Editorial Open Access
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pharmacol Ther. May 6, 2015; 6(2): 10-16
Published online May 6, 2015. doi: 10.4292/wjgpt.v6.i2.10
Inflammatory bowel disease: Traditional knowledge holds the seeds for the future
Giovanni C Actis, Floriano Rosina, Hepatogastroenterology Division, Ospedale Gradenigo, 10153 Torino, Italy
Rinaldo Pellicano, Division of Gastroenterology, Ospedale Molinette, 10126 Torino, Italy
Author contributions: All authors contributed to this manuscript.
Conflict-of-interest: We hereby denie any conflict of interest with regard to the present paper.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Giovanni C Actis, MD, Hepatogastroenterology Division, Ospedale Gradenigo, Corso Regina Margherita, 8, 10153 Torino, Italy. segreteria.gel@h-gradenigo.it
Telephone: +39-011-8151211 Fax: +39-011-8151388
Received: January 16, 2015
Peer-review started: January 18, 2015
First decision: February 7, 2015
Revised: March 2, 2015
Accepted: April 1, 2015
Article in press: April 7, 2015
Published online: May 6, 2015
Processing time: 102 Days and 22.1 Hours

Abstract

Despite the level of sophistication they have reached nowadays, the available tools for treatment of inflammatory bowel disease (IBD) can at best chronicize the disease but not cure it. Chances to make leap forward from this hold-back may include designs to reach personalized treatment strategies taking advantage of modern genome associated studies, and shift resources towards unfolding inciting pathogenetic steps rather than continuing to develop drugs that address down-stream phenomena. We have arbitrarily chosen to scrutinize a few projects that may make their way in 2015 and mark the history of IBD research. The list includes: the role of appendix as a regulating factor in pathogenesis of ulcerative colitis/proctitis; the reappraisal of (auto)immune phenomena in the era of microbiome; projects to treat IBD by stem cell infusion; recognition of the crucial pathogenetic role of gut microbiome, and attempts to modify it to treat enteric diseases, from clostridium difficile infection to IBD.

Key Words: Inflammatory bowel disease; Microbiome; Stem cells; Future treatments; Curative appendectomy

Core tip: The inflammatory diseases of the gut (inflammatory bowel disease) continue to both constitute a medical challenge, and a formidable intellectual stimulus. The latter statement is based on the accumulating evidence that the IBDS are indeed syndromes whereby a few poorly penetrating polymorphic genes can affect at once the inflammatory balance in the barrier systems of the gut, the skin, and the airways. The former statement reflects the very fact that, though described in the 19th century, IBD continues to defeat our struggle to cure it, invading yet the hitherto unaffected landscapes of the Eastern World, almost as it was a response to our efforts. We deem that the address of the initiating factors, rather than the downstream phenomena, may be a strategy to wriggle out of the hold-up. The description of interventions such as appendectomy or microbiome replacement, among other options, witnesses our own way to interpret this need in the present editorial.



INTRODUCTION

Inflammatory bowel disease (IBD) is now understood as a dysfunction of a barrier organ, whereby the antigenic gut luminal contents (from diet and autochthonous flora) come in an undue contact with the reactive sub-mucosal tissue. The players in this event include: polymorphisms of the genes governing cytokine networks; passive defense devices (defensins and epithelial sealings); inborn errors of functional structures of innate immunity (the NOD system e.g.); inborn knock-out of genes coding for down-regulatory circuits [es interleukin (IL)10-/-); the polyfunctional microbiome. From a general prospective, this universe is ruled by a plethora of low-penetrance genes, needing to come about in a critical mass to induce disease phenotypically. Needless to say, various treatment attempts at impacting this scenario have often proven deceptive, calling for a shifted frame of mind bound to overcome the simple search for the next biological formulation following failure of the former. We have arbitrarily chosen to describe a few examples whereby the authors have essayed to see the matters from a different angle.

In one of these attempts, the authors were inspired by the observation that the gut inflammation that develops in IL-10 knock-out mice seems to have an appendiceal origin; based on this, they pursued the study of the consequences of appendectomy, finding that appendectomy tends to exert a prevalent down-regulatory modulation. Back in 2009, a large clinical study enrolled humans to receive appendectomy for their ulcerative proctitis, achieving at least clinical remission in a patient subset. It is hoped that basic and clinical research in this field will march at the same pace to identify a revolutionary strategy to tackle the problem of gut inflammation and proctitis specifically.

Cutting edge research has recently confirmed that tissues and body fluids can no longer be considered “conventionally” sterile, insofar as containg a myriad of genomic (bacterial and virologic) messages. Since these determinants are reasonably able to elicit strong immune reactions against themselves inciting inflammation, the authors argue that a few chronically inflamed patients (including Crohn’s) should be immune stimulated to wipe out the indwellers, rather than immune suppress them.

Some years ago, the early claim of “cure” of a few cases of Crohn’s disease after bone marrow transplant had paved the way towards the strategy of reprogramming progenitor cell lineage to terminate IBD. Programs of stem cell transplant are now very active and the clinical harvest seems promising so far.

The rapidly growing understanding of the microbiome could not avoid to bear significant impact on our clinical address on IBD. There is now consistent evidence that microbiome composition is profoundly altered in IBD, lending rationale to the use of fecal transplant as a treatment option. This is a rapidly growing matter that will not fail to produce results in the near future.

Conclusively, there are at least two added values attached to this novel mindframe. Firstly, it may take us even closer to the now legendary promised land of personalized medicine; Secondly, we are finally driving the coach towards understanding the roots of the disease, rather than blindly aiming at its epiphenomena.

IBD: TRADITIONAL KNOWLEDGE HOLDS THE SEEDS FOR THE FUTURE

Certain anatomic/functional structures have evolved to discern between the inner “sterile” milieu and the outer “polluted” environment. The pivotal components in such “barrier organs”[1] (the gut, skin, the airways, urinary tract) consist of a mucosal immune system (biased to tolerance) and an underneath lymphoid tissue (primed to react).

Owing to their functions, inflammation in barrier organs is constitutive; it may grow to be induced if the balance between pro- and anti-inflammatory forces is breached. Specifically, the players in this balance at the colonic level are the diet constituents, the local immune system, and the microbiome[2,3].

In 2009, we compiled a scrutiny of the elements that factor in colon pathophysiology (unpublished data). In the lines to follow, we reappraise this rather outdated paper, with the bias to uncover current and future links to research in colonic physiology and disease.

THE MAIN COMPONENTS IN THE SYSTEM
Barrier alterations

Insofar as preventing the rise of inflammation by avoiding contact between luminal antigens and the overreactive lymphoid tissue underneath the mucosa, epithelial integrity, inter-cell sealing, and production of defensive substances are essential. Chimeric mice for a defective cadherin[4] (a crucial factor in the sealing properties of tight junctions) exhibited unchecked intestinal inflammation; patients with active Crohn’s disease showed a 50% reduction of secretion of defensins[5], that are Paneth cell-derived cationic peptides endowed with antibacterial activity. Noteworthy, updated research is now showing that correct production and release of beta-defensins is under the control of the vitamin D receptor (see below)[6].

Alteration of gut flora

This topic has largely been treated by others[7] and ourselves[8]. Such trillion-individual metagenomic world in our digestive tract has been shown to affect a range of conditions including diabetes[9,10], obesity[11], inflammatory disease[12], and behavioral changes[13]. Just two examples showing that microbiome components might influence inflammatory circuits are the following. Microbiome-derived free-fatty-acids might regulate size and function of regulatory T-cells (T-regs), activating SMAD 3 and 4[14,15], and ameliorating experimental colitis; Prevotella Copri can educate T-lymphocytes to secrete IL17, a key cytokine in rheumatoid arthritis[16]. Evidence that microbiome composition can be modified by diet, has prompted intensive study programs aiming at determining the therapeutic role of fecal flora transplantation in treatment of both IBD and Clostridium difficile infection (CDI)[17].

Alteration of innate immunity

Evolution has endowed us with a number of sensors to check the outer environment for invaders[18]. The toll-like receptors (TLR)[19] are membrane confined elements, the nucleotide oligomerization domains are cytoplasmic. The NODs[20] comprise a leucine-rich repeat, a central NOD structure facilitating oligomerization, and a terminal caspase-recruitment domain. Essentially, the final common action of both TLRs and NODs leads to activation of cytoplasmic NFκB[21], which, upon nuclear translocation, will induce the genes of pro-inflammatory cytokines, as part of a defensive program. As a key-stone discovery by two independent teams in 2001, a loss-of-function NOD mutation was described in a significant proportion of Western Crohn’s patients, but not in those of an oriental descent[22].

Alteration of adaptive immunity

These may encompass both B-cells and T-cells misfunctions. The B-cell products ASCA and ANCA antibodies are well-studied markers of Crohn’s[23] and UC[24] respectively. On the other hand, anomalous T-cell clones may arise in IBD as a consequence of a changed dendritic cell antigen presentation, or presentation by non-professional cells[25]. Among such T-cell phenotype variants, the Th17 cells have received most of the attention recently.

The Th-17 lymphocytes[26]. We wish to devote a deal of attention to these cells as they are destined to be further discussed below. Derived from TCD4+ lymphocytes, and CD4+CD25-Foxp3 lymphocytes, can mainly release IL17, as driven by IL-23 dependent STAT-3 activation[27].

Physiologic roles

Rise of Th17 cells was initially demonstrated in fungi and bacteria infected milieus, suggesting a protective mission for these cells; klebsiella pneumonitis, Candida infection, and mycoplasma invasions were all demonstrated to constitute an arena for Th17 cells[28].

Pathophysiologic roles

In the unstable milieu of the sub-clinical intestinal inflammation, Th17 cells can easily be traced to the lamina propria; in full-blown pathologic conditions, they can easily be shown to migrate to inflamed areas[29]. The chemokine-ligand interaction CCr6-CCL20 has been found to be crucial for the homing of Th17 cells to the distal colon[29] (see below). Arthritis has long been recognized as a co-morbidity of IBD and Th17 cells have recently been reckoned to be effectors in this pathologic events[30]. Interaction of the chemokine CCR6 with its homologous synovial chemokine CCL20 have been shown to allow Th17 homing to arthritic sites, thus initiating bone resorption.

FUTURE RESEARCH SEEDS

The chain of evolution and function of Th17 cells as summarized above allows us to open the list of future endeavors with this topic. This list will therefore comprise: (1) The appendicitis/appendectomy model; (2) Metagenome and autoimmunity; (3) Bone marrow transplants; and (4) Microbiome modulation.

The T-cell receptor-α mutant mice (TCR-α-/-), obtained by gene targeting of the TCR-alpha gene in embryonic stem cells, is a popular mouse model that spontaneously develop ulcerative colitis-like inflammation of the colon[31]. In 1996, the team of Bhan published the results of experiments aiming to define the reciprocal roles of appendix associated lymphoid follicles (ALF) vs that of Peyer’s patches (PP) in such diseased mice. They found that: (1) the proliferative index in ALF was twice that of PP; and (2) The frequency of IgG secreting B cells in ALF of mutant mice largely exceeded that of non-mutant animals. Early appendectomy in mutant strains had two orders of consequences: (1) the number of mesenteric lymph nodes got significantly reduced; and (2) appendix ablation at 1 mo of age suppressed the development of IBD[31]. The tenet that appendicectomized humans might be protected from ulcerative colitis in fact relies on these basic data of the 1990’s. Specifically, a clinical paper issued in 2009[32], followed in 2011 by a short communication in a letter format[33], have shown that appendectomy might ameliorate symptoms in a limited group of patients with ulcerative proctitis. The team of Cheluvappa et al[34] in Sydney has recently reappraised the basic information on Th17 cells we collected above, to design an animal model. BALB/c mice were subjected to experimental appendicitis and appendectomy (AA), then distal colon samples were harvested. Results were validated using reverse-transription-polymerase chain reaction. The authors mainly found that prior AA ameliorated experimental colitis. CCL20 expression was suppressed in the most distal colon 3 and 28 d after the AA was done at the proximal colon[34]. Another piece of study from the same group[35] has suggested that suppression of a few endothelin genes may be a mechanism in these findings. The authors conclude by wishing that this expanded knowledge on the Th17 system and CCR6/CCL20 interaction can be transferred to clinical grounds before long.

The team of Amy Proall has conducted extensive basic research on the human microbiome, pushing her findings to somewhat extreme consequences[36]. The author starts out by stressing that modern techniques are now demonstrating that not only the usual sites such as the colon are dwelled by abundant microbiome species, but virtually all tissues or fluids within our bodies harbor trillions of yet unknown bacterial and viral phila. The authors list a few of the implications of these revolutionary findings: (1) The inner milieu can no longer be considered sterile; (2) The concept itself of autoimmunity might be reduced to a concept of a reaction against antigenic determinants of this overwhelming microbiome, or against modified self-antigens; (3) Given these premises, the correct approach to treatment of inflammatory disease would be immunostimulation to get rid of the indwellers, rather than immune suppression. The latter will obviously lend symptom relief but will promote persistence of the inciting causes, whether bacterial, viral or else[37]; and (4) Worth of note, this overriding antigenemia might also be fueled by the action of active transport systems. A recent paper[38] dealing with peptide transport from the intestine, has described a carrier, pepT1, which, belonging to the superfamily of proton -coupled oligopeptide transporters, can transport oligopeptides through the cells to the bloodstream thanks to coupling with hydrogen ion. Interestingly, the authors pin-point that the activity of pep T1, can turn out to be heightened during intestinal disease such as IBD, wherein in this case bacterial flora (metagenomic) by-products may become the transported antigenic material. As a consequence of this shift, mounting of inflammatory and auto-inflammatory responses can easily be predicted. Thus, the findings of such independent work seems to lend fuel to Proall’s speculation.

The authors conduct an interesting focus on the vit D receptor (VDR). Of the two recognized classes of VDR, the first, segregating to the cell nucleus, belongs to the family of the class 2 steroidal hormones receptors, and is closely linked with the retinoic acid and thyroid hormone receptors. As a protein of 427 aminoacids, the human VDR couples DNA, links the ligand, and self-activates through its three respective domains. Functionally, VDR heterodimerizes with retinoid X receptor (RXR), activating gene transcription (vit Response Elements) and protein synthesis. The other VDR is a membrane element, and as a non-genomic action, catalizes release of cellular messengers. Noteworthy, the VDR complex conditions release of a huge number of protective molecules. When thwarted by a load of bacterial ligands it may cease producing crucial protective compounds from cathelicidine to difensins[39], thus fully impacting on IBD pathophysiology; in addition also Vit D handling might be damaged, and a receptor leaking 1,25 vit D has been described in inflammatory conditions including Crohn’s. Vit D itself, on the other hand, bears the structure of a secosteroid. Because exerting in fact a down-regulatory effect on various immunologic steps, it should be considered an immune suppressor. Based on this, the authors express doubts as to the indication for vit D in a few inflammatory conditions, including IBD.

Coherently with these premises, the authors declare to have studied the possibility of alternative non-suppressive regimes for immune-inflammatory conditions, including satanic derivatives.

C STEM CELL THERAPY FOR IBD

The issue has recently been addressed in an exhaustive review[40]. Stem cells characteristically undergo a process of asymmetrical cell division, giving birth to a cell with the same properties as the original cell, and another cell of multilineage differentiation potency, depending on environmental conditions. The comprehensive term “stem cells”[41] includes: (1) embryonic stem cells, e.g., pluripotent cells obtained from embryos; (2) multipotent adult stem cells including hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) found in all body tissues; and (3) induced pluripotent stem cells, defined as artificial pluripotent stem cells generated from somatic cells by the introduction of reprogramming factors.

HSC and MSC are currently used and evaluated to treat therapy - resistant Crohn’s disease. The only protocol that is officially accepted requires infusion of autologous HSC[42] following a program of cell mobilization and myeloablation[43]. Briefly, the patient first receives cyclophosphamide and granulocyte colony stimulating factor to stimulate production and release of stem cells from blood marrow; these cells are then collected from peripheral blood and then cryopreserved until re-infusion. The therapeutic objective of autologous HSCT[44] is the resetting of the patient’s immune system thanks to the myeloablation program, which effects T-lymphocyte and memory T-cells elimination.

The first case reporting the efficacy of HSCT in the control of CD was published in 1993[45]. It is difficult to firmly evaluate the effectiveness of this technique in CD, given the relatively low number of published cases. In the series published by Burt et al[46] in 2010, the most updated series, all of the 24 patients entered remission after transplantation.

Most clinical studies have shown that MSCs can be obtained from bone marrow, adipose tissue, and umbilical cord. Being not significantly immunogenic, MSCs can be administered without a conditioning phase[47-49].

Systemic administration of MSCs for treatment of IBD. The results of phase 1 studies have recently been published. In 2012, Liang et al[50] reported the results obtained in 7 patients with IBD (4 CD and 3 UC). Remission was achieved in 5 subjects and maintained for over 24 mo in 2 of them; endoscopic improvement was demonstrated in 3 subjects. Side effects were mild

Local MSCs therapy in fistulizing CD. The initial study dates back to 2008[51] and reported remission in 7 of 9 CD patients with complex peri-anal fistula. At present, a phase 3 study is under way, involving the use of expanded MSCs from adipose tissue to treat complicated fistula.

D MICROBIOME MODULATION

The bacterial cells pertaining to the human microbiome are estimated to attain the notable number of 1014, dwarfing the few thousands of indwelling somatic cells. The protean characteristics and functions of the microbiome have been addressed in a number of reviews from others and ourselves[7,8]. Results from various studies are now accumulating to point to the astonishing variety of targets that are touched by the microbiome, including effects on immunity, determination of diabetic and overweight statuses, up to influence behavior and mental health. No wonder that a deal of efforts has concentrated onto the endeavor to modulate microbiome composition and function. The array of means and strategies that have been assayed include pre-biotics, pro-biotics, antibiotics, and fecal transplant (FT). The latter technique has received a special deal of attention, and to challenge the feasibility of its translation to clinical practice, two questions may be particularly relevant: (1) Is it effective? (2) How long does its action last.

As to the former question, FT has been convincingly shown to treat CDI[52]. A recent meta-analysis[53] has examined the role of FT as a therapy for IBD. Elaboration of the data from 18 studies including 122 patients led this study to conclude that FT may be safe and effective, but controlled trials, donor selection and standardization of microbiome analysis are strongly needed.

As to the length of effect, studies on CDI have reported encouraging results. The diseased microbiome of IBD, by contrast, has shown a deal of resiliency against the actions of FT. Most of the authors have concluded that prolonged and repeated treatments are probably needed to achieve some consistent results in these premises[54]. Last but not least, cutting-edge data from current research work[55] are showing that a number of host genes, some with known involvement with microbial handling, exhibited consistent effects on the taxonomic structure of the microbiome across multiple cohorts. Specifically, NOD mapping work showed links between NOD polymorphisms and gut colonization with Enterobacteriacee, allowing for the first time to envisage the chance of genetic transmission of IBD strains along with innate immunity sensors such as the NODs.

CONCLUDING REMARKS

The succinct lines above, stress the need to progressively move towards a mindset that sees IBD as a contextualized polyfactorial syndrome of outer environment misrecognition, whereby innumerous co-morbidities recognize shared roots and immunological circuits, the microbiome being the crucial but not the only player. Against this background, traditional immune suppression, including the novel biologics, has revealed its inadequacy to eradicate the disease. Having set this, we arbitrarily chose to gain more insight into the projects put forward by a few world leading teams in basic and clinical IBD research. Based on previously encouraging clinical hints, Cheluvappa’s team has studied the immune-regulatory consequences of appendectomy in IBD patients and is actively pursuing a pathway to render the idea amenable to clinical application. Programs of stem cell infusion are probably bound to be the most rewarding ones in the future, yet intrinsic risks continue to require balance against the clinical gains. Facing this sometime chaotic wealth of evidence, Proall and her team see immune-inflamed patients including the IBD subjects as immune-depressed individuals which deserve immune reconstitution far more than immune suppression. Already successfully applied to the treatment of hepatitis B[56], this proposition is less fanciful than it appears. Despite this, the gap between conceptual refinements of these approaches, and their clinical transition is still significantly wide. FT has already shown exciting promise in the treatment of CDI. Its transition to clinical treatment of IBD will depend on the availability of pharmacological strategies to overcome the resilience of microbiome in the inflammatory intestinal states.

In terms of world-wide epidemiology, one can identify at least two opposite driving forces. Rapid “occidentalization” is providing IBD with unprecedentedly wide areas of expansion in huge landscapes like China[57]. On the other hand, one knows that life and evolution may sometimes reveal their complexity presenting as “erase-and-rewind” processes. On this line, poor or regressing life standards in certain world areas tend to make violent infection agents prevail over “sophisticated” immune inflammatory condition, threatening to absorb mental and financial energies in the future[58], perhaps distracting commitment from the programs illustrated above.

ACKNOWLEDGMENTS

This is dedicated to O Della Casa-Alberighi, MD, who profoundly influenced my career with continuous friendship, advice, and support.

Footnotes

P- Reviewer: Akiho H, Blonski W, Naser SA S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ

References
1.  Schreiber S, Rosenstiel P, Albrecht M, Hampe J, Krawczak M. Genetics of Crohn disease, an archetypal inflammatory barrier disease. Nat Rev Genet. 2005;6:376-388.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011;365:1713-1725.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380:1590-1605.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Hermiston ML, Gordon JI. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science. 1995;270:1203-1207.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, Shen B, Schaeffeler E, Schwab M, Linzmeier R. Reduced Paneth cell alpha-defensins in ileal Crohn’s disease. Proc Natl Acad Sci USA. 2005;102:18129-18134.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Froicu M, Cantorna MT. Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunol. 2007;8:5.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Seksik P. [Gut microbiota and IBD]. Gastroenterol Clin Biol. 2010;34 Suppl 1:S44-S51.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Actis GC. The gut microbiome. Inflamm Allergy Drug Targets. 2014;13:217-223.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860-867.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116:1793-1801.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444:1022-1023.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  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.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Crumeyrolle-Arias M, Jaglin M, Bruneau A, Vancassel S, Cardona A, Daugé V, Naudon L, Rabot S. Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology. 2014;42:207-217.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Monteleone G, Kumberova A, Croft NM, McKenzie C, Steer HW, MacDonald TT. Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J Clin Invest. 2001;108:601-609.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Fantini MC, Rizzo A, Fina D, Caruso R, Sarra M, Stolfi C, Becker C, Macdonald TT, Pallone F, Neurath MF. Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. Gastroenterology. 2009;136:1308-1316, 1308-1316.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, Rostron T, Cerundolo V, Pamer EG, Abramson SB. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife. 2013;2:e01202.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Flint HJ. The impact of nutrition on the human microbiome. Nutr Rev. 2012;70 Suppl 1:S10-S13.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Davies JM, Abreu MT. The innate immune system and inflammatory bowel disease. Scand J Gastroenterol. 2015;50:24-33.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004;5:987-995.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599-603.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Wei J, Feng J. Signaling pathways associated with inflammatory bowel disease. Recent Pat Inflamm Allergy Drug Discov. 2010;4:105-117.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Yamazaki K, Takazoe M, Tanaka T, Kazumori T, Nakamura Y. Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn’s disease. J Hum Genet. 2002;47:469-472.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Kaul A, Hutfless S, Liu L, Bayless TM, Marohn MR, Li X. Serum anti-glycan antibody biomarkers for inflammatory bowel disease diagnosis and progression: a systematic review and meta-analysis. Inflamm Bowel Dis. 2012;18:1872-1884.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Kuna AT. Serological markers of inflammatory bowel disease. Biochem Med (Zagreb). 2013;23:28-42.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Roda G, Sartini A, Zambon E, Calafiore A, Marocchi M, Caponi A, Belluzzi A, Roda E. Intestinal epithelial cells in inflammatory bowel diseases. World J Gastroenterol. 2010;16:4264-4271.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Kim CH. Migration and function of Th17 cells. Inflamm Allergy Drug Targets. 2009;8:221-228.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q, O’Malley JT, Kapur R, Levy DE, Kansas GS, Kaplan MH. Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol. 2007;178:4901-4907.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Ye P, Garvey PB, Zhang P, Nelson S, Bagby G, Summer WR, Schwarzenberger P, Shellito JE, Kolls JK. Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am J Respir Cell Mol Biol. 2001;25:335-340.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Wang C, Kang SG, Lee J, Sun Z, Kim CH. The roles of CCR6 in migration of Th17 cells and regulation of effector T-cell balance in the gut. Mucosal Immunol. 2009;2:173-183.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, Yamaguchi T, Nomura T, Ito H, Nakamura T. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med. 2007;204:2803-2812.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Mizoguchi A, Mizoguchi E, Chiba C, Bhan AK. Role of appendix in the development of inflammatory bowel disease in TCR-alpha mutant mice. J Exp Med. 1996;184:707-715.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Bolin TD, Wong S, Crouch R, Engelman JL, Riordan SM. Appendicectomy as a therapy for ulcerative proctitis. Am J Gastroenterol. 2009;104:2476-2482.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Bageacu S, Coatmeur O, Lemaitre JP, Lointier P, Del Tedesco E, Phelip JM, Roblin X. Appendicectomy as a potential therapy for refractory ulcerative proctitis. Aliment Pharmacol Ther. 2011;34:257-258.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Cheluvappa R. Experimental appendicitis and appendectomy modulate the CCL20-CCR6 axis to limit inflammatory colitis pathology. Int J Colorectal Dis. 2014;29:1181-1188.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Cheluvappa R, Eri R, Luo AS, Grimm MC. Endothelin and vascular remodelling in colitis pathogenesis--appendicitis and appendectomy limit colitis by suppressing endothelin pathways. Int J Colorectal Dis. 2014;29:1321-1328.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Proal AD, Albert PJ, Blaney GP, Lindseth IA, Benediktsson C, Marshall TG. Immunostimulation in the era of the metagenome. Cell Mol Immunol. 2011;8:213-225.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Proal AD, Albert PJ, Marshall TG. Inflammatory disease and the human microbiome. Discov Med. 2014;17:257-265.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Freeman HJ. Clinical relevance of intestinal peptide uptake. World J Gastrointest Pharmacol Ther. 2015;In press.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Auvynet C, Rosenstein Y. Multifunctional host defense peptides: antimicrobial peptides, the small yet big players in innate and adaptive immunity. FEBS J. 2009;276:6497-6508.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Martínez-Montiel Mdel P, Gómez-Gómez GJ, Flores AI. Therapy with stem cells in inflammatory bowel disease. World J Gastroenterol. 2014;20:1211-1227.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Kolios G, Moodley Y. Introduction to stem cells and regenerative medicine. Respiration. 2013;85:3-10.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Tyndall A, Gratwohl A. Blood and marrow stem cell transplants in auto-immune disease: a consensus report written on behalf of the European League against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 1997;19:643-645.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Oyama Y, Craig RM, Traynor AE, Quigley K, Statkute L, Halverson A, Brush M, Verda L, Kowalska B, Krosnjar N. Autologous hematopoietic stem cell transplantation in patients with refractory Crohn’s disease. Gastroenterology. 2005;128:552-563.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Leung Y, Geddes M, Storek J, Panaccione R, Beck PL. Hematopoietic cell transplantation for Crohn‘s disease; is it time? World J Gastroenterol. 2006;12:6665-6673.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Drakos PE, Nagler A, Or R. Case of Crohn’s disease in bone marrow transplantation. Am J Hematol. 1993;43:157-158.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Burt RK, Craig RM, Milanetti F, Quigley K, Gozdziak P, Bucha J, Testori A, Halverson A, Verda L, de Villiers WJ. Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up. Blood. 2010;116:6123-6132.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C, Taureau C, Cousin B, Abbal M, Laharrague P. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol. 2005;129:118-129.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Najar M, Raicevic G, Boufker HI, Fayyad Kazan H, De Bruyn C, Meuleman N, Bron D, Toungouz M, Lagneaux L. Mesenchymal stromal cells use PGE2 to modulate activation and proliferation of lymphocyte subsets: Combined comparison of adipose tissue, Wharton’s Jelly and bone marrow sources. Cell Immunol. 2010;264:171-179.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Yoo KH, Jang IK, Lee MW, Kim HE, Yang MS, Eom Y, Lee JE, Kim YJ, Yang SK, Jung HL. Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues. Cell Immunol. 2009;259:150-156.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Liang J, Zhang H, Wang D, Feng X, Wang H, Hua B, Liu B, Sun L. Allogeneic mesenchymal stem cell transplantation in seven patients with refractory inflammatory bowel disease. Gut. 2012;61:468-469.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, Minelli A, Alvisi C, Vanoli A, Calliada F. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut. 2011;60:788-798.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Brandt LJ, Aroniadis OC. An overview of fecal microbiota transplantation: techniques, indications, and outcomes. Gastrointest Endosc. 2013;78:240-249.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  Colman RJ, Rubin DT. Fecal microbiota transplantation as therapy for inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis. 2014;8:1569-1581.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Xu Z, Knight R. Dietary effects on human gut microbiome diversity. Br J Nutr. 2015;113 Suppl:S1-S5.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  Knights D, Silverberg MS, Weersma RK, Gevers D, Dijkstra G, Huang H, Tyler AD, van Sommeren S, Imhann F, Stempak JM. Complex host genetics influence the microbiome in inflammatory bowel disease. Genome Med. 2014;6:107.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 302]  [Cited by in F6Publishing: 269]  [Article Influence: 26.9]  [Reference Citation Analysis (0)]
56.  Han Q, Lan P, Zhang J, Zhang C, Tian Z. Reversal of hepatitis B virus-induced systemic immune tolerance by intrinsic innate immune stimulation. J Gastroenterol Hepatol. 2013;28 Suppl 1:132-137.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Ng SC. Emerging leadership lecture: Inflammatory bowel disease in Asia: Emergence of a “Western” disease. J Gastroenterol Hepatol. 2015;30:440-445.  [PubMed]  [DOI]  [Cited in This Article: ]
58.  Boulton J. Ebola: where did it come from and where might it go? Br J Nurs. 2014;23:988-991.  [PubMed]  [DOI]  [Cited in This Article: ]