AG: Campylobacter jejuni induces transcellular translocation of commensal bacteria via lipid rafts. Gut Pathog 2009, 1:2.
- Lamb-Rosteski JM, Kalischuk LD, Inglis GD, Buret AG: Epidermal growth factor inhibits Campylobacter jejuni-induced claudin-4 disruption, loss of epithelial barrier function, and Escherichia coli translocation. Infect Immun 2008, 76:3390–8.
- Thomson JM, Hansen R, Berry SH, Hope ME, Murray GI, Mukhopadhya I, McLean MH, Shen Z, Fox JG, El-Omar E, Hold GL: Enterohepatic helicobacter in ulcerative colitis: potential pathogenic entities? PLoS One 2011, 6:e17184.
- Bullock NR, Booth JCL, Gibson GR: Comparative composition of bacteria in the human intestinal microflora during remission and active ulcerative colitis. Curr Issues Intest Microbiol 2004, 5:59–64.
- Strober W: Impact of the gut microbiome on mucosal inflammation. Trends Immunol 2013, 34:423–430.
- Du Z, Hudcovic T, Mrazek J, Kozakova H, Srutkova D, Schwarzer M, Tlaskalova-Hogenova H, Kostovcik M, Kverka M: Development of gut inflammation in mice colonized with mucosa-associated bacteria from patients with ulcerative colitis. Gut Pathog 2015, 7:32.
- Caselli M, Tosini D, Gafà R, Gasbarrini A, Lanza G: Segmented filamentous bacteria-like organisms in histological slides of ileo-cecal valves in patients with ulcerative colitis. Am J Gastroenterol 2013, 108:860–1.
- Kim SC, Tonkonogy SL, Albright CA, Tsang J, Balish EJ, Braun J, Huycke MM, Sartor RB: Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology 2005, 128:891–906.
- Morgan XC, Tickle TL, Sokol H, Gevers D, Devaney KL, Ward D V, Reyes JA, Shah SA, LeLeiko N, Snapper SB, Bousvaros A, Korzenik J, Sands BE, Xavier RJ, Huttenhower C: Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 2012, 13:R79.
- Furusawa Y, Obata Y, Fukuda S, Endo T a, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H: Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013, 504:446–50.
- Hartog A, Belle FN, Bastiaans J, De Graaff P, Garssen J, Harthoorn LF, Vos AP: A potential role for regulatory T-cells in the amelioration of DSS induced colitis by dietary non-digestible polysaccharides. J Nutr Biochem 2015, 26:227–233.
- Millard AL, Mertes PM, Ittelet D, Villard F, Jeannesson P, Bernard J: Butyrate affects differentiation, maturation and function of human monocyte-derived dendritic cells and macrophages. Clin Exp Immunol 2002, 130:245–55.
- Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, Glickman JN, Garrett WS: The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013, 341:569–73.
- Vinolo MAR, Rodrigues HG, Nachbar RT, Curi R: Regulation of inflammation by short chain fatty acids. Nutrients 2011, 3:858–876.
- Guzman JR, Conlin VS, Jobin C: Diet, Microbiome, and the Intestinal Epithelium: An Essential Triumvirate? Biomed Res Int 2013, 2013:1–12.
- Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR: Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 2007, 104:13780–5.
- Marchesi JR, Holmes E, Khan F, Kochhar S, Scanlan P, Shanahan F, Wilson ID, Wang Y: Rapid and noninvasive metabonomic characterization of inflammatory bowel disease. J Proteome Res 2007, 6:546–51.
- Pitcher MCL: The contribution of sulphate reducing bacteria and 5-aminosalicylic acid to faecal sulphide in patients with ulcerative colitis. Gut 2000, 46:64–72.
- Smith FM, Coffey JC, Kell MR, O’Sullivan M, Redmond HP, Kirwan WO: A characterization of anaerobic colonization and associated mucosal adaptations in the undiseased ileal pouch. Color Dis 2005, 7:563–570.
- Roediger WE, Duncan A, Kapaniris O, Millard S: Reducing sulfur compounds of the colon impair colonocyte nutrition: implications for ulcerative colitis. Gastroenterology 1993, 104:802–9.
- Lepage P, Häsler R, Spehlmann ME, Rehman A, Zvirbliene A, Begun A, Ott S, Kupcinskas L, Doré J, Raedler A, Schreiber S: Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology 2011, 141:227–36.
- Willing BP, Dicksved J, Halfvarson J, Andersson AF, Lucio M, Zheng Z, Järnerot G, Tysk C, Jansson JK, Engstrand L: A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 2010, 139:1844–1854.e1.
- Varela E, Manichanh C, Gallart M, Torrej??n A, Borruel N, Casellas F, Guarner F, Antolin M: Colonisation by Faecalibacterium prausnitzii and maintenance of clinical remission in patients with ulcerative colitis. Aliment Pharmacol Ther 2013, 38:151–161.
- Nguyen TD, Taffet SM: A model system to study Connexin 43 in the immune system. Mol Immunol 2009, 46:2938–46.
- Vigsnæs LK, Brynskov J, Steenholdt C, Wilcks A, Licht TR: Gram-negative bacteria account for main differences between faecal microbiota from patients with ulcerative colitis and healthy controls. Benef Microbes 2012, 3:287–97.
- Berry D, Schwab C, Milinovich G, Reichert J, Ben Mahfoudh K, Decker T, Engel M, Hai B, Hainzl E, Heider S, Kenner L, Müller M, Rauch I, Strobl B, Wagner M, Schleper C, Urich T, Loy A: Phylotype-level 16S rRNA analysis reveals new bacterial indicators of health state in acute murine colitis. ISME J 2012, 6:2091–106.
- Andrews CN, Griffiths TA, Kaufman J, Vergnolle N, Surette MG, Rioux KP: Mesalazine (5-aminosalicylic acid) alters faecal bacterial profiles, but not mucosal proteolytic activity in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2011, 34:374–383.
- Thorkildsen LT, Nwosu FC, Avershina E, Ricanek P, Perminow G, Brackmann S, Vatn MH, Rudi K: Dominant fecal microbiota in newly diagnosed untreated inflammatory bowel disease patients. Gastroenterol Res Pract 2013, 2013:636785.
- Hashash JG, Binion DG: Managing Clostridium difficile in Inflammatory Bowel Disease (IBD). Curr Gastroenterol Rep 2014, 16:14–19.
- Nitzan O, Elias M, Peretz A, Saliba W: Role of antibiotics for treatment of inflammatory bowel disease. World J Gastroenterol 2016, 22:1078–87.
- Swidsinski A, Loening-Baucke V, Bengmark S, Scholze J, Doerffel Y: Bacterial Biofilm Suppression with Antibiotics for Ulcerative and Indeterminate Colitis: Consequences of Aggressive Treatment. Arch Med Res 2008, 39:198–204.
- Busquets D, Mas-de-Xaxars T, López-Siles M, Martínez-Medina M, Bahí A, Sàbat M, Louvriex R, Miquel-Cusachs JO, Garcia-Gil JL, Aldeguer X: Anti-tumour Necrosis Factor Treatment with Adalimumab Induces Changes in the Microbiota of Crohn’s Disease. J Crohns Colitis 2015, 9:899–906.
- Antonopoulos DA, Huse SM, Morrison HG, Schmidt TM, Sogin ML, Young VB: Reproducible community dynamics of the gastrointestinal microbiota following antibiotic perturbation. Infect Immun 2009, 77:2367–2375.
- Dethlefsen L, Relman DA: Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A 2011, 108 Suppl :4554–4561.
- Tosh PK, McDonald LC: Infection control in the multidrug-resistant era: Tending the human microbiome. Clin Infect Dis 2012, 54:707–713.
- Tong M, Li X, Parfrey LW, Roth B, Ippoliti A, Wei B, Borneman J, McGovern DPB, Frank DN, Li E, Horvath S, Knight R, Braun J: A modular organization of the human intestinal mucosal microbiota and its association with inflammatory bowel disease. PLoS One 2013, 8:1–14.
- Rowan F, Docherty NG, Murphy M, Murphy TB, Coffey JC, O’Connell PR: Bacterial colonization of colonic crypt mucous gel and disease activity in ulcerative colitis. Ann Surg 2010, 252:869–75.
- Kolho K-L, Korpela K, Jaakkola T, Pichai MVA, Zoetendal EG, Salonen A, de Vos WM: Fecal Microbiota in Pediatric Inflammatory Bowel Disease and Its Relation to Inflammation. Am J Gastroenterol 2015, 110:921–30.
- Tyler AD, Kirsch R, Milgrom R, Stempak JM, Kabakchiev B, Silverberg MS: Microbiome Heterogeneity Characterizing Intestinal Tissue and Inflammatory Bowel Disease Phenotype. Inflamm Bowel Dis 2016, 22:807–16.
- Donaldson GP, Lee SM, Mazmanian SK: Gut biogeography of the bacterial microbiota. Nat Rev Microbiol 2015, 14:20–32.
- Castro-Mejiá J, Jakesevic M, Krych Ł, Nielsen DS, Hansen LH, Sondergaard BC, Kvist PH, Hansen AK, Holm TL: Treatment with a Monoclonal Anti-IL-12p40 Antibody Induces Substantial Gut Microbiota Changes in an Experimental Colitis Model. Gastroenterol Res Pract 2016, 2016.
- Zakirova S: Restore and Maintaining of Human Gut Microbiota During the Antibacterial Therapy. Int Sci Conf Probiotics Prebiotics Proc 2015:118–119.
- Gibson GR, Roberfroid MB: Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 1995, 125:1401–1412.
- Derikx LAAP, Dieleman LA, Hoentjen F: Probiotics and prebiotics in ulcerative colitis. Best Pract Res Clin Gastroenterol 2016, 30:55–71.
- Hutkins RW, Krumbeck JA, Bindels LB, Cani PD, Fahey G, Goh YJ, Hamaker B, Martens EC, Mills DA, Rastal RA, Vaughan E, Sanders ME: Prebiotics: why definitions matter. Curr Opin Biotechnol 2016, 37:1–7.
- Martinez RCR, Bedani R, Saad SMI: Scientific evidence for health effects attributed to the consumption of probiotics and prebiotics: an update for current perspectives and future challenges. Br J Nutr 2015:1–23.
- Gibson GR, Beatty ER, Wang X, Cummings JH: Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterology 1995, 108:975–982.
- Damaskos D, Kolios G: Probiotics and prebiotics in inflammatory bowel disease: Microflora “on the scope.” Br J Clin Pharmacol 2008, 65:453–467.
- Muccioli GG, Naslain D, Bäckhed F, Reigstad CS, Lambert DM, Delzenne NM, Cani PD: The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol 2010, 6:392.
- Guarner F: Prebiotics in inflammatory bowel diseases. Br J Nutr 2007, 98 Suppl 1:S85–S89.
- Hoentjen F, Welling GW, Harmsen HJM, Zhang X, Snart J, Tannock GW, Lien K, Churchill T a, Lupicki M, Dieleman L a: Reduction of colitis by prebiotics in HLA-B27 transgenic rats is associated with microflora changes and immunomodulation. Inflamm Bowel Dis 2005, 11:977–985.
- Kleessen B, Hartmann L, Blaut M: Oligofructose and long-chain inulin: influence on the gut microbial ecology of rats associated with a human faecal flora. Br J Nutr 2001, 86:291–300.
- Videla S, Vilaseca J, Antol??n M, Garc??a-Lafuente A, Guarner F, Crespo E, Casalots J, Salas A, Malagelada JR: Dietary inulin improves distal colitis induced by dextran sodium sulfate in the rat. Am J Gastroenterol 2001, 96:1486–1493.
- Bouhnik Y, Attar a, Joly F a, Riottot M, Dyard F, Flourié B: Lactulose ingestion increases faecal bifidobacterial counts: a randomised double-blind study in healthy humans. Eur J Clin Nutr 2004, 58:462–466.
- Clark MJ, Robien K, Slavin JL: Effect of prebiotics on biomarkers of colorectal cancer in humans: A systematic review. Nutr Rev 2012, 70:436–443.
- Foster KJ, Lin S, Turck CJ: Current and Emerging Strategies for Treating Hepatic Encephalopathy. Crit Care Nurs Clin North Am 2010, 22:341–350.
- Panesar PS, Kumari S: Lactulose: Production, purification and potential applications. Biotechnol Adv 2011, 29:940–948.
- Schumann C: Medical, nutritional and technological properties of lactulose. An update. Eur J Nutr 2002, 41(SUPPL. 1):17–25.
- Waghray A, Waghray N, Mullen K: Management of covert hepatic encephalopathy. J Clin Exp Hepatol 2015, 5:S75–S81.
- Hafer A, Krämer S, Duncker S, Krüger M, Manns MP, Bischoff SC: Effect of oral lactulose on clinical and immunohistochemical parameters in patients with inflammatory bowel disease: a pilot study. BMC Gastroenterol 2007, 7:1–11.
- Kanauchi O, Iwanaga T, Mitsuyama K: Germinated Barley Foodstuff Feeding. Digestion 2001, 63(suppl 1):60–67.
- Kanauchi O, Mitsuyama K, Homma T, Takahama K, Fujiyama Y, Andoh A, Araki Y, Suga T, Hibi T, Naganuma M, Asakura H, Nakano H, Shimoyama T, Hida N, Haruma K, Koga H, Sata M, Tomiyasu N, Toyonaga A, Fukuda M, Kojima A, Bamba T, Andow A, Araki Y, Suga T, Hibi T, Naganuma M, Asakura H, Nakano H, Shimoyama T, et al.: Treatment of ulcerative colitis patients by long-term administration of germinated barley foodstuff: Multi-center open trial. Int J Mol Med 2003, 12:701–704.
- Hanai H, Kanauchi O, Mitsuyama K, Andoh A, Takeuchi K, Takayuki I, Araki Y, Fujiyama Y, Toyonaga A, Sata M, Kojima A, Fukuda M, Bamba T: Germinated barley foodstuff prolongs remission in patients with ulcerative colitis. Int J Mol Med 2004, 13:643–647.
- Mitsuyama K, Saiki T, Kanauchi O, Iwanaga T, Tomiyasu N, Nishiyama T, Tateishi H, Shirachi A, Ide M, Suzuki A, Noguchi K, Ikeda H, Toyonaga A, Sata M: Treatment of ulcerative colitis with germinated barley foodstuff feeding: a pilot study. Aliment Pharmacol Ther 1998, 12:1225–30.
- Casellas F, Borruel N, Torrejón A, Varela E, Antolin M, Guarner F, Malagelada JR: Oral oligofructose-enriched inulin supplementation in acute ulcerative colitis is well tolerated and associated with lowered faecal calprotectin. Aliment Pharmacol Ther 2007, 25:1061–1067.
- Suzuki A, Mitsuyama K, Koga H, Tomiyasu N, Masuda J, Takaki K, Tsuruta O, Toyonaga A, Sata M: Bifidogenic growth stimulator for the treatment of active ulcerative colitis: A pilot study. Nutrition 2006, 22:76–81.
- Fernandez-Banares F, Hinojosa J, Sanchcz-Lombrana JL, Navarro E, Martinez-Salmeron JF, Garcia-Pug??s A, Gonzalez-Huix F, Riera J, Gonzalez-Lara V, Dominguez-Abascal F, Gine JJ, Moles J, Gomollon F, Gassull M.d MA: Randomized clinical trial of Plantago ovata seeds (Dietary fiber) as compared with mesalamine in maintaining remission in ulcerative colitis. Am J Gastroenterol 1999, 94:427–433.
- Fujimori S, Gudis K, Mitsui K, Seo T, Yonezawa M, Tanaka S, Tatsuguchi A, Sakamoto C: A randomized controlled trial on the efficacy of synbiotic versus probiotic or prebiotic treatment to improve the quality of life in patients with ulcerative colitis. Nutrition 2009, 25:520–525.
- Furrie E, Macfarlane S, Kennedy A, Cummings JH, Walsh S V, O’neil DA, Macfarlane GT: Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial. Gut 2005, 54:242–9.
- Friedman G, George J: Treatment of refractory “Pouchitis” with prebiotic and probiotic therapy. Gastroenterology 2000, 118:A778.
- C.F. Welters CF, Heineman E, Thunnissen F., van den Bogaard a. E, Soeters PB, Baeten CG: Effect of dietary inulin supplementation on in fl ammation of pouchmucosa in patients with an ileal pouch-anal anastomosis. Dis Colon Rectum 2002, 45:621–627.
- Schultz M, Munro K, Tannock GW, Melchner I, Göttl C, Schwietz H, Schölmerich J, Rath HC: Effects of feeding a probiotic preparation (SIM) containing inulin on the severity of colitis and on the composition of the intestinal microflora in HLA-B27 transgenic rats. Clin Diagn Lab Immunol 2004, 11:581–587.
- Chen X, Zhai X, Shi J, Liu WW, Tao H, Sun X, Kang Z: Lactulose mediates suppression of dextran sodium sulfate-induced colon inflammation by increasing hydrogen production. Dig Dis Sci 2013, 58:1560–1568.
- Hussain FN, Ajjan RA, Moustafa M, Weir NW, Riley SA: Mesalazine release from a pH dependent formulation: Effects of omeprazole and lactulose co-administration. Br J Clin Pharmacol 1998, 46:173–175.
- Katsuma M, Watanabe S, Kawai H, Takemura S, Masuda Y, Fukui M: Studies on lactulose formulations for colon-specific drug delivery. Int J Pharm 2002, 249:33–43.