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Gastroenterology Research and Practice
Volume 2011, Article ID 971938, 16 pages
http://dx.doi.org/10.1155/2011/971938
Review Article

Probiotics, Nuclear Receptor Signaling, and Anti-Inflammatory Pathways

Sonia S. Yoon1 and Jun Sun1,2

1Division of Gastroenterology and Hepatology, Department of Medicine, Strong Memorial Hospital, University of Rochester Mediacal Center, University of Rochester, Rochester, NY 14642, USA
2Department of Microbiology and Immunology, University of Rochester, P.O. Box 646, 601 Elmwood Avenue, Rochester, NY 14642, USA

Received 2 February 2011; Revised 28 March 2011; Accepted 19 May 2011

Academic Editor: Genevieve B. Melton-Meaux

Copyright © 2011 Sonia S. Yoon and Jun Sun. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

There is increased investigation of the human microbiome as it relates to health and disease. Dysbiosis is implicated in various clinical conditions including inflammatory bowel disease (IBD). Probiotics have been explored as a potential treatment for IBD and other diseases. The mechanism of action for probiotics has yet to be fully elucidated. This paper discusses novel mechanisms of action for probiotics involving anti-inflammatory signaling pathways. We highlight recent progress in probiotics and nuclear receptor signaling, such as peroxisome-proliferator-activated receptor gamma (PPAR ) and vitamin D receptor (VDR). We also discuss future areas of investigation.

1. Introduction

Probiotics are ingestible microorganisms with health benefits. Increased interest in the intestinal microbiome and its effect on health and disease is evidenced by the concomitant increase in peer-reviewed clinical trials investigating probiotics as therapy since 1999 [1]. Studies of the various signaling pathways involved in the response to bacteria and inflammation have led to a more detailed understanding of mechanisms and actions of probiotics. This paper discusses progress in understanding how probiotics contribute to intestinal mucosal function, particularly in relation to anti-inflammatory signaling pathways.

2. Intestinal Microflora

The intestinal microflora, as a whole, serves important functions in metabolism, intestinal epithelial cell function and health, immunity, and inflammatory signaling [2, 3]. Recently, there has been increasing interest in the role of the intestinal microflora and its total genetic composition, together referred to as the microbiome in the development, maintenance, and perpetuation of various clinical conditions, both intestinal and extraintestinal.

Dysbiosis has been implicated in various clinical conditions including atopy, irritable bowel syndrome (IBS), colorectal cancer, alcoholic liver disease in animal and human studies, obesity and other metabolic disorders, and chronic inflammatory diseases such as IBD [4–11]. Decreased diversity of the intestinal microbiota was seen in fecal samples obtained from children who subsequently developed allergic disease [6, 7]. Altered microbiota composition in colon cancer patients when compared to patients with normal colonoscopies and in patients with IBS compared to unaffected patients has also been demonstrated [5, 9]. Alcohol feeding resulted in enteric bacterial overgrowth in a mouse model [8]. The role of the microbiota in obesity has been extensively studied and carefully reviewed in the literature [12, 13]. Microbial composition in IBD patients with ulcerative colitis (UC) or Crohn’s disease (CD) as compared to unaffected individuals has been studied and shows decreased diversity [4, 14–19]. This altered microflora may have significant implications for the intestinal milieu, with as yet incompletely understood effects. The pathogenesis of IBD likely involves a combination of factors including intestinal dysbiosis in conjunction with environmental factors in a genetically susceptible host [20].

Based on the concept of a dysregulated or dysfunctional microbiota in disease, various methods to attenuate the effects of an altered microbiome have been attempted.

3. Probiotics

“Probiotics’’ were first described in the literature by Lilly and Stillwell in 1965 as growth-promoting factors produced by certain microorganisms [21] although it may have been described as early as 1908 [22]. Recently, probiotics were defined as “live organisms which, when consumed in adequate amounts as part of food, confer a health benefit on the host” (Report of a Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria (October 2001), “Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria”, Food and Agriculture Organization of the United Nations, World Health Organization). The mechanisms of action of probiotics include immune modulation, direct effect on commensal and pathogenic bacteria to inhibit infection and restore homeostasis, and modification of pathogenic toxins and host products [23]. The efficacy of probiotics in various clinical conditions both in the pediatric and adult patient population has been extensively studied and carefully reviewed [1, 19, 24–32].

Rectal infusion of normal stool via enemas to treat pseudomembranous colitis has been described as early as 1958 [70]. Infusion of stool via nasogastric tube to the small intestine or via colonoscopy to the colon for CDAD has also been described and shows high response rates [71–74]. A recent study showed that fecal bacteriotherapy was effective in relief of clinical symptoms in a patient with recurrent CDAD and that this was accompanied by the repopulation of the diseased intestinal microbiota with beneficial species that were diminished pretreatment [75]. Other methods to supply live, nonpathogenic organisms to the intestinal microbiota in AAD and CDAD include orally administered probiotics. The efficacy of various probiotic formulations in AAD and CDAD has been extensively studied and carefully reviewed [1]. A recent study showed that the probiotics Lactobacillus acidophilus and Lactobacillus casei were well tolerated and effective in reducing the risk of the development of AAD and CDAD [76]. The utility of the probiotic yeast Saccharomyces boulardii for a variety of conditions including traveler’s diarrhea, enteral nutrition-associated diarrhea, AAD, and CDAD has been investigated, and according to a recent meta-analysis, strong evidence exists for advocating its use in traveler’s diarrhea and AAD [77]. Recent trials using Bifidobacterium bifidum and Saccharomyces boulardii demonstrated improvement in clinical IBS symptoms and quality of life [78, 79], and several reviews of the evidence for the utility of probiotics in IBS have been published [80–82].

For IBD therapy, treatment with different strains of probiotics has shown varied results. Small trials have shown promise for probiotic use in the induction and maintenance of remission in UC. VSL#3 has been shown to be safe and effective in the treatment of acute mild to moderately active UC [83]. Patients with mild to moderate UC unresponsive to conventional therapy achieved a combined induction remission/response rate of 77% with treatment with VSL#3 [84]. E. coli Nissle 1917 was found to be effective and equivalent to mesalazine in maintaining remission in UC [85]. In another study, Lactobacillus rhamnosus GG (LGG) was equivalent to mesalazine in the maintenance of remission in UC, however, appeared to be more effective in prolonging the relapse-free time [86]. Evidence also exists for the role of probiotics in prophylaxis of pouchitis after surgery in UC patients as well as induction of remission in chronic pouchitis [87, 88].

Studies of probiotic use in induction and maintenance of remission and prevention of postoperative recurrence in CD have been less consistent than those for UC. A small study of LGG for the prevention of recurrence after surgery in CD did not show any improvement over placebo [89]; however, Saccharomyces boulardii appears useful in maintaining remission in CD [90, 91]. The progress in the use of probiotics for IBD has been carefully reviewed [92, 93]; however, there remains a relative lack of well-designed, large, randomized, placebo-controlled trials.

Several barriers exist to advocating broad use of probiotics in clinical practice, not least of which is the considerable heterogeneity in the experimental designs with respect to species and strains of probiotics and the various animal models utilized [94]. Although clinical trials examining the role of probiotics in the treatment and/or prevention of AAD, CDAD, IBD including UC, CD, and pouchitis, necrotizing enterocolitis, infectious gastroenteritis, radiation-induced enteritis, and colitis, IBS and various atopic diseases have been reported [1, 24, 25, 28, 29, 31, 87, 95–97]; in many cases, results have been inconsistent, and large, well-designed trials are lacking. An additional complicating factor pertains to issues of quality control. Determining whether a commercially available probiotic actually contains the live organisms it purports to contain and determining if there is rational selection of component probiotic strains in “cocktails” are issues that must be considered [22]. Future research to refine techniques to accurately identify “normal” and “diseased” microbiota and to further elucidate the specific effects and mechanisms of actions of individual probiotic strains will aid in optimizing therapeutic efficacy.

4. Mechanisms for Probiotics in Anti-Inflammation

There has been and continues to be considerable research in delineating the underlying mechanisms by which probiotics exert their beneficial effects. The mechanisms regulating the function of probiotics are very diverse. It is well accepted that probiotics use distinct cellular and molecular mechanisms, including blocking pathogenic bacterial effects, regulating immune responses, and altering intestinal epithelial homeostasis by promoting cell survival, enhancing barrier function, and stimulating protective responses [32].

Table 1 outlines representative publications on probiotic mechanisms of actions. The probiotic-host interaction is complex and further complicated by the fact that certain probiotic effects appear to be species and strain specific. Different probiotics have been shown to exert both pro-inflammatory [98] and anti-inflammatory effects on dendritic cells [99]. A recent study demonstrated that the anti-inflammatory effect of certain lactobacilli is via NOD2-mediated signaling [100]. NOD2/CARD15 is a member of a superfamily of genes involved in intracellular bacterial recognition and has been identified as an important susceptibility gene for CD [101, 102]. The authors speculate that the inconsistent clinical results of lactobacilli use in patients with CD may be related to a relative deficiency of NOD2. Probiotic effect on the innate immune responsive pathways including toll-like receptor (TLR), nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase (JNK) has been extensively investigated (Table 1). Activation of specific TLRs also appears to be species specific [47, 48]. The action of E. coli Nissle 1917 on Caco-2 cells was found to be mediated by flagellin possibly via a TLR pathway [103]. The probiotic-induced effect on the NF-κB signaling pathway is well represented in the literature and is generally characterized by inhibition (Table 1).

tab1
Table 1: Summary for molecular mechanisms and probiotics.

Defective epithelial barrier function has been implicated in IBD and can predict relapse during clinical remission [104–109]. One way by which probiotics have been shown exert their action is by stabilizing tight junctions (TJs) and enhancing barrier function of intestinal epithelial cells (Table 1).

Abnormal STAT/suppressor of cytokine signaling (SOCS) signaling has been demonstrated in CD patients [110], and probiotics are also shown to modulate the JAK-STAT signaling in human placental trophoblast cells [111]. Increasing evidence further demonstrates that metabolism, xenobiotics, and nuclear receptor signaling are involved in the action of probiotics [67, 68].

Induction of heat shock proteins (HSPs) and endogenous antimicrobial peptides (defensins) via activation of NF-κB, MAPK, and JNK has also been linked to probiotic action [35, 41, 43]. Since defensins are implicated in the pathogenesis of IBD, increased expression by probiotics provides a possible mechanism for clinical efficacy seen in certain IBD patients and deserves further study.

5. Defensins and Nuclear Receptor Signaling

Defensins are a class of endogenous antimicrobial peptides involved in innate immunity which is highly evolutionarily conserved and represents a primary line of defense against various microbial pathogens [112–114]. Antimicrobial peptides are widely distributed throughout the animal and plant kingdom, and despite their evolutionary heritage, remain effective antimicrobial agents [114]. This is due, in large part, to their mechanism of action involving membrane disruption and pore formation, which is not easily exploited by pathogens to confer resistance [112–115]. Important antimicrobial peptides in humans include defensins, cathelicidins, lysozymes, and other antimicrobial antiproteases [116]. There are three known defensin subfamilies; α and β defensins are expressed mainly in immune cells and epithelial cells while the θ defensin is found mainly in immune cells of the Rhesus macaque [117, 118]. In the gastrointestinal tract, β defensin expression is seen in multiple sites, whereas α defensin expression is largely in the small intestine [119]. In the uninflamed colon, human β defensin 1 is the predominant defensin and human β defensin 2 and 3 are induced with inflammation or infection [120]. In mice lacking functional cryptidins (murine α defensins), increased survival and virulence of orally administered bacteria were seen and intestinal peptide preparations had decreased antimicrobial activity [121].

The possible role of a deficiency in defensins in the pathogenesis of IBD has been proposed [116, 122]. The Paneth cells of the small intestine are the major source of endogenous antimicrobials, including α defensins [102]. In addition, The Paneth cells have been shown to express NOD2 [123]. In patients with ileal CD, human α defensin 5 and 6 production is reduced, and this effect is magnified in those patients with a concomitant NOD2 mutation [124]. For β defensins, CD patients with colonic disease exhibit normal levels of β defensin 2 and 3 whereas UC patients have increased levels, suggesting a role of failure of β defensin induction in the pathogenesis of CD [125]. Constitutive human β defensin 1 expression is reduced in CD patients with colonic involvement independent of inflammation, and recently, the maintenance of constitutive β defensin expression was shown to be activated by the nuclear receptor peroxisome-proliferator-activated receptor gamma (PPARγ) [122].

Further contributing to the effect of a defensin deficiency in the pathogenesis of IBD may be the diminished diversity of the intestinal microbiota seen in IBD patients. The interaction of commensal bacteria with antimicrobial peptide synthesis is not well understood; however, it has been suggested that commensal bacteria provide chronic stimulation of epithelial cells to produce antimicrobial peptides at levels sufficient to kill microbial pathogens [114, 126].

Probiotics, but not fecal isolates, have been shown to induce human β defensin 2 in intestinal epithelial cells [41, 42]. Wehkamp et al. and Schlee et al. have reported that NF-κB and activator protein-1 (AP-1) mediate induction of human β defensin 2 in intestinal epithelial cells by the probiotic E. coli Nissle 1917 and VSL#3 [41, 42].

Interestingly, nuclear receptors are known to regulate the expressions of defensins [122, 127]. Nuclear receptors represent a class of intracellular transcription factors activated by ligands which can directly interact with DNA; as a result, nuclear receptors play significant roles in the regulation of metabolic, reproductive, developmental, and immune processes [128–131]. Nuclear receptors regulate transcriptional activity by several distinct mechanisms, including “ligand-dependent transactivation, ligand-independent repression, and ligand-dependent transrepression” although the range of transcriptional activities of each nuclear receptor varies and even the transcriptional effects of a single nuclear receptor may be cell specific [132]. A detailed discussion of nuclear receptors and their mechanisms of action is beyond the scope of this article; however, further discussion of two nuclear receptors (peroxisome-proliferator-activated receptor gamma (PPARγ) and vitamin D receptor (VDR)) with putative roles in inflammation is warranted.

PPARγ is a member of a class of nuclear receptors that form obligate heterodimers with the retinoid X receptor (RXR) [129]. The PPAR family has been shown to affect various cellular functions including “adipocyte differentiation, fatty-acid oxidation, and glucose metabolism” [129]. PPARγ is highly expressed in the large intestine [133], and its activation has been shown to be protective in animal models of colitis [134, 135]. Decreased PPARγ expression in UC patients has been shown [136], and the anti-inflammatory compound 5-aminosalicylic acid (5-ASA) commonly utilized in IBD therapy was shown to be a PPARγ agonist, thereby establishing a possible mechanism by which it exerts its anti-inflammatory effects [137]. PPARγ also plays a role in the maintenance of “constitutive epithelial expression of a subset of β defensins in the colon” [122].

6. Vitamin D and Vitamin D Receptor (VDR)

Vitamin D receptor (VDR) is a nuclear receptor that mediates most known functions of 1,25-dihydroxyvitamin D (1,25(OH)2D3), the active form of vitamin D [138]. VDR heterodimerizes with RXR once VDR is activated by 1,25(OH)2D3. VDR binds to the vitamin D response element in the target gene promoter to regulate gene transcription [139]. VDR downstream target genes include antimicrobial peptides such as cathelicidin and β defensin.

VDR is critical in regulating intestinal homeostasis by preventing pathogenic bacterial invasion, inhibiting inflammation, and maintaining cell integrity [140–145]. Vitamin D directly modulates the T-cell receptor (TCR) [146], and vitamin D has also been shown to downregulate the expression of proinflammatory cytokines and have regulatory effects on autophagy and various immune cells including T cells, B cells, macrophages, dendritic cells, and epithelial cells [147, 148]. It has been reported that 1,25(OH)2D3 suppresses the development of IBD in animal models [149]. Deficiency of 1,25(OH)2D3 has been reported in patients with IBD [150, 151], and, recently, using a novel vitamin D bioavailability test, vitamin D deficiency or insufficiency was seen in more than 70% of patients with quiescent CD [152]. Given the diverse immune functions of vitamin D, deficient levels may have important implications for the development and maintenance of intestinal homeostasis. A possible role of vitamin D status and VDR signaling in modulating the effects of intestinal microflora in other conditions such as asthma and obesity has been suggested [100]. While present literature has primarily focused on elucidating the immunoregulatory effects of vitamin D, there is a paucity of data on the status and function of VDR [147]. In addition, probiotic-induced modulation of anti-inflammatory VDR signaling in colitis remains virtually unexplored.

Recent studies indicate that VDR−/− mice have increased bacterial loading in the intestine [145, 153]. Our microarray data found that VDR signaling responds to pathogenic Salmonella in intestinal colitis in vivo [154]. Data from a recent study demonstrate that bacterial stimulation, both commensal and pathogenic, regulates VDR expression and location and that VDR negatively regulates bacterial-induced intestinal NF-κB activation [153]. In general, probiotic-induced nuclear receptor signaling is not well characterized. The probiotic VSL3# was associated with nuclear receptor signaling in the IL10−/− colitis model [67]. Nuclear receptors have been shown to negatively regulate bacterial-stimulated NF-κB activity in intestinal epithelium [153, 155]. Our recent data show probiotic treatment is able to enhance VDR expression and activity in the host. An increase in VDR expression and a concomitant increase in cathelicidin mRNA in cultured intestinal epithelial cells when treated with Lactobacillus plantarum were seen [156]. We used a probiotic monoassociated pig model to assess the probiotic effect on VDR expression in vivo and found intestinal VDR increased significantly after probiotic colonization compared to the ex-germ-free pig. Furthermore, our unpublished data indicate that probiotics did not inhibit inflammation in mice lacking VDR.

The presence of VDR in various tissues along with its ability to exert diverse actions in differentiation, growth, and anti-inflammation sets the stage for exploitation of VDR ligands for the treatment of various inflammatory conditions [157, 158]. Although the potential importance of VDR as a therapeutic target has been appreciated [159], no approach to date has safely and effectively altered VDR’s activity. Hence, understanding VDR’s contribution to probiotic-induced anti-inflammation may provide significant insight in the pathogenesis of inflammatory conditions such as IBD, and thereby, guide the development of novel treatments. Further investigation of the complex interplay of nuclear receptors, defensins, probiotics, and inflammatory pathways may provide significant insight into the mechanisms of action of probiotics in anti-inflammation.

7. Current Problems and Future Directions

The individual diversity of the intestinal microflora underscores the difficulty of identifying the entire human microbiota and poses barriers to this field of research. In addition, it is apparent that the actions of probiotics are species and strain specific [19]. It is also apparent that even a single strain of probiotic may exert its actions via multiple, concomitant pathways. Current investigation into the mechanism of action of specific probiotics has focused on probiotic-induced changes in the innate immune functions involving TLRs and its downstream systems including NF-κB, JAK-STAT, MAPK, and SAPK/JNK pathways. Future research on novel mechanisms of action for probiotics involving nuclear receptor signaling, including PPARγ and VDR, is needed. With evolving knowledge, effective probiotic therapy will be possible in the future.

Abbreviations

AAD:Antibiotic-associated diarrhea
AP-1:Activator protein-1
CD:Crohn’s disease
CDAD:Clostridium-difficile-associated disease
CDM:Chemically defined media
CM:Conditioned media
CTFR:Cystic fibrosis transmembrane conductance regulator
ECN:E. coli Nissle 1917
EGFR:Epidermal growth factor receptor
EHEC:E. coli O157:H7
EPEC:Enteropathogenic E. coli
ERK:Extracellular-signal-regulated kinase
GSH:Glutathione
hBD:Human beta defensin
HSP:Heat shock proteins
IBD:Inflammatory bowel disease
IBS:Irritable bowel syndrome
IEC:Intestinal epithelial cell
IFN:Interferon
IL:Interleukin
IκB:Inhibitor of kappa B
JAK/STAT:Janus kinase/signal transducers and activators of transcription
La:Lactobacillus acidophilus
Lc:Lactobacillus casei
LcS:Lactobacillus casei Shirota
LGG:Lactobacillus rhamnosus GG
LI-LPMC:Large intestinal lamina propria mononuclear cells
LP:Lactobacillus plantarum
LPS:Lipopolysaccharide
Lr:Lactobacillus rhamnosus
MAPK:Mitogen-activated protein kinase
MCP:Monocyte chemotactic protein
NEC:Necrotizing enterocolitis
NF-κB:Nuclear factor kappa B
PKC:Protein kinase C
PPARγ:Peroxisome-proliferator-activated receptor gamma
ROS:Reactive oxygen species
RXR:Retinoid X receptor
SAPK/JNK:Stress-activated protein kinase/c-Jun NH2-terminal kinase
Sb:Saccharomyces boulardii
SOCS:Suppressor of cytokine signaling
TCR:T-cell receptor
TER:Transepithelial electrical resistance
TJs:Tight junctions
TLR:Toll-like receptor
TNF:Tumor necrosis factor
UC:Ulcerative colitis
UCB:Unconjugated bilirubin
VDR:Vitamin D receptor
ZO:Zonula occludens.

Acknowledgments

This work was supported by the National Institutes of Health (DK075386-0251, R03DK089010-01) and the IDEAL award from the New York State’s Empire State Stem Cell Board (N09G-279) to J. Sun.

References

  1. L. V. McFarland, “Evidence-based review of probiotics for antibiotic-associated diarrhea and Clostridium difficile infections,” Anaerobe, vol. 15, no. 6, pp. 274–280, 2009. View at Publisher · View at Google Scholar · View at Scopus
  2. A. S. Neish, “Microbes in gastrointestinal health and disease,” Gastroenterology, vol. 136, no. 1, pp. 65–80, 2009. View at Publisher · View at Google Scholar · View at Scopus
  3. W. S. Garrett, J. I. Gordon, and L. H. Glimcher, “Homeostasis and Inflammation in the Intestine,” Cell, vol. 140, no. 6, pp. 859–870, 2010. View at Publisher · View at Google Scholar · View at Scopus
  4. M. Joossens, G. Huys, M. Cnockaert et al., “Dysbiosis of the faecal microbiota in patients with Crohn's disease and their unaffected relatives,” Gut, vol. 60, no. 5, pp. 631–637, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. I. Sobhani, J. Tap, F. Roudot-Thoraval et al., “Microbial dysbiosis in colorectal cancer (CRC) patients,” PLoS ONE, vol. 6, no. 1, Article ID e16393, 2011. View at Publisher · View at Google Scholar
  6. Y. M. Sjögren, M. C. Jenmalm, M. F. Böttcher, B. Björkstén, and E. Sverremark-Ekström, “Altered early infant gut microbiota in children developing allergy up to 5 years of age,” Clinical and Experimental Allergy, vol. 39, no. 4, pp. 518–526, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. B. Björkstén, P. Naaber, E. Sepp, and M. Mikelsaar, “The intestinal microflora in allergic Estonian and Swedish 2-year-old children,” Clinical and Experimental Allergy, vol. 29, no. 3, pp. 342–346, 1999. View at Publisher · View at Google Scholar
  8. A. W. Yan, D. E. Fouts, J. Brandl et al., “Enteric dysbiosis associated with a mouse model of alcoholic liver disease,” Hepatology, vol. 53, no. 1, pp. 96–105, 2011. View at Publisher · View at Google Scholar
  9. A. Kassinen, L. Krogius-Kurikka, H. Mäkivuokko et al., “The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects,” Gastroenterology, vol. 133, no. 1, pp. 24–33, 2007. View at Publisher · View at Google Scholar · View at Scopus
  10. R. E. Ley, P. J. Turnbaugh, S. Klein, and J. I. Gordon, “Microbial ecology: human gut microbes associated with obesity,” Nature, vol. 444, no. 7122, pp. 1022–1023, 2006. View at Publisher · View at Google Scholar · View at Scopus
  11. M. Vijay-Kumar, J. D. Aitken, F. A. Carvalho et al., “Metabolie syndrome and altered gut microbiota in mice lacking toll-like receptor 5,” Science, vol. 328, no. 5975, pp. 228–231, 2010. View at Publisher · View at Google Scholar · View at Scopus
  12. R. E. Ley, “Obesity and the human microbiome,” Current Opinion in Gastroenterology, vol. 26, no. 1, pp. 5–11, 2010. View at Publisher · View at Google Scholar · View at Scopus
  13. R. E. Ley, F. Bäckhed, P. Turnbaugh, C. A. Lozupone, R. D. Knight, and J. I. Gordon, “Obesity alters gut microbial ecology,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 31, pp. 11070–11075, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. C. Manichanh, L. Rigottier-Gois, E. Bonnaud et al., “Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach,” Gut, vol. 55, no. 2, pp. 205–211, 2006. View at Publisher · View at Google Scholar · View at Scopus
  15. D. N. Frank, A. L. S. Amand, R. A. Feldman, E. C. Boedeker, N. Harpaz, and N. R. Pace, “Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 34, pp. 13780–13785, 2007. View at Publisher · View at Google Scholar · View at Scopus
  16. M. P. Conte, S. Schippa, I. Zamboni et al., “Gut-associated bacterial microbiota in paediatric patients with inflammatory bowel disease,” Gut, vol. 55, no. 12, pp. 1760–1767, 2006. View at Publisher · View at Google Scholar · View at Scopus
  17. R. B. Sartor, “Microbial influences in inflammatory bowel diseases,” Gastroenterology, vol. 134, no. 2, pp. 577–594, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. C. D. Packey and R. B. Sartor, “Interplay of commensal and pathogenic bacteria, genetic mutations, and immunoregulatory defects in the pathogenesis of inflammatory bowel diseases,” Journal of Internal Medicine, vol. 263, no. 6, pp. 597–606, 2008. View at Publisher · View at Google Scholar · View at Scopus
  19. C. Reiff and D. Kelly, “Inflammatory bowel disease, gut bacteria and probiotic therapy,” International Journal of Medical Microbiology, vol. 300, no. 1, pp. 25–33, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. R. B. Sartor, “Mechanisms of disease: pathogenesis of crohn's disease and ulcerative colitis,” Nature Clinical Practice Gastroenterology and Hepatology, vol. 3, no. 7, pp. 390–407, 2006. View at Publisher · View at Google Scholar
  21. D. M. Lilly and R. H. Stillwell, “Probiotics: growth-promoting factors produced by microorganisms,” Science, vol. 147, no. 3659, pp. 747–748, 1965. View at Google Scholar · View at Scopus
  22. E. M. Quigley, “Probiotics in gastrointestinal disorders,” Hospital Practice, vol. 38, no. 4, pp. 122–129, 2010. View at Google Scholar
  23. T. A. Oelschlaeger, “Mechanisms of probiotic actions—a review,” International Journal of Medical Microbiology, vol. 300, no. 1, pp. 57–62, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. B. G. Spyropoulos, E. P. Misiakos, C. Fotiadis, and C. N. Stoidis, “Antioxidant properties of probiotics and their protective effects in the pathogenesis of radiation-induced enteritis and coliti,” Digestive Diseases and Sciences, vol. 52, no. 2, pp. 285–294, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. F. Yan and D. B. Polk, “Probiotics as functional food in the treatment of diarrhea,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 9, no. 6, pp. 717–721, 2006. View at Publisher · View at Google Scholar · View at Scopus
  26. K. Madsen, “Probiotics in critically ill patients,” Journal of Clinical Gastroenterology, vol. 42, supplement 3, pp. S116–S118, 2008. View at Google Scholar · View at Scopus
  27. C. I. Fotiadis, C. N. Stoidis, B. G. Spyropoulos, and E. D. Zografos, “Role of probiotics, prebiotics and synbiotics in chemoprevention for colorectal cancer,” World Journal of Gastroenterology, vol. 14, no. 42, pp. 6453–6457, 2008. View at Publisher · View at Google Scholar · View at Scopus
  28. R. Francavilla, V. Miniello, A. M. Magistà et al., “A randomized controlled trial of lactobacillus GG in children with functional abdominal pain,” Pediatrics, vol. 126, no. 6, pp. e1445–e1452, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. D. W. Thomas, F. R. Greer, J. J. S. Bhatia et al., “Clinical report—probiotics and prebiotics in pediatrics,” Pediatrics, vol. 126, no. 6, pp. 1217–1231, 2010. View at Publisher · View at Google Scholar · View at Scopus
  30. D. Damaskos and G. Kolios, “Probiotics and prebiotics in inflammatory bowel disease: microflora 'on the scope',” British Journal of Clinical Pharmacology, vol. 65, no. 4, pp. 453–467, 2008. View at Publisher · View at Google Scholar · View at Scopus
  31. A. Tursi, G. Brandimarte, A. Papa et al., “Treatment of relapsing mild-to-moderate ulcerative colitis with the probiotic VSL3 as adjunctive to a standard pharmaceutical treatment: a double-blind, randomized, placebo-controlled study,” American Journal of Gastroenterology, vol. 105, no. 10, pp. 2218–2227, 2010. View at Publisher · View at Google Scholar · View at Scopus
  32. C. Vanderpool, F. Yan, and D. B. Polk, “Mechanisms of probiotic action: implications for therapeutic applications in inflammatory bowel diseases,” Inflammatory Bowel Diseases, vol. 14, no. 11, pp. 1585–1596, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. T. Watanabe, H. Nishio, T. Tanigawa et al., “Probiotic Lactobacillus casei strain Shirota prevents indomethacin-induced small intestinal injury: involvement of lactic acid,” American Journal of Physiology, vol. 297, no. 3, pp. G506–G513, 2009. View at Publisher · View at Google Scholar
  34. L. Zhang, N. Li, R. Caicedo, and J. Neu, “Alive and dead Lactobacillus rhamnosus GG decrease tumor necrosis factor-α-induced interleukin-8 production in Caco-2 cells,” Journal of Nutrition, vol. 135, no. 7, pp. 1752–1756, 2005. View at Google Scholar · View at Scopus
  35. E. O. Petrof, K. Kojima, M. J. Ropeleski et al., “Probiotics inhibit nuclear factor-κB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition,” Gastroenterology, vol. 127, no. 5, pp. 1474–1487, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. E. O. Petrof, E. C. Claud, J. Sun et al., “Bacteria-free solution derived from Lactobacillus plantarum inhibits multiple NF-kappaB pathways and inhibits proteasome function,” Inflammatory Bowel Diseases, vol. 15, no. 10, pp. 1537–1547, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. B. Wang, J. Li, J. Chen, Q. Huang, N. Li, and J. Li, “Effect of live Lactobacillus plantarum L2 on TNF-α-induced MCP-1 production in Caco-2 cells,” International Journal of Food Microbiology, vol. 142, no. 1-2, pp. 237–241, 2010. View at Publisher · View at Google Scholar · View at Scopus
  38. M. T. Tien, S. E. Girardin, B. Regnault et al., “Anti-inflammatory effect of Lactobacillus casei on Shigella-infected human intestinal epithelial cells,” Journal of Immunology, vol. 176, no. 2, pp. 1228–1237, 2006. View at Google Scholar · View at Scopus
  39. P. A. Ruiz, M. Hoffmann, S. Szcesny, M. Blaut, and D. Haller, “Innate mechanisms for Bifidobacterium lactis to activate transient pro-inflammatory host responses in intestinal epithelial cells after the colonization of germ-free rats,” Immunology, vol. 115, no. 4, pp. 441–450, 2005. View at Publisher · View at Google Scholar · View at Scopus
  40. F. S. Martins, G. Dalmasso, R. M. E. Arantes et al., “Interaction of Saccharomyces boulardii with Salmonella enterica serovar typhimurium protects mice and modifies T84 cell response to the infection,” PLoS ONE, vol. 5, no. 1, Article ID e8925, 2010. View at Publisher · View at Google Scholar · View at Scopus
  41. M. Schlee, J. Harder, B. Köten, E. F. Stange, J. Wehkamp, and K. Fellermann, “Probiotic lactobacilli and VSL#3 induce enterocyte β-defensin 2,” Clinical and Experimental Immunology, vol. 151, no. 3, pp. 528–535, 2008. View at Publisher · View at Google Scholar · View at Scopus
  42. J. Wehkamp, J. Harder, K. Wehkamp et al., “NF-κB- and AP-1-mediated induction of human beta defensin-2 in intestinal epithelial cells by Escherichia coli Nissle 1917: a novel effect of a probiotic bacterium,” Infection and Immunity, vol. 72, no. 10, pp. 5750–5758, 2004. View at Publisher · View at Google Scholar · View at Scopus
  43. Y. Tao, K. A. Drabik, T. S. Waypa et al., “Soluble factors from Lactobacillus GG activate MAPKs and induce cytoprotective heat shock proteins in intestinal epithelial cells,” American Journal of Physiology, vol. 290, no. 4, pp. C1018–C1030, 2006. View at Publisher · View at Google Scholar · View at Scopus
  44. X. Chen, J. Fruehauf, J. D. Goldsmith et al., “Saccharomyces boulardii inhibits EGF receptor signaling and intestinal tumor growth in Apc(min) mice,” Gastroenterology, vol. 137, no. 3, pp. 914–923, 2009. View at Publisher · View at Google Scholar · View at Scopus
  45. D. Ghadimi, M. De Vrese, K. J. Heller, and J. Schrezenmeir, “Effect of natural commensal-origin DNA on toll-like receptor 9 (TLR9) signaling cascade, chemokine IL-8 expression, and barrier integritiy of polarized intestinal epithelial cells,” Inflammatory Bowel Diseases, vol. 16, no. 3, pp. 410–427, 2010. View at Publisher · View at Google Scholar · View at Scopus
  46. M. G. Vizoso Pinto, M. Rodriguez Gómez, S. Seifert, B. Watzl, W. H. Holzapfel, and C. M. A. P. Franz, “Lactobacilli stimulate the innate immune response and modulate the TLR expression of HT29 intestinal epithelial cells in vitro,” International Journal of Food Microbiology, vol. 133, no. 1-2, pp. 86–93, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. D. Rachmilewitz, K. Katakura, F. Karmeli et al., “Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis,” Gastroenterology, vol. 126, no. 2, pp. 520–528, 2004. View at Publisher · View at Google Scholar · View at Scopus
  48. A. Grabig, D. Paclik, C. Guzy et al., “Escherichia coli strain Nissle 1917 ameliorates experimental colitis via toll-like receptor 2- and toll-like receptor 4-dependent pathways,” Infection and Immunity, vol. 74, no. 7, pp. 4075–4082, 2006. View at Publisher · View at Google Scholar · View at Scopus
  49. R. Kaji, J. Kiyoshima-Shibata, M. Nagaoka, M. Nanno, and K. Shida, “Bacterial teichoic acids reverse predominant IL-12 production induced by certain lactobacillus strains into predominant IL-10 production via TLR2-dependent ERK activation in macrophages,” Journal of Immunology, vol. 184, no. 7, pp. 3505–3513, 2010. View at Publisher · View at Google Scholar · View at Scopus
  50. A. Seth, F. Yan, D. B. Polk, and R. K. Rao, “Probiotics ameliorate the hydrogen peroxide-induced epithelial barrier disruption by a PKC- And MAP kinase-dependent mechanism,” American Journal of Physiology, vol. 294, no. 4, pp. G1060–G1069, 2008. View at Publisher · View at Google Scholar
  51. J. B. Ewaschuk, H. Diaz, L. Meddings et al., “Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function,” American Journal of Physiology, vol. 295, no. 5, pp. G1025–G1034, 2008. View at Publisher · View at Google Scholar
  52. R. C. Anderson, A. L. Cookson, W. C. McNabb et al., “Lactobacillus plantarum MB452 enhances the function of the intestinal barrier by increasing the expression levels of genes involved in tight junction formation,” BMC Microbiology, vol. 10, article 316, 2010. View at Publisher · View at Google Scholar
  53. Y. Zhou, H. Qin, M. Zhang et al., “Lactobacillus plantarum inhibits intestinal epithelial barrier dysfunction induced by unconjugated bilirubin,” British Journal of Nutrition, vol. 104, no. 3, pp. 390–401, 2010. View at Publisher · View at Google Scholar · View at Scopus
  54. R. C. Anderson, A. L. Cookson, W. C. McNabb, W. J. Kelly, and N. C. Roy, “Lactobacillus plantarum DSM 2648 is a potential probiotic that enhances intestinal barrier function,” FEMS Microbiology Letters, vol. 309, no. 2, pp. 184–192, 2010. View at Publisher · View at Google Scholar · View at Scopus
  55. J. Karczewski, F. J. Troost, I. Konings et al., “Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier,” American Journal of Physiology, vol. 298, no. 6, pp. G851–G859, 2010. View at Publisher · View at Google Scholar
  56. L. Khailova, K. Dvorak, K. M. Arganbright et al., “Bifidobacterium bifidum improves intestinal integrity in a rat model of necrotizing enterocolitis,” American Journal of Physiology, vol. 297, no. 5, pp. G940–G949, 2009. View at Publisher · View at Google Scholar
  57. R. Mennigen, K. Nolte, E. Rijcken et al., “Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis,” American Journal of Physiology, vol. 296, no. 5, pp. G1140–G1149, 2009. View at Publisher · View at Google Scholar
  58. G. Moorthy, M. R. Murali, and S. N. Devaraj, “Lactobacilli facilitate maintenance of intestinal membrane integrity during Shigella dysenteriae 1 infection in rats,” Nutrition, vol. 25, no. 3, pp. 350–358, 2009. View at Publisher · View at Google Scholar · View at Scopus
  59. H. Putaala, T. Salusjärvi, M. Nordström et al., “Effect of four probiotic strains and Escherichia coli O157:H7 on tight junction integrity and cyclo-oxygenase expression,” Research in Microbiology, vol. 159, no. 9-10, pp. 692–698, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. S. N. Ukena, A. Singh, U. Dringenberg et al., “Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity,” PLoS ONE, vol. 2, no. 12, Article ID e1308, 2007. View at Publisher · View at Google Scholar · View at Scopus
  61. A. A. Zyrek, C. Cichon, S. Helms, C. Enders, U. Sonnenborn, and M. A. Schmidt, “Molecular mechanisms underlying the probiotic effects of Escherichia coli Nissle 1917 involve ZO-2 and PKCζ redistribution resulting in tight junction and epithelial barrier repair,” Cellular Microbiology, vol. 9, no. 3, pp. 804–816, 2007. View at Publisher · View at Google Scholar
  62. K. C. Johnson-Henry, K. A. Donato, G. Shen-Tu, M. Gordanpour, and P. M. Sherman, “Lactobacillus rhamnosus strain GG prevents enterohemorrhagic Escherichia coli O157:H7-induced changes in epithelial barrier function,” Infection and Immunity, vol. 76, no. 4, pp. 1340–1348, 2008. View at Publisher · View at Google Scholar · View at Scopus
  63. S. Resta-Lenert and K. E. Barrett, “Probiotics and commensals reverse TNF-α- and IFN-γ-induced dysfunction in human intestinal epithelial cells,” Gastroenterology, vol. 130, no. 3, pp. 731–746, 2006. View at Publisher · View at Google Scholar · View at Scopus
  64. S. Matsumoto, T. Hara, T. Hori et al., “Probiotic Lactobacillus-induced improvement in murine chronic inflammatory bowel disease is associated with the down-regulation of pro-inflammatory cytokines in lamina propria mononuclear cells,” Clinical and Experimental Immunology, vol. 140, no. 3, pp. 417–426, 2005. View at Publisher · View at Google Scholar · View at Scopus
  65. N. Jandu, Z. J. Zeng, K. C. Johnson-Henry, and P. M. Sherman, “Probiotics prevent enterohaemorrhagic Escherichia coli O157 : H7-mediated inhibition of interferon-γ-induced tyrosine phosphorylation of STAT-1,” Microbiology, vol. 155, no. Pt 2, pp. 531–540, 2009. View at Publisher · View at Google Scholar · View at Scopus
  66. F. S. Martins, S. D. A. Elian, A. T. Vieira et al., “Oral treatment with Saccharomyces cerevisiae strain UFMG 905 modulates immune responses and interferes with signal pathways involved in the activation of inflammation in a murine model of typhoid fever,” International Journal of Medical Microbiology, vol. 301, no. 4, pp. 359–364, 2011. View at Publisher · View at Google Scholar
  67. C. Reiff, M. Delday, G. Rucklidge et al., “Balancing inflammatory, lipid, and xenobiotic signaling pathways by VSL#3, a biotherapeutic agent, in the treatment of inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 15, no. 11, pp. 1721–1736, 2009. View at Publisher · View at Google Scholar · View at Scopus
  68. A. K. Rooj, Y. Kimura, and R. K. Buddington, “Metabolites produced by probiotic Lactobacilli rapidly increase glucose uptake by Caco-2 cells,” BMC Microbiology, vol. 10, article 16, 2010. View at Publisher · View at Google Scholar · View at Scopus
  69. P. W. Lin, L. E. S. Myers, L. Ray et al., “Lactobacillus rhamnosus blocks inflammatory signaling in vivo via reactive oxygen species generation,” Free Radical Biology and Medicine, vol. 47, no. 8, pp. 1205–1211, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. B. Eiseman, W. Silen, G. S. Bascom, and A. J. Kauvar, “Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis,” Surgery, vol. 44, no. 5, pp. 854–859, 1958. View at Google Scholar
  71. J. Aas, C. E. Gessert, and J. S. Bakken, “Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube,” Clinical Infectious Diseases, vol. 36, no. 5, pp. 580–585, 2003. View at Publisher · View at Google Scholar · View at Scopus
  72. S. E. Persky and L. J. Brandt, “Treatment of recurrent Clostridium difficile-associated diarrhea by administration of donated stool directly through a colonoscope,” American Journal of Gastroenterology, vol. 95, no. 11, pp. 3283–3285, 2000. View at Publisher · View at Google Scholar · View at Scopus
  73. S. S. Yoon and L. J. Brandt, “Treatment of refractory/recurrent C. difficile-associated disease by donated stool transplanted via colonoscopy: a case series of 12 patients,” Journal of Clinical Gastroenterology, vol. 44, no. 8, pp. 562–566, 2010. View at Publisher · View at Google Scholar · View at Scopus
  74. G. Russell, J. Kaplan, M. Ferraro, and I. C. Michelow, “Fecal bacteriotherapy for relapsing Clostridium difficile infection in a child: a proposed treatment protocol,” Pediatrics, vol. 126, no. 1, pp. e239–e242, 2010. View at Publisher · View at Google Scholar · View at Scopus
  75. A. Khoruts, J. Dicksved, J. K. Jansson, and M. J. Sadowsky, “Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent clostridium difficile-associated diarrhea,” Journal of Clinical Gastroenterology, vol. 44, no. 5, pp. 354–360, 2010. View at Publisher · View at Google Scholar · View at Scopus
  76. X. W. Gao, M. Mubasher, C. Y. Fang, C. Reifer, and L. E. Miller, “Dose-response efficacy of a proprietary probiotic formula of lactobacillus acidophilus CL1285 and lactobacillus casei LBC80R for antibiotic-associated diarrhea and clostridium difficile-associated diarrhea prophylaxis in adult patients,” American Journal of Gastroenterology, vol. 105, no. 7, pp. 1636–1641, 2010. View at Publisher · View at Google Scholar · View at Scopus
  77. L. V. McFarland, “Systematic review and meta-analysis of saccharomyces boulardii in adult patients,” World Journal of Gastroenterology, vol. 16, no. 18, pp. 2202–2222, 2010. View at Publisher · View at Google Scholar · View at Scopus
  78. S. Guglielmetti, D. Mora, M. Gschwender, and K. Popp, “Randomised clinical trial: bifidobacterium bifidum MIMBb75 significantly alleviates irritable bowel syndrome and improves quality of life—a double-blind, placebo-controlled study,” Alimentary Pharmacology and Therapeutics, vol. 33, no. 10, pp. 1123–1132, 2011. View at Publisher · View at Google Scholar
  79. C. H. Choi, S. Y. Jo, H. J. Park, S. K. Chang, J.-S. Byeon, and S.-J. Myung, “A randomized, double-blind, placebo-controlled multicenter trial of saccharomyces boulardii in irritablebowel syndrome: effect on quality of life,” Journal of Clinical Gastroenterology. In press.
  80. G. C. Parkes, J. D. Sanderson, and K. Whelan, “Treating irritable bowel syndrome with probiotics: the evidence,” Proceedings of the Nutrition Society, vol. 69, no. 2, pp. 187–194, 2010. View at Publisher · View at Google Scholar · View at Scopus
  81. P. Moayyedi, A. C. Ford, N. J. Talley et al., “The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review,” Gut, vol. 59, no. 3, pp. 325–332, 2010. View at Publisher · View at Google Scholar · View at Scopus
  82. D. M. Brenner, M. J. Moeller, W. D. Chey, and P. S. Schoenfeld, “The utility of probiotics in the treatment of irritable bowel syndrome: a systematic review,” American Journal of Gastroenterology, vol. 104, no. 4, pp. 1033–1049, 2009. View at Publisher · View at Google Scholar · View at Scopus
  83. A. Sood, V. Midha, G. K. Makharia et al., “The probiotic preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative colitis,” Clinical Gastroenterology and Hepatology, vol. 7, no. 11, pp. 1202–1209, 2009. View at Publisher · View at Google Scholar
  84. R. Bibiloni, R. N. Fedorak, G. W. Tannock et al., “VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis,” American Journal of Gastroenterology, vol. 100, no. 7, pp. 1539–1546, 2005. View at Publisher · View at Google Scholar · View at Scopus
  85. W. Kruis, P. Frič, J. Pokrotnieks et al., “Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine,” Gut, vol. 53, no. 11, pp. 1617–1623, 2004. View at Publisher · View at Google Scholar · View at Scopus
  86. M. A. Zocco, L. Z. Dal Verme, F. Cremonini et al., “Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis,” Alimentary Pharmacology and Therapeutics, vol. 23, no. 11, pp. 1567–1574, 2006. View at Publisher · View at Google Scholar · View at Scopus
  87. P. Gionchetti, F. Rizzello, U. Helwig et al., “Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial,” Gastroenterology, vol. 124, no. 5, pp. 1202–1209, 2003. View at Publisher · View at Google Scholar · View at Scopus
  88. T. Mimura, F. Rizzello, U. Helwig et al., “Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis,” Gut, vol. 53, no. 1, pp. 108–114, 2004. View at Publisher · View at Google Scholar · View at Scopus
  89. C. Prantera, M. L. Scribano, G. Falasco, A. Andreoli, and C. Luzi, “Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn's disease: a randomised controlled trial with Lactobacillus GG,” Gut, vol. 51, no. 3, pp. 405–409, 2002. View at Publisher · View at Google Scholar · View at Scopus
  90. E. Garcia Vilela, M. De Lourdes De Abreu Ferrari, H. Oswaldo Da Gama Torres et al., “Influence of Saccharomyces boulardii on the intestinal permeability of patients with Crohn's disease in remission,” Scandinavian Journal of Gastroenterology, vol. 43, no. 7, pp. 842–848, 2008. View at Publisher · View at Google Scholar · View at Scopus
  91. M. Guslandi, G. Mezzi, M. Sorghi, and P. A. Testoni, “Saccharomyces boulardii in maintenance treatment of Crohn's disease,” Digestive Diseases and Sciences, vol. 45, no. 7, pp. 1462–1464, 2000. View at Publisher · View at Google Scholar · View at Scopus
  92. J. B. Ewaschuk and L. A. Dieleman, “Probiotics and prebiotics in chronic inflammatory bowel diseases,” World Journal of Gastroenterology, vol. 12, no. 37, pp. 5941–5950, 2006. View at Google Scholar · View at Scopus
  93. C. Hedin, K. Whelan, and J. O. Lindsay, “Evidence for the use of probiotics and prebiotics in inflammatory bowel disease: a review of clinical trials,” Proceedings of the Nutrition Society, vol. 66, no. 3, pp. 307–315, 2007. View at Publisher · View at Google Scholar · View at Scopus
  94. S. C. Ng, A. L. Hart, M. A. Kamm, A. J. Stagg, and S. C. Knight, “Mechanisms of action of probiotics: recent advances,” Inflammatory Bowel Diseases, vol. 15, no. 2, pp. 300–310, 2009. View at Publisher · View at Google Scholar · View at Scopus
  95. K. Alfaleh and D. Bassler, “Probiotics for prevention of necrotizing enterocolitis in preterm infants,” Cochrane Database of Systematic Reviews, no. 1, article CD005496, 2008. View at Google Scholar · View at Scopus
  96. A. Bousvaros, S. Guandalini, R. N. Baldassano et al., “A randomized, double-blind trial of lactobacillus GG versus placebo in addition to standard maintenance therapy for children with Crohn's disease,” Inflammatory Bowel Diseases, vol. 11, no. 9, pp. 833–839, 2005. View at Publisher · View at Google Scholar · View at Scopus
  97. M. Schultz, A. Timmer, H. H. Herfarth, R. B. Sartor, J. A. Vanderhoof, and H. C. Rath, “Lactobacillus GG in inducing and maintaining remission of Crohn's disease,” BMC Gastroenterology, vol. 4, article 5, 2004. View at Publisher · View at Google Scholar · View at Scopus
  98. M. Mohamadzadeh, S. Olson, W. V. Kalina et al., “Lactobacilli active human dendritic cells that skew T cells toward T helper 1 polarization,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 8, pp. 2880–2885, 2005. View at Publisher · View at Google Scholar · View at Scopus
  99. A. L. Hart, K. Lammers, P. Brigidi et al., “Modulation of human dendritic cell phenotype and function by probiotic bacteria,” Gut, vol. 53, no. 11, pp. 1602–1609, 2004. View at Publisher · View at Google Scholar · View at Scopus
  100. E. M. Fernandez, V. Valenti, C. Rockel et al., “Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide,” Gut, vol. 60, no. 8, pp. 1050–1059, 2011. View at Google Scholar
  101. M. Chamaillard, S. E. Girardin, J. Viala, and D. J. Philpott, “Nods, nalps and naip: intracellular regulators of bacterial-induced inflammation,” Cellular Microbiology, vol. 5, no. 9, pp. 581–592, 2003. View at Publisher · View at Google Scholar · View at Scopus
  102. J. Wehkamp and E. F. Stange, “Is there a role for defensins in IBD?” Inflammatory Bowel Diseases, vol. 14, supplement 2, pp. S85–S87, 2008. View at Google Scholar
  103. M. Schlee, J. Wehkamp, A. Altenhoefer, T. A. Oelschlaeger, E. F. Stange, and K. Fellermann, “Induction of human β-defensin 2 by the probiotic Escherichia coli Nissle 1917 is mediated through flagellin,” Infection and Immunity, vol. 75, no. 5, pp. 2399–2407, 2007. View at Publisher · View at Google Scholar · View at Scopus
  104. D. Hollander, “Crohn's disease—a permeability disorder of the tight junction?” Gut, vol. 29, no. 12, pp. 1621–1624, 1988. View at Google Scholar · View at Scopus
  105. J. D. Schulzke, S. Ploeger, M. Amasheh et al., “Epithelial tight junctions in intestinal inflammation,” Annals of the New York Academy of Sciences, vol. 1165, pp. 294–300, 2009. View at Publisher · View at Google Scholar · View at Scopus
  106. C. R. Weber, S. C. Nalle, M. Tretiakova, D. T. Rubin, and J. R. Turner, “Claudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation,” Laboratory Investigation, vol. 88, no. 10, pp. 1110–1120, 2008. View at Publisher · View at Google Scholar · View at Scopus
  107. S. Zeissig, N. Bürgel, D. Günzel et al., “Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn's disease,” Gut, vol. 56, no. 1, pp. 61–72, 2007. View at Publisher · View at Google Scholar · View at Scopus
  108. I. D. R. Arnott, K. Kingstone, and S. Ghosh, “Abnormal intestinal permeability predicts relapse in inactive Crohn disease,” Scandinavian Journal of Gastroenterology, vol. 35, no. 11, pp. 1163–1169, 2000. View at Google Scholar · View at Scopus
  109. J. Wyatt, H. Vogelsang, W. Hubl, T. Waldhoer, and H. Lochs, “Intestinal permeability and the prediction of relapse in Crohn's disease,” Lancet, vol. 341, no. 8858, pp. 1437–1439, 1993. View at Publisher · View at Google Scholar · View at Scopus
  110. P. Lovato, C. Brender, J. Agnholt et al., “Constitutive STAT3 activation in intestinal T cells from patients with Crohn's disease,” Journal of Biological Chemistry, vol. 278, no. 19, pp. 16777–16781, 2003. View at Publisher · View at Google Scholar · View at Scopus
  111. M. Yeganegi, C. G. Leung, A. Martins et al., “Lactobacillus rhamnosus GR-1-induced IL-10 production in human placental trophoblast cells involves activation of JAK/STAT and MAPK pathways,” Reproductive Sciences, vol. 17, no. 11, pp. 1043–1051, 2010. View at Publisher · View at Google Scholar · View at Scopus
  112. A. Giuliani, G. Pirri, and S. F. Nicoletto, “Antimicrobial peptides: an overview of a promising class of therapeutics,” Central European Journal of Biology, vol. 2, no. 1, pp. 1–33, 2007. View at Publisher · View at Google Scholar · View at Scopus
  113. H. G. Boman, “Peptide antibiotics and their role in innate immunity,” Annual Review of Immunology, vol. 13, pp. 61–92, 1995. View at Google Scholar · View at Scopus
  114. M. Zasloff, “Antimicrobial peptides of multicellular organisms,” Nature, vol. 415, no. 6870, pp. 389–395, 2002. View at Publisher · View at Google Scholar · View at Scopus
  115. B. M. Peters, M. E. Shirtliff, and M. A. Jabra-Rizk, “Antimicrobial peptides: primeval molecules or future drugs?” PLoS Pathogens, vol. 6, no. 10, Article ID e1001067, 2010. View at Publisher · View at Google Scholar · View at Scopus
  116. J. Wehkamp, E. F. Stange, and K. Fellermann, “Defensin-immunology in inflammatory bowel disease,” Gastroentérologie Clinique et Biologique, vol. 33, supplement 3, pp. S137–144, 2009. View at Google Scholar
  117. Y. Q. Tang, J. Yuan, G. Ösapay et al., “A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated α-defensins,” Science, vol. 286, no. 5439, pp. 498–502, 1999. View at Publisher · View at Google Scholar · View at Scopus
  118. A. J. Ouellette and C. L. Bevins, “Paneth cell defensins and innate immunity of the small bowel,” Inflammatory Bowel Diseases, vol. 7, no. 1, pp. 43–50, 2001. View at Google Scholar
  119. J. Wehkamp, K. Fellermann, K. R. Herrlinger, C. L. Bevins, and E. F. Stange, “Mechanisms of disease: defensins in gastrointestinal diseases,” Nature Clinical Practice Gastroenterology and Hepatology, vol. 2, no. 9, pp. 406–415, 2005. View at Publisher · View at Google Scholar
  120. S. Jager, E. F. Stange, and J. Wehkamp, “Antimicrobial peptides in gastrointestinal inflammation,” International Journal of Inflammation, vol. 2010, Article ID 910283, 11 pages, 2010. View at Publisher · View at Google Scholar
  121. C. L. Wilson, A. J. Ouellette, D. P. Satchell et al., “Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense,” Science, vol. 286, no. 5437, pp. 113–117, 1999. View at Publisher · View at Google Scholar · View at Scopus
  122. L. Peyrin-Biroulet, J. Beisner, G. Wang et al., “Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 19, pp. 8772–8777, 2010. View at Publisher · View at Google Scholar · View at Scopus
  123. S. Lala, Y. Ogura, C. Osborne et al., “Crohn's disease and the NOD2 gene: a role for paneth cells,” Gastroenterology, vol. 125, no. 1, pp. 47–57, 2003. View at Publisher · View at Google Scholar · View at Scopus
  124. J. Wehkamp, J. Harder, M. Weichenthal et al., “NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal α-defensin expression,” Gut, vol. 53, no. 11, pp. 1658–1664, 2004. View at Publisher · View at Google Scholar · View at Scopus
  125. J. Wehkamp, J. Harder, M. Weichenthal et al., “Inducible and constitutive beta-defensins are differentially expressed in Crohn's disease and ulcerative colitis,” Inflammatory Bowel Diseases, vol. 9, no. 4, pp. 215–223, 2003. View at Google Scholar · View at Scopus
  126. H. G. Boman, “Innate immunity and the normal microflora,” Immunological Reviews, vol. 173, pp. 5–16, 2000. View at Publisher · View at Google Scholar · View at Scopus
  127. P. T. Liu, M. Schenk, V. P. Walker et al., “Convergence of IL-1β and VDR activation pathways in human TLR2/1-induced antimicrobial responses,” PLoS ONE, vol. 4, no. 6, Article ID e5810, 2009. View at Publisher · View at Google Scholar · View at Scopus
  128. R. M. Evans, “The steroid and thyroid hormone receptor superfamily,” Science, vol. 240, no. 4854, pp. 889–895, 1988. View at Google Scholar · View at Scopus
  129. S. J. Bensinger and P. Tontonoz, “Integration of metabolism and inflammation by lipid-activated nuclear receptors,” Nature, vol. 454, no. 7203, pp. 470–477, 2008. View at Publisher · View at Google Scholar · View at Scopus
  130. K. Wang and Y. J. Y. Wan, “Nuclear receptors and inflammatory diseases,” Experimental Biology and Medicine, vol. 233, no. 5, pp. 496–506, 2008. View at Publisher · View at Google Scholar · View at Scopus
  131. D. J. Mangelsdorf, C. Thummel, M. Beato et al., “The nuclear receptor super-family: the second decade,” Cell, vol. 83, no. 6, pp. 835–839, 1995. View at Google Scholar · View at Scopus
  132. C. K. Glass and S. Ogawa, “Combinatorial roles of nuclear receptors in inflammation and immunity,” Nature Reviews Immunology, vol. 6, no. 1, pp. 44–55, 2006. View at Publisher · View at Google Scholar · View at Scopus
  133. L. Fajas, D. Auboeuf, E. Raspé et al., “The organization, promoter analysis, and expression of the human PPARγ gene,” Journal of Biological Chemistry, vol. 272, no. 30, pp. 18779–18789, 1997. View at Publisher · View at Google Scholar · View at Scopus
  134. M. Adachi, R. Kurotani, K. Morimura et al., “Peroxisome proliferator activated receptor γ in colonic epithelial cells protects against experimental inflammatory bowel disease,” Gut, vol. 55, no. 8, pp. 1104–1113, 2006. View at Publisher · View at Google Scholar · View at Scopus
  135. J. Bassaganya-Riera, K. Reynolds, S. Martino-Catt et al., “Activation of PPAR γ and δ by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease,” Gastroenterology, vol. 127, no. 3, pp. 777–791, 2004. View at Publisher · View at Google Scholar
  136. L. Dubuquoy, E. Å Jansson, S. Deeb et al., “Impaired expression of peroxisome proliferator-activated receptor γin ulcerative colitis,” Gastroenterology, vol. 124, no. 5, pp. 1265–1276, 2003. View at Publisher · View at Google Scholar · View at Scopus
  137. C. Rousseaux, B. Lefebvre, L. Dubuquoy et al., “Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-γ,” Journal of Experimental Medicine, vol. 201, no. 8, pp. 1205–1215, 2005. View at Publisher · View at Google Scholar · View at Scopus
  138. M. R. Haussler, G. K. Whitfield, C. A. Haussler et al., “The nuclear vitamin D receptor: biological and molecular regulatory properties revealed,” Journal of Bone and Mineral Research, vol. 13, no. 3, pp. 325–349, 1998. View at Publisher · View at Google Scholar · View at Scopus
  139. S. Kato, “The function of vitamin D receptor in vitamin D action,” Journal of Biochemistry, vol. 127, no. 5, pp. 717–722, 2000. View at Google Scholar · View at Scopus
  140. D. L. Kamen and V. Tangpricha, “Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity,” Journal of Molecular Medicine, vol. 88, no. 5, pp. 441–450, 2010. View at Publisher · View at Google Scholar · View at Scopus
  141. J. C. Waterhouse, T. H. Perez, and P. J. Albert, “Reversing bacteria-induced vitamin D receptor dysfunction is key to autoimmune disease,” Annals of the New York Academy of Sciences, vol. 1173, pp. 757–765, 2009. View at Publisher · View at Google Scholar · View at Scopus
  142. P. T. Liu, S. R. Krutzik, and R. L. Modlin, “Therapeutic implications of the TLR and VDR partnership,” Trends in Molecular Medicine, vol. 13, no. 3, pp. 117–124, 2007. View at Publisher · View at Google Scholar · View at Scopus
  143. A. F. Gombart, N. Borregaard, and H. P. Koeffler, “Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3,” FASEB Journal, vol. 19, no. 9, pp. 1067–1077, 2005. View at Publisher · View at Google Scholar · View at Scopus
  144. J. Kong, Z. Zhang, M. W. Musch et al., “Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier,” American Journal of Physiology, vol. 294, no. 1, pp. G208–G216, 2008. View at Publisher · View at Google Scholar
  145. V. Lagishetty, A. V. Misharin, N. Q. Liu et al., “Vitamin D deficiency in mice impairs colonic antibacterial activity and predisposes to colitis,” Endocrinology, vol. 151, no. 6, pp. 2423–2432, 2010. View at Publisher · View at Google Scholar · View at Scopus
  146. M. R. Von Essen, M. Kongsbak, P. Schjerling, K. Olgaard, N. Ødum, and C. Geisler, “Vitamin D controls T cell antigen receptor signaling and activation of human T cells,” Nature Immunology, vol. 11, no. 4, pp. 344–349, 2010. View at Publisher · View at Google Scholar · View at Scopus
  147. J. Sun, “Vitamin D and mucosal immune function,” Current Opinion in Gastroenterology, vol. 26, no. 6, pp. 591–595, 2010. View at Publisher · View at Google Scholar · View at Scopus
  148. S. Wu and J. Sun, “Vitamin D, vitamin D receptor, and macroautophagy in inflammation and infection,” Discovery Medicine, vol. 11, no. 59, pp. 325–335, 2011. View at Google Scholar
  149. M. T. Cantorna, C. Munsick, C. Bemiss, and B. D. Mahon, “1,25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease,” Journal of Nutrition, vol. 130, no. 11, pp. 2648–2652, 2000. View at Google Scholar · View at Scopus
  150. T. A. Sentongo, E. J. Semaeo, N. Stettler, D. A. Piccoli, V. A. Stallings, and B. S. Zemel, “Vitamin D status in children, adolescents, and young adults with Crohn disease,” American Journal of Clinical Nutrition, vol. 76, no. 5, pp. 1077–1081, 2002. View at Google Scholar · View at Scopus
  151. M. T. Abreu, Y. Kantorovich, E. A. Vasiliauskas et al., “Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn's disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density,” Gut, vol. 53, no. 8, pp. 1129–1136, 2004. View at Publisher · View at Google Scholar · View at Scopus
  152. F. A. Farraye et al., “Use of a novel vitamin d bioavailability test demonstrates that vitamin D absorption is decreased in patients with quiescent crohn's disease,” Inflammatory Bowel Diseases.
  153. S. Wu, A. P. Liao, Y. Xia et al., “Vitamin D receptor negatively regulates bacterial-stimulated NF-κB activity in intestine,” American Journal of Pathology, vol. 177, no. 2, pp. 686–697, 2010. View at Publisher · View at Google Scholar · View at Scopus
  154. X. Liu, R. Lu, Y. Xia, and J. Sun, “Global analysis of the eukaryotic pathways and networks regulated by Salmonella typhimurium in mouse intestinal infection in vivo,” BMC Genomics, vol. 11, no. 1, p. 722, 2010. View at Publisher · View at Google Scholar · View at Scopus
  155. D. Kelly, J. I. Campbell, T. P. King et al., “Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shutting of PPAR-γ and ReIA,” Nature Immunology, vol. 5, no. 1, pp. 104–112, 2004. View at Publisher · View at Google Scholar
  156. S. Yoon, S. Wu, and Y. Zhang, “Probiotic regulation of vitamin D receptor in intestinal inflammation,” Oral Presentation DDW, 2011.
  157. E. Gocek and G. P. Studzinski, “Vitamin D and differentiation in cancer Signaling differentiation E. Gocek and G. P. Studzinski,” Critical Reviews in Clinical Laboratory Sciences, vol. 46, no. 4, pp. 190–209, 2009. View at Publisher · View at Google Scholar · View at Scopus
  158. S. Samuel and M. D. Sitrin, “Vitamin D's role in cell proliferation and differentiation,” Nutrition Reviews, vol. 66, supplement 2, no. 10, pp. S116–S124, 2008. View at Publisher · View at Google Scholar · View at Scopus
  159. M. B. Demay, “Mechanism of vitamin D receptor action,” Annals of the New York Academy of Sciences, vol. 1068, no. 1, pp. 204–213, 2006. View at Publisher · View at Google Scholar · View at Scopus