RESUMO
We report on a clinical case of capecitabine-induced acute ileitis in a patient treated with pre-operative concurrent chemoradiation with capecitabine for locally advanced rectal cancer and provide a comprehensive literature review. This a rare, but life-threatening, clinical situation, that clinicians should be aware of. Severe persistent diarrhea is the most frequent clinical feature and computed tomography is a valid tool for diagnosis. Conservative management includes capecitabine withdrawal, antidiarrheal therapy and endovenous hydration, together with dietary modifications and broad-spectrum antibiotics. Pelvic irradiation represents an adjunctive risk factor, which may increase the likelihood of occurrence of terminal ileitis. Early recognition and prompt intervention are crucial for successful clinical management.
Assuntos
Ileíte , Neoplasias Retais , Humanos , Capecitabina/efeitos adversos , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/cirurgia , Quimiorradioterapia/métodos , Ileíte/tratamento farmacológicoRESUMO
A 45-year-old male, with a recent surgery for odontoid fracture, presented to the emergency department with a 15-days history of abdominal pain associated with fever and weight loss. He reported a recent history of antibiotic therapy due to respiratory infection and a frequent use of anti-inflammatory drugs (NSAIDs) in the last three months.
Assuntos
Doença de Crohn , Ileíte , Masculino , Humanos , Pessoa de Meia-Idade , Doença de Crohn/tratamento farmacológico , Ileíte/tratamento farmacológico , Antibacterianos/uso terapêutico , Dor Abdominal , Anti-Inflamatórios/uso terapêuticoRESUMO
BACKGROUND There is a recognized association between inflammatory bowel disease (IBD) and hepatobiliary autoimmune disease, particularly primary sclerosing cholangitis (PSC). There have been fewer reported cases of IBD and primary biliary cholangitis (PBC), which is treated with ursodeoxycholic acid (UDCA). This report presents the case of a 60-year-old woman with PBC who was diagnosed with Crohn's ileitis after suspension of UDCA treatment. CASE REPORT A 66-year-old female patient with PBC was admitted to our department for irrepressible chronic diarrhea and recurrent abdominal pain. PBC was diagnosed on the basis of serological data: chronic (>6 months) increase in alkaline phosphatase (ALP) associated with positivity for specific anti-nuclear antibodies (sp100 and gp210), without requiring a liver biopsy and a magnetic resonance cholangiopancreatography to rule out PSC. Given the intolerance and non-responsiveness according to the Toronto criteria (ALP <1.67 times the normal limit after 2 years) to UDCA at 15 mg/kg/day, an oral monotherapy treatment using obeticholic acid at 5 mg/day was prescribed. The patient complained of abdominal pain and upper gastrointestinal symptoms. The endoscopic/histologic and radiologic examinations supported the diagnosis of Crohn's ileitis. Given the potential benefits to PBC patients of what is described as off-label therapy, budesonide at a dosage of 9 mg/day p.o. was also administered. One month after discharge, an improvement was observed both in the cholestasis indices and in gastrointestinal symptoms. CONCLUSIONS This report presents a case of PBC in which the patient was diagnosed with Crohn's ileitis after cessation of treatment with UDCA, and highlights the importance of recognizing the association between autoimmune hepatobiliary disease and IBD.
Assuntos
Doenças Autoimunes , Doença de Crohn , Ileíte , Doenças Inflamatórias Intestinais , Cirrose Hepática Biliar , Feminino , Humanos , Idoso , Pessoa de Meia-Idade , Ácido Ursodesoxicólico/uso terapêutico , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Fosfatase Alcalina , Doença de Crohn/complicações , Doença de Crohn/tratamento farmacológico , Budesonida/efeitos adversos , Dor Abdominal , Ileíte/diagnóstico , Ileíte/tratamento farmacológicoRESUMO
BACKGROUND AND AIMS: Crohn's disease is a debilitating chronic inflammatory disorder of the mammalian gastrointestinal tract. Current interventions using anti-tumour necrosis factor [anti-TNF] biologics show long-term benefit in only half of patients. This study focused on the role of the TNF receptor 1 [TNFR1] in pathogenesis in a TNF-driven model of ileitis. METHODS: We studied TNFΔAU-rich element [ARE]/+ [TNFdARE] mice, which develop progressive ileitis similar to Crohn's ileitis. Histopathological analysis and gene expression profiling were used to characterize disease progression from 5 to 16 weeks. Mice with TNFR1 hemizygosity [TNFdARE/R1het] allowed us to assess gene dosage effects. Transcriptional profiling established inflection points in disease progression; inflammatory gene expression increased at 8 weeks with a plateau by 10 weeks, so these were selected as endpoints of treatment using the TNF biologic infliximab and the TNFR1-specific XPro1595. Differences in recruitment of cells in the lamina propria were assessed using flow cytometry. RESULTS: TNFdARE/R1het mice displayed stable long-term protection from disease, associated with decreased recruitment of CD11bhiF4/80lo monocytes and CD11bhiLy6Ghi neutrophils, suggesting an important role of TNFR1 signalling in pathogenesis, and indicating potential benefit from TNFR1-specific intervention. Treatment with infliximab and XPro1595 both showed a similar impact on disease in TNFdARE mice. Importantly, these beneficial effects were greatly surpassed by hemizygosity at the TNFR1 locus. CONCLUSIONS: Treatment with either infliximab or XPro1595 produced moderate protection from ileitis in TNFdARE mice. However, hemizygosity at the TNFR1 locus in TNFdARE mice showed far better protection, implicating TNFR1 signalling as a key mediator of TNF-driven disease.
Assuntos
Doença de Crohn , Ileíte , Animais , Doença de Crohn/complicações , Progressão da Doença , Ileíte/tratamento farmacológico , Ileíte/etiologia , Ileíte/prevenção & controle , Infliximab/farmacologia , Infliximab/uso terapêutico , Mamíferos/metabolismo , Camundongos , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Inhibitors of bromodomain and extra-terminal motif (BET) proteins are emerging epigenetic therapeutics that suppress gene expressions that drive cancer and inflammation. The present study examined anti-inflammatory effects of a quinazoline-based BET inhibitor, CN210, in a murine ileitis model. CN210 was given orally 30 min before and 24 h after a subcutaneous administration of indomethacin. Macroscopic and histological evidences of ileitis, mucosal myeloperoxidase (MPO) activity and cytokine expressions were evaluated 48 h after the indomethacin administration. To further characterize the anti-inflammatory pathways modulated by CN210, its effects on RAW264 cells treated with lipopolysaccharide (LPS) were investigated. Competitive ligand binding and docking studies of CN210 to CREB-binding protein (CBP) and p300 were also performed. Oral administration of CN210 significantly reduced the severity of ileitis, normalized both proinflammatory MPO activity and concomitant cytokine expressions induced by indomethacin administration. Furthermore, CN210 attenuated the expression of cytokines and reversed the activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPK) induced by LPS. Competitive ligand binding assays showed that CN210 bound to the bromodomains of two paralogous histone acetyltransferases, CBP and p300, in addition to the bromodomains of BET proteins. Docking studies of CN210 to the bromodomains of CBP and p300 showed a similarity to the binding mode of SGC-CBP30, a specific CBP/p300 inhibitor. CN210 ameliorates indomethacin-induced ileitis by inhibiting the expression of inflammatory cytokines through the attenuation of NF-κB and MAPK pathways. CN210 thus represents a new mode of therapy for non-steroidal anti-inflammatory drug-induced ileitis and inflammatory bowel disease.
Assuntos
Anti-Inflamatórios/farmacologia , Citocinas/antagonistas & inibidores , Ileíte/tratamento farmacológico , Indometacina/efeitos adversos , Proteínas/antagonistas & inibidores , Animais , Citocinas/biossíntese , Proteína p300 Associada a E1A/metabolismo , Ileíte/induzido quimicamente , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/fisiologia , Peroxidase/metabolismo , Fosfoproteínas/metabolismo , Quinazolinas/farmacologia , Células RAW 264.7RESUMO
Symptomatic cytomegalovirus (CMV) infection in immunocompetent hosts has traditionally been considered to have a benign, self-limited course, and those who need intensive therapy are rare. Moreover, there are few reports of CMV infection with protein-losing enteropathy (PLE). We present an immunocompetent 74-year-old woman with CMV ileitis with PLE, which was diagnosed due to severe hypoalbuminemia and edema of the lower extremities. The patient was not immunocompromised, because a human immunodeficiency virus (HIV) antibody test was negative and she had not been taking immunosuppressants. Imaging tests including colonoscopy revealed ileitis with shallow widespread ulcers. 99mTc-human serum albumin (HAS-D) scintigraphy suggested a possibility of protein loss in the ileum based on selective accumulation of nuclides in the right abdomen. Histological findings of the biopsy showed ulcerative mucosa with abnormal cells, which had enlarged nuclei with intranuclear inclusion bodies, including typical Cowdry A type. In immunohistochemistry, these cells were positive for anti-CMV staining. She was successfully treated with medical treatments including intravenous injection of ganciclovir (GCV) (500 mg/day). We described an extremely rare case of CMV ileitis with PLE in an immunocompetent adult who was treated successfully with medical treatments, including GCV.
Assuntos
Infecções por Citomegalovirus , Ileíte , Enteropatias Perdedoras de Proteínas , Adulto , Idoso , Antivirais/uso terapêutico , Citomegalovirus , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/tratamento farmacológico , Feminino , Ganciclovir/uso terapêutico , Humanos , Ileíte/complicações , Ileíte/diagnóstico , Ileíte/tratamento farmacológico , Enteropatias Perdedoras de Proteínas/diagnóstico , Enteropatias Perdedoras de Proteínas/tratamento farmacológico , Enteropatias Perdedoras de Proteínas/etiologiaRESUMO
In this case, we present an uncommon gastrointestinal infection in an immunocompromised patient that was solely diagnosed because of close collaboration between treating physicians and microbiologists. The patient is a 42-year-old male who underwent heart transplantation 5 years earlier. He presented with fever, weight loss, diarrhoea and tiredness. Initial investigations could not elucidate the aetiology of his symptoms. The patient was referred to the department of infectious diseases for further evaluation. Serology for Yersinia species was ordered and the result was suggestive for the possibility of a Yersinia species infection. Close collaboration between treating physicians and microbiologists followed and led to additional investigations, which revealed the diagnosis of a Yersinia pseudotuberculosis infection with extensive lesions in the gastrointestinal tract. Treatment with ciprofloxacin resulted in complete resolution of symptoms and healing of the gastrointestinal lesions. In conclusion, this case underlines the need for a multidisciplinary approach to complex patients of which symptoms have yet to be understood.
Assuntos
Transplante de Coração , Ileíte/diagnóstico , Hospedeiro Imunocomprometido , Úlcera/diagnóstico , Infecções por Yersinia pseudotuberculosis/diagnóstico , Adulto , Antibacterianos/uso terapêutico , Ciprofloxacina/uso terapêutico , Humanos , Ileíte/tratamento farmacológico , Ileíte/microbiologia , Valva Ileocecal/microbiologia , Masculino , Úlcera/tratamento farmacológico , Úlcera/microbiologia , Infecções por Yersinia pseudotuberculosis/tratamento farmacológicoRESUMO
BACKGROUND: Lymphocytes recirculate from tissues to blood following the sphingosine-1-phosphate (S1P) gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, among which the S1P lyase (SPL) irreversibly degrades S1P. The role of SPL in the intestine, both during homeostasis and IBD, is poorly understood. We hypothesized that modulation of tissue S1P levels might be advantageous over S1P receptor (S1PR) agonists (eg, fingolimod, ozanimod, etrasimod), as without S1PR engagement there might be less likelihood of potential off-target effects. METHODS: First we examined SPL mRNA transcripts and SPL localization in tissues by quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The in vivo effects of the SPL inhibitors 4-deoxypyridoxine hydrochloride (30 mg/L) and 2-acetyl-4 (tetrahydroxybutyl)imidazole (50 mg/L) were assessed through their oral administration to adult TNF∆ARE mice, which spontaneously develop Crohn's-like chronic ileitis. The effect of SPL inhibition on circulating and tissue lymphocytes, transcriptional regulation of proinflammatory cytokines, and on the histological severity of ileitis was additionally examined. Tissue S1P levels were determined by liquid chromatography-mass spectrometry. Mechanistically, the potential effects of high S1P tissue levels on intestinal leukocyte apoptosis were assessed via terminal deoxynucleotidyl transferase dUTP nick end-labeling assay and annexin 5 staining. Finally, we examined the ability of T cells to home to the intestine, along with the effects of SPL inhibition on cellular subsets within immune compartments via flow and mass cytometry. RESULTS: S1P lyase was ubiquitously expressed. In the gut, immunohistochemistry predominantly localized it to small intestinal epithelia, although the lamina propria leukocyte fraction had higher mRNA transcripts. Inhibition of SPL markedly increased local intestinal S1P levels, induced peripheral lymphopenia, downregulated proinflammatory cytokines, and attenuated chronic ileitis in mice. SPL inhibition reduced T and myeloid cells in secondary lymphoid tissues and the intestine and decreased naïve T-cell recruitment. The anti-inflammatory activity of SPL inhibition was not mediated by leukocyte apoptosis, nor by interference with the homing of lymphocytes to the intestine, and was independent of its peripheral lymphopenic effect. However, SPL inhibition promoted thymic atrophy and depleted late immature T cells (CD4+CD8+ double positive), with accumulation of mature CD4+CD8- and CD4-CD8+ single-positive cells. CONCLUSIONS: Inhibition of the S1P lyase alters the S1P gradient and attenuates chronic ileitis via central immunosuppression. SPL inhibition could represent a potential way to tame an overactive immune response during IBD and other T-cell-mediated chronic inflammatory diseases.
Assuntos
Aldeído Liases/antagonistas & inibidores , Anti-Inflamatórios/farmacologia , Doença de Crohn/tratamento farmacológico , Ileíte/tratamento farmacológico , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Timócitos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Animais , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Ileíte/metabolismo , Ileíte/patologia , Camundongos , Esfingosina/metabolismo , Timócitos/patologia , Fator de Necrose Tumoral alfa/genéticaRESUMO
Mycoplasma pneumoniae infection can present with a plethora of symptoms and result in a systemic vasculitis by activating a cascade of autoimmune reactions. In this case report, a young man without relevant past medical history was admitted to the hospital with diarrhea, abdominal pain and spiking fever. A CT-scan showed terminal ileitis. A 5-day broad spectrum antibiotic treatment (ciprofloxacin/clindamycin) did not result in any clinical improvement. On the contrary, the patient developed a cholestatic hepatitis, bilateral anterior uveitis and a dry cough. Extensive serological testing finally led to the diagnosis of a M. pneumoniae infection by paired serology (≥4-fold rise in IgG titer). In the diagnostic work-up, a PET-CT was performed and showed increased tracer uptake in the carotids and vertebral arteries, suggesting the diagnosis of vasculitis. After start of azithromycin and low-dose corticosteroids (0.5 mg/kg/day), a gradual clinical and biochemical improvement was observed. But subsequently, the patients relapsed and presented with an acute coronary syndrome. Coronary angiography revealed aneurysmatic deformation of the three coronary arteries, leading to the assumption of coronary vasculitis. Clinical improvement was achieved with high-dose corticosteroids (1 mg/kg/day). This case shows that M. pneumoniae is not merely a pulmonary infection, but that its primary symptoms can be diverse and misleading. All clinicians should be aware of its extrapulmonary manifestations.
Assuntos
Síndrome Coronariana Aguda/fisiopatologia , Aneurisma Coronário/fisiopatologia , Hepatite/fisiopatologia , Ileíte/fisiopatologia , Pneumonia por Mycoplasma/fisiopatologia , Uveíte Anterior/fisiopatologia , Vasculite/fisiopatologia , Dor Abdominal , Síndrome Coronariana Aguda/etiologia , Adulto , Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Colestase/etiologia , Colestase/fisiopatologia , Aneurisma Coronário/etiologia , Tosse/etiologia , Tosse/fisiopatologia , Diarreia/tratamento farmacológico , Diarreia/etiologia , Diarreia/fisiopatologia , Febre , Glucocorticoides/uso terapêutico , Hepatite/tratamento farmacológico , Hepatite/etiologia , Humanos , Ileíte/tratamento farmacológico , Ileíte/etiologia , Masculino , Infecções por Mycoplasma/complicações , Infecções por Mycoplasma/tratamento farmacológico , Infecções por Mycoplasma/fisiopatologia , Mycoplasma pneumoniae , Pneumonia por Mycoplasma/complicações , Pneumonia por Mycoplasma/tratamento farmacológico , Recidiva , Uveíte Anterior/tratamento farmacológico , Uveíte Anterior/etiologia , Vasculite/tratamento farmacológico , Vasculite/etiologiaRESUMO
BACKGROUND A Neisseria gonorrhoea infection is one of the most common sexually transmitted diseases and can present both urogenitally and extragenitally. CASE DESCRIPTION A 55-year-old woman presented at the emergency room with general malaise, abdominal pain and fever. Despite extensive surgical, gynaecological and radiological investigations no clear cause could initially be found. She was subsequently admitted to the surgical unit for observation. During the admission period the patient developed diffuse peritonitis and her infection parameters were rising. Diagnostic laparoscopy revealed extensive terminal ileitis with a reactive infiltrate of the uterine fundus and purulent peritonitis. A PCR test of the abdominal exudate was strongly positive for Neisseria gonorrhoeae, but cultures remained negative. Following an 8-day course of antibiotic treatment with intravenous ceftriaxone, the patient recovered from her symptoms. CONCLUSION Terminal ileitis with peritonitis is an unusual extragenital manifestation of a gonococcal infection. In order to make a diagnosis, surgical exploration with cultures is sometimes indicated.
Assuntos
Ceftriaxona/administração & dosagem , Ileíte , Neisseria gonorrhoeae/isolamento & purificação , Peritonite , Antibacterianos/administração & dosagem , Diagnóstico Diferencial , Feminino , Gonorreia/diagnóstico , Gonorreia/fisiopatologia , Gonorreia/terapia , Humanos , Ileíte/tratamento farmacológico , Ileíte/microbiologia , Ileíte/fisiopatologia , Pessoa de Meia-Idade , Peritonite/tratamento farmacológico , Peritonite/microbiologia , Peritonite/fisiopatologia , Resultado do TratamentoRESUMO
PURPOSE OF REVIEW: The purpose is to make aware of the existence of the rare and exclusive small intestine (SI) diseases, namely cryptogenic multifocal ulcerating stenosing enteropathy (CMUSE) or chronic non-specific multiple ulcers of the small intestine (CNSU) and non-granulomatous ulcerating jejunoileitis (NGUJI). The article will elucidate their epidemiology, pathogenesis, clinical features, diagnosis, differentiating features and management. RECENT FINDINGS: Recent papers have published the clinical features and diagnostic criteria of CMUSE/CNSU and NGUJI. CNSU/CMUSE is caused by gene mutations involved in the prostaglandin pathways. Although capsule endoscopy can detect these lesions, it carries a risk of retention. TNF antagonists and azathioprine have shown response in few cases. CMUSE/CNSU and NGUJI are uncommon diseases that cause relapsing SI obstruction and bleed due to short-segment strictures and multiple shallow ulcers. This article focuses on current knowledge and novel insights regarding their pathogenesis, genetics, clinical features, diagnostic criteria and management. Multicentric clinical and genetic studies are the need of the hour.
Assuntos
Enterite/diagnóstico , Obstrução Intestinal/diagnóstico , Intestino Delgado , Úlcera/diagnóstico , Enterite/tratamento farmacológico , Enterite/etiologia , Fármacos Gastrointestinais/uso terapêutico , Predisposição Genética para Doença , Fosfolipases A2 do Grupo IV/genética , Humanos , Ileíte/diagnóstico , Ileíte/tratamento farmacológico , Ileíte/etiologia , Obstrução Intestinal/tratamento farmacológico , Obstrução Intestinal/etiologia , Mutação , Transportadores de Ânions Orgânicos/genética , Úlcera/tratamento farmacológico , Úlcera/etiologiaRESUMO
Secondary non-response to biological treatments tends to occur in a high number of patients who undergo treatment with antiTNF, and it has also been observed in patients treated with vedolizumab or ustekinumab. The initial rescue guideline recommends intensifying the treatment by reducing the interval or increasing maintenance dosage. In the case of ustekinumab, the patients who began this treatment prior to its approval for treatment of Crohn's disease, were given a subcutaneous induction with no defined guideline and a maintenance dosage of 90 mg every eight weeks. Following secondary non-response in these patients, it was proposed that rescue be undertaken via intravenous reinduction adjusted for weight. We present a case of a patient with Crohn's disease with failure to respond to infliximab, adalimumab and vedolizumab who began treatment with ustekinumab prior to official approval. There was non-response at eight months but remission was achieved after reinduction with ustekinumab, adjusted for weight. This rescue guideline could be a cost-effective way to reinduce remission in this group of patients.
Assuntos
Doença de Crohn/tratamento farmacológico , Ileíte/tratamento farmacológico , Ustekinumab/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Quimioterapia de Indução/métodos , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Retratamento/métodos , Ustekinumab/efeitos adversosRESUMO
We present the case of a woman infected with the HIV type 1, controlled with highly active antiretroviral therapy. In the meantime, she developed a severe perianal disease, with complex fistulae and chronic anal fissures. After developing a severe chronic diarrhea, a total ileocolonoscopy with biopsies was performed, showing multiple ileal and segmental colonic erosions. Histology favoured a Crohn's disease diagnosis. Despite the limited experience of anti-tumour necrosis factor agents in the HIV-infected population, infliximab was started in this patient, due to her severe and symptomatic Crohn's disease, with a controlled HIV infection. No side effects were reported and her bowel movements and perianal disease improved right after induction regimen with infliximab. 1 year after starting this therapy she is in clinical and endoscopic remission. The CD4+ T-cell count remained stable, the HIV-RNA undetectable and no opportunistic infections were reported during follow-up period. Data concerning the use of anti-tumour necrosis factor drugs is limited in patients with both inflammatory bowel disease and HIV infection. Only three cases of Crohn's disease and concomitant HIV infection treated with infliximab were reported in the literature. This case report might help future decisions in patients with a similar clinical situation.
Assuntos
Doença de Crohn/tratamento farmacológico , Infecções por HIV/complicações , HIV-1 , Infliximab/uso terapêutico , Proctite/tratamento farmacológico , Colite/complicações , Colite/tratamento farmacológico , Colite/patologia , Doença de Crohn/complicações , Doença de Crohn/patologia , Feminino , Humanos , Ileíte/complicações , Ileíte/tratamento farmacológico , Ileíte/patologia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Proctite/complicações , Proctite/patologia , Resultado do TratamentoRESUMO
The globally rising incidences of multidrug-resistant (MDR) Pseudomonas aeruginosa (Psae) in humans and live-stock animals has prompted the World Health Organization to rate MDR Psae as serious threat for human health. Only little is known, however, regarding factors facilitating gastrointestinal Psae-acquisition by the vertebrate host and subsequently induced inflammatory sequelae. In the present study, we addressed whether subacute ileitis predisposed mice harboring a human gut microbiota for intestinal MDR Psae carriage and whether inflammatory responses might be induced following peroral challenge with the opportunistic pathogen. To accomplish this, secondary abiotic mice were associated with a human gut microbiota by fecal microbiota transplantation. Ten days later (i.e., on day 0), subacute ileitis was induced in human microbiota associated (hma) mice by peroral low-dose Toxoplasma gondii infection. On day 5 post-infection, mice were perorally challenged with 109 colony forming units of a clinical MDR Psae isolate by gavage and the fecal bacterial loads surveyed thereafter. Four days post-peroral challenge, only approximately one third of mice with a human gut microbiota and subacute ileitis harbored the opportunistic pathogen in the intestinal tract. Notably, the gut microbiota composition was virtually unaffected by the Psae-carriage status during subacute ileitis of hma mice. The Psae challenge resulted, however, in more pronounced intestinal epithelial apoptotic cell and T lymphocyte responses upon ileitis induction that were not restricted to the ileum, but also affected the large intestines. Higher Psae-induced abundances of T cells could additionally be observed in extra-intestinal compartments including liver, kidney, lung, and heart of hma mice with subacute ileitis. Furthermore, higher apoptotic cell numbers, but lower anti-inflammatory IL-10 concentrations were assessed in the liver of Psae as compared to mock treated mice with ileitis. Remarkably, Psae-challenge was accompanied by even more pronounced systemic secretion of pro-inflammatory cytokines such as TNF and IL-6 at day 9 post ileitis induction. In conclusion, whereas in one third of hma mice with subacute ileitis Psae could be isolated from the intestines upon peroral challenge, the opportunistic pathogen was responsible for inflammatory sequelae in intestinal, extra-intestinal, and even systemic compartments and thus worsened subacute ileitis outcome irrespective of the Psae-carrier status.
Assuntos
Antibacterianos/farmacologia , Ileíte/diagnóstico , Ileíte/etiologia , Microbiota , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Animais , Apoptose , Carga Bacteriana , Modelos Animais de Doenças , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Ileíte/tratamento farmacológico , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológicoAssuntos
Colite/diagnóstico , Doença de Crohn/diagnóstico , Ileíte/diagnóstico , Tuberculose Gastrointestinal/diagnóstico , Adulto , Antituberculosos/uso terapêutico , Colite/diagnóstico por imagem , Colite/tratamento farmacológico , Colonoscopia , Diagnóstico Diferencial , Humanos , Ileíte/diagnóstico por imagem , Ileíte/tratamento farmacológico , Masculino , Tuberculoma/diagnóstico , Tuberculoma/diagnóstico por imagem , Tuberculoma/tratamento farmacológico , Tuberculose Gastrointestinal/diagnóstico por imagem , Tuberculose Gastrointestinal/tratamento farmacológico , Tuberculose Pulmonar/complicaçõesRESUMO
BACKGROUND AND AIMS: Magnetic resonance enterography [MRE] is the gold standard for assessing ileal inflammation in Crohn's disease [CD]. The aim of the present study was to correlate faecal calprotectin [FC] to MRE via a simple score in an exclusive ileal cohort with long-term follow-up for association with time to surgery or biologic therapy. METHODS: In total, 150 MRE studies with matched FC [±30 days] were identified from the Edinburgh FC Register [2008-12; n = 18138]. Scans were re-read blinded to clinical data, independently, by two expert gastrointestinal radiologists, to generate a simple MRE score [range 0-10] from assessment of the worst intestinal segment plus total disease extent. RESULTS: In total, 119 MRE scans were evaluated from 104 patients with ileal CD [L1 or L3 with panproctocolectomy]. Receiver operating characteristic analysis showed an area under the curve of 0.77 [0.67-0.87, p < 0.0001] for FC and MRE score >1, with an optimal cut-off of 145 µg/g for severe inflammation on MRE with 69.3% [57.6-79.5] sensitivity and 71.4% [53.7-85.4] specificity. Long-term follow-up over a median [interquartile range] of 2086 days [1786-2353] revealed FC ≥ 145 µg/g was associated with reduced biologic-free survival until 3 years following MRE, whereas MRE score [severe vs absent] was associated with reduced surgery- and biologic-free survival throughout follow-up. Backwards stepwise logistic regression revealed that length of ileal disease (odds ratio [OR] 3.8, 1.1-13.2, p = 0.034) and increased bowel wall thickness at MRE [OR 4.2, 1.6-10.7, p < 0.0001] or female sex [OR 5.2, 1.5-18.7, p = 0.011] increased the risk of biologic use or surgery, respectively. CONCLUSIONS: FC correlates well with MRE assessment of ileal CD with MRE parameters associated with long-term biologic- and surgery-free remission.
Assuntos
Doença de Crohn/diagnóstico por imagem , Doença de Crohn/metabolismo , Fezes/química , Ileíte/diagnóstico por imagem , Ileíte/metabolismo , Complexo Antígeno L1 Leucocitário/análise , Adulto , Área Sob a Curva , Produtos Biológicos/uso terapêutico , Colectomia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/cirurgia , Feminino , Seguimentos , Humanos , Ileíte/tratamento farmacológico , Ileíte/cirurgia , Ileostomia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Protectomia , Curva ROC , Índice de Gravidade de Doença , Fatores Sexuais , Fatores de TempoRESUMO
Crohn's disease (CD) is a chronic, relapsing, inflammatory disease that is often associated with malnutrition because of inflammation in the small intestine. Autotaxin (ATX) is a secreted enzyme that produces extracellular lysophosphatidic acid. Increasing evidence suggests that ATX is upregulated during inflammation, and inhibition of ATX has been effective in attenuating chronic inflammatory conditions, such as arthritis and pulmonary fibrosis. This study aims to determine whether inhibition of ATX alleviates CD-associated inflammation and malnutrition by using SAMP1/Fc mice, a model of CD-like ileitis. SAMP1/Fc mice were treated the ATX inhibitor PF-8380 for 4 wk. Inhibition of ATX led to increased weight gain in SAMP1/Fc mice, decreased T helper 2 cytokine expression, including IL-4, IL-5, and IL-13, and attenuated immune cell migration. SAMP1/Fc mice have low expression of Na+-dependent glucose transporter 1 (SGLT1), suggesting impaired nutrient absorption associated with ileitis. PF-8380 treatment significantly enhanced SGLT1 expression in SAMP1/Fc mice, which could reflect the increased weight changes. However, IL-4 or IL-13 did not alter SGLT1 expression in Caco-2 cells, ruling out their direct effects on SGLT1 expression. Immunofluorescence analysis showed that the expression of sucrase-isomaltase, a marker for intestinal epithelial cell (IEC) differentiation, was decreased in inflamed regions of SAMP1/Fc mice, which was partially restored by PF-8380. Moreover, expression of Na+/H+ exchanger 3 was also improved by PF-8380, suggesting that suppression of inflammation by PF-8380 enhanced IEC differentiation. Our study therefore suggests that ATX is a potential target for treating intestinal inflammation and restoration of the absorptive function of the intestine. NEW & NOTEWORTHY This study is the first, to our knowledge, to determine whether autotoxin (ATX) inhibition improves inflammation and body weights in SAMP1/Fc mice, a mouse model of ileitis. ATX inhibition increased body weights of SAMP1/Fc mice and increased Na+-dependent glucose transporter 1 (SGLT1) expression. Increased SGLT1 expression in the inflamed regions was not a direct effect of cytokines but an indirect effect of increased epithelial cell differentiation upon ATX inhibition.
Assuntos
Anti-Inflamatórios/uso terapêutico , Benzoxazóis/uso terapêutico , Ileíte/tratamento farmacológico , Diester Fosfórico Hidrolases/metabolismo , Piperazinas/uso terapêutico , Transportador 1 de Glucose-Sódio/metabolismo , Trocador 3 de Sódio-Hidrogênio/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Benzoxazóis/farmacologia , Células CACO-2 , Citocinas/genética , Citocinas/metabolismo , Humanos , Ileíte/genética , Íleo/efeitos dos fármacos , Íleo/metabolismo , Absorção Intestinal , Masculino , Proteínas de Membrana/genética , Camundongos , Proteínas Nucleares/genética , Piperazinas/farmacologia , Transportador 1 de Glucose-Sódio/genética , Trocador 3 de Sódio-Hidrogênio/genéticaRESUMO
Purpose To evaluate whether dual-selectin-targeted US molecular imaging allows longitudinal monitoring of anti-inflammatory treatment effects in an acute terminal ileitis model in swine. Materials and Methods The Institutional Animal Care and Use Committee approved all animal studies. Fourteen swine with chemically induced acute terminal ileitis (day 0) were randomized into the following groups: (a) an anti-inflammatory treatment group (n = 8; meloxicam, 0.25 mg per kilogram of body weight; prednisone, 0.5 mg/kg) and (b) a control group (n = 6; saline). US molecular imaging was performed with a clinical US machine after intravenous injection of clinically translatable dual P- and E-selectin-targeted microbubbles (5 × 108/kg). Three inflamed bowel segments per swine were imaged at baseline, as well as on days 1, 3, and 6 after treatment initiation. At day 6, bowel segments were analyzed ex vivo for selectin expression levels by using quantitative immunofluorescence. Results After induction of inflammation, US molecular imaging signal increased at day 1 in both animal groups (P < .001). At day 3, signal in the treatment group decreased (P < .001 vs day 1), while signal in control animals did not significantly change (P = .18 vs day 1) and was higher (P = .001) compared with that in the treatment group. At day 6, signal in the treatment group further decreased and remained lower (P = .02) compared with that in the control group. Immunofluorescence confirmed significant (P ≤ .04) downregulation of both P- and E-selectin expression levels in treated versus control bowel segments. Conclusion Dual-selectin-targeted US molecular imaging allows longitudinal monitoring of anti-inflammatory treatment effects in a large-animal model of acute ileitis. This supports further clinical development of this quantitative and radiation-free technique for monitoring inflammatory bowel disease. © RSNA, 2018 Online supplemental material is available for this article.