Engineering the Microbiome: a Novel Approach to Immunotherapy for ...

4 downloads 2427 Views 391KB Size Report
Jul 5, 2015 - Abstract. The incidence of immune disorders is growing parallel with practices associated with westernization, such as dietary changes, ...
Curr Allergy Asthma Rep (2015) 15: 39 DOI 10.1007/s11882-015-0538-9

IMMUNOTHERAPY AND IMMUNOMODULATORS (B VICKERY, SECTION EDITOR)

Engineering the Microbiome: a Novel Approach to Immunotherapy for Allergic and Immune Diseases Nan Shen 1 & Jose C. Clemente 1,2

Published online: 5 July 2015 # Springer Science+Business Media New York 2015

Abstract The incidence of immune disorders is growing parallel with practices associated with westernization, such as dietary changes, increased use of antibiotics, or elevated rates of Cesarean section. These practices can significantly impact the gut microbiota, the collection of bacteria residing in the human gastrointestinal tract, and subsequently disrupt the delicate balance existing between commensal flora and host immune responses. Restoring this balance by modifying the microbiota has thus emerged as a promising therapeutic approach. Here, we discuss the interaction between gut commensals and immunity, along with the potential of different interventions on the microbiota as treatment for inflammatory and allergic diseases. Keywords Microbiome . Allergy . IBD . Antibiotics . Dietary intervention . Fecal transplant

Introduction The prevalent rates of chronic immune and inflammatory disorders, such as food allergies, inflammatory bowel disease (IBD), and asthma, are rapidly increasing worldwide [1, 2]. For instance, peanut allergy in US children has increased from This article is part of the Topical Collection on Immunotherapy and Immunomodulators * Jose C. Clemente [email protected] 1

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

2

Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

0.4 to 1.4 % in merely 10 years [1], with similar observations in other developed countries [3, 4]. The rapid increase in the prevalence of immune disorders cannot be explained by genetic factors alone, suggesting that environmental factors play an important role in the pathogenesis of these conditions. These trends have happened in parallel with the westernization of many countries [5], a process associated with practices that significantly impact the bacterial communities of the host: increased rates of Cesarean section [6], overuse of antibiotics [7], and transition towards protein-rich, high-calorie diets [8]. Changes in gut microbiota due to these practices are thought to be one of the potential mechanisms to explain the dramatic increase in the incidence of IBD [9], food allergies [10•], or asthma [11•]. In the absence of disease or selective pressures, the gut microbiota remains at a dynamic equilibrium through adulthood, which is crucial to human health [12, 13]. The trillions of microbes inhabiting the gastrointestinal (GI) tract serve as an Borgan^ that offers functional traits not encoded in the human genome. Most intestinal bacteria encode a rich collection of catabolic enzymes to ferment complex polysaccharides indigestible for humans, like cellulose and xylans [14]. One of the main outputs of the fermentation of these compounds by the microbiota are short-chain fatty acids (SCFAs), which provide energy to the host and can have anti-carcinogenic and anti-inflammatory properties by modifying the production of cytokines [15] and promoting GI epithelial barrier integrity [16]. Regulation and maintenance of these functions provided by the gut microbiota is critical for the well-being of the host, and their modulation through various types of interventions offers a clear target for the treatment of conditions associated with bacterial imbalances. In this review, we will discuss the mechanisms by which gut bacterial communities are related to inflammatory and immune diseases, and how can we manipulate the microbiota for therapeutic purposes.

39 Page 2 of 10

Curr Allergy Asthma Rep (2015) 15: 39

The Microbiota as an Immune Modulator

The Microbiota in Food Allergies

The microbiota can exert a strong impact on the development of adaptive immunity. The structure and function of the gut microbiota matures by the age of three in all human populations studied to date [17], which coincides with the development of the major components of adaptive immunity [18]. In this period, the gut microbiota plays a crucial role in reprograming the mucosal immune system from neonatal to adult status [19]. During pregnancy, type 2 T helper cells (TH2) response is dominant in the fetus to prevent rejection. However, dominance of TH2 after birth would activate mast cells and increase the risk of allergic diseases [20]. The gut microbiota stimulates the development of a TH1 phenotype and IgA secretion and inhibits IgE synthesis [21, 22], which allows for tolerance to food allergens and reduction of antigen presented to the mucosal immune system [22]. During adulthood, the gut microbiota generates a variety of signals to modulate both innate and adaptive immunity. Generally, microbial-associated molecular patterns continuously stimulate receptors on the epithelial surface, such as NODand Toll-like receptors (TLR), which help to induce the secretion of anti-bacterial peptides to prevent invasion by potential pathogens [23]. Species like Lactobacillus plantarum can also attenuate downstream transduction of TLR4 signaling pathway and induce lipopolysaccharide tolerance [24] (Fig. 1). Butyrate and acetate, two SCFAs generated as part of microbial metabolism in the gut, are critically involved in the maintenance of intestinal barrier integrity [16, 25], which helps to block bacterial antigens from direct contact with epithelial Toll-like receptors and thus prevents the activation of immune responses. Recent studies have also revealed that T cell differentiation and cytokine secretion are mediated by the gut microbiota. For instance, segmented filamentous bacteria (SFB) are responsible for the bacterial ATP-mediated increase of TH17 cell counts and IL-17 production in the colon [26, 27] (Fig. 1). Regulatory T cells (Treg) can be promoted by several bacterial species. Bacteroides fragilis promotes Foxp3+ Treg response through polysaccharide A (PSA)-activated TLR2 signaling pathway [28, 29]. Members of the Clostridium genus provide a TGF-β-rich environment that promotes Foxp3+ Treg cell accumulation [30]. Faecalibacterium prausnitzzii has also been shown to up-regulate interleukin 10(IL-10)-producing Treg cells in the gut [31]. These results strongly suggest that it is therefore possible to modulate intestinal immune status by altering the composition of the gut microbiota. Furthermore, the effects of such modulation might not be limited to the GI tract alone, as demonstrated in a recent study that showed how dendritic cells exposed to gut microbiota metabolites can be recruited to other body sites during inflammation and shape immune responses at the new location [11•].

In IgE-mediated food allergies, immune response is triggered by the binding of allergens to specific IgE on the cell surface of macrophages and mast cells [32]. The immunological environment in IgE-mediated food allergies is dominated by TH2, which recruit inflammatory cells through the secretion of IL-4 and IL-13 [33]. Tregs, on the contrary, are essential in the induction of oral tolerance to food allergens [34]. The correlation between increased antibiotic consumption and prevalence of allergic disease [35] along with the failure to induce immune tolerance in germ-free animal models [36] suggests a role for the gut microbiota in food allergy. In a recent study, a mouse model of food allergies was shown to harbor a specific microbiome that, when reconstituted in WT germ-free animals challenged with a high OVA dose, promoted OVA-specific IgE and induced anaphylaxis [10•]. Intake of probiotics such as Lactobacillus GG has also been shown to increase the levels of C reactive proteins, IL-6, and IFN-ϒ in children allergic to cow milk protein [37, 38], suggesting that there is an allergy-specific microbiota that can be intervened to attenuate allergic symptoms. Non-IgE-mediated food allergies are on the other hand cellmediated reactions in the absence of IgE. Although evidence for the role of the gut microbiota in non-IgE allergies is scarce, it has been observed that the celiac disease patients are enriched in Bacteroides spp. [39] and have lower abundance of Bifidobacterium spp. and Bifidobacterium longum [40, 41]. This trend was not corrected after patients switched to a gluten-free diet [39–41], indicating that there is a bacterial profile characteristic of the disease not due to inflammation alone. The Microbiota in IBD IBD is a set of chronic inflammatory conditions of the gastrointestinal tract arising from inappropriate mucosal immune reaction against components of the gut microbiota [42]. Although genetic factors are involved in the development of IBD, the concordance rates among monozygotic twins suffering the main forms of IBD, Crohn’s disease (CD), and ulcerative colitis (UC) are relative low [43–45]. Furthermore, carrying high-IBD-risk alleles does not necessarily imply the disease will manifest [46], and the incidence and prevalence has increased rapidly over the last 50 years [2]. All these results strongly suggest that environmental factors are critical in the pathogenesis of IBD, with several lines of evidence pointing to a causative role for the microbiota. Inflammatory lesions are distributed mostly in the colon and distal ileum, where there are high concentrations of anaerobic bacteria and bacterial components that can activate intestinal epithelial cells, mucosal macrophages, and T cells and probably cause

Curr Allergy Asthma Rep (2015) 15: 39 Dietary Fibers

Page 3 of 10 39

Polyphenol

Proteins

E. rectale

Fatty Acids Sat Fat

Bifidobacteria

Bile Acids

F. prausnitzii

Taurocholic Acid

Roseburia

Prevotella SCFAs

B. wadsworthia L. plantarum

B. fragilis PSA

GPR43

Energy Supply

TLR4 Signaling

H2S

SFB LPS

Mucus

Mucosal Epithelial Barrier Treg

Antigen presenting cell

IgA B Cell TCDD

Vitamin A

Vitamin D

IEL

Th17

Th2

FICZ AhR Ligands

PC

Fig. 1 Interaction between diet, microbiota, and host immune responses. B. fragilis promotes Foxp3+ Treg cell response via PSA-activated TLR2 signaling pathway. SCFA derived from dietary fiber provide energy to enterocytes and strengthen intestinal barrier. SCFAs also promote the formation of Treg cells through GPR43. L. plantarum attenuates downstream transduction of TLR4 signaling pathway and induces LPS tolerance. SFB mediate the increase of TH17 cells in the colon, mucosal IgA secretion, and IELs recruitment. High protein intake suppresses Roseburia and E. rectale. Proteins and dietary fat induce higher bile acid production, resulting in a strong selective pressure on the intestinal

microbiota. Saturated fats induce an increase in taurocholic acid secretion, promoting the growth of the H2S producer B. wadsworthia. H2S can also impair intestinal epithelial cells. Dietary polyphenols enhance the abundance of Bifidobacterium. Retinoic acid, metabolite of vitamin A, modulates Treg cells and IgA-secreting B cell. Lack of vitamin D leads to decreased CD8αα IELs in the mucosa. The AhR ligand TCDD induces Treg cells. FICZ, another AhR ligand, promotes T H 17 cell differentiation. Lack of PC, a component of biological membranes and mucus layer, causes increased permeability of intestinal barrier and bacterial translocation

local inflammation [47]. IBD is also attenuated or cannot be induced in germ-free animal models [48], although the addition of specific bacteria can induce this phenotype [49–52]. Finally, the microbiota of IBD patients has been found to be significantly distinct to that of healthy controls, both in composition [53, 54], diversity [55], and encoded functions [56].

microbiota by providing an initial source of commensal bacteria to the infant [62, 63]. During the first years of life, the gut microbiota of the infant is quickly shaped into an adult-like configuration [17]. In the absence of disease or specific interventions, the microbiota of an individual reaches a dynamic equilibrium that persists throughout adulthood, with occasional variation involving mostly relative abundance changes [12, 13, 64]. One of the interventions that can modify the gut microbiota most significantly is diet, either by introducing new species or bacterial genes [65] or through the modulation of the abundance of existing microbes in the community [66] (Fig. 1, top). Dietary fat, for example, is positively correlated with the abundance of Bacteroides spp. [66]. Changes in microbiota composition induced by dietary fat can be related to the secretion of bile acids, which exert a strong selective pressure on the intestinal flora [67]. Interestingly, the variation of bile acid composition mediated by different types of fatty acids can lead to different changes in gut microbiota. In mice, saturated fats induce an increase in taurocholic acid secretion, which promotes colonization of Deltaproteobacteria such as Bilophila wadsworthia and that elicits the production of pro-inflammatory cytokines and the development of UC [50]. High dietary protein intake, which is considered a risk factor in

Engineering the Microbiota for Therapeutic Purposes Diet Shapes the Gut Microbiota and Modulates Immunity During infancy, human milk provides various benefits to the newborn that are usually absent in formula. Oligosaccharides, which are enriched in breast milk, favor the colonization of the SCFA-producing bacteria Bifidobacterium spp. [57], while at the same time serve as anti-adhesion agents that prevents pathogen adhesion to host ligands [58]. Lactoferrin, lysozyme, and IgA are anti-bacterial molecules only present in human milk [59], and soluble pathogen receptors such as TLR2 and CD14 can also modulate microbiota structure [60, 61]. Breast milk, meanwhile, plays a critical role in the maturation of the gut

39 Page 4 of 10

IBD [68], is associated with decreased abundance of Roseburia and Eubacterium rectale in overweight subjects following a protein-rich/reduced carbohydrate diet as compared to those on a diet rich in resistant starch [69]. Luminal pH is also a major modulator of the intestinal ecosystem, with the natural pH being approximately seven in the ileum and five in the colon [70]. In an in vitro fermenter system, low percentage G + C gram-positive Firmicutes were found to be dominant when pH was around 5.5, while Bacteroides spp. were more competitive at pH 6.7 [71]. Dietary fibers whose final product is SCFAs are one of the main determinants of luminal pH, and vegans have a significantly lower stool pH and higher prevalence of Enterobacteriaceae compared to omnivores [72]. As carbohydrate suppliers, fermentable polysaccharides can regulate gut microbiota through more than just changes in luminal pH. High fiber diet favors the outgrowth of bacteria capable of fermenting dietary fibers, such as Bifidobacterium and Lactobacillus, followed by increase of serum SCFA level and inhibition of TH2 differentiation [11•, 73]. Dietary fiber-derived SCFAs serve as important immune regulators. Butyrate provides energy to enterocytes and strengthens intestinal barrier, limiting the exposure of mucosal immune system to luminal bacteria [16]. Butyrate also promotes the formation of Treg cells by elevating the expression of Treg-specific forkhead transcription factor FoxP3 [74]. Acetate, another SCFA, can prevent Escherichia coli infection by maintaining gut barrier function [75]. G protein-coupled receptor 43 (GPR43), a SCFA receptor, has also been shown to mediate inflammatory responses, and deficiency of GPR43 leads to colitis, arthritis, and asthma in murine models [76]. It has been reported that SCFAs generated in the gut induced a systemic response and repressed inflammation in the lung, suggesting that dietary interventions targeting the microbiome can have anti-inflammatory properties not only in the gut but also at distal sites [11•]. It is important to notice that diet can also modulate immunity through mechanisms not mediated by changes in gut microbiota composition. The initial introduction route and dosage of antigens can have a strong influence on the development of allergies [32]. Breast milk, for instance, carries allergens that can mediate immune tolerance to these molecules and prevent food allergy [77] and asthma [78]. After weaning, various food components are also involved in immune modulation (Fig. 1, bottom). Retinoic acid, a metabolite of vitamin A, modulates regulatory T cell differentiation and IgA-secreting B cells and promotes lymph cells gut homing receptors α4β7 and CCR9 [79–82]. Vitamin D can also play a role in T and C cell homing and inhibits TH17 cells in vivo [83], and lack of vitamin D leads to decrease in CD8αα-positive regulatory intraepithelial lymphocytes (IELs) in the mucosa [84]. Cruciferous vegetables such as broccoli, cabbage, or Brussels sprouts are rich in ligands of the aryl hydrocarbon receptor (AhR), which is critical in postnatal development of RORϒt+innate lymphoid cells and formation of intestinal lymphoid follicles [85]. Deficiency of

Curr Allergy Asthma Rep (2015) 15: 39

AhR results in loss of ϒδ IELs [86], CD8αα IELs, and lymphoid tissue inducer cells in the gut [87], subsequently increasing the risk of experimental colitis [87]. AhR also modulates mucosal adaptive immunity: while the AhR ligand 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD) induces Treg cells and suppresses experimental autoimmune encephalomyelitis (EAE), the ligand 6-formylindolo(3,2-b)carbazole (FICZ) promotes TH17 cell differentiation and exasperates EAE [88]. Western Diet Alters Gut Microbiota: Implications for Immune and Allergic Disorders Over the last few decades, the dietary composition and total calorie intake in most Western countries has changed dramatically. Based on the data from US National Health and Nutrition Examination Survey, the adult total calorie intake has increased 6.9 % in men and 21.7 % in women from 1970 to 2000 [89]. Cane and beet sugar, plant-derived unsaturated fat, dietary fibers, and resistant starches have been replaced by corn-derived sweeteners, animal-based saturated fats, and simple sugars. This has resulted in major alterations to our microbiota that could account for the extremely quick rise of allergic and immune disease incidence in developed countries. Comparison of the microbiome of African and South American native populations with that of US subjects has revealed significant reduction of diversity, major alterations of composition (particularly in the decrease of SCFA-producing bacteria), and drastic shifts from herbivore-like functional profiles (characterized by an enrichment in amino acid biosynthesis and degradation of complex polysaccharides) to a carnivore-like profile (enriched in amino acid degradation and catabolism of simple sugars) [17, 90, 91]. Burkina Faso children exhibit a significant enrichment in Bacteroidetes and a lower abundance of Firmicutes than Italian children, as well as higher levels of SCFA [92]. Higher ingestion of dietary fat can also increase intestinal epithelial permeability and increase levels of serum lipopolysaccharides and mucosal inflammatory markers [93]. Although the mechanisms by which changes in the microbiome can promote the pathogenesis of immune and allergic conditions are still being elucidated, comparative studies of the microbiome of different populations have the potential to uncover bacterial biomarkers with beneficial or deleterious effects in the host and are therefore critical to guide the design of targeted therapeutic interventions. Diet as a Microbiome-Mediated Therapeutic Tool Interventions that manipulate nutritional intake to modulate immune responses are a promising therapeutic approach given their low risk profile. Perhaps one of the conditions in which dietary interventions have been most comprehensively studied is IBD. Low sulfur diet limits the production of H2S, which impairs the utilization of butyrate by colonocytes and can increase epithelial permeability, and has been shown to be

Curr Allergy Asthma Rep (2015) 15: 39

associated with a decrease in the likelihood of relapse in UC patients [94]. Specific carbohydrate diet contains mostly complex carbohydrates and eliminates simple sugars, and has been shown to be beneficial in pediatric CD [95, 96]. Exclusive enteral nutrition (EEN) is a dietary therapy that uses exclusive liquid feeding with either elemental or polymeric formulae for a period of 6–8 weeks, during which patients cannot ingest solid foods. EEN has been successful in achieving remission of CD in children [97, 98]. In adults, poor compliance due to unpalatability reduces the efficacy of this intervention, although there is evidence that EEN can be effective in newly diagnosed patients that can adhere to the regimen [99]. EEN improves mucosal healing [100] and significantly reduces levels of proinflammatory acetic acid, while increasing the concentration of the anti-inflammatory butyric acid [101]. It should however be noted that a significant reduction of the protective bacteria Faecalibacterium prausnitzii has also been observed [102], suggesting that alternative mechanisms could be responsible for the beneficial effects of EEN in CD. Diet can also help in the management and treatment of asthma through changes in gut microbiota composition. Ingestion of dietary fibers attenuates airway allergic inflammation through the production of SCFAs, which modulate T cell differentiation [11•]. Low-energy diet has also been shown to improve asthma-related quality of life in obese patients [103]. Calorie restriction actually repressed chronic inflammation though activation of NFκB transcription factor, which regulates gene expression of several pro-inflammatory factors [104]. In food allergies, long-chain polyunsaturated fatty acids (LCPUFAs) and Chinese herb formula (FAHF-2) have been shown to be effective in inhibiting allergic symptoms. LCPUFA-rich fish oil is able to enhance intestinal and systemic Treg cells and reduce allergic symptoms in murine models allergic to whey or peanuts [105–107]. The beneficial effects of n-3 PUFAs in food allergies are probably related to the enrichment of commensal bacteria, like Lactobacillus and Bifidobacteria, and the reduction of immune cell infiltration in responsive to n-3 PUFA supplement [108]. FAHF-2 is a traditional Chinese herb formula containing three alkaloids: berberine, palmatine, and jatrorrhizine. These alkaloids are able to inhibit IgE production in B cells [109], an effect that could be partially mediated by changes in microbiome composition. Berberine, for instance, has been previously shown to suppress a large number of intestinal bacteria, while at the same time selectively enriching for SCFA producers such as Blautia and Allobaculum in a high-fat diet murine model [110]. FAHF-2 has been proved effective in improving allergy against fish, egg, and peanuts and is currently under clinical trial [111]. The capacity to treat allergic and immune conditions through dietary-mediated changes in the microbiota without the side effects of more aggressive therapies has so far spurred great interest. Dietary interventions can rapidly modify the composition of the gut microbiota, although most human

Page 5 of 10 39

studies so far have been short term and shown a quick regression to baseline composition after cessation of the intervention [66, 112]. Long-term dietary studies that can induce stable changes in the microbiota and demonstrate clinical remission are therefore needed [113]. Antibiotic Therapy Antibiotics can drastically affect bacterial composition and functional capacity [114]. Their potential to reshape the gut microbiota has been often utilized in the treatment of IBD. In mild to moderately acute CD, ciprofloxacin has been shown to be comparable to mesalazine, a traditional steroid regime [115]. An anti-mycobacterial recipe consisting of clarithromycin, rifabutin, and clofazimine was effective in initiating remission of active CD, although it failed to maintain a long-term effect [116]. Rifaximin with extended intestinal release not only induced remission but also had less adverse effects than other antibiotics [117]. Several other antibiotics have however been tested without significant improvement in remission rates over placebo [118–121], although in patients with confined disease location, the efficacy was higher [120, 121]. Results from studies on the efficacy of antibiotic therapy in UC have also been mixed. A triple antibiotic regimen combining metronidazole, amoxicillin, and tetracycline was proved effective in patients with chronic, active UC with Fusobacterim varium infection [122]. Ciprofloxacin has been shown to be effective for a subset of UC patients insensitive to steroids and mesalamine [123–125], while vancomycin [126], a mixture of metronidazole and tobramycin [127], and a combination of rifaximin and ciprofloxacin [128] all failed to demonstrate efficacy in different trials. The varying degrees of success of antibiotic treatments in IBD can be due to various factors such as disease severity, differences in dosage, delivery method, or study duration. We hypothesize that the efficacy of antibiotics can also be different among individuals due to per-subject differences in response to treatment, as it has been observed with ciprofloxacin in a small group of healthy subjects [129]. Although adverse effects and concerns on drug resistance limit their general applicability, studies addressing personalized treatment will shed further light upon how to best reshape the gut microbiota using antibiotics to treat inflammatory and allergic conditions. Restoring Gut Ecology Through Fecal Microbiota Transplantation Fecal microbiota transplantation (FMT), the infusion of gut microbiota from a healthy donor into the intestine of a recipient, has received widespread attention recently due to its extremely high efficacy in the treatment of refractory Clostridium difficile infection (CDI) [130, 131]. Different infusion methods exist [132], and more recently, a frozen capsulized FMT approach

39 Page 6 of 10

Curr Allergy Asthma Rep (2015) 15: 39

has also been proposed [133•]. The application of FMT in conditions other than CDI has thus gained interest, and particularly so in the treatment of IBD [134]. A recent review summarizing 31 reports involving 113 patients with either UC or CD showed that 71 % IBD patients achieved resolution or reduction of symptoms after FMT, with no differences observed among UC and CD [135]. The comorbidity of IBD with CDI however decreases the efficacy of this procedure in treating CDI [135]. Longitudinal studies after FMT suggest that the microbiota of the recipient initially resembles that of the donor [136], although this effect might be transitory [113]. Anecdotal evidence exists for the potential of FMT in the treatment of other conditions, such as in three patients with multiple sclerosis or a case with idiopathic thrombocytopenic purpura [137]. Further studies will be required to determine whether multiple FMT infusions are efficient for patients with severe or chronic diseases, if particular donors can achieve higher remission rates among all recipients, and whether other allergic and immune disease can equally benefit from this promising approach.

References Papers of particular interest, published recently, have been highlighted as: • Of importance

1.

2.

3.

4.

5. 6.

Conclusion The microbiota is an effective modulator of host immune responses that can be targeted for therapeutic purposes. Antibiotics, dietary interventions, or fecal microbiota transplantation have been explored as tools to reshape the gut bacterial communities and to treat allergic and immune conditions. Antibiotics have had relative success in IBD, although the side effects associated with long-term usage limit their usefulness. Diet is an attractive alternative due to its near absence of side effects. Adherence in prolonged interventions, which might be necessary for chronic conditions, might however reduce the effectiveness of this approach. The extreme efficacy of fecal transplant in treating CDI has left us with a lack of understanding mechanisms of action, which will be critical to improve the success rate of FMT in treating other conditions such as IBD. Advancing our understanding of the structure, function, and dynamics of the gut microbial ecosystem will facilitate the development of personalized combination therapies that can suppress pro-inflammatory responses in a sustained manner for immune disorders.

7.

8.

9.

10.•

11.•

12. Acknowledgments SUCCESS.

JCC was partially supported by funding from 13.

Compliance with Ethics Guidelines 14. Conflict of Interest Nan Shen and Jose C. Clemente declare that they have no conflicts of interest. 15. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

16.

Sicherer SH, Munoz-Furlong A, Godbold JH, Sampson HA. US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up. J Allergy Clin Immunol. 2010;125:1322–6. doi:10.1016/j.jaci.2010.03.029. Molodecky NA et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46–54. doi:10.1053/j.gastro. 2011.10.001. e42; quiz e30. Grundy J, Matthews S, Bateman B, Dean T, Arshad SH. Rising prevalence of allergy to peanut in children: data from 2 sequential cohorts. J Allergy Clin Immunol. 2002;110:784–9. Mullins RJ, Dear KB, Tang ML. Characteristics of childhood peanut allergy in the Australian Capital Territory, 1995 to 2007. J Allergy Clin Immunol. 2009;123:689–93. doi:10.1016/j.jaci. 2008.12.1116. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med. 2006;355:2226–35. doi:10.1056/NEJMra054308. Dominguez-Bello MG et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010;107:11971–5. doi: 10.1073/pnas.1002601107. Cox LM et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. 2014;158:705–21. doi:10.1016/j.cell.2014.05.052. Thorburn AN, Macia L, Mackay CR. Diet, metabolites, and Bwestern-lifestyle^ inflammatory diseases. Immunity. 2014;40: 833–42. doi:10.1016/j.immuni.2014.05.014. Garrett WS et al. Communicable ulcerative colitis induced by Tbet deficiency in the innate immune system. Cell. 2007;131:33– 45. doi:10.1016/j.cell.2007.08.017. Noval Rivas M et al. A microbiota signature associated with experimental food allergy promotes allergic sensitization and anaphylaxis. J Allergy Clin Immunol. 2013;131:201–12. doi:10. 1016/j.jaci.2012.10.026. This article demonstrates the existence of transmissible allergy-prone microbiota, linking gut microbiota to food allergy directly for the first time. Trompette A et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med. 2014;20:159–66. doi:10.1038/nm.3444. This study shows evidence at the cellular level of an association between gut microbiota and bone marrow hemapoiesis, suggesting the microbiota can be a target for immune disorders at some sites other than in the GI tract. Rajilic-Stojanovic M, Heilig HG, Tims S, Zoetendal EG, de Vos WM. Long-term monitoring of the human intestinal microbiota composition. Environ Microbiol. 2012. doi:10.1111/1462-2920. 12023. Faith JJ et al. The long-term stability of the human gut microbiota. Science. 2013;341:1237439. doi:10.1126/science.1237439. Koropatkin NM, Cameron EA, Martens EC. How glycan metabolism shapes the human gut microbiota. Nat Rev Microbiol. 2012;10:323–35. doi:10.1038/nrmicro2746. Bird JJ et al. Helper T cell differentiation is controlled by the cell cycle. Immunity. 1998;9:229–37. Peng L, He Z, Chen W, Holzman IR, Lin J. Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of

Curr Allergy Asthma Rep (2015) 15: 39

17. 18.

19. 20.

21.

22.

23.

24.

25.

26. 27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

intestinal barrier. Pediatr Res. 2007;61:37–41. doi:10.1203/01.pdr. 0000250014.92242.f3. Yatsunenko T et al. Human gut microbiome viewed across age and geography. Nature. 2012;486:222–7. doi:10.1038/nature11053. Martin R et al. Early life: gut microbiota and immune development in infancy. Benefic Microbes. 2010;1:367–82. doi:10.3920/ BM2010.0027. Ouwehand AC. Antiallergic effects of probiotics. J Nutr. 2007;137:794S–7. Debock I, Flamand V. Unbalanced neonatal CD4(+) T-cell immunity. Front Immunol. 2014;5:393. doi:10.3389/fimmu.2014. 00393. von der Weid T, Bulliard C, Schiffrin EJ. Induction by a lactic acid bacterium of a population of CD4(+) T cells with low proliferative capacity that produce transforming growth factor beta and interleukin-10. Clin Diagn Lab Immunol. 2001;8:695–701. doi:10. 1128/CDLI.8.4.695-701.2001. Kirjavainen PV, Gibson GR. Healthy gut microflora and allergy: factors influencing development of the microbiota. Ann Med. 1999;31:288–92. Artis D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol. 2008;8:411–20. doi:10.1038/nri2316. Kim HG et al. Lactobacillus plantarum lipoteichoic acid downregulated Shigella flexneri peptidoglycan-induced inflammation. Mol Immunol. 2011;48:382–91. doi:10.1016/j.molimm.2010.07. 011. Fukuda S, Toh H, Taylor TD, Ohno H, Hattori M. Acetateproducing bifidobacteria protect the host from enteropathogenic infection via carbohydrate transporters. Gut Microbes. 2012;3: 449–54. doi:10.4161/gmic.21214. Esplugues E et al. Control of TH17 cells occurs in the small intestine. Nature. 2011;475:514–8. doi:10.1038/nature10228. Ivanov II et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139:485–98. doi:10.1016/j.cell. 2009.09.033. Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell. 2005;122:107–18. doi:10.1016/ j.cell.2005.05.007. Round JL et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011;332:974–7. doi:10.1126/science.1206095. Atarashi K et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331:337–41. doi:10. 1126/science.1198469. Sokol H et al. Faecalibacterium prausnitzii is an antiinflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105:16731–6. doi:10.1073/pnas. 0804812105. Wang J. Food allergy: recent advances in pathophysiology and treatment. Allergy Asthma Immunol Res. 2009;1:19–29. doi:10. 4168/aair.2009.1.1.19. Kunisawa J, Kiyono H. Aberrant interaction of the gut immune system with environmental factors in the development of food allergies. Curr Allergy Asthma Rep. 2010;10:215–21. doi:10. 1007/s11882-010-0097-z. Berin MC, Mayer L. Can we produce true tolerance in patients with food allergy? J Allergy Clin Immunol. 2013;131:14–22. doi: 10.1016/j.jaci.2012.10.058. Noverr MC, Huffnagle GB. The ‘microflora hypothesis’ of allergic diseases. Clin Exp Allergy : J Br Soc Allergy Clin Immunol. 2005;35:1511–20. doi:10.1111/j.1365-2222.2005.02379.x. Penders J, Stobberingh EE, van den Brandt PA, Thijs C. The role of the intestinal microbiota in the development of atopic

Page 7 of 10 39 disorders. Allergy. 2007;62:1223–36. doi:10.1111/j.13989995.2007.01462.x. 37. Viljanen M et al. Probiotics in the treatment of atopic eczema/ dermatitis syndrome in infants: a double-blind placebo-controlled trial. Allergy. 2005;60:494–500. doi:10.1111/j.1398-9995.2004. 00514.x. 38. Pohjavuori E et al. Lactobacillus GG effect in increasing IFNgamma production in infants with cow’s milk allergy. J Allergy Clin Immunol. 2004;114:131–6. doi:10.1016/j.jaci.2004.03.036. 39. Sanchez E, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y. Intestinal Bacteroides species associated with coeliac disease. J Clin Pathol. 2010;63:1105–11. doi:10.1136/jcp.2010.076950. 40. Collado MC, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y. Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease. J Clin Pathol. 2009;62:264–9. doi:10.1136/ jcp.2008.061366. 41. Collado MC, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y. Imbalances in faecal and duodenal Bifidobacterium species composition in active and non-active coeliac disease. BMC Microbiol. 2008;8:232. doi:10.1186/1471-2180-8-232. 42. Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006;3:390–407. doi:10.1038/ncpgasthep0528. 43. Spehlmann ME et al. Epidemiology of inflammatory bowel disease in a German twin cohort: results of a nationwide study. Inflamm Bowel Dis. 2008;14:968–76. doi:10.1002/ibd.20380. 44. Orholm M, Binder V, Sorensen TI, Rasmussen LP, Kyvik KO. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol. 2000;35: 1075–81. 45. Halfvarson J, Bodin L, Tysk C, Lindberg E, Jarnerot G. Inflammatory bowel disease in a Swedish twin cohort: a longterm follow-up of concordance and clinical characteristics. Gastroenterology. 2003;124:1767–73. 46. Prescott NJ et al. A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn’s disease and is independent of CARD15 and IBD5. Gastroenterology. 2007;132:1665–71. doi:10.1053/j. gastro.2007.03.034. 47. Sartor RB. Current concepts of the etiology and pathogenesis of ulcerative colitis and Crohn’s disease. Gastroenterol Clin N Am. 1995;24:475–507. 48. Sellon RK et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect Immun. 1998;66:5224–31. 49. Kullberg MC et al. Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12- and gamma interferon-dependent mechanism. Infect Immun. 1998;66:5157–66. 50. Devkota S et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature. 2012;487:104–8. doi:10.1038/nature11225. 51. Balish E, Warner T. Enterococcus faecalis induces inflammatory bowel disease in interleukin-10 knockout mice. Am J Pathol. 2002;160:2253–7. doi:10.1016/S0002-9440(10)61172-8. 52. Kim SC et al. Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology. 2005;128:891–906. 53. Machiels K et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut. 2014;63:1275– 83. doi:10.1136/gutjnl-2013-304833. 54. Gevers D et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe. 2014;15:382–92. doi:10. 1016/j.chom.2014.02.005. 55. Tong M et al. A modular organization of the human intestinal mucosal microbiota and its association with inflammatory bowel

39 Page 8 of 10 disease. PLoS One. 2013;8, e80702. doi:10.1371/journal.pone. 0080702. 56. Morgan XC et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 2012;13:R79. doi:10.1186/gb-2012-13-9-r79. 57. Turroni F et al. Diversity of bifidobacteria within the infant gut microbiota. PLoS One. 2012;7, e36957. doi:10.1371/journal. pone.0036957. 58. Le Pendu J. Histo-blood group antigen and human milk oligosaccharides: genetic polymorphism and risk of infectious diseases. Adv Exp Med Biol. 2004;554:135–43. 59. Verhasselt V. Neonatal tolerance under breastfeeding influence. Curr Opin Immunol. 2010;22:623–30. doi:10.1016/j.coi.2010. 08.008. 60. Labeta MO et al. Innate recognition of bacteria in human milk is mediated by a milk-derived highly expressed pattern recognition receptor, soluble CD14. J Exp Med. 2000;191: 1807–12. 61. LeBouder E et al. Soluble forms of Toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk. J Immunol. 2003;171:6680–9. 62. Martin R et al. Cultivation-independent assessment of the bacterial diversity of breast milk among healthy women. Res Microbiol. 2007;158:31–7. doi:10.1016/j.resmic.2006.11.004. 63. Adlerberth I, Wold AE. Establishment of the gut microbiota in Western infants. Acta Paediatr. 2009;98:229–38. doi:10.1111/j. 1651-2227.2008.01060.x. 64. Jalanka-Tuovinen J et al. Intestinal microbiota in healthy adults: temporal analysis reveals individual and common core and relation to intestinal symptoms. PLoS One. 2011;6, e23035. doi:10. 1371/journal.pone.0023035. 65. Hehemann JH et al. Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota. Nature. 2010;464: 908–12. doi:10.1038/nature08937. 66. Wu GD et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334:105–8. doi:10.1126/science. 1208344. 67. Begley M, Gahan CG, Hill C. The interaction between bacteria and bile. FEMS Microbiol Rev. 2005;29:625–51. doi:10.1016/j. femsre.2004.09.003. 68. Jantchou P, Morois S, Clavel-Chapelon F, Boutron-Ruault MC, Carbonnel F. Animal protein intake and risk of inflammatory bowel disease: the E3N prospective study. Am J Gastroenterol. 2010;105:2195–201. doi:10.1038/ajg.2010.192. 69. Walker AW et al. Dominant and diet-responsive groups of bacteria within the human colonic microbiota. ISME J. 2011;5:220–30. doi:10.1038/ismej.2010.118. 70. Fallingborg J. Intraluminal pH of the human gastrointestinal tract. Dan Med Bull. 1999;46:183–96. 71. Duncan SH, Louis P, Thomson JM, Flint HJ. The role of pH in determining the species composition of the human colonic microbiota. Environ Microbiol. 2009;11:2112–22. doi:10.1111/j.14622920.2009.01931.x. 72. Zimmer J et al. A vegan or vegetarian diet substantially alters the human colonic faecal microbiota. Eur J Clin Nutr. 2012;66:53–60. doi:10.1038/ejcn.2011.141. 73. Watson D et al. Selective carbohydrate utilization by lactobacilli and bifidobacteria. J Appl Microbiol. 2013;114:1132–46. doi:10. 1111/jam.12105. 74. Furusawa Y et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504: 446–50. doi:10.1038/nature12721. 75. Fukuda S et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature. 2011;469:543–7. doi:10.1038/nature09646.

Curr Allergy Asthma Rep (2015) 15: 39 76.

Maslowski KM et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461:1282–6. doi:10.1038/nature08530. 77. Palmer DJ, Makrides M. Diet of lactating women and allergic reactions in their infants. Curr Opin Clin Nutr Metab Care. 2006;9:284–8. doi:10.1097/01.mco.0000222113.46042.50. 78. Verhasselt V et al. Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma. Nat Med. 2008;14:170–5. doi:10.1038/nm1718. 79. Coombes JL et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGFbeta and retinoic acid-dependent mechanism. J Exp Med. 2007;204:1757–64. doi:10.1084/jem.20070590. 80. Mora JR et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science. 2006;314:1157–60. doi:10. 1126/science.1132742. 81. Mucida D et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007;317:256–60. doi: 10.1126/science.1145697. 82. Iwata M et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity. 2004;21:527–38. doi:10.1016/j.immuni.2004.08. 011. 83. Chang JH, Cha HR, Lee DS, Seo KY, Kweon MN. 1,25Dihydroxyvitamin D3 inhibits the differentiation and migration of T(H)17 cells to protect against experimental autoimmune encephalomyelitis. PLoS One. 2010;5, e12925. doi:10.1371/journal. pone.0012925. 84. Bruce D, Cantorna MT. Intrinsic requirement for the vitamin D receptor in the development of CD8alphaalpha-expressing T cells. J Immunol. 2011;186:2819–25. doi:10.4049/jimmunol.1003444. 85. Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol. 2011;12:383–90. doi:10.1038/ni.2025. 86. Li Y et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell. 2011;147:629–40. doi:10.1016/j.cell.2011.09.025. 87. Kiss EA et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science. 2011;334: 1561–5. doi:10.1126/science.1214914. 88. Schulz VJ et al. Activation of the aryl hydrocarbon receptor suppresses sensitization in a mouse peanut allergy model. Toxicol Sci : Off J Soc Toxicol. 2011;123:491–500. doi:10.1093/toxsci/ kfr175. 89. Wright JD, Wang CY. Trends in intake of energy and macronutrients in adults from 1999-2000 through 2007–2008. NCHS Data Brief 2010; 1–8. 90. Clemente JC, et al. The microbiome of uncontacted Amerindians. Sci Adv. 2015. 91. Muegge BD et al. Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science. 2011;332:970–4. doi:10.1126/science.1198719. 92. De Filippo C et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A. 2010;107:14691–6. doi:10. 1073/pnas.1005963107. 93. de La Serre CB et al. Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am J Physiol Gastrointest Liver Physiol. 2010;299: G440–8. doi:10.1152/ajpgi.00098.2010. 94. Jowett SL et al. Influence of dietary factors on the clinical course of ulcerative colitis: a prospective cohort study. Gut. 2004;53: 1479–84. doi:10.1136/gut.2003.024828. 95. Cohen SA et al. Clinical and mucosal improvement with specific carbohydrate diet in pediatric Crohn disease. J Pediatr Gastroenterol Nutr. 2014;59:516–21. doi:10.1097/MPG. 0000000000000449.

Curr Allergy Asthma Rep (2015) 15: 39 96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

Suskind DL, Wahbeh G, Gregory N, Vendettuoli H, Christie D. Nutritional therapy in pediatric Crohn disease: the specific carbohydrate diet. J Pediatr Gastroenterol Nutr. 2014;58:87–91. doi:10. 1097/MPG.0000000000000103. Day AS et al. Exclusive enteral feeding as primary therapy for Crohn’s disease in Australian children and adolescents: a feasible and effective approach. J Gastroenterol Hepatol. 2006;21:1609– 14. doi:10.1111/j.1440-1746.2006.04294.x. Day AS, Burgess L. Exclusive enteral nutrition and induction of remission of active Crohn’s disease in children. Expert Rev Clin Immunol. 2013;9:375–83. doi:10.1586/eci.13.12. quiz 384. Wall CL, Day AS, Gearry RB. Use of exclusive enteral nutrition in adults with Crohn’s disease: a review. World J Gastroenterol: WJG. 2013;19:7652–60. doi:10.3748/wjg.v19.i43.7652. Heuschkel RB, Menache CC, Megerian JT, Baird AE. Enteral nutrition and corticosteroids in the treatment of acute Crohn’s disease in children. J Pediatr Gastroenterol Nutr. 2000;31:8–15. Tjellstrom B et al. Effect of exclusive enteral nutrition on gut microflora function in children with Crohn’s disease. Scand J Gastroenterol. 2012;47:1454–9. doi:10.3109/00365521.2012. 703234. Gerasimidis K et al. Decline in presumptively protective gut bacterial species and metabolites are paradoxically associated with disease improvement in pediatric Crohn’s disease during enteral nutrition. Inflamm Bowel Dis. 2014;20:861–71. doi:10.1097/ MIB.0000000000000023. Luna-Pech JA, Torres-Mendoza BM, Garcia-Cobas CY, Navarrete-Navarro S, Elizalde-Lozano AM. Normocaloric diet improves asthma-related quality of life in obese pubertal adolescents. Int Arch Allergy Immunol. 2014;163:252–8. doi:10.1159/ 000360398. Kim HJ, Yu BP, Chung HY. Molecular exploration of age-related NF-kappaB/IKK downregulation by calorie restriction in rat kidney. Free Radic Biol Med. 2002;32:991–1005. van den Elsen LW et al. CD25+ regulatory T cells transfer n-3 long chain polyunsaturated fatty acids-induced tolerance in mice allergic to cow’s milk protein. Allergy. 2013;68:1562–70. doi:10.1111/ all.12300. van den Elsen LW et al. Dietary long chain n-3 polyunsaturated fatty acids prevent allergic sensitization to cow’s milk protein in mice. Clin Exp Allergy : J Br Soc Allergy Clin Immunol. 2013;43: 798–810. doi:10.1111/cea.12111. van den Elsen LW et al. DHA-rich tuna oil effectively suppresses allergic symptoms in mice allergic to whey or peanut. J Nutr. 2014;144:1970–6. doi:10.3945/jn.114.198515. Ghosh S et al. Fish oil attenuates omega-6 polyunsaturated fatty acid-induced dysbiosis and infectious colitis but impairs LPS dephosphorylation activity causing sepsis. PLoS One. 2013;8, e55468. doi:10.1371/journal.pone.0055468. Yang N, Song Y, Sampson H, Li X. Bioactivities of berberine, palmatine, and jatrorrhizine isolated from Food Allergy Herbal Formula 2 (FAHF-2). J Allergy Clin Immunol. 2011;127: AB240. doi:10.1016/j.jaci.2010.12.956. Zhang X et al. Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. PLoS One. 2012;7, e42529. doi:10. 1371/journal.pone.0042529. Wang J. Treatment of food anaphylaxis with traditional Chinese herbal remedies: from mouse model to human clinical trials. Curr Opin Allergy Clin Immunol. 2013;13:386–91. doi:10.1097/ACI. 0b013e3283615bc4. David LA et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–63. doi:10.1038/ nature12820. Berg D, Clemente JC, Colombel JF. Can inflammatory bowel disease be permanently treated with short-term interventions on

Page 9 of 10 39

114. 115.

116.

117.

118.

119.

120. 121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

the microbiome?. Expert Rev Gastroenterol Hepatol. 2015; 1–15, doi:10.1586/17474124.2015.1013031. Modi SR, Collins JJ, Relman DA. Antibiotics and the gut microbiota. J Clin Invest. 2014;124:4212–8. doi:10.1172/JCI72333. Colombel JF et al. A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn’s disease. Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID). Am J Gastroenterol. 1999;94:674–8. doi: 10.1111/j.1572-0241.1999.935_q.x. Selby W et al. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn’s disease. Gastroenterology. 2007;132:2313–9. doi:10.1053/j.gastro.2007. 03.031. Prantera C et al. Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn’s disease. Gastroenterology. 2012;142:473–81. doi:10.1053/j.gastro.2011. 11.032. e474. Leiper K et al. Clinical trial: randomized study of clarithromycin versus placebo in active Crohn’s disease. Aliment Pharmacol Ther. 2008;27:1233–9. doi:10.1111/j.1365-2036.2008.03661.x. Afdhal NH, Long A, Lennon J, Crowe J, O’Donoghue DP. Controlled trial of antimycobacterial therapy in Crohn’s disease. Clofazimine versus placebo. Dig Dis Sci. 1991;36:449–53. Sutherland L et al. Double blind, placebo controlled trial of metronidazole in Crohn’s disease. Gut. 1991;32:1071–5. Steinhart AH et al. Combined budesonide and antibiotic therapy for active Crohn’s disease: a randomized controlled trial. Gastroenterology. 2002;123:33–40. Ohkusa T et al. Newly developed antibiotic combination therapy for ulcerative colitis: a double-blind placebo-controlled multicenter trial. Am J Gastroenterol. 2010;105:1820–9. doi:10.1038/ajg. 2010.84. Turunen UM et al. Long-term treatment of ulcerative colitis with ciprofloxacin: a prospective, double-blind, placebo-controlled study. Gastroenterology. 1998;115:1072–8. Mantzaris GJ et al. A prospective randomized controlled trial of intravenous ciprofloxacin as an adjunct to corticosteroids in acute, severe ulcerative colitis. Scand J Gastroenterol. 2001;36:971–4. Mantzaris GJ et al. A prospective randomized controlled trial of oral ciprofloxacin in acute ulcerative colitis. Am J Gastroenterol. 1997;92:454–6. Dickinson RJ et al. Double blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbations of idiopathic colitis. Gut. 1985;26:1380–4. Mantzaris GJ, Hatzis A, Kontogiannis P, Triadaphyllou G. Intravenous tobramycin and metronidazole as an adjunct to corticosteroids in acute, severe ulcerative colitis. Am J Gastroenterol. 1994;89:43–6. Gionchetti P et al. Antibiotic combination therapy in patients with chronic, treatment-resistant pouchitis. Aliment Pharmacol Ther. 1999;13:713–8. Dethlefsen L, Huse S, Sogin ML, Relman DA. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 2008;6, e280. doi:10. 1371/journal.pbio.0060280. Mattila E et al. Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology. 2012;142:490–6. doi:10.1053/j.gastro.2011. 11.037. van Nood E et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–15. doi:10. 1056/NEJMoa1205037. Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis : Off Publ Infect Dis Soc Am. 2011;53:994–1002. doi:10.1093/cid/cir632.

39 Page 10 of 10 133.• Youngster I et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014;312:1772–8. doi:10.1001/jama.2014.13875. This study shows a novel form of FMT using encapsulated frozen microbiota, opening the way for safer and more efficient ways to modulate microbiome content. 134. Damman CJ, Miller SI, Surawicz CM, Zisman TL. The microbiome and inflammatory bowel disease: is there a therapeutic role for fecal microbiota transplantation? Am J Gastroenterol. 2012;107:1452–9. doi:10.1038/ajg.2012.93. 135. Ianiro G, Bibbo S, Scaldaferri F, Gasbarrini A, Cammarota G. Fecal microbiota transplantation in inflammatory bowel disease:

Curr Allergy Asthma Rep (2015) 15: 39

136.

137.

beyond the excitement. Medicine. 2014;93:e97. doi:10.1097/MD. 0000000000000097. Shankar V et al. Species and genus level resolution analysis of gut microbiota in Clostridium difficile patients following fecal microbiota transplantation. Microbiome. 2014;2:13. doi:10.1186/20492618-2-13. Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M. Therapeutic potential of fecal microbiota transplantation. Gastroenterology. 2013;145:946–53. doi:10.1053/j.gastro.2013. 08.058.