Browsing by Author "Sorrentino, Dario"
Now showing 1 - 7 of 7
Results Per Page
Sort Options
- Capturing the Biologic Onset of Inflammatory Bowel Diseases: Impact on Translational and Clinical ScienceSorrentino, Dario; Nguyen, Vu Q.; Chitnavis, Maithili V. (MDPI, 2019-06-06)While much progress has been made in the last two decades in the treatment and the management of inflammatory bowel diseases (IBD)—both ulcerative colitis (UC) and Crohn’s Disease (CD)—as of today these conditions are still diagnosed only after they have become symptomatic. This is a major drawback since by then the inflammatory process has often already caused considerable damage and the disease might have become partially or totally unresponsive to medical therapy. Late diagnosis in IBD is due to the lack of accurate, non-invasive indicators that would allow disease identification during the pre-clinical stage—as it is often done in many other medical conditions. Here, we will discuss what is known about the biologic onset and pre-clinical CD with an emphasis on studies conducted in patients’ first degree relatives. We will then review the possible strategies to diagnose IBD very early in time including screening, available disease markers and imaging, and the possible clinical implications of treating these conditions at or close to their biologic onset. Later, we will review the potential impact of conducting translational research in IBD during the pre-clinical stage, especially focusing on the role of the microbiome in disease etiology and pathogenesis. Finally, we will highlight possible future developments in the field and how they can impact IBD management and our scientific knowledge of these conditions.
- Immunomodulation and Generation of Tolerogenic Dendritic Cells by Probiotic Bacteria in Patients with Inflammatory Bowel DiseaseGhavami, Shaghayegh Baradaran; Yadegar, Abbas; Aghdaei, Hamid Asadzadeh; Sorrentino, Dario; Farmani, Maryam; Mir, Adil Shamim; Azimirad, Masoumeh; Balaii, Hedieh; Shahrokh, Shabnam; Zali, Mohammad Reza (2020-09)In inflammatory bowel diseases (IBD), the therapeutic benefit and mucosal healing from specific probiotics may relate to the modulation of dendritic cells (DCs). Herein, we assessed the immunomodulatory effects of four probiotic strains includingLactobacillus salivarius,Bifidobacterium bifidum,Bacillus coagulansandBacillus subtilisnatto on the expression of co-stimulatory molecules, cytokine production and gene expression of signal-transducing receptors in DCs from IBD patients. Human monocyte-derived DCs from IBD patients and healthy controls were exposed to four probiotic strains. The expression of co-stimulatory molecules was assessed and supernatants were analyzed for anti-inflammatory cytokines. The gene expression of toll-like receptors (TLRs), IL-12p40 and integrin alpha v beta 8 were also analyzed. CD80 and CD86 were induced by most probiotic strains in ulcerative colitis (UC) patients whereas onlyB. bifiduminduced CD80 and CD86 expression in Crohn's disease (CD) patients. IL-10 and TGF-beta production was increased in a dose-independent manner while TLR expression was decreased by all probiotic bacteria exceptB. bifidumin DCs from UC patients. TLR-4 and TLR-9 expression was significantly downregulated while integrin ss8 was significantly increased in the DCs from CD patients. IL-12p40 expression was only significantly downregulated in DCs from CD patients. Our findings point to the general beneficial effects of probiotics in DC immunomodulation and indicate that probiotic bacteria favorably modulate the expression of co-stimulatory molecules, proinflammatory cytokines and TLRs in DCs from IBD patients.
- Low Dose Infliximab for Prevention of Postoperative Recurrence of Crohn's Disease: Long Term Follow-Up and Impact of Infliximab Trough Levels and Antibodies to InfliximabSorrentino, Dario; Marino, Marco; Dassopoulos, Themistocles; Zarifi, Dimitra; Del Bianco, Tiziana (PLOS, 2015-12-15)Objective In patients with postoperative recurrence of Crohn’s disease endoscopic and clinical remission can be maintained for up to 1 year with low infliximab doses (3 mg/Kg). However, in theory low-dose infliximab treated patients could develop subtherapeutic trough levels, infiximab antibodies, and might loose response to therapy. To verify this hypothesis infliximab pharmacokinetics and clinical/endoscopic response were checked in a group of patients treated in the long term with low infliximab doses. Design Infliximab antibodies, infliximab levels, highly-sensitive CRP and fecal calprotectin were measured during the 8-week interval in 5 consecutive patients in clinical (Crohn’s Disease Activity Index < 150) and endoscopic (Rutgeerts scores 0–1) remission after one year of therapy with infliximab 3 mg/Kg. For comparison with reported standards, infliximab pharmacokinetics and inflammatory parameters were also tested in 6 Crohn’s disease patients who did not undergo surgery and who were in clinical remission while on infliximab 5 mg/Kg. Patients on low infliximab dose also underwent colonoscopy after 18 additional months of therapy. Results Highly sensitive CRP and fecal calprotectin increased in all patients during the 8-week interval. Infliximab trough levels were lower in patients treated with the low dose compared to controls (mean±SE: 2.0±0.3 vs 4.75±0.83 μg/mL respectively p<0.05). Infliximab antibodies were present in two of the subjects treated with low infliximab dose and in none of the controls. However, in low dose-treated patients after 18 additional months of therapy endoscopy continued to show mucosal remission and none of them developed clinical recurrence or side effects. Conclusions Patients treated with low infliximab doses had lower trough levels compared to patients treated with 5 mg/Kg and some developed antibodies to infliximab. However, low infliximab doses sustained clinical and endoscopic remission for a total of 30 months of treatment.
- Microbial dysbiosis in spouses of ulcerative colitis patients: any clues to disease pathogenesis?Sorrentino, Dario (2017-10-07)A number of alterations have been found within the gut microbial profile of patients with inflammatory bowel diseases when compared with the healthy population; however, it is unclear whether such dysbiosis is the cause or simply the consequence of the disease state. In ulcerative colitis, the environment seems to play a crucial role in disease etiology since monozygotic twins show a concordance rate of only 8%-10% though it is unclear whether it does so by acting through the microbiome. In this study, the authors investigated the influence of cohabitation on the gut microbial community in healthy partners of ulcerative colitis patients - with the intent of clarifying some of these issues. As expected, ulcerative colitis patients had a significant dysbiosis and alterations in microbial metabolism. Interestingly, these abnormal fecal microbial communities were relatively similar amongst patients and their spouses. Thus, this study shows that the microbial profile might be partially transferred from ulcerative colitis patients to healthy individuals. Whether this finding impacts on disease development or has any implication for the role of the microbiome in inflammatory bowel disease etiology remains to be determined.
- Noncanonical NF-kappa B Signaling Upregulation in Inflammatory Bowel Disease Patients is Associated With Loss of Response to Anti-TNF AgentsNguyen, Vu Q.; Eden, Kristin; Morrison, Holly A.; Sammons, Megan B.; Knight, Kristin K.; Sorrentino, Siena; Brock, Rebecca M.; Grider, Douglas J.; Allen, Irving C.; Sorrentino, Dario (2021-06-10)Objectives: Targeting tumor necrosis factor (TNF) with biologic agents, such as infliximab and adalimumab, is a widely used and effective therapeutic strategy in inflammatory bowel disease (IBD). Unfortunately, a significant number of patients fail to respond or lose response over time to these agents. Previous studies have defined multiple complex roles for canonical NF-kappa B signaling in the pathogenesis of IBD. However, preliminary evidence suggests that the lesser defined noncanonical NF-kappa B signaling pathway also contributes to disease pathogenesis and response to anti-TNF agents. The objective of this study was to evaluate this hypothesis in Crohn's disease (CD) and ulcerative colitis (UC) patients. Design: A total of 27 subjects with IBD (19 with CD and 8 with UC) and 15 control subjects were tested. Clinical criteria, patient history, and endoscopic disease activity were factors used to categorize patients and define therapeutic response. Biopsy specimens were collected during colonoscopy and expression was determined for 88 target genes known to be associated with noncanonical NF-kappa B signaling and IBD. Results: Noncanonical NF-kappa B signaling was significantly upregulated in IBD patients and was associated with increased gastrointestinal inflammation, epithelial cell death, lymphocyte migration, and Nod-like receptor signaling. Furthermore, noncanonical NF-kappa B signaling was further upregulated in patients unresponsive to anti-TNF agents and was suppressed in responsive patients. MAP3K14, NFKB2, CCL19, CXCL12, and CXCL13 were significantly dysregulated, as were genes that encode pathway regulators, such as CYLD, NLRP12, and BIRC2/3. Conclusion: Our study identifies a previously uncharacterized role for the understudied noncanonical NF-kappa B signaling pathway in the pathogenesis of IBD and anti-TNF therapy responsiveness. The genes and pathways identified may ultimately prove useful in IBD management and could potentially be used as biomarkers of drug response.
- Timely Monitoring of Inflammation by Fecal Lactoferrin Rapidly Predicts Therapeutic Response in Inflammatory Bowel DiseaseSorrentino, Dario; Gray, James M. (Oxford University Press, 2021-08)Background: Fecal lactoferrin (FL) levels may mirror drug-induced changes in inflammation in ulcerative colitis and Crohn disease in a timely way and could be used to assess loss of response (LOR) to biologics. Methods: This study is a retrospective outcome review in 61 patients on adalimumab, infliximab, or vedolizumab managed in our center and followed for 6 to 24 months. Patients were 1) in clinical remission or 2) were experiencing possible LOR. Results: For group 1, in 71% of 31 patients, FL slowly increased during the therapeutic interval (R-2=0.769; P<0.001), thus reflecting increasing inflammation as drug concentrations decreased. In the remaining patients, FL was undetectable throughout the therapeutic interval because of a stronger suppression of inflammation. For group 2, in 30 patients negative for infections, FL levels measured 1 to 3 days after infusion/injection compared to preadministration values either increased (nonresponders)-in these patients the medication was switched to another class; partially decreased (partial responders)-the therapeutic interval was shortened; or were normal throughout (responders)-causes for symptoms unrelated to disease activity were found for all. After FL-based management, 3-month standardized clinical scores were normalized in both partial responders (0.580.21 vs 0.130.09; P<0.001) and nonresponders (0.810.17 vs 0.12 +/- 0.08; P<0.001), and FL levels dropped by up to 99%. Conclusions: Levels of FL reflect drug-induced changes in mucosal inflammation in a timely way, thus enabling rapid assessment of therapeutic response in patients with ulcerative colitis and with Crohn disease. In patients with suspected LOR, FL levels before and after infusion/injection accurately separated responders, partial responders, and nonresponders. The strategy proposed here is simple, accurate, and easily applicable to clinical practice.
- Wireless Capsule Endoscopy for Diagnosis and Management of Post-Operative Recurrence of Crohn’s DiseaseMir, Adil Shamim; Nguyen, Vu Q.; Soliman, Youssef; Sorrentino, Dario (MDPI, 2021-06-23)Despite aggressive medical therapy, many patients with Crohn’s disease require surgical intervention over time. After surgical resection, disease recurrence is common. Ileo-colonoscopy and the Rutgeerts score are commonly used for diagnosis and monitoring of post-operative endoscopic recurrence. The latter is the precursor of clinical recurrence and therefore it impacts prognosis and patient management. However, due to the limited length of bowel assessed by ileo-colonoscopy, this procedure can miss out-of-reach, more proximal lesions in the small bowel. This limitation introduces an important uncertainty when evaluating post-operative relapse by ileo-colonoscopy. In addition, the Rutgeerts score ‘per se’ bears a number of ambiguities. Here we will discuss the pros and cons of ileo-colonoscopy and other imaging studies including wireless capsule endoscopy to diagnose and manage post-operative recurrence of Crohn’s disease. A number of studies provide evidence that wireless capsule endoscopy is a potentially more accurate as well as less invasive and less costly alternative to conventional techniques including ileo-colonoscopy.