Ailsa Hart

Modulation of human dendritic cell phenotype and function by probiotic bacteria

Background: “Probiotic” bacteria are effective in treating some inflammatory bowel diseases. However which bacteria confer benefit and mechanisms of action remain poorly defined. Dendritic cells, which are pivotal in early bacterial recognition, tolerance induction, and shaping of T cell responses, may be central in mediating the effects of these bacteria. Aims: To assess effects of different probiotic bacteria on dendritic cell function. Methods: Human intestinal lamina propria mononuclear cells, whole blood, or an enriched blood dendritic cell population were cultured with cell wall components of the eight bacterial strains in the probiotic preparation VSL#3 (four lactobacilli, three bifidobacteria, and one streptococcal strains). Dendritic cells were identified and changes in dendritic cell maturation/costimulatory markers and cytokine production in response to probiotic bacteria were analysed by multicolour flow cytometry, in addition to subsequent effects on T cell polarisation. Results: VSL#3 was a potent inducer of IL-10 by dendritic cells from blood and intestinal tissue, and inhibited generation of Th1 cells. Individual strains within VSL#3 displayed distinct immunomodulatory effects on dendritic cells; the most marked anti-inflammatory effects were produced by bifidobacteria strains which upregulated IL-10 production by dendritic cells, decreased expression of the costimulatory molecule CD80, and decreased interferon-γ production by T cells. VSL#3 diminished proinflammatory effects of LPS by decreasing LPS induced production of IL-12 while maintaining IL-10 production. Conclusions: Probiotic bacteria differ in their immunomodulatory activity and influence polarisation of immune responses at the earliest stage of antigen presentation by dendritic cells.

Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

Ulcerative colitis and Crohns disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

The gut microbiota and host health: a new clinical frontier

Over the last 10–15 years, our understanding of the composition and functions of the human gut microbiota has increased exponentially. To a large extent, this has been due to new ‘omic’ technologies that have facilitated large-scale analysis of the genetic and metabolic profile of this microbial community, revealing it to be comparable in influence to a new organ in the body and offering the possibility of a new route for therapeutic intervention. Moreover, it might be more accurate to think of it like an immune system: a collection of cells that work in unison with the host and that can promote health but sometimes initiate disease. This review gives an update on the current knowledge in the area of gut disorders, in particular metabolic syndrome and obesity-related disease, liver disease, IBD and colorectal cancer. The potential of manipulating the gut microbiota in these disorders is assessed, with an examination of the latest and most relevant evidence relating to antibiotics, probiotics, prebiotics, polyphenols and faecal microbiota transplantation.

Mechanisms of Action of Probiotics : Recent Advances

&NA; The intestinal microbiota plays a fundamental role in maintaining immune homeostasis. In controlled clinical trials probiotic bacteria have demonstrated a benefit in treating gastrointestinal diseases, including infectious diarrhea in children, recurrent Clostridium difficile‐induced infection, and some inflammatory bowel diseases. This evidence has led to the proof of principle that probiotic bacteria can be used as a therapeutic strategy to ameliorate human diseases. The precise mechanisms influencing the crosstalk between the microbe and the host remain unclear but there is growing evidence to suggest that the functioning of the immune system at both a systemic and a mucosal level can be modulated by bacteria in the gut. Recent compelling evidence has demonstrated that manipulating the microbiota can influence the host. Several new mechanisms by which probiotics exert their beneficial effects have been identified and it is now clear that significant differences exist between different probiotic bacterial species and strains; organisms need to be selected in a more rational manner to treat disease. Mechanisms contributing to altered immune function in vivo induced by probiotic bacteria may include modulation of the microbiota itself, improved barrier function with consequent reduction in immune exposure to microbiota, and direct effects of bacteria on different epithelial and immune cell types. These effects are discussed with an emphasis on those organisms that have been used to treat human inflammatory bowel diseases in controlled clinical trials.

The dendritic cell: its role in intestinal inflammation and relationship with gut bacteria

Dendritic cells are antigen presenting cells that are likely to be pivotal in the balance between tolerance and active immunity to commensal microorganisms that is fundamental to inflammatory conditions, including Crohn’s disease and ulcerative colitis. Interactions between dendritic cells and microbial products are discussed and how they contribute to regulation of immune responses. The concept that interactions between dendritic cells and commensal organisms may be responsible for maintaining intestinal immune homeostasis is also explored.

Randomised, double-blind, placebo-controlled trial of fructo-oligosaccharides in active Crohn's disease

Introduction The commensal intestinal microbiota drive the inflammation associated with Crohns disease. However, bacteria such as bifidobacteria and Faecalibacterium prausnitzii appear to be immunoregulatory. In healthy subjects the intestinal microbiota are influenced by prebiotic carbohydrates such as fructo-oligosaccharides (FOS). Preliminary data suggest that FOS increase faecal bifidobacteria, induce immunoregulatory dendritic cell (DC) responses and reduce disease activity in patients with Crohns disease. Aims and methods To assess the impact of FOS in patients with active Crohns disease using an adequately powered randomised double-blind placebo-controlled trial with predefined clinical, microbiological and immunological end points. Patients with active Crohns disease were randomised to 15 g/day FOS or non-prebiotic placebo for 4 weeks. The primary end point was clinical response at week 4 (fall in Crohns Disease Activity Index of ≥70 points) in the intention-to-treat (ITT) population. Results 103 patients were randomised to receive FOS (n=54) or placebo (n=49). More patients receiving FOS (14 (26%) vs 4 (8%); p=0.018) withdrew before the 4-week end point. There was no significant difference in the number of patients achieving a clinical response between the FOS and placebo groups in the ITT analysis (12 (22%) vs 19 (39%), p=0.067). Patients receiving FOS had reduced proportions of interleukin (IL)-6-positive lamina propria DC and increased DC staining of IL-10 (p<0.05) but no change in IL-12p40 production. There were no significant differences in the faecal concentration of bifidobacteria and F prausnitzii between the groups at baseline or after the 4-week intervention. Conclusion An adequately powered placebo-controlled trial of FOS showed no clinical benefit in patients with active Crohns disease, despite impacting on DC function. ISRCTN50422530.

Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders

aDepartment of Pharmacology and Therapeutics, University of Porto; MedInUP, Centre for Drug Discovery and Innovative Medicines; Centro Hospitalar São João, Porto, Portugal bIBD Unit, DIMEC, University of Bologna, Bologna, Italy cDepartment of Gastroenterology and Hepatology, Chaim Sheba Medical Center, Tel Hashomer, Israel dGastrointestinal Unit ASST Fatebenefratelli Sacco—University of Milan—Milan, Italy eIBD Unit Complesso Integrato Columbus, Gastroenterological and Endocrino-Metabolical Sciences Department, Fondazione Policlinico Universitario Gemelli Universita’ Cattolica del Sacro Cuore, Rome, Italy fDepartment of Gastroenterology, IBD Unit, University Hospital Santiago De Compostela (CHUS), A Coruña, Spain gDepartment of Gastroenterology, North Zealand University Hospital, Frederikssund, Denmark hFirst Department of Medicine, Semmelweis University, Budapest, Hungary iIBD Unit, St Mark’s Hospital, Middlesex, UK jDepartment of Gastroenterology, University Hospital of Ghent, Ghent, Belgium kInstitute of Pathology, Medical University of Graz, Graz, Austria lDepartment of Gastroenterology, Pennine Acute Hospitals NHS Trust; Institute of Inflammation and Repair, University of Manchester, Manchester, UK mUnit of General Surgery, Second University of Naples, Napoli, Italy nMaria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Department of Oncological Gastroenterology Warsaw; Medical Centre for Postgraduate Education, Department of Gastroenterology, Hepatology and Clinical Oncology, Warsaw, Poland oDepartment of Medicine, University of Cambridge, Cambridge, UK pImperial College London; Chelsea and Westminster Hospital, London, UK qDepartment of Pathobiology /NC22, Lerner Research Institute; Department of Gastroenterology, Hepatology and Nutrition/A3, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

A global consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn's disease

Objective To develop a consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohns disease (pCD), based on best available evidence. Methods Based on a systematic literature review, statements were formed, discussed and approved in multiple rounds by the 20 working group participants. Consensus was defined as at least 80% agreement among voters. Evidence was assessed using the modified GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. Results Highest diagnostic accuracy can only be established if a combination of modalities is used. Drainage of sepsis is always first line therapy before initiating immunosuppressive treatment. Mucosal healing is the goal in the presence of proctitis. Whereas antibiotics and thiopurines have a role as adjunctive treatments in pCD, anti-tumour necrosis factor (anti-TNF) is the current gold standard. The efficacy of infliximab is best documented although adalimumab and certolizumab pegol are moderately effective. Oral tacrolimus could be used in patients failing anti-TNF therapy. Definite surgical repair is only of consideration in the absence of luminal inflammation. Conclusions Based on a multidisciplinary approach, items relevant for fistula management were identified and algorithms on diagnosis and treatment of pCD were developed.

Mechanisms of initiation and perpetuation of gut inflammation by stress

Inflammatory bowel disease involves an interaction between genetic susceptibility, a host mucosal immune response and the enteric flora. However, the relapsing and remitting course underlines the importance of other modifiers, such as psychological stress. Doctors and patients share the view that stress plays a role in the initiation and perpetuation of disease. Levels of chronic perceived stress have been shown to correlate with symptom relapse and mucosal appearance, and stress management therapy has been shown to be beneficial. Animal models provide further evidence that stress may play a role in disease initiation and reactivation.

Use of probiotics in the treatment of inflammatory bowel disease.

The gut flora plays a fundamental role in maintaining normal intestinal function. A disturbance of this flora, or the host response to this flora, has been clearly demonstrated to play a role in the pathogenesis of inflammatory bowel disease (IBD). This has led to attempts to modify the bacterial flora with “live non-pathogenic organisms that confer health benefits by improving the microbial balance,” otherwise known as probiotics. Recent attention has focused on this potential strategy to treat or prevent IBD. The potential therapeutic benefit is enhanced by the natural and apparently safe approach that probiotics offer. Animal models of colitis have provided the proof of principle that probiotics can prevent and treat established intestinal inflammation. Controlled clinical studies have demonstrated the efficacy of probiotics in the maintenance of remission of pouchitis, prophylaxis of pouchitis after the formation of an ileoanal reservoir, maintenance of remission of ulcerative colitis, and treatment of Crohns disease. However, large controlled trials are needed to definitively establish the place for probiotics in the treatment of IBD and resolve issues such as the dose, duration, frequency of treatment, and use of single or multiple strains. Research is focusing on establishing the mechanism of action, so that treatments with individually tailored properties are developed and innovative approaches are explored.