The Intricate Link among Gut "Immunological Niche," Microbiota, and Xenobiotics in Intestinal Pathology.

Inflammatory bowel diseases (IBDs) are diseases characterized by various degrees of inflammation involving the gastrointestinal tract. Ulcerative colitis and Crohn's disease are characterized by a dysregulated immune response leading to structural gut alterations in genetically predisposed individuals. Diverticular disease is characterized by abnormal immune response to normal gut microbiota. IBDs are linked to a lack of physiological tolerance of the mucosal immune system to resident gut microbiota and pathogens. The disruption of immune tolerance involves inflammatory pathways characterized by an unbalance between the anti-inflammatory regulatory T cells and the proinflammatory Th1/Th17 cells. The interaction among T cell subpopulations and their related cytokines, mediators of inflammation, gut microbiota, and the intestinal mucosa constitute the gut "immunological niche." Several evidences have shown that xenobiotics, such as rifaximin, can positively modulate the inflammatory pathways at the site of gut immunological niche, acting as anti-inflammatory agents. Xenobiotics may interfere with components of the immunological niche, leading to activation of anti-inflammatory pathways and inhibition of several mediators of inflammation. In summary, xenobiotics may reduce disease-related gut mucosal alterations and clinical symptoms. Studying the complex interplay between gut immunological niche and xenobiotics will certainly open new horizons in the knowledge and therapy of intestinal pathologies.

Gut Microbiota, Inflammatory Bowel Disease, and Cancer: The Role of Guardians of Innate Immunity.

Inflammatory bowel diseases (IBDs) are characterized by a persistent low-grade inflammation that leads to an increased risk of colorectal cancer (CRC) development. Several factors are implicated in this pathogenetic pathway, such as innate and adaptive immunity, gut microbiota, environment, and xenobiotics. At the gut mucosa level, a complex interplay between the immune system and gut microbiota occurs; a disequilibrium between these two factors leads to an alteration in the gut permeability, called 'leaky gut'. Subsequently, an activation of several inflammatory pathways and an alteration of gut microbiota composition with a proliferation of pro-inflammatory bacteria, known as 'pathobionts', take place, leading to a further increase in inflammation. This narrative review provides an overview on the principal Pattern Recognition Receptors (PRRs), including Toll-like receptors (TLRs) and NOD-like receptors (NLRs), focusing on their recognition mechanisms, signaling pathways, and contributions to immune responses. We also report the genetic polymorphisms of TLRs and dysregulation of NLR signaling pathways that can influence immune regulation and contribute to the development and progression of inflammatory disease and cancer.

The Role of Gut Microbiota in Heart Failure: When Friends Become Enemies.

Heart failure is a complex health issue, with important consequences on the overall wellbeing of patients. It can occur both in acute and chronic forms and, in the latter, the immune system appears to play an important role in the pathogenesis of the disease. In particular, in the forms with preserved ejection fraction or with only mildly reduced ejection fraction, some specific associations with chronic inflammatory diseases have been observed. Another interesting aspect that is worth considering is the role of microbiota modulation, in this context: given the importance of microbiota in the modulation of immune responses, it is possible that changes in its composition may somewhat influence the progression and even the pathogenesis of heart failure. In this narrative review, we aim to examine the relationship between immunity and heart failure, with a special focus on the role of microbiota in this pathological condition.

The Gemelli Ultrasound Chronic Pancreatitis Score: A Non-invasive Tool for the Diagnosis of Chronic Pancreatitis.

A dedicated ultrasound (US) score, the Gemelli Ultrasound Chronic Pancreatitis (USCP) score, could be useful in the follow-up of patients with chronic pancreatitis (CP). However, its role in the diagnosis of CP has not been investigated. We aimed to evaluate the role of the Gemelli USCP score in the diagnosis of CP and the agreement with standard imaging techniques. Ninety-three patients clinically suspected of having CP and referred to the pancreatic outpatient clinic of A. Gemelli Hospital for endoscopic ultrasound (EUS) were prospectively enrolled. All patients underwent pancreatic US to calculate the Gemelli USCP score. A receiver operating characteristic curve analysis was also performed to assess the performance of the US score in CP diagnosis. The Gemelli USCP score was inversely related to the Rosemont score for both total value (p < 0.0001) and each parameter evaluated (p < 0.0001). This score was significantly higher in patients with CP with an excellent area under the receiver operating characteristic curve (0.946) and the optimal cutoff of 5. Moreover, we found a significant correlation between the Gemelli USCP score and laboratory parameters related to pancreatic exocrine insufficiency (p < 0.0001). The development of a dedicated ultrasound score could be useful as a non-invasive tool in the diagnosis of CP.

Efforts to Improve the Seasonal Influenza Vaccine.

Seasonal influenza is an acute syndrome, principally involving the respiratory tract caused by influenza viruses that are globally present [...].

A new ultrasound score for the assessment and follow-up of chronic pancreatitis: The 'Gemelli USCP score'.

BACKGROUND: Ultrasound (US) is frequently the first line imaging technique used in patients with abdominal pain and clinical suspicion of chronic pancreatitis (CP), but its role in the diagnosis and follow-up of CP is still controversial. AIMS: We aimed to develop a dedicated score for the US staging of CP and to evaluate the agreement of this score with standard imaging techniques. METHODS: Ninety consecutive patients with a diagnosis of CP referred to the pancreatic outpatient clinic of A. Gemelli Hospital between June and September 2018 were recruited in the study. Patients underwent pancreatic US to evaluate different morphological parameters to develop an US based score system, called the Gemelli UltraSound Chronic Pancreatitis (USCP) score. RESULTS: The Gemelli USCP score significantly increased according to the Cambridge score for both mean value (p<0.0001) and each parameter evaluated (p<0.0001). Moreover, we found a significant correlation between the score and laboratory parameters related to pancreatic exocrine insufficiency such as vitamin D, B9, and B12 deficiency and fecal elastase values (p<0.0001). CONCLUSIONS: The development of a dedicated US score could be useful in the follow up of patients with CP as alternative non-invasive technique to standard radiological imaging.

Anticoagulant therapy in the treatment of splanchnic vein thrombosis associated to acute pancreatitis: a 3-year single-centre experience.

Splanchnic vein thrombosis (SVT) is a possible complication of acute pancreatitis (AP). There are no precise guidelines on the use of anticoagulant therapy (AT) in these patients. The aim of the study was to determine the safety and the efficacy of AT in AP-associated SVT. Two hundred twenty-one patients were retrospectively and consecutively enrolled from the Pancreatic Outpatient Clinic of the "A. Gemelli" hospital. Patients had a diagnosis of AP and a diagnostic imaging to evaluate whether they had or not SVT. Twenty-seven out of 221 AP patients had SVT (12.21%) and AT therapy was administered to 16 patients (59.3%), for 5.2 ± 2.2 months. A therapeutic dose of low molecular weight heparin was administered (100 UI/kg b.i.d.) at the diagnosis, with fondaparinux 7.5 mg/day, or vitamin K antagonist, or the novel direct oral anti-coagulants, upon discharge. The presence of SVT resulted significantly associated to male sex (p = 0.002). The recanalization rates were 11/16 (68.7%) in patients who received AT, and 3/11 (27.3%) in patients who did not receive it. There was a significant difference between the recanalization rates with and without AT (p = 0.03, OR 5.87). No SVT recurrence was registered during follow-up. No treated patient developed haemorrhagic complications after AT. No deaths were recorded, either in the group undergoing AT or in the one that was not. In conclusion, AT in AP-associated SVT appears to be safe and effective; yet prospective clinical trials are needed to confirm our results.

Early oral vs parenteral nutrition in acute pancreatitis: a retrospective analysis of clinical outcomes and hospital costs from a tertiary care referral center.

Nutritional support is a crucial issue in Acute Pancreatitis (AP) management. Recommendations on nutrition in AP are still not completely translated in the clinical practice. We aimed to compare and evaluate the effects of parenteral nutrition (PN) vs oral/enteral nutrition (EN) on several clinical and economic outcomes in AP. This is a retrospective monocentric study conducted in a tertiary care center for pancreatic diseases. The primary outcomes were length of hospital stay (LOS) and associated costs. The secondary outcomes were the use and cost of antibiotics and fluid therapy, and the complication's rates. One hundred seventy-one patients were included from January 2015 to January 2018. Patients were 69 (40.4%) in PN group and 102 (59.6%) in EN group. There was a significant reduction in LOS in EN vs PN group in both mild AP (p < 0.0001), and moderate-severe AP (p < 0.005). There was a significant reduction in the total hospitalization costs in EN group vs PN group in both mild AP (p < 0.0001), and moderate-severe AP (p < 0.005). There was a significant reduction in the total costs of antibiotics and pain therapy in EN vs PN group (p < 0.0001 and p = 0.05, respectively). Finally, a significant reduction in the infected peri-pancreatic fluid collections rate (p = 0.04) was observed in EN vs PN group. The use of EN in AP is associated with substantial clinical and economic benefits. Thus, the application of the standard of care in nutrition and following AP guidelines is the best way to cure patients and improve healthcare system costs.

Multicentric Italian survey on daily practice for autoimmune pancreatitis: Clinical data, diagnosis, treatment, and evolution toward pancreatic insufficiency.

BACKGROUND: Autoimmune pancreatitis (AIP) is a rare, and relatively new, form of chronic pancreatitis. The management of AIP can vary considerably among different centres in daily clinical practice. OBJECTIVES: The aim of this study is to present a picture of epidemiological, clinical characteristics, outcomes, and the real-life practice in terms of management in several academic and non-academic centres in Italy. METHODS: Data on the clinical presentation, diagnostic work-up, treatments, frequency of relapses, and long-term outcomes were retrospectively collected in a cohort of AIP patients diagnosed at 14 centres in Italy. RESULTS: One hundred and six patients were classified as type 1 AIP, 48 as type 2 AIP, and 19 as not otherwise specified. Epidemiological, clinical, radiological, and serological characteristics, and relapses were similar to those previously reported for different types of AIP. Endoscopic cytohistology was available in 46.2% of cases, and diagnostic for AIP in only 35.2%. Steroid trial to aid diagnosis was administered in 43.3% cases, and effective in 93.3%. Steroid therapy was used in 70.5% of cases, and effective in 92.6% of patients. Maintenance therapy with low dose of steroid (MST) was prescribed in 25.4% of cases at a mean dose of 5 (±1.4) mg/die, and median time of MST was 60 days. Immunosuppressive drugs were rarely used (10.9%), and rituximab in 1.7%. Faecal elastase-1 was evaluated in only 31.2% of patients, and was pathological in 59.2%. CONCLUSIONS: In this cohort of AIP patients, diagnosis and classification for subtype was frequently possible, confirming the different characteristics of AIP1 and AIP2 previously reported. Nevertheless, we observed a low use of histology and steroid trial for a diagnosis of AIP. Steroid treatment was the most used therapy in our cohort. Immunosuppressants and rituximab were rarely used. The evaluation of exocrine pancreatic insufficiency is underemployed considering its high prevalence.

Cellular mediators of inflammation: tregs and TH17 cells in gastrointestinal diseases.

Human lymphocyte subpopulations were originally classified as T- and B-cells in the 70s. Later, with the development of monoclonal antibodies, it became possible to recognize, within the T-cells, functional populations: CD4(+) and CD8(+). These populations were usually referred to as "helper" and "suppressor" cells, respectively. However several investigations within the CD8 cells failed to detect a true suppressor activity. Therefore the term suppressor was neglected because it generated confusion. Much later, true suppressor activity was recognized in a subpopulation of CD4 cells characterized by high levels of CD25. The novel population is usually referred to as T regulatory cells (Tregs) and it is characterized by the expression of FoxP3. The heterogeneity of CD4 cells was further expanded by the recent description of a novel subpopulation characterized by production of IL-17. These cells are generally referred to as T(H)17. They contribute to regulate the overall immune response together with other cytokine-producing populations. Treg and T(H)17 cells are related because they could derive from a common progenitor, depending on the presence of certain cytokines. The purpose of this review is to summarize recent findings of the role of these novel populations in the field of human gastroenterological disease.

The Challenge of Autoimmune Pancreatitis: A Portrayal From the Pediatric Perspective.

Autoimmune pancreatitis (AIP) is a rare disorder characterized by prompt clinical response to corticosteroids. Lost tolerance to a variety of pancreatic antigens and subsequent development of autoantibodies are presumably involved in the initiation of AIP. Even pediatric patients have been reported with features of AIP, and awareness of this disorder is increasing among different clinicians. The terms lymphoplasmacytic sclerosing pancreatitis and idiopathic duct-centric pancreatitis refer to the different histologic patterns of AIP, named type 1 and type 2, respectively. A combination of serologic, radiologic, and histologic investigations is needed to assess diagnosis of AIP and rule out neoplastic disorders. In addition, type 1 AIP can be distinguished by raised levels of serum immunoglobulin G4 and should be considered as part of systemic immunoglobulin G4-related disease. Conversely, type 2 AIP is frequently reported in younger patients and has less clear immune-mediated pathogenetic mechanisms. The natural history of pediatric AIP is obscure, and the diagnostic usefulness of different autoimmune abnormalities found in adults with AIP is limited for children. Tips to manage pediatric patients with AIP have been recently drafted through a set of recommendation statements. This review describes the current data about AIP and the pathogenic contribution of specific autoantibodies expressly in the pediatric population.

Is capsule endoscopy appropriate for elderly patients? The influence of ageing on findings and diagnostic yield: An Italian retrospective study.

BACKGROUND: Few data are available on the use of capsule endoscopy in the elderly. METHODS: We performed a retrospective study on 1008 consecutive patients referred to our centre between December 1, 2002 and January 30, 2014 who underwent capsule endoscopy for various indications. Patients were enrolled and divided into 3 sub-groups according to their age (Group A: <50 years; Group B: 50-69 years; Group C: >70 years). The Pillcam diagnostic yield, clinically significant findings and post-treatment outcomes were compared between groups. RESULTS: Diagnostic yield was significantly higher in Group C vs. Groups A and B (65.2% vs. 42.3% and 47.5%, respectively; p<0.05). The most common diagnosis in the elderly was angiodysplasia (42.5%). In 84.5% of elderly patients (Group C) capsule endoscopy results modified patient management. CONCLUSIONS: Capsule endoscopy has a high diagnostic yield and positive impact on management in patients aged >70 years.

The role of "bone immunological niche" for a new pathogenetic paradigm of osteoporosis.

Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue. The etiology and pathogenetic mechanisms of osteoporosis have not been clearly elucidated. Osteoporosis is linked to bone resorption by the activation of the osteoclastogenic process. The breakdown of homeostasis among pro- and antiosteoclastogenic cells causes unbalanced bone remodeling. The complex interactions among these cells in the bone microenvironment involve several mediators and proinflammatory pathways. Thus, we may consider the bone microenvironment as a complex system in which local and systemic immunity are regulated and we propose to consider it as an "immunological niche." The study of the "bone immunological niche" will permit a better understanding of the complex cell trafficking which regulates bone resorption and disease. The goal of a perfect therapy for osteoporosis would be to potentiate good cells and block the bad ones. In this scenario, additional factors may take part in helping or hindering the proosteoblastogenic factors. Several proosteoblastogenic and antiosteoclastogenic agents have already been identified and some have been developed and commercialized as biological therapies for osteoporosis. Targeting the cellular network of the "bone immunological niche" may represent a successful strategy to better understand and treat osteoporosis and its complications.

How the Intricate Interaction among Toll-Like Receptors, Microbiota, and Intestinal Immunity Can Influence Gastrointestinal Pathology.

The gut is able to maintain tolerance to microbial and food antigens. The intestine minimizes the number of harmful bacteria by shaping the microbiota through a symbiotic relationship. In healthy human intestine, a constant homeostasis is maintained by the perfect regulation of microbial load and the immune response generated against it. Failure of this balance may result in various pathological conditions. Innate immune sensors, such as Toll-like receptors (TLRs), may be considered an interface among intestinal epithelial barrier, microbiota, and immune system. TLRs pathway, activated by pathogens, is involved in the pathogenesis of several infectious and inflammatory diseases. The alteration of the homeostasis between physiologic and pathogenic bacteria of intestinal flora causes a condition called dysbiosis. The breakdown of homeostasis by dysbiosis may increase susceptibility to inflammatory bowel diseases. It is evident that environment, genetics, and host immunity form a highly interactive regulatory triad that controls TLR function. Imbalanced relationships within this triad may promote aberrant TLR signaling, critically contributing to acute and chronic intestinal inflammatory processes, such as in IBD, colitis, and colorectal cancer. The study of interactions between different components of the immune systems and intestinal microbiota will open new horizons in the knowledge of gut inflammation.

Uncomplicated diverticular disease: innate and adaptive immunity in human gut mucosa before and after rifaximin.

BACKGROUND/AIM: Uncomplicated diverticular disease (UDD) is a frequent condition in adults. The pathogenesis of symptoms remains unknown. Bacteria are able to interact with Toll-like receptors (TLRs) and to induce inflammation through both innate immunity and T-cell recruitment. We investigated the pattern of TLRs 2 and 4 and the intestinal homing in patients with UDD before and after a course of Rifaximin. METHODS: Forty consecutive patients with UDD and 20 healthy asymptomatic subjects were enrolled. Among UDD patients, 20 were assigned to a 2-month course of treatment with Rifaximin 1.2 g/day for 15 days/month and 20 received placebo. Blood sample and colonic biopsies were obtained from patients and controls. The samples were collected and analyzed at baseline and at the end of treatment. Flow cytometry was performed using monoclonal antibodies (CD3, CD4, CD8, CD103, TCR-gamma/delta, CD14, TLR2, and TLR4). RESULTS: In UDD, TLR2 and TLR4 expression on immune cell subpopulations from blood and mucosa of the affected colon are altered as compared with controls. Rifaximin treatment induced significant modifications of altered conditions. CONCLUSIONS: Our data show the role of TLRs in the development of inflammation in UDD. TLRs distribution is altered in UDD and these alterations are reversed after antibiotic treatment. This trial is registered with ClinicalTrials.gov: NCT02068482.

The role of IL-15 in gastrointestinal diseases: a bridge between innate and adaptive immune response.

IL-15 is a member of the IL-2 family of cytokines whose signaling pathways are a bridge between innate and adaptive immune response. IL-15 is part of the intestinal mucosal barrier, and functions to modulate gut homeostasis. IL-15 has pivotal roles in the control of development, proliferation and survival of both innate and adaptive immune cells. IL-15 becomes up-regulated in the inflamed tissue of intestinal inflammatory disease, such as IBD, Celiac Disease and related complications. Indeed, several studies have reported that IL-15 may participate to the pathogenesis of these diseases. Furthermore, although IL-15 seems to be responsible for inflammation and autoimmunity, it also may increase the immune response against cancer. For these reasons, we decided to study the intestinal mucosa as an 'immunological niche', in which immune response, inflammation and local homeostasis are modulated. Understanding the role of the IL-15/IL-15R system will provide a scientific basis for the development of new approaches that use IL-15 for immunotherapy of autoimmune diseases and malignancies. Indeed, a better understanding of the complexity of the mucosal immune system will contribute to the general understanding of immuno-pathology, which could lead to new therapeutical tools for widespread immuno-mediated diseases.