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BACKGROUND & AIMS: Whether preoperative treatment of inflammatory bowel disease (IBD) with tumor necrosis factor inhibitors (TNFis) increases the risk of postoperative infectious complications remains controversial. The primary aim of this study was to determine whether preoperative exposure to TNFis is an independent risk factor for postoperative infectious complications within 30 days of surgery. METHODS: We conducted a multicenter prospective observational study of patients with IBD undergoing intra-abdominal surgery across 17 sites from the Crohn's & Colitis Foundation Clinical Research Alliance. Infectious complications were categorized as surgical site infections (SSIs) or non-SSIs. Current TNFi exposure was defined as use within 12 weeks of surgery, and serum was collected for drug-level analyses. Multivariable models for occurrence of the primary outcome, any infection, or SSI were adjusted by predefined covariates (age, sex, preoperative steroid use, and disease type), baseline variables significantly associated (P < .05) with any infection or SSI separately, and TNFi exposure status. Exploratory models used TNFi exposure based on serum drug concentration. RESULTS: A total of 947 patients were enrolled from September 2014 through June 2017. Current TNFi exposure was reported by 382 patients. Any infection (18.1% vs 20.2%, P = .469) and SSI (12.0% vs 12.6%, P = .889) rates were similar in patients currently exposed to TNFis and those unexposed. In multivariable analysis, current TNFi exposure was not associated with any infection (odds ratio, 1.050; 95% confidence interval, 0.716-1.535) or SSI (odds ratio, 1.249; 95% confidence interval, 0.793-1.960). Detectable TNFi drug concentration was not associated with any infection or SSI. CONCLUSIONS: Preoperative TNFi exposure was not associated with postoperative infectious complications in a large prospective multicenter cohort.
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Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Estudios de Cohortes , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/cirugía , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/cirugía , Estudios Prospectivos , Estudios Retrospectivos , Infección de la Herida Quirúrgica/epidemiología , Infección de la Herida Quirúrgica/etiología , Inhibidores del Factor de Necrosis Tumoral/efectos adversos , Factor de Necrosis Tumoral alfaRESUMEN
Inflammatory bowel disease (IBD) is characterized by damage to the gut mucosa and systemic inflammation. We sought to evaluate the role of chronic inflammation on circulating T-cell activation in human subjects with Crohn's disease and ulcerative colitis. We studied 54 patients with IBD and 28 healthy controls. T-cell activation and cycling were assessed in whole blood samples by flow cytometry. Levels of lipopolysaccharide (LPS) were measured in serum by Limulus amoebocyte lysate assay, and plasma levels of inflammatory markers and LPS-binding proteins were measured by ELISA. The proportions of circulating CD4(+) and CD8(+) T lymphocytes in cycle (Ki67(+) ) are increased in patients with IBD compared with these proportions in controls. CD8(+) T cells from patients with IBD are also enriched for cells that expressed CD38 and HLA-DR, and proportions of these cells are related to plasma levels of interleukin-6 and C-reactive protein in these patients. Intracellular interleukin-2 and interferon-γ levels were elevated in resting and polyclonally activated CD4(+) and CD8(+) T cells in patients with IBD when compared with levels from healthy controls. Surprisingly, we did not find increased levels of LPS in the serum of patients with IBD. We did, however, find a signature of recent microbial translocation, as levels of LPS-binding protein are increased in the plasma of patients with IBD compared with plasma levels in healthy controls; LPS-binding protein levels are also directly related to proportions of CD38 HLA-DR-expressing CD4(+) and CD8(+) T cells. Local damage to the gastrointestinal tract in IBD may result in systemic inflammation and T-cell activation.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Mediadores de Inflamación/sangre , Enfermedades Inflamatorias del Intestino/inmunología , ADP-Ribosil Ciclasa 1/sangre , Adulto , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Estudios de Cohortes , Colitis Ulcerosa/sangre , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/sangre , Enfermedad de Crohn/inmunología , Femenino , Antígenos HLA-DR/sangre , Humanos , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/microbiología , Interferón gamma/sangre , Interleucina-2/sangre , Interleucina-6/sangre , Lipopolisacáridos/sangre , Activación de Linfocitos , Masculino , Glicoproteínas de Membrana/sangre , Persona de Mediana EdadRESUMEN
BACKGROUND: Cure rates of Clostridium difficile infection (CDI) with fecal microbiota transplant (FMT) have been promising. However, there is debate regarding success of FMT in patients with comorbidities. METHODS: Electronic chart review was done to collect data on patients who underwent FMT from January 2015 to August 2017. Charts were analyzed in November 2018 with a median follow-up of 25.4 months (interquartile range 20 - 31 months). RESULTS: Twenty patients underwent FMT. The primary success rate at our institution was 90% and overall success rate was 100%. Six patients (43%) had FMT failure (two early and four late). CONCLUSIONS: This case series is a description of our center's initial experience with FMT for treatment of recurrent CDI. Our high success rate reiterates the efficacy and safety of FMT in this population including patients with comorbidities.
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BACKGROUND: Isolated chronic ileitis in the terminal ileum, without accompanying chronic colitis, is not an uncommon finding present in biopsy specimens from patients being evaluated for chronic diarrhea. Among the many entities that should be included in the differential diagnosis are Crohn's disease and nonsteroidal antiinflammatory drugs (NSAIDs)-induced enterocolitis. In high-prevalence Crohn's disease populations, focal enhanced or active gastritis (FEG) may be a good predictor of Crohn's disease; however, this criterion may not apply in a general clinical setting. Our goal was to determine if FEG is a pathological marker of Crohn's disease in patients with isolated chronic ileitis in the terminal ileum. METHODS: We examined 46 consecutive cases of isolated chronic ileitis with concurrent stomach biopsies. These patients did not have evidence or previous history of inflammatory bowel disease. The diagnostic criteria of chronic ileitis included crypt distortion and inflammation, plasmacytosis in the lamina propria, ulceration, and/or pyloric gland metaplasia. RESULTS: Of the 46 cases reviewed, 25 (54%) cases were diagnosed with Crohn's disease later, confirmed by clinical manifestations and/or biopsies with a follow-up of up to 4 years. The stomach biopsies of these patients were either normal or demonstrated a spectrum of histological findings, including FEG, chronic gastritis with or without Helicobacter pylori organisms, chemical gastropathy, and normal tissues. FEG was more commonly present in Crohn's disease patients (36%) than in non-Crohn's disease patients (5%) (P < 0.01). CONCLUSIONS: The presence of FEG is a good indicator for the diagnosis of Crohn's disease in adult patients with isolated chronic ileitis.
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Enfermedad de Crohn/diagnóstico , Gastritis/complicaciones , Ileítis/complicaciones , Adulto , Anciano , Enfermedad Crónica , Enfermedad de Crohn/complicaciones , Femenino , Gastritis/patología , Humanos , Ileítis/patología , Masculino , Persona de Mediana Edad , Estómago/patologíaRESUMEN
Although inflammatory bowel disease (IBD) usually presents in adolescents and young adults, both ulcerative colitis and Crohn's disease can also present in older adults. The diagnosis of IBD in the elderly is often difficult and can easily be confused with diverticulitis or ischaemic colitis. The symptoms and complications of IBD in the elderly are similar to those found in younger patients. However, when IBD presents later in life the disease is often less extensive and milder. Older IBD patients are treated with the same medications as younger patients, although the risk for drug toxicity is greater, especially with corticosteroid therapy. Comorbid illness in older patients often has a significant impact on the outcome of medical and surgical therapy for IBD but, in the absence of significant co-morbid disease, most elderly IBD patients can expect a good response to therapy.
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Enfermedades Inflamatorias del Intestino , Anciano , Diagnóstico Diferencial , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/terapiaRESUMEN
Although little data exist directly evaluating the utility and safety of endoscopy in the pregnant woman with IBD, it appears to be well tolerated by both mother and fetus, and provides useful clinical information. When performed to evaluate gastrointestinal bleeding, EGD has a high diagnostic yield, while EGD for nausea and vomiting is less informative. In the patient without IBD presenting with hematochezia, unexplained diarrhea, severe abdominal pain, or severe rectal pain, careful sigmoidoscopic examination is indicated, often leading to a diagnosis of new-onset or unsuspected IBD. Likewise, the pregnant IBD patient with worsening symptoms, despite appropriate medical therapy, may also benefit from sigmoidoscopy. Colonoscopy is less often indicated, but can be safely performed in the carefully selected pregnant patient. In all cases obstetrical consultation should be obtained prior to endoscopy, and the risks and benefits of endoscopy to both mother and child should be considered. Close attention should be paid to appropriate drug selection for conscious sedation, and sedation should be administered to provide patient comfort, while avoiding oversedation. Extrapolating from data obtained during endoscopic examination of the pregnant non-IBD patient, fetal monitoring is generally not indicated, although it should be considered for the high-risk or late third-trimester patient. Following these principles assures that endoscopy can be safely performed in the pregnant IBD patient with the best possible outcome for both mother and baby.
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Endoscopía Gastrointestinal , Enfermedades Inflamatorias del Intestino/diagnóstico , Complicaciones del Embarazo/diagnóstico , Sedación Consciente , Endoscopía Gastrointestinal/efectos adversos , Endoscopía Gastrointestinal/métodos , Femenino , Humanos , EmbarazoRESUMEN
Pouchitis is an inflammatory complication after restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA). IPAA is the surgical treatment of choice in patients with ulcerative colitis (UC) who require colectomy. Initial episodes of acute pouchitis generally respond to antibiotics but significant numbers of cases eventually become dependent on or refractory to antibiotics. Management of chronic antibiotic refractory pouchitis is challenging and can ultimately lead to pouch failure. The etiopathogenesis is unknown though recent studies have implicated bacterial dysbiosis of the pouch microbiota, NOD2 polymorphism, and Clostridium difficile infection in the development of severe pouchitis. Early identification of risk factors can help in tailoring therapy and reducing cases of chronic pouchitis.
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BACKGROUND: The commensal bacterial flora plays a critical role in the postoperative recurrence of Crohn's disease (CD). We conducted a randomized, double-blind, placebo-controlled 6-month pilot trial of ciprofloxacin for the prevention of endoscopic recurrence in patients with CD who underwent surgery. METHODS: Thirty-three patients with CD, who had undergone surgery with ileocolonic anastomosis within the previous 2 weeks, were randomized to treatment with ciprofloxacin (500 mg twice daily) or placebo tablets for 6 months. Endpoints were endoscopic recurrence at 6 months and safety and tolerability of long-term ciprofloxacin therapy. RESULTS: Thirty-three patients were randomized; 14 patients discontinued the study early. Significant endoscopic recurrence was observed in 3 of 9 patients (33%) in the ciprofloxacin group and 5 of 10 patients (50%) in the placebo group at 6 months after surgery (P < 0.578). The intention-to-treat analysis demonstrated endoscopic recurrence in 11 of 17 patients (65%) in the ciprofloxacin group and 11 of 16 patients (69%) in the placebo group at month 6 (P < 0.805). Thirty-six adverse events occurred in 19 of 33 patients (58%). Possible drug-associated adverse events occurred significantly more often in the ciprofloxacin group (P < 0.043), leading to study drug discontinuation in 24% (4 of 17) and 6% of patients (1 of 16) in the ciprofloxacin and placebo groups, respectively (P < 0.166). CONCLUSIONS: In this pilot study, ciprofloxacin was not more effective than placebo for the prevention of postoperative recurrence in patients with CD. Long-term ciprofloxacin therapy is limited by drug-associated side effects. Future studies in postoperative prevention of CD should evaluate antibiotic approaches with a more favorable safety profile.
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Antiinfecciosos/uso terapéutico , Ciprofloxacina/uso terapéutico , Enfermedad de Crohn/cirugía , Complicaciones Posoperatorias/prevención & control , Prevención Secundaria , Adolescente , Adulto , Anastomosis Quirúrgica , Método Doble Ciego , Endoscopía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Proyectos Piloto , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: Crohn's disease (CD) patients may be at increased risk for the development of Hodgkin's lymphoma (HL) or non-Hodgkin's lymphoma (NHL), either through exposure to immunosuppressive medications or due to their underlying chronic inflammatory illness. There are limited data regarding the natural history of CD following treatment of lymphoma. We present a series of CD patients who were treated for lymphoma and describe the natural history of their CD following lymphoma treatment. METHODS: Retrospective case series from three academic referral centers was used. All CD patients with a history of lymphoma were identified. Demographic data, CD medication exposure, and surgical procedures before and after lymphoma treatment were recorded. RESULTS: Nine CD patients with a history of lymphoma were identified. Eight individuals received chemotherapy, while one patient was observed without treatment. Eight patients remained free of lymphoma for a mean of 72.8 months (range 1-276 months). The ninth patient had recurrence of his HL 3 years after lymphoma diagnosis. Following lymphoma treatment, two patients had quiescent CD with no specific therapy. Three patients demonstrated significant clinical relapse of their CD and a fourth patient developed CD after treatment of her lymphoma, which ultimately required long-term immunomodulator therapy with 6-mercaptopurine or methotrexate in the first three patients, and azathioprine in the fourth. Four patients required CD surgery after lymphoma treatment. CONCLUSION: We report on the clinical course of CD in patients who develop lymphoma. Significant clinical relapse of CD following successful medical treatment of lymphoma occurred frequently in patients with a history of this neoplasm.
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Enfermedad de Crohn/complicaciones , Linfoma/complicaciones , Adolescente , Adulto , Antineoplásicos/uso terapéutico , Niño , Enfermedad de Crohn/tratamiento farmacológico , Femenino , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Linfoma/tratamiento farmacológico , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/tratamiento farmacológico , Masculino , Mercaptopurina/efectos adversos , Mercaptopurina/uso terapéutico , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Prevention of the postoperative recurrence of Crohn's disease (CD) remains a challenging clinical problem. The majority of patients with CD will need surgery for treatment of the disease, most of these patients will develop recurrent symptoms within 5 years postoperatively, and many patients will need reoperation within 10 years. In patients with an ileocolic anastomosis, endoscopic recurrence precedes clinical recurrence and the severity of endoscopic recurrence correlates with the risk of clinical recurrence. Despite multiple studies, the best postoperative prophylactic therapy remains uncertain. Numerous randomized controlled trials of 5-aminosalicylates have shown only modest effect. Antibiotics, including metronidazole and ornidazole, decrease short-term, but not long-term endoscopic recurrence and are limited by side effects. Immunomodulators have yet to be extensively evaluated, although limited data suggest possible efficacy in preventing postoperative recurrence, particularly in high-risk patients. This review will evaluate the current state of the art therapy for postoperative prophylaxis in CD, with an emphasis on critical analysis of the available randomized controlled trials.
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Antibacterianos/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Cuidados Posoperatorios/métodos , Enfermedad de Crohn/diagnóstico , Endoscopía Gastrointestinal , Humanos , Prevención Secundaria , Resultado del TratamientoRESUMEN
Optimal care of the inflammatory bowel diseases, Crohn's disease and ulcerative colitis, requires a broad understanding of disease pathophysiology and therapeutic alternatives. The goals of therapy are accurate diagnosis and timely treatment to both induce and maintain a clinical remission and improve patient quality of life. Most patients can be adequately treated using a combination or aminosalicylates, antibiotics, and corticosteroids, though many patients with Crohn's disease will require immunomodulators, such as azathioprine or 6-mercaptopurine. The development of novel biologic therapies, particularly infliximab, have dramatically improved our ability to medically manage more severe Crohn's disease and ulcerative colitis patients. This review will focus on the medical management of inflammatory bowel disease in adults.
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Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Adulto , Antibacterianos/uso terapéutico , Antirreumáticos/uso terapéutico , Humanos , Lisina/análogos & derivados , Lisina/uso terapéutico , Inducción de Remisión , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
BACKGROUND & AIMS: Fractalkine (FKN/CX3CL1) is a unique chemokine combining adhesive and chemotactic properties. We investigated FKN production by the mucosal microvasculature in inflammatory bowel disease (IBD), its capacity for leukocyte recruitment into the gut, and the number of CX3CR1+ cells in the circulation and mucosa of IBD patients. METHODS: The expression of FKN by human intestinal microvascular endothelial cells (HIMECs) and CX3CR1 by circulating cells was evaluated by flow cytometry, and mucosal CX3CR1+ cells were enumerated by immunohistochemistry. The capacity of FKN to mediate leukocyte binding to HIMECs was assessed by immunoblockade, and to induce HIMEC transmigration by a Transwell system. RESULTS: The spontaneously low HIMEC FKN expression was enhanced markedly by tumor necrosis factor-alpha plus interferon-gamma stimulation, or direct leukocyte contact. This effect was significantly stronger in IBD than control HIMECs. Up-regulation of HIMEC FKN expression was dependent on p38 and extracellular signal-regulated kinase phosphorylation, as was abrogated by selective mitogen-activated protein kinase inhibitors. Circulating T cells contained significantly higher numbers of CX3CR1+ cells in active IBD than inactive IBD or healthy subjects, and IBD mucosa contained significantly more CX3CR1+ cells than control mucosa. Antibody-blocking experiments showed that FKN was a major contributor to T- and monocytic-cell adhesion to HIMECs. Finally, FKN enhanced the expression of active beta1 integrin on leukocytes and mediated leukocyte HIMEC transmigration. CONCLUSIONS: In view of the capacity of FKN to mediate leukocyte adhesion, chemoattraction, and transmigration, its increased production by mucosal microvascular cells and increased numbers of circulating and mucosal CX3CR1+ cells in IBD point to a significant role of FKN in disease pathogenesis.
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Movimiento Celular/inmunología , Quimiocinas CX3C/metabolismo , Células Endoteliales/citología , Enfermedades Inflamatorias del Intestino/inmunología , Proteínas de la Membrana/metabolismo , Receptores de Quimiocina/metabolismo , Linfocitos T/citología , Receptor 1 de Quimiocinas CX3C , Adhesión Celular/inmunología , Células Cultivadas , Quimiocina CX3CL1 , Quimiocinas CX3C/inmunología , Citocinas/farmacología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Citometría de Flujo , Humanos , Enfermedades Inflamatorias del Intestino/patología , Integrina beta1/metabolismo , Mucosa Intestinal/irrigación sanguínea , Mucosa Intestinal/inmunología , Células Jurkat , Sistema de Señalización de MAP Quinasas/inmunología , Proteínas de la Membrana/inmunología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores de Quimiocina/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Regulación hacia Arriba/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND & AIMS: Gastroesophageal reflux disease is a condition frequently associated with esophagitis and motor abnormalities. Recent evidence suggests that proinflammatory cytokines, such as interleukin (IL)-1beta and IL-6, may be implicated because they reduce esophageal muscle contractility, but these results derive from in vitro or animal models of esophagitis. This study used human esophageal cells and tissues to identify the cellular source of cytokines in human esophagitis investigate whether cytokines can be induced by gastric refluxate, and examine whether esophageal tissue- or cell-derived mediators affect muscle contractility. METHODS: Endoscopic mucosal biopsy specimens were obtained from patients with and without esophagitis, organ-cultured, and undernatants were assessed for cytokine content. The cytokine profile of esophageal epithelial, fibroblast, and muscle cells was analyzed, and esophageal mucosa and cell products were tested in an esophageal circular muscle contraction assay. RESULTS: The mucosa of esophagitis patients produced significantly greater amounts of IL-1beta and IL-6 compared with those of control patients. Cultured esophageal epithelial cells produced IL-6, as did fibroblasts and muscle cells. Epithelial cells exposed to buffered, but not denatured, gastric juice produced IL-6. Undernatants of mucosal biopsy cultures from esophagitis patients reduced esophageal muscle contraction, as did supernatants from esophageal epithelial cell cultures. CONCLUSIONS: The human esophagus produces cytokines capable of reducing contractility of esophageal muscle cells. Exposure to gastric juice is sufficient to stimulate esophageal epithelial cells to produce IL-6, a cytokine able to alter esophageal contractility. These results indicate that classic cytokines are important mediators of the motor disturbances associated with human esophageal inflammation.
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Trastornos de la Motilidad Esofágica/inmunología , Trastornos de la Motilidad Esofágica/patología , Reflujo Gastroesofágico/inmunología , Reflujo Gastroesofágico/patología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Animales , Biopsia , Gatos , Línea Celular , Esofagitis/inmunología , Esofagitis/patología , Esófago/citología , Jugo Gástrico , Humanos , Interleucina-1beta/genética , Interleucina-6/genética , Queratinocitos/citología , Queratinocitos/metabolismo , Membrana Mucosa/inmunología , Membrana Mucosa/patología , Contracción Muscular , Músculo Liso/fisiología , Técnicas de Cultivo de Órganos , Reacción en Cadena de la Polimerasa , ARN Mensajero/metabolismoRESUMEN
Antibiotic-associated diarrhea is a common clinical problem occurring in up to 25% of patients, with diarrhea owing to Clostridium difficile accounting for up to a quarter of cases. The clinical and economic costs of antibiotic-associated diarrhea are significant and better treatments are needed. Probiotics may offer potential effective therapy for antibiotic-associated diarrhea by restoring intestinal microbial balance. A number of different probiotics have been evaluated in the prevention and treatment of antibiotic-associated diarrhea in adults and children, including the nonpathogenic yeast Saccharomyces boulardii and multiple lactic-acid fermenting bacteria such as Lactobacillus rhamnosus GG (LGG). A careful review of the literature supports the efficacy of S. boulardii in the prevention of antibiotic-associated diarrhea recurrent C. difficile infection in adults, whereas LGG is useful in the treatment of antibiotic-associated diarrhea in children. Not enough data exist to currently support the use of other probiotic preparations in these conditions. Although generally safe and well tolerated, both S. boulardii and LGG should be used cautiously in immunocompromised patients. Further study of probiotics, including large, well-designed, randomized controlled dose-ranging trials, comparative trials, and cost-benefit analyses are necessary.
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Antibacterianos/efectos adversos , Clostridioides difficile , Infecciones por Clostridium/complicaciones , Infecciones por Clostridium/prevención & control , Diarrea/prevención & control , Probióticos/farmacología , Niño , Diarrea/inducido químicamente , Diarrea/microbiología , Humanos , Lactobacillus , SaccharomycesRESUMEN
There is growing interest in and knowledge about the potential health-promoting benefits of both probiotics and prebiotics. Multiple mechanisms of action for the beneficial effect of probiotics and prebiotics have been postulated, including prevention of pathogenic bacteria growth, production of antimicrobial agents, stimulation of mucosal barrier function, and altering immunoregulation. Clinical trials support the efficacy of probiotics in the treatment of acute infectious diarrhea, the prevention of antibiotic associated diarrhea, and the prevention of recurrent Clostridium difficile infection. Although some data support the potential benefit of probiotic therapy in traveler's diarrhea, diverticular disease, and Helicobacter pylori, the strength of this evidence is limited. This paper will review the recent literature relevant to the mechanism of action and utility of probiotics and prebiotics in the treatment of gastrointestinal infections.
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The CD40/CD40 ligand (CD40L) pathway is involved in Crohn's disease (CD) pathogenesis. In the patients' circulation, soluble CD40L (sCD40L) levels are elevated and surface CD40L is increased in platelets and T cells, whereas in the intestine CD40 is overexpressed in the microvasculature and CD40L in platelets and T cells. The therapeutic effects of infliximab in CD are attributed to its systemic anti-TNF-alpha action, but because TNF-alpha modulates both CD40 and CD40L, we investigated whether infliximab affects the CD40/CD40L pathway in the intestine. Eighteen CD patients were evaluated before and after infliximab therapy. Plasma sCD40L was measured by ELISA and platelet and peripheral blood T cell (PBT) CD40L expression by flow cytometry. Microvascular CD40 and VCAM-1 expression were assessed in mucosal biopsies by immunohistochemistry and by flow cytometry in human intestinal microvascular endothelial cells (HIMEC). Cell cultures were performed in the presence and absence of infliximab. Infliximab treatment significantly reduced plasma sCD40L levels and eliminated CD40 and VCAM-1 from mucosal microvessels. In vitro infliximab prevented TNF-alpha-induced CD40 and VCAM-1 expression by HIMEC, and reduced PBT, but not platelet, surface CD40L expression and sCD40L release. In addition, infliximab decreased T cell-induced VCAM-1 expression in HIMEC by down-regulating CD40L in T cells and promoting T cells apoptosis. These findings point to a novel mechanism of action of infliximab, i.e., the disruption of CD40/CD40L-dependent cognate interactions between intestinal microvessels and T cells. Thus, in addition to neutralizing TNF-alpha and inducing T cell death, the therapeutic effects of infliximab in CD appear to be also mediated by inhibition of vascular inflammation in the gut.
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Anticuerpos Monoclonales/farmacología , Antígenos CD40/metabolismo , Ligando de CD40/metabolismo , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/metabolismo , Regulación hacia Abajo , Mucosa Intestinal/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Anticuerpos Monoclonales/uso terapéutico , Apoptosis/efectos de los fármacos , Plaquetas/inmunología , Plaquetas/metabolismo , Antígenos CD40/inmunología , Ligando de CD40/inmunología , Enfermedad de Crohn/patología , Enfermedad de Crohn/terapia , Células Endoteliales/metabolismo , Femenino , Humanos , Inmunoterapia , Infliximab , Mucosa Intestinal/irrigación sanguínea , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
Corticosteroids are a mainstay in the treatment of inflammatory bowel disease. Administered topically, orally, or intravenously corticosteroids rapidly and consistently improve moderate to severe active ulcerative colitis and Crohn's disease, although they are ineffective in the maintenance of remission in either illness. The beneficial effects of corticosteroid therapy are counterbalanced by their many side effects. A better understanding of the mechanism of steroid action and toxicity has led to the development of novel corticosteroids that offer the promise of continued efficacy with minimal toxicity. This article reviews the role of conventional and novel corticosteroids in the management of inflammatory bowel disease.