Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of radiotherapy and chemotherapy treatment. Clinically, mucositis is associated with pain, bacteremia, and malnutrition. Furthermore, mucositis is a frequent reason to postpone chemotherapy treatment, ultimately leading towards a higher mortality in cancer patients. According to the model introduced by Sonis, both inflammation and apoptosis of the mucosal barrier result in its discontinuity, thereby promoting bacterial translocation. According to this five-phase model, the intestinal microbiota plays no role in the pathophysiology of mucositis. However, research has implicated a prominent role for the commensal intestinal microbiota in the development of several inflammatory diseases like inflammatory bowel disease, pouchitis, and radiotherapy-induced diarrhea. Furthermore, chemotherapeutics have a detrimental effect on the intestinal microbial composition (strongly decreasing the numbers of anaerobic bacteria), coinciding in time with the development of chemotherapy-induced mucositis. We hypothesize that the commensal intestinal microbiota might play a pivotal role in chemotherapy-induced mucositis. In this review, we propose and discuss five pathways in the development of mucositis that are potentially influenced by the commensal intestinal microbiota: 1) the inflammatory process and oxidative stress, 2) intestinal permeability, 3) the composition of the mucus layer, 4) the resistance to harmful stimuli and epithelial repair mechanisms, and 5) the activation and release of immune effector molecules. Via these pathways, the commensal intestinal microbiota might influence all phases in the Sonis model of the pathogenesis of mucositis. Further research is needed to show the clinical relevance of restoring dysbiosis, thereby possibly decreasing the degree of intestinal mucositis.
Citation: van Vliet MJ, Harmsen HJM, de Bont ESJM, Tissing WJE (2010) The Role of Intestinal Microbiota in the Development and Severity of Chemotherapy-Induced Mucositis. PLoS Pathog 6(5): e1000879. https://doi.org/10.1371/journal.ppat.1000879
Editor: Marianne Manchester, University of California San Diego, United States of America
Published: May 27, 2010
Copyright: © 2010 van Vliet et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The reserach of M. J. van Vliet is supported by a grant from the Groningen Foundation for Pediatric Oncology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of radiotherapy and chemotherapy treatment . It is characterized by both inflammation and cell loss in the epithelial barrier lining the gastrointestinal tract , . Clinically, mucositis is associated with bacteremia, malnutrition, the use of total parenteral nutrition, and an increment in the use of intravenous analgesics. These complications all lead to longer hospitalizations and increasing health care costs. Moreover, mucositis is a frequent reason for reducing the dosages of chemotherapeutics or to postpone chemotherapy treatment, ultimately leading towards a higher mortality in cancer patients , .
Historically, research has focused on oral mucositis. More recently, attention has been drawn towards the pathophysiology and clinical symptoms of intestinal mucositis, which is characterized by symptoms like nausea, bloating, vomiting, abdominal pain, and severe diarrhea , .
According to the model introduced by Sonis, five phases are important in the pathophysiology of mucositis: (1) the formation of reactive oxygen species leading to the activation of nuclear factor kappa B (NFκB) during the initiation phase, (2) the induction of messenger molecules such as tumor necrosis factor alpha (TNFα), resulting in treatment-related tissue inflammation and apoptosis during the upregulation/message generation phase, (3) the amplification of messenger molecules in the amplification/signaling phase, leading to more inflammation and apoptosis, (4) discontinuity of the epithelial barrier resulting from apoptosis during the ulcerative phase, thereby promoting bacterial translocation, and (5) a spontaneous healing phase, characterized by cell proliferation . According to this five-phase model, the intestinal microbiota plays no role in the pathophysiology of mucositis. However, research has implicated a role for the commensal intestinal microbiota in several local and systemic inflammatory diseases like inflammatory bowel disease, pouchitis, radiotherapy-induced diarrhea, atopic disease, obesity, and diabetes –. Recent studies have also shown that both chemotherapeutics and (prophylactically used) antibiotics do have an effect on intestinal microbial composition –. Moreover, the effects of the changing commensal intestinal microbiota on the development and severity of mucositis are being unravelled. Research has shown that bacteria play a role in the metabolism of certain chemotherapeutics. The outgrowth of these bacteria might lead to the formation of active toxic metabolites of the chemotherapeutic drug, which directly affects the progression of intestinal mucositis . However, the commensal intestinal microbiota might also have beneficial effects on the development of intestinal mucositis, as the mere presence of resident intestinal bacteria might offer protection against its development. In this review, we propose and discuss five pathways in the development of mucositis that are potentially influenced by the commensal intestinal microbiota: 1) the inflammatory process and oxidative stress, 2) intestinal permeability, 3) the composition of the mucus layer, 4) the resistance towards harmful stimuli and epithelial repair mechanisms, and 5) the activation and release of immune effector molecules (Figures 1 and 2).
The mechanical barrier is increased further by a mucus layer. Binding of bacteria to TLRs present on epithelial cells results in the activation of NFκB, ultimately resulting in the release of pro-inflammatory and anti-inflammatory cytokines. After phagocytosis, bacterial products are internalized and then are recognized by receptors of the NOD family (NLRs), resulting in the modulation of the inflammatory response. Dendritic cells are capable of internalizing bacteria sampled from the lumen, after which bacteria are presented to immune effector cells. HSPs, heat shock proteins; NLR, NOD-like receptor; sIgA, secretory immunoglobulin A; TLR, Toll-like receptor.
Depicted are five possible ways in which intestinal bacteria can attenuate or aggrevate mucositis: 1) influencing the inflammatory process, 2) influencing intestinal permeability, 3) influencing the composition of the mucus layer, 4) influencing resistance to harmful stimuli and enhancing epithelial repair, and finally, 5) the activation and release of immune effector molecules.
A detailed review of the communication pathways between the intestinal microbiota and the human host is beyond the scope of this article and this communication is therefore only shortly reviewed.
The epithelial barrier lining the gastrointestinal tract is composed of a single layer of epithelial cells intertwined by tight junctions . These epithelial cells have two important functions. Firstly, they form a mechanical barrier separating the inside of the human body from the outside world. Secondly, they are essential in the communication between the human body and the intestinal microbiota –.
An important aspect of these two functions of the epithelial cells is the dual mucus layer at the apical side of the epithelial cells , . The inner layer strengthens the epithelial barrier, whereas the loose outer layer is proposed to be important in the communication between epithelial cells and microbiota , .
With respect to the communication between microbes and the gut, two groups of receptors are thought to be important in the communication between the human body and the resident microbiota: the Toll-like receptor (TLR) family and the nucleotide oligomerisation domain (NOD) receptor family –. Both groups of receptors play an important role in the genesis and modulation of the inflammatory response. The TLRs are present at the outer membrane of the epithelial cells. Bacteria are recognized by the extracellularly located part of TLRs, leading to activation of NFκB , . In turn, activation of NFκB results in the development of an inflammatory response. So far, multiple members of the TLR family have been described in mammals. The most extensively researched receptors are TLR-2, TLR-3, TLR-4, TLR-5, and TLR-9 , , –. TLR-2 is activated by peptidoglycan, a part of the cell wall of gram-positive bacteria, whereas TLR-4 is activated by lipopolysaccharide (LPS), a substance of gram-negative microorganisms. TLR-3 is activated by viral DNA, TLR-9 is activated by bacterial DNA, and TLR-5 is activated by the protein flagellin, present in flagellated bacteria. After binding to TLRs, bacteria are processed and bacterial parts are transported intracellularly. Here they bind to receptors of the NOD family. It is believed that activation of NOD receptors modulates the inflammatory response activated by TLR binding . This theory is supported by the fact that NOD−/− mice are profoundly susceptible to intestinal inflammation , . Moreover, mutations in NOD2 are associated with the development of Crohn's disease in humans –.
Not only epithelial cells, but also local dendritic cells are thought to play a role in the initiation and/or modulation of intestinal inflammation and, in addition, in the induction of tolerance –. Dendritic cells sample bacteria from the intestinal lumen, after which these bacteria are transported to the local lymph nodes. Here, the bacteria are presented to immune cells, whose activation can result in the activation of the innate and adaptive immune system. Why certain microbial stimuli result in tolerance where others induce an inflammatory response is still largely unknown.
Pathways Describing the Role of Commensal Intestinal Microbiota in Mucositis
1) Influencing the Inflammatory Process and Modulating Oxidative Stress
The healthy human intestine is characterized by a state of low-grade inflammation. The resident microbiota guarantees a constant exposure to TLR ligands such as peptidoglycan, LPS, and bacterial DNA. This ensures a continuous basal activation of downstream signaling pathways, resulting in low-grade physiological inflammation , . Paradoxically, commensal bacteria are also capable of suppressing more severe inflammatory responses, and their disappearance may even result in incremental inflammation –. For example, Bacteroides thetaiotaomicron and Bifidobacterium infantis both decrease NFκB activation , , leading to a decrease in endotoxin levels and plasma interleukin (IL)-6 levels . The Clostridium XIVa group has been proposed to attenuate intestinal inflammation by exerting an effect on polyamine secretion, which in turn regulates the expression of TLR-2 , .
Bacteria or bacterial parts, as well as their secreted products, relieve inflammatory symptoms. For example, Faecalibacterium prausnitzii secretes a substance capable of decreasing NFκB activation. This so far unidentified substance induces the production of the anti-inflammatory IL-10, thereby attenuating inflammation. B. infantis also secretes an unidentified product that attenuates colitis in mice , . Several intestinal bacteria produce short chain fatty acids (SCFAs), with butyrate being the most thoroughly investigated. Butyrate is produced by F. prausnitzii and Clostridium XIVa and has been shown to have profound anti-inflammatory effects –. Substitution of butyrate attenuates inflammatory symptoms in (diversion) colitis and chemotherapy-induced mucositis in vivo in mice , –. Moreover, butyrate not only attenuates inflammation, but also reduces intestinal permeability and stimulates the activation of immune effector molecules.
In short, multiple intestinal bacteria are capable of decreasing NFκB activation, resulting in a diminished production of inflammatory cytokines. The exact nature and relevance of the relationship between chemotherapy-induced mucositis, inflammation, and intestinal microbiota is subject to ongoing research.
2) Influencing Intestinal Permeability
Intestinal permeability increases after chemotherapy treatment, and has been shown to be one of the hallmarks of the third and fourth phases of mucositis as reported by Sonis , , . One of the mechanisms resulting in a chemotherapy-induced increase in permeability is probably villous atrophy. Atrophy leads to an increase of intestinal permeability, as has been shown both in vivo and in vitro . However, the resident intestinal microbiota has also been proposed to influence intestinal permeability , . Indeed, several commensal bacteria have been shown to improve the epithelial barrier function both in vitro and in vivo, although not all in vivo studies were able to confirm these improvements , –. For example, TLR-2 ligands stimulate the phosphorylation of protein kinase C, leading to a decrease in intestinal permeability . This decrease in permeability is proposed to be the result of changes in tight junctions. Administration of bifidobacteria is associated with an enhanced expression of proteins forming tight junctions , and has been shown to decrease intestinal permeability . Both bifidobacteria and lactobacilli have been shown to increase tight junction protein expression and restore intestinal permeability –.
Another factor contributing to attenuating intestinal permeability is the bacterial induction of heat shock proteins (HSPs). These HSPs are thought to preserve the viability of epithelial cells in stress conditions –, thereby reducing intestinal permeability.
Finally, the bacterial production of SCFAs is associated with a reduction in intestinal permeability. This effect of SCFAs is also proposed to be mediated by an increase in epithelial cell viability , , .
Epithelial cell loss is a hallmark of the third phase of the five-phase mucositis model, eventually resulting in an increased permeability. The commensal intestinal microbiota attenuates cellular atrophy and increases tight junction strength. Therefore, we propose that changes in the commensal intestinal microbiota influence the third phase of mucositis. This way, the commensal intestinal microbiota might influence the eventual severity of mucositis encountered in the ulcerative phase.
3) Influencing the Composition of the Mucus Layer
As mentioned before, the mucus layer covering the intestinal epithelium strengthens the mechanical epithelial barrier. The protective mucus layer is comprised of glycoproteins, trefoil factors, and mucins. These mucins are produced by goblet cells, which are specialized epithelial cells . The composition of the mucus layer is important in the protection against bacterial infections and inflammation. For example, it has been shown that mucin type 2 knockout mice develop severe colitis after harmful stimuli, in contrast to mice capable of producing mucin 2. Furthermore, in animals lacking mucin 2, bacteria are detected deep down in the normally sterile crypts of the intestine , .
The commensal intestinal microbiota is proposed to play a role in the maintenance of the mucus layer. Indeed, the absence of these intestinal microbiota is associated with a decrease in goblet cells, which are also smaller in size . Furthermore, the thickness of the mucus layer is decreased in animals devoid of intestinal microbiota.
The genes encoding mucins are directly regulated by bacteria and their products –, and in response to intestinal microbes and/or their secreted products the secretion of mucus increases , . For example, both Lactobacillus rhamnosus Gorbach and Goldin (GG) and Lactobacillus plantarum increase the expression of MUC-2 and MUC-3 genes, and Lactobacillus acidophilus upregulates MUC-2 gene expression , . Furthermore, bacteria producing butyrate are thought to play a role in the composition of the mucus layer, as butyrate is capable of increasing mucin synthesis as well .
The commensal resident microbiota not only interferes with the expression of MUC genes, but also interferes with the expression and/or activity of cell glycosyltransferases. These enzymes induce changes in the carbohydrate repertoire of mucins, which might change their efficacy in bacterial defense , .
Thus, the intestinal microbiota influences the composition of the mucus layer covering the epithelium, thereby increasing the strength of the epithelial barrier. A strengthened barrier decreases the risk of bacterial translocation, thereby possibly attenuating inflammation present in the ulcerative phase of the Sonis mucositis model.
4) Influencing Resistance to Harmful Stimuli and Influencing Epithelial Repair
The commensal intestinal microbiota contributes to epithelial repair. In germ-free animals, the mitotic index and cell turnover of epithelial cells are lower as compared to normally colonized animals , . Moreover, the transit time of epithelial cells migrating towards the top of the intestinal villi is prolonged . These changes result in a retarded renewal, i.e., a retarded repair, of the intestinal epithelium.
Bacterial induction of NFκB not only controls the physiological state of low-grade inflammation in the intestine, it also stimulates the repair of, for example, mechanical-induced epithelial damage . The importance of bacterial ligands in this process is shown in TLR-4−/− epithelial cells. These cells, which are not capable of recognizing the resident microbiota, exhibit severe repair defects in response to harmful chemical stimuli. This is probably due to a reduced capacity of NFκB-induced cytoprotective factors such as HSPs and IL-6 , . When TLR ligands were administered to germ-free mice, this was sufficient to protect them against artificially induced colitis .
Bacteria acting as TLR ligands are not the only ones that play an important role in increasing the resistance towards harmful stimuli and enhancing epithelial repair. Again, butyrate plays an important role. Butyrate stimulates the migration of epithelial cells, thereby enhancing mucosal healing , . Other bacterial products, such as the peptides secreted by L. rhamnosus GG, have been shown to inhibit cytokine-induced apoptosis and promote cell growth, thereby also enhancing mucosal repair .
Therefore, we again propose that the commensal intestinal microbiota might attenuate the epithelial damage in the third phase of mucositis. As the commensal intestinal microbiota stimulates epithelial repair mechanisms, it can be hypothesized that the microbiota also attenuates mucositis by influencing the healing phase of mucositis.
5) Influencing the Production and Release of Immune Effector Molecules
The commensal intestinal microbiota regulates the expression and release of immune effector molecules. These molecules are pivotal for maintaining intestinal homeostasis , –. For example, if the contact between microbiota and intestinal epithelium suddenly increases, the expression of RegIIIγ increases. This C-type lectin has antimicrobial activity and limits bacterial translocation. Furthermore, it maintains intestinal integrity and homeostasis , .
Another immune effector molecule influenced by the resident microbiota is immunoglobulin A (IgA). IgA is produced by mucosa-associated immune effector cells , , . Intestinal microbiota is capable of regulating the expression of IgA, which in turn regulates the composition of the intestinal microbiota. For example, suppletion of bifidobacteria is associated with an increase in the expression of secretory IgA .
Both live bacteria and their products are capable of upregulating immune effector molecules. For example, SCFAs such as butyrate regulate the production of cathelicidins, which exhibit broad-spectrum anti-bacterial activity against potential pathogens .
By influencing the expression and release of immune effector molecules, the commensal intestinal microbiota regulates itself and maintains homeostasis in the intestinal tract. In the end, this will positively influence all five phases described in Sonis's mucositis model.
Conclusion; an Extended Five-Phase Model for Mucositis
Although the protective role of commensal intestinal bacteria in human disease is increasingly being appreciated, research concerning the relationship between intestinal bacteria and chemotherapy-induced mucositis is still scarce. Most studies that investigate the role of bacteria in human disease have focused on inflammatory bowel disease, which is caused by a chronic inflammatory process instead of the acute damage induced by chemotherapeutics.
In the model introduced by Sonis to explain the pathogenesis of radiotherapy-induced and chemotherapy-induced mucositis, the resident intestinal microbiota played no role . However, recently it has been shown that chemotherapy treatment is associated with a decrease in the number of anaerobic bacteria and a decrease in microbial diversity , . Furthermore, the resident intestinal bacteria have been shown to play a role in radiotherapy-induced diarrhea . Moreover, research has shown that a decreasing microbial diversity coincides in time with the development of severe chemotherapy-induced mucositis (M. van Vliet et al., unpublished data). We hypothesize that the commensal intestinal microbiota might play a pivotal role in both radiotherapy-induced and chemotherapy-induced mucositis when the intestine is irradiated or when chemotherapeutics are used that deregulate intestinal microbial homeostasis, as the disappearance of the intestinal microbiota will minimize their protection of enterocytes against harmful stimuli. Further research is needed to show whether the commensal intestinal bacteria should be incorporated as a meaningful factor in Sonis's five-phase model for mucositis. Theoretically, the commensal intestinal microbiota could influence all phases of the pathogenesis of mucositis: the initiation phase, the phase of upregulation and message generation, the phase of amplification and signalling, the ulcerative phase, and the healing phase.
Further research will also have to show the clinical relevance of restoring dysbiosis, thereby possibly decreasing the degree of intestinal mucositis. This would not only increase the quality of life of patients, but could also positively influence treatment intensity, probably decreasing the morbidity and mortality of cancer patients. Completely restoring dysbiosis might be a clinical problem, since whole live bacteria used as probiotics have already been described as causing invasive infections in immunocompromised patients and were associated with increased mortality in patients with severe pancreatitis –. However, it has been shown that substitution of bacterial parts instead of whole live bacteria might be sufficient to attenuate local and systemic inflammation without the risk of invasive infections , , .
- 1. Bellm LA, Epstein JB, Rose-Ped A, Martin P, Fuchs HJ (2000) Patient reports of complications of bone marrow transplantation. Support Care Cancer 8: 33–39.LA BellmJB EpsteinA. Rose-PedP. MartinHJ Fuchs2000Patient reports of complications of bone marrow transplantation.Support Care Cancer83339
- 2. Blijlevens NM, Donnelly JP, De Pauw BE (2000) Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview. Bone Marrow Transplant 25: 1269–1278.NM BlijlevensJP DonnellyBE De Pauw2000Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview.Bone Marrow Transplant2512691278
- 3. Sonis ST (2004) The pathobiology of mucositis. Nat Rev Cancer 4: 277–284.ST Sonis2004The pathobiology of mucositis.Nat Rev Cancer4277284
- 4. Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, et al. (2001) Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 19: 2201–2205.ST SonisG. OsterH. FuchsL. BellmWZ Bradford2001Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation.J Clin Oncol1922012205
- 5. Blijlevens NM, Donnelly JP, DePauw BE (2005) Inflammatory response to mucosal barrier injury after myeloablative therapy in allogeneic stem cell transplant recipients. Bone Marrow Transplant 36: 703–707.NM BlijlevensJP DonnellyBE DePauw2005Inflammatory response to mucosal barrier injury after myeloablative therapy in allogeneic stem cell transplant recipients.Bone Marrow Transplant36703707
- 6. Lutgens LC, Blijlevens NM, Deutz NE, Donnelly JP, Lambin P, et al. (2005) Monitoring myeloablative therapy-induced small bowel toxicity by serum citrulline concentration: a comparison with sugar permeability tests. Cancer 103: 191–199.LC LutgensNM BlijlevensNE DeutzJP DonnellyP. Lambin2005Monitoring myeloablative therapy-induced small bowel toxicity by serum citrulline concentration: a comparison with sugar permeability tests.Cancer103191199
- 7. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, et al. (2008) Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57: 1470–1481.PD CaniR. BibiloniC. KnaufA. WagetAM Neyrinck2008Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice.Diabetes5714701481
- 8. Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, et al. (2007) Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 104: 13780–13785.DN FrankAL St AmandRA FeldmanEC BoedekerN. Harpaz2007Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases.Proc Natl Acad Sci U S A1041378013785
- 9. Gosselink MP, Schouten WR, van Lieshout LM, Hop WC, Laman JD, et al. (2004) Eradication of pathogenic bacteria and restoration of normal pouch flora: comparison of metronidazole and ciprofloxacin in the treatment of pouchitis. Dis Colon Rectum 47: 1519–1525.MP GosselinkWR SchoutenLM van LieshoutWC HopJD Laman2004Eradication of pathogenic bacteria and restoration of normal pouch flora: comparison of metronidazole and ciprofloxacin in the treatment of pouchitis.Dis Colon Rectum4715191525
- 10. Manichanh C, Varela E, Martinez C, Antolin M, Llopis M, et al. (2008) The gut microbiota predispose to the pathophysiology of acute postradiotherapy diarrhea. Am J Gastroenterol 103: 1754–1761.C. ManichanhE. VarelaC. MartinezM. AntolinM. Llopis2008The gut microbiota predispose to the pathophysiology of acute postradiotherapy diarrhea.Am J Gastroenterol10317541761
- 11. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, et al. (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444: 1027–1031.PJ TurnbaughRE LeyMA MahowaldV. MagriniER Mardis2006An obesity-associated gut microbiome with increased capacity for energy harvest.Nature44410271031
- 12. Edlund C, Nord CE (2000) Effect on the human normal microflora of oral antibiotics for treatment of urinary tract infections. J Antimicrob Chemother 46: Suppl 141–48.C. EdlundCE Nord2000Effect on the human normal microflora of oral antibiotics for treatment of urinary tract infections.J Antimicrob Chemother46Suppl 14148
- 13. Stringer AM, Gibson RJ, Bowen JM, Logan RM, Ashton K, et al. (2009) Irinotecan-induced mucositis manifesting as diarrhoea corresponds with an amended intestinal flora and mucin profile. Int J Exp Pathol 90: 489–499.AM StringerRJ GibsonJM BowenRM LoganK. Ashton2009Irinotecan-induced mucositis manifesting as diarrhoea corresponds with an amended intestinal flora and mucin profile.Int J Exp Pathol90489499
- 14. van Vliet MJ, Tissing WJ, Dun CA, Meessen NE, Kamps WA, et al. (2009) Chemotherapy treatment in pediatric patients with acute myeloid leukemia receiving antimicrobial prophylaxis leads to a relative increase of colonization with potentially pathogenic bacteria in the gut. Clin Infect Dis 49: 262–270.MJ van VlietWJ TissingCA DunNE MeessenWA Kamps2009Chemotherapy treatment in pediatric patients with acute myeloid leukemia receiving antimicrobial prophylaxis leads to a relative increase of colonization with potentially pathogenic bacteria in the gut.Clin Infect Dis49262270
- 15. Powell DW (1981) Barrier function of epithelia. Am J Physiol 241: G275–G288.DW Powell1981Barrier function of epithelia.Am J Physiol241G275G288
- 16. Cario E (2005) Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2. Gut 54: 1182–1193.E. Cario2005Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2.Gut5411821193
- 17. Medzhitov R (2007) Recognition of microorganisms and activation of the immune response. Nature 449: 819–826.R. Medzhitov2007Recognition of microorganisms and activation of the immune response.Nature449819826
- 18. Sartor RB (2008) Microbial influences in inflammatory bowel diseases. Gastroenterology 134: 577–594.RB Sartor2008Microbial influences in inflammatory bowel diseases.Gastroenterology134577594
- 19. Atuma C, Strugala V, Allen A, Holm L (2001) The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo. Am J Physiol Gastrointest Liver Physiol 280: G922–G929.C. AtumaV. StrugalaA. AllenL. Holm2001The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo.Am J Physiol Gastrointest Liver Physiol280G922G929
- 20. Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L, et al. (2008) The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci U S A 105: 15064–15069.ME JohanssonM. PhillipsonJ. PeterssonA. VelcichL. Holm2008The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria.Proc Natl Acad Sci U S A1051506415069
- 21. Swidsinski A, Loening-Baucke V, Theissig F, Engelhardt H, Bengmark S, et al. (2007) Comparative study of the intestinal mucus barrier in normal and inflamed colon. Gut 56: 343–350.A. SwidsinskiV. Loening-BauckeF. TheissigH. EngelhardtS. Bengmark2007Comparative study of the intestinal mucus barrier in normal and inflamed colon.Gut56343350
- 22. Constans A (2005) Giving a nod2 the right target. The scientist 19: 24–25.A. Constans2005Giving a nod2 the right target.The scientist192425
- 23. Doyle SL, O'Neill LA (2006) Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity. Biochem Pharmacol 72: 1102–1113.SL DoyleLA O'Neill2006Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity.Biochem Pharmacol7211021113
- 24. Franchi L, Warner N, Viani K, Nunez G (2009) Function of Nod-like receptors in microbial recognition and host defense. Immunol Rev 227: 106–128.L. FranchiN. WarnerK. VianiG. Nunez2009Function of Nod-like receptors in microbial recognition and host defense.Immunol Rev227106128
- 25. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118: 229–241.S. Rakoff-NahoumJ. PaglinoF. Eslami-VarzanehS. EdbergR. Medzhitov2004Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.Cell118229241
- 26. Cario E, Gerken G, Podolsky DK (2004) Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. Gastroenterology 127: 224–238.E. CarioG. GerkenDK Podolsky2004Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C.Gastroenterology127224238
- 27. Cario E (2008) Therapeutic impact of toll-like receptors on inflammatory bowel diseases: a multiple-edged sword. Inflamm Bowel Dis 14: 411–421.E. Cario2008Therapeutic impact of toll-like receptors on inflammatory bowel diseases: a multiple-edged sword.Inflamm Bowel Dis14411421
- 28. Chen J, Rao JN, Zou T, Liu L, Marasa BS, et al. (2007) Polyamines are required for expression of Toll-like receptor 2 modulating intestinal epithelial barrier integrity. Am J Physiol Gastrointest Liver Physiol 293: G568–G576.J. ChenJN RaoT. ZouL. LiuBS Marasa2007Polyamines are required for expression of Toll-like receptor 2 modulating intestinal epithelial barrier integrity.Am J Physiol Gastrointest Liver Physiol293G568G576
- 29. Fukata M, Michelsen KS, Eri R, Thomas LS, Hu B, et al. (2005) Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am J Physiol Gastrointest Liver Physiol 288: G1055–G1065.M. FukataKS MichelsenR. EriLS ThomasB. Hu2005Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis.Am J Physiol Gastrointest Liver Physiol288G1055G1065
- 30. Rachmilewitz D, Katakura K, Karmeli F, Hayashi T, Reinus C, et al. (2004) Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 126: 520–528.D. RachmilewitzK. KatakuraF. KarmeliT. HayashiC. Reinus2004Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis.Gastroenterology126520528
- 31. Vicente-Suarez I, Takahashi Y, Cheng F, Horna P, Wang HW, et al. (2007) Identification of a novel negative role of flagellin in regulating IL-10 production. Eur J Immunol 37: 3164–3175.I. Vicente-SuarezY. TakahashiF. ChengP. HornaHW Wang2007Identification of a novel negative role of flagellin in regulating IL-10 production.Eur J Immunol3731643175
- 32. Vijay-Kumar M, Wu H, Aitken J, Kolachala VL, Neish AS, et al. (2007) Activation of toll-like receptor 3 protects against DSS-induced acute colitis. Inflamm Bowel Dis 13: 856–864.M. Vijay-KumarH. WuJ. AitkenVL KolachalaAS Neish2007Activation of toll-like receptor 3 protects against DSS-induced acute colitis.Inflamm Bowel Dis13856864
- 33. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, et al. (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307: 731–734.KS KobayashiM. ChamaillardY. OguraO. HenegariuN. Inohara2005Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract.Science307731734
- 34. Watanabe T, Kitani A, Murray PJ, Wakatsuki Y, Fuss IJ, et al. (2006) Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis. Immunity 25: 473–485.T. WatanabeA. KitaniPJ MurrayY. WakatsukiIJ Fuss2006Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis.Immunity25473485
- 35. Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, et al. (2001) Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 357: 1925–1928.J. HampeA. CuthbertPJ CroucherMM MirzaS. Mascheretti2001Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations.Lancet35719251928
- 36. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, et al. (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411: 599–603.JP HugotM. ChamaillardH. ZoualiS. LesageJP Cezard2001Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.Nature411599603
- 37. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, et al. (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411: 603–606.Y. OguraDK BonenN. InoharaDL NicolaeFF Chen2001A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.Nature411603606
- 38. Bjorck P, Beilhack A, Herman EI, Negrin RS, Engleman EG (2008) Plasmacytoid dendritic cells take up opsonized antigen leading to CD4+ and CD8+ T cell activation in vivo. J Immunol 181: 3811–3817.P. BjorckA. BeilhackEI HermanRS NegrinEG Engleman2008Plasmacytoid dendritic cells take up opsonized antigen leading to CD4+ and CD8+ T cell activation in vivo.J Immunol18138113817
- 39. Hapfelmeier S, Muller AJ, Stecher B, Kaiser P, Barthel M, et al. (2008) Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent step in DeltainvG S. Typhimurium colitis. J Exp Med 205: 437–450.S. HapfelmeierAJ MullerB. StecherP. KaiserM. Barthel2008Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent step in DeltainvG S. Typhimurium colitis.J Exp Med205437450
- 40. Niess JH, Reinecker HC (2006) Dendritic cells in the recognition of intestinal microbiota. Cell Microbiol 8: 558–564.JH NiessHC Reinecker2006Dendritic cells in the recognition of intestinal microbiota.Cell Microbiol8558564
- 41. Borody TJ, Warren EF, Leis S, Surace R, Ashman O (2003) Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol 37: 42–47.TJ BorodyEF WarrenS. LeisR. SuraceO. Ashman2003Treatment of ulcerative colitis using fecal bacteriotherapy.J Clin Gastroenterol374247
- 42. Frick JS, Schenk K, Quitadamo M, Kahl F, Koberle M, et al. (2007) Lactobacillus fermentum attenuates the proinflammatory effect of Yersinia enterocolitica on human epithelial cells. Inflamm Bowel Dis 13: 83–90.JS FrickK. SchenkM. QuitadamoF. KahlM. Koberle2007Lactobacillus fermentum attenuates the proinflammatory effect of Yersinia enterocolitica on human epithelial cells.Inflamm Bowel Dis138390
- 43. Kelly D, Campbell JI, King TP, Grant G, Jansson EA, et al. (2004) Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA. Nat Immunol 5: 104–112.D. KellyJI CampbellTP KingG. GrantEA Jansson2004Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA.Nat Immunol5104112
- 44. Khan MA, Ma C, Knodler LA, Valdez Y, Rosenberger CM, et al. (2006) Toll-like receptor 4 contributes to colitis development but not to host defense during Citrobacter rodentium infection in mice. Infect Immun 74: 2522–2536.MA KhanC. MaLA KnodlerY. ValdezCM Rosenberger2006Toll-like receptor 4 contributes to colitis development but not to host defense during Citrobacter rodentium infection in mice.Infect Immun7425222536
- 45. O'Hara AM, O'Regan P, Fanning A, O'Mahony C, Macsharry J, et al. (2006) Functional modulation of human intestinal epithelial cell responses by Bifidobacterium infantis and Lactobacillus salivarius. Immunology 118: 202–215.AM O'HaraP. O'ReganA. FanningC. O'MahonyJ. Macsharry2006Functional modulation of human intestinal epithelial cell responses by Bifidobacterium infantis and Lactobacillus salivarius.Immunology118202215
- 46. Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, et al. (2008) Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 105: 16731–16736.H. SokolB. PigneurL. WatterlotO. LakhdariLG Bermudez-Humaran2008Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients.Proc Natl Acad Sci U S A1051673116736
- 47. Beg AA (2004) ComPPARtmentalizing NF-kappaB in the gut. Nat Immunol 5: 14–16.AA Beg2004ComPPARtmentalizing NF-kappaB in the gut.Nat Immunol51416
- 48. Matsumoto M, Benno Y (2007) The relationship between microbiota and polyamine concentration in the human intestine: a pilot study. Microbiol Immunol 51: 25–35.M. MatsumotoY. Benno2007The relationship between microbiota and polyamine concentration in the human intestine: a pilot study.Microbiol Immunol512535
- 49. Ewaschuk JB, Diaz H, Meddings L, Diederichs B, Dmytrash A, et al. (2008) Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am J Physiol Gastrointest Liver Physiol 295: G1025–G1034.JB EwaschukH. DiazL. MeddingsB. DiederichsA. Dmytrash2008Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function.Am J Physiol Gastrointest Liver Physiol295G1025G1034
- 50. Barcenilla A, Pryde SE, Martin JC, Duncan SH, Stewart CS, et al. (2000) Phylogenetic relationships of butyrate-producing bacteria from the human gut. Appl Environ Microbiol 66: 1654–1661.A. BarcenillaSE PrydeJC MartinSH DuncanCS Stewart2000Phylogenetic relationships of butyrate-producing bacteria from the human gut.Appl Environ Microbiol6616541661
- 51. Duncan SH, Hold GL, Harmsen HJ, Stewart CS, Flint HJ (2002) Growth requirements and fermentation products of Fusobacterium prausnitzii, and a proposal to reclassify it as Faecalibacterium prausnitzii gen. nov., comb. nov. Int J Syst Evol Microbiol 52: 2141–2146.SH DuncanGL HoldHJ HarmsenCS StewartHJ Flint2002Growth requirements and fermentation products of Fusobacterium prausnitzii, and a proposal to reclassify it as Faecalibacterium prausnitzii gen. nov., comb. nov.Int J Syst Evol Microbiol5221412146
- 52. Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, et al. (2008) Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther 27: 104–119.HM HamerD. JonkersK. VenemaS. VanhoutvinFJ Troost2008Review article: the role of butyrate on colonic function.Aliment Pharmacol Ther27104119
- 53. Hamer HM, Jonkers DM, Bast A, Vanhoutvin SA, Fischer MA, et al. (2008) Butyrate modulates oxidative stress in the colonic mucosa of healthy humans. Clin Nutr. HM HamerDM JonkersA. BastSA VanhoutvinMA Fischer2008Butyrate modulates oxidative stress in the colonic mucosa of healthy humans.Clin Nutr
- 54. Nancey S, Bienvenu J, Coffin B, Andre F, Descos L, et al. (2002) Butyrate strongly inhibits in vitro stimulated release of cytokines in blood. Dig Dis Sci 47: 921–928.S. NanceyJ. BienvenuB. CoffinF. AndreL. Descos2002Butyrate strongly inhibits in vitro stimulated release of cytokines in blood.Dig Dis Sci47921928
- 55. Di Sabatino A, Morera R, Ciccocioppo R, Cazzola P, Gotti S, et al. (2005) Oral butyrate for mildly to moderately active Crohn's disease. Aliment Pharmacol Ther 22: 789–794.A. Di SabatinoR. MoreraR. CiccocioppoP. CazzolaS. Gotti2005Oral butyrate for mildly to moderately active Crohn's disease.Aliment Pharmacol Ther22789794
- 56. Harig JM, Soergel KH, Komorowski RA, Wood CM (1989) Treatment of diversion colitis with short-chain-fatty acid irrigation. N Engl J Med 320: 23–28.JM HarigKH SoergelRA KomorowskiCM Wood1989Treatment of diversion colitis with short-chain-fatty acid irrigation.N Engl J Med3202328
- 57. Ramos MG, Bambirra EA, Cara DC, Vieira EC, Alvarez-Leite JI (1997) Oral administration of short-chain fatty acids reduces the intestinal mucositis caused by treatment with Ara-C in mice fed commercial or elemental diets. Nutr Cancer 28: 212–217.MG RamosEA BambirraDC CaraEC VieiraJI Alvarez-Leite1997Oral administration of short-chain fatty acids reduces the intestinal mucositis caused by treatment with Ara-C in mice fed commercial or elemental diets.Nutr Cancer28212217
- 58. Venkatraman A, Ramakrishna BS, Shaji RV, Kumar NS, Pulimood A, et al. (2003) Amelioration of dextran sulfate colitis by butyrate: role of heat shock protein 70 and NF-kappaB. Am J Physiol Gastrointest Liver Physiol 285: G177–G184.A. VenkatramanBS RamakrishnaRV ShajiNS KumarA. Pulimood2003Amelioration of dextran sulfate colitis by butyrate: role of heat shock protein 70 and NF-kappaB.Am J Physiol Gastrointest Liver Physiol285G177G184
- 59. Wang Q, Wang XD, Jeppsson B, Andersson R, Karlsson B, et al. (1996) Influence of colostomy on in vivo and in vitro permeability of the rat colon. Dis Colon Rectum 39: 663–670.Q. WangXD WangB. JeppssonR. AnderssonB. Karlsson1996Influence of colostomy on in vivo and in vitro permeability of the rat colon.Dis Colon Rectum39663670
- 60. Samonte VA, Goto M, Ravindranath TM, Fazal N, Holloway VM, et al. (2004) Exacerbation of intestinal permeability in rats after a two-hit injury: burn and Enterococcus faecalis infection. Crit Care Med 32: 2267–2273.VA SamonteM. GotoTM RavindranathN. FazalVM Holloway2004Exacerbation of intestinal permeability in rats after a two-hit injury: burn and Enterococcus faecalis infection.Crit Care Med3222672273
- 61. Eutamene H, Lamine F, Chabo C, Theodorou V, Rochat F, et al. (2007) Synergy between Lactobacillus paracasei and its bacterial products to counteract stress-induced gut permeability and sensitivity increase in rats. J Nutr 137: 1901–1907.H. EutameneF. LamineC. ChaboV. TheodorouF. Rochat2007Synergy between Lactobacillus paracasei and its bacterial products to counteract stress-induced gut permeability and sensitivity increase in rats.J Nutr13719011907
- 62. Heyman M, Terpend K, Menard S (2005) Effects of specific lactic acid bacteria on the intestinal permeability to macromolecules and the inflammatory condition. Acta Paediatr Suppl 94: 34–36.M. HeymanK. TerpendS. Menard2005Effects of specific lactic acid bacteria on the intestinal permeability to macromolecules and the inflammatory condition.Acta PaediatrSuppl 943436
- 63. Qin HL, Zheng JJ, Tong DN, Chen WX, Fan XB, et al. (2008) Effect of Lactobacillus plantarum enteral feeding on the gut permeability and septic complications in the patients with acute pancreatitis. Eur J Clin Nutr 62: 923–930.HL QinJJ ZhengDN TongWX ChenXB Fan2008Effect of Lactobacillus plantarum enteral feeding on the gut permeability and septic complications in the patients with acute pancreatitis.Eur J Clin Nutr62923930
- 64. Stratiki Z, Costalos C, Sevastiadou S, Kastanidou O, Skouroliakou M, et al. (2007) The effect of a bifidobacter supplemented bovine milk on intestinal permeability of preterm infants. Early Hum Dev 83: 575–579.Z. StratikiC. CostalosS. SevastiadouO. KastanidouM. Skouroliakou2007The effect of a bifidobacter supplemented bovine milk on intestinal permeability of preterm infants.Early Hum Dev83575579
- 65. Zeng J, Li YQ, Zuo XL, Zhen YB, Yang J, et al. (2008) Clinical trial: effect of active lactic acid bacteria on mucosal barrier function in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 28: 994–1002.J. ZengYQ LiXL ZuoYB ZhenJ. Yang2008Clinical trial: effect of active lactic acid bacteria on mucosal barrier function in patients with diarrhoea-predominant irritable bowel syndrome.Aliment Pharmacol Ther289941002
- 66. Liu Q, Nobaek S, Adawi D, Mao Y, Wang M, et al. (2001) Administration of Lactobacillus plantarum 299v reduces side-effects of external radiation on colon anastomotic healing in an experimental model. Colorectal Dis 3: 245–252.Q. LiuS. NobaekD. AdawiY. MaoM. Wang2001Administration of Lactobacillus plantarum 299v reduces side-effects of external radiation on colon anastomotic healing in an experimental model.Colorectal Dis3245252
- 67. Qin HL, Shen TY, Gao ZG, Fan XB, Hang XM, et al. (2005) Effect of lactobacillus on the gut microflora and barrier function of the rats with abdominal infection. World J Gastroenterol 11: 2591–2596.HL QinTY ShenZG GaoXB FanXM Hang2005Effect of lactobacillus on the gut microflora and barrier function of the rats with abdominal infection.World J Gastroenterol1125912596
- 68. Moorthy G, Murali MR, Devaraj SN (2008) Lactobacilli facilitate maintenance of intestinal membrane integrity during Shigella dysenteriae 1 infection in rats. Nutrition. G. MoorthyMR MuraliSN Devaraj2008Lactobacilli facilitate maintenance of intestinal membrane integrity during Shigella dysenteriae 1 infection in rats.Nutrition
- 69. Aijaz S, Sanchez-Heras E, Balda MS, Matter K (2007) Regulation of tight junction assembly and epithelial morphogenesis by the heat shock protein Apg-2. BMC Cell Biol 8: 49.S. AijazE. Sanchez-HerasMS BaldaK. Matter2007Regulation of tight junction assembly and epithelial morphogenesis by the heat shock protein Apg-2.BMC Cell Biol849
- 70. Arvans DL, Vavricka SR, Ren H, Musch MW, Kang L, et al. (2005) Luminal bacterial flora determines physiological expression of intestinal epithelial cytoprotective heat shock proteins 25 and 72. Am J Physiol Gastrointest Liver Physiol 288: G696–G704.DL ArvansSR VavrickaH. RenMW MuschL. Kang2005Luminal bacterial flora determines physiological expression of intestinal epithelial cytoprotective heat shock proteins 25 and 72.Am J Physiol Gastrointest Liver Physiol288G696G704
- 71. Matsuo K, Zhang X, Ono Y, Nagatomi R (2009) Acute stress-induced colonic tissue HSP70 expression requires commensal bacterial components and intrinsic glucocorticoid. Brain Behav Immun 23: 108–115.K. MatsuoX. ZhangY. OnoR. Nagatomi2009Acute stress-induced colonic tissue HSP70 expression requires commensal bacterial components and intrinsic glucocorticoid.Brain Behav Immun23108115
- 72. Venkatraman A, Ramakrishna BS, Pulimood AB (1999) Butyrate hastens restoration of barrier function after thermal and detergent injury to rat distal colon in vitro. Scand J Gastroenterol 34: 1087–1092.A. VenkatramanBS RamakrishnaAB Pulimood1999Butyrate hastens restoration of barrier function after thermal and detergent injury to rat distal colon in vitro.Scand J Gastroenterol3410871092
- 73. Moncada DM, Kammanadiminti SJ, Chadee K (2003) Mucin and Toll-like receptors in host defense against intestinal parasites. Trends Parasitol 19: 305–311.DM MoncadaSJ KammanadimintiK. Chadee2003Mucin and Toll-like receptors in host defense against intestinal parasites.Trends Parasitol19305311
- 74. Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, et al. (2006) Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131: 117–129.M. Van der SluisBA De KoningAC De BruijnA. VelcichJP Meijerink2006Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection.Gastroenterology131117129
- 75. Kandori H, Hirayama K, Takeda M, Doi K (1996) Histochemical, lectin-histochemical and morphometrical characteristics of intestinal goblet cells of germfree and conventional mice. Exp Anim 45: 155–160.H. KandoriK. HirayamaM. TakedaK. Doi1996Histochemical, lectin-histochemical and morphometrical characteristics of intestinal goblet cells of germfree and conventional mice.Exp Anim45155160
- 76. Caballero-Franco C, Keller K, De Simone C, Chadee K (2007) The VSL#3 probiotic formula induces mucin gene expression and secretion in colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol 292: G315–G322.C. Caballero-FrancoK. KellerC. De SimoneK. Chadee2007The VSL#3 probiotic formula induces mucin gene expression and secretion in colonic epithelial cells.Am J Physiol Gastrointest Liver Physiol292G315G322
- 77. Kim Y, Kim SH, Whang KY, Kim YJ, Oh S (2008) Inhibition of Escherichia coli O157:H7 attachment by interactions between lactic acid bacteria and intestinal epithelial cells. J Microbiol Biotechnol 18: 1278–1285.Y. KimSH KimKY WhangYJ KimS. Oh2008Inhibition of Escherichia coli O157:H7 attachment by interactions between lactic acid bacteria and intestinal epithelial cells.J Microbiol Biotechnol1812781285
- 78. Mattar AF, Teitelbaum DH, Drongowski RA, Yongyi F, Harmon CM, et al. (2002) Probiotics up-regulate MUC-2 mucin gene expression in a Caco-2 cell-culture model. Pediatr Surg Int 18: 586–590.AF MattarDH TeitelbaumRA DrongowskiF. YongyiCM Harmon2002Probiotics up-regulate MUC-2 mucin gene expression in a Caco-2 cell-culture model.Pediatr Surg Int18586590
- 79. Barcelo A, Claustre J, Moro F, Chayvialle JA, Cuber JC, et al. (2000) Mucin secretion is modulated by luminal factors in the isolated vascularly perfused rat colon. Gut 46: 218–224.A. BarceloJ. ClaustreF. MoroJA ChayvialleJC Cuber2000Mucin secretion is modulated by luminal factors in the isolated vascularly perfused rat colon.Gut46218224
- 80. Mack DR, Ahrne S, Hyde L, Wei S, Hollingsworth MA (2003) Extracellular MUC3 mucin secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro. Gut 52: 827–833.DR MackS. AhrneL. HydeS. WeiMA Hollingsworth2003Extracellular MUC3 mucin secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro.Gut52827833
- 81. Bourlioux P, Koletzko B, Guarner F, Braesco V (2003) The intestine and its microflora are partners for the protection of the host: report on the Danone Symposium “The Intelligent Intestine,” held in Paris, June 14, 2002. Am J Clin Nutr 78: 675–683.P. BourliouxB. KoletzkoF. GuarnerV. Braesco2003The intestine and its microflora are partners for the protection of the host: report on the Danone Symposium “The Intelligent Intestine,” held in Paris, June 14, 2002.Am J Clin Nutr78675683
- 82. Hooper LV, Gordon JI (2001) Commensal host-bacterial relationships in the gut. Science 292: 1115–1118.LV HooperJI Gordon2001Commensal host-bacterial relationships in the gut.Science29211151118
- 83. Rolls BA, Turvey A, Coates ME (1978) The influence of the gut microflora and of dietary fibre on epithelial cell migration in the chick intestine. Br J Nutr 39: 91–98.BA RollsA. TurveyME Coates1978The influence of the gut microflora and of dietary fibre on epithelial cell migration in the chick intestine.Br J Nutr399198
- 84. Webb P, Chanana AD, Cronkite EP, Laissue JA, Joel DD (1980) Comparison of DNA renewal in germ-free and conventional mice using [125I]iododeoxyuridine and [3H]thymidine. Cell Tissue Kinet 13: 227–237.P. WebbAD ChananaEP CronkiteJA LaissueDD Joel1980Comparison of DNA renewal in germ-free and conventional mice using [125I]iododeoxyuridine and [3H]thymidine.Cell Tissue Kinet13227237
- 85. Savage DC, Siegel JE, Snellen JE, Whitt DD (1981) Transit time of epithelial cells in the small intestines of germfree mice and ex-germfree mice associated with indigenous microorganisms. Appl Environ Microbiol 42: 996–1001.DC SavageJE SiegelJE SnellenDD Whitt1981Transit time of epithelial cells in the small intestines of germfree mice and ex-germfree mice associated with indigenous microorganisms.Appl Environ Microbiol429961001
- 86. Karrasch T, Steinbrecher KA, Allard B, Baldwin AS, Jobin C (2006) Wound-induced p38MAPK-dependent histone H3 phosphorylation correlates with increased COX-2 expression in enterocytes. J Cell Physiol 207: 809–815.T. KarraschKA SteinbrecherB. AllardAS BaldwinC. Jobin2006Wound-induced p38MAPK-dependent histone H3 phosphorylation correlates with increased COX-2 expression in enterocytes.J Cell Physiol207809815
- 87. Yan F, Cao H, Cover TL, Whitehead R, Washington MK, et al. (2007) Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology 132: 562–575.F. YanH. CaoTL CoverR. WhiteheadMK Washington2007Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth.Gastroenterology132562575
- 88. Ayabe T, Satchell DP, Wilson CL, Parks WC, Selsted ME, et al. (2000) Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol 1: 113–118.T. AyabeDP SatchellCL WilsonWC ParksME Selsted2000Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria.Nat Immunol1113118
- 89. Cash HL, Whitham CV, Behrendt CL, Hooper LV (2006) Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313: 1126–1130.HL CashCV WhithamCL BehrendtLV Hooper2006Symbiotic bacteria direct expression of an intestinal bactericidal lectin.Science31311261130
- 90. Strober W (2006) Immunology. Unraveling gut inflammation. Science 313: 1052–1054.W. Strober2006Immunology. Unraveling gut inflammation.Science31310521054
- 91. Di Giacinto C, Marinaro M, Sanchez M, Strober W, Boirivant M (2005) Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells. J Immunol 174: 3237–3246.C. Di GiacintoM. MarinaroM. SanchezW. StroberM. Boirivant2005Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells.J Immunol17432373246
- 92. Wang Z, Xiao G, Yao Y, Guo S, Lu K, et al. (2006) The role of bifidobacteria in gut barrier function after thermal injury in rats. J Trauma 61: 650–657.Z. WangG. XiaoY. YaoS. GuoK. Lu2006The role of bifidobacteria in gut barrier function after thermal injury in rats.J Trauma61650657
- 93. Muller CA, Autenrieth IB, Peschel A (2005) Innate defenses of the intestinal epithelial barrier. Cell Mol Life Sci 62: 1297–1307.CA MullerIB AutenriethA. Peschel2005Innate defenses of the intestinal epithelial barrier.Cell Mol Life Sci6212971307
- 94. Stringer AM, Gibson RJ, Logan RM, Bowen JM, Yeoh AS, et al. (2009) Gastrointestinal microflora and mucins may play a critical role in the development of 5-Fluorouracil-induced gastrointestinal mucositis. Exp Biol Med (Maywood) 234: 430–441.AM StringerRJ GibsonRM LoganJM BowenAS Yeoh2009Gastrointestinal microflora and mucins may play a critical role in the development of 5-Fluorouracil-induced gastrointestinal mucositis.Exp Biol Med (Maywood)234430441
- 95. Besselink MG, van Santvoort HC, Buskens E, Boermeester MA, van Goor H, et al. (2008) Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 371: 651–659.MG BesselinkHC van SantvoortE. BuskensMA BoermeesterH. van Goor2008Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial.Lancet371651659
- 96. Cannon JP, Lee TA, Bolanos JT, Danziger LH (2005) Pathogenic relevance of Lactobacillus: a retrospective review of over 200 cases. Eur J Clin Microbiol Infect Dis 24: 31–40.JP CannonTA LeeJT BolanosLH Danziger2005Pathogenic relevance of Lactobacillus: a retrospective review of over 200 cases.Eur J Clin Microbiol Infect Dis243140
- 97. Ledoux D, Labombardi VJ, Karter D (2006) Lactobacillus acidophilus bacteraemia after use of a probiotic in a patient with AIDS and Hodgkin's disease. Int J STD AIDS 17: 280–282.D. LedouxVJ LabombardiD. Karter2006Lactobacillus acidophilus bacteraemia after use of a probiotic in a patient with AIDS and Hodgkin's disease.Int J STD AIDS17280282
- 98. Liong MT (2008) Safety of probiotics: translocation and infection. Nutr Rev 66: 192–202.MT Liong2008Safety of probiotics: translocation and infection.Nutr Rev66192202
- 99. Katakura K, Lee J, Rachmilewitz D, Li G, Eckmann L, et al. (2005) Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J Clin Invest 115: 695–702.K. KatakuraJ. LeeD. RachmilewitzG. LiL. Eckmann2005Toll-like receptor 9-induced type I IFN protects mice from experimental colitis.J Clin Invest115695702
- 100. Rachmilewitz D, Karmeli F, Takabayashi K, Hayashi T, Leider-Trejo L, et al. (2002) Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology 122: 1428–1441.D. RachmilewitzF. KarmeliK. TakabayashiT. HayashiL. Leider-Trejo2002Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis.Gastroenterology12214281441