The changing phenotype of Inflammatory Bowel Disease

It is widely known that there have been improvements in patient care and an increased incidence of Inflammatory Bowel Disease (IBD) worldwide in recent decades. However, less well known are the phenotypic changes that have occurred; these are discussed in this review. Namely, we discuss the emergence of obesity in patients with IBD, elderly onset disease, mortality rates, colorectal cancer risk, the burden of medications and comorbidities, and the improvement in surgical treatment with a decrease in surgical rates in recent decades

How to swim with sharks: a perspective on Voltaire Cousteau’s primer

Voltaire Cousteau’s primer on how to swim with sharks first appeared 45 years ago and stands alone, timeless.[1,2] At once quirky, yet clear, concise, clever; it continues to raise a smile. Swimming with sharks is not, of course, a required pastime or needed for most successful careers. It is, however, a valuable survival skill, particularly for those with ambition to explore the privileges that a life in medicine can offer. Medicine is a sea of opportunities, which encompass and transcend healthcare, science, education, leadership and entrepreneurship. In such waters, encounters with sharks are common. William Osler likened the study of medicine without books to sailing in uncharted sea, while studying without patients as not to go to sea at all.[3] Similarly, Cousteau warned that books cannot substitute for practice when learning how to swim with sharks. Having abided by his guidance, I offer a survivor’s comments in grateful tribute to Cousteau

Human methanogen diversity and incidence in healthy and diseased colonic groups using mcrA gene analysis

<p>Abstract</p> <p>Background</p> <p>The incidence and diversity of human methanogens are insufficiently characterised in the gastrointestinal tract of both health and disease. A PCR and clone library methodology targeting the <it>mcrA </it>gene was adopted to facilitate the two-fold aim of surveying the relative incidence of methanogens in health and disease groups and also to provide an overview of methanogen diversity in the human gastrointestinal tract.</p> <p>Results</p> <p>DNA faecal extracts (207 in total) from a group of healthy controls and five gastrointestinal disease groups were investigated. Colorectal cancer, polypectomised, irritable bowel syndrome and the control group had largely equivalent numbers of individuals positive for methanogens (range 45–50%). Methanogen incidence in the inflammatory bowel disease groups was reduced, 24% for ulcerative colitis and 30% for Crohn's disease. Four unique <it>mcrA </it>gene restriction fragment length polymorphism profiles were identified and bioinformatic analyses revealed that the majority of all sequences (94%) retrieved from libraries were 100% identical to <it>Methanobrevibacter smithii mcrA </it>gene. In addition, <it>mcrA </it>gene sequences most closely related to <it>Methanobrevibacter oralis </it>and members of the order <it>Methanosarcinales </it>were also recovered.</p> <p>Conclusion</p> <p>The <it>mcrA </it>gene serves as a useful biomarker for methanogen detection in the human gut and the varying trends of methanogen incidence in the human gut could serve as important indicators of intestinal function. Although <it>Methanobrevibacter smithii </it>is the dominant methanogen in both the distal colon of individuals in health and disease, the diversity of methanogens is greater than previously reported. In conclusion, the low incidence of methanogens in Inflammatory Bowel Disease, the functionality of the methanogens and impact of methane production in addition to competitive interactions between methanogens and other microbial groups in the human gastrointestinal tract warrants further investigation.</p

Shining a Light on Intestinal Traffic

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is associated with enhanced leukocyte infiltration to the gut, which is directly linked to the clinical aspects of these disorders. Thus, leukocyte trafficking is a major target for IBD therapy. Past and emerging techniques to study leukocyte trafficking both in vitro and in vivo have expanded our knowledge of the leukocyte migration process and the role of inhibitors. Various strategies have been employed to target chemokine- and integrin-ligand interactions within the multistep adhesion cascade and the S1P/S1PR1 axis in leukocyte migration. Though there is an abundance of preclinical data demonstrating efficacy of leukocyte trafficking inhibitors, many have yet to be confirmed in clinical studies. Vigilance for toxicity and further research is required into this complex and emerging area of IBD therapy

The effect of exercise interventions on inflammatory biomarkers in healthy, physically inactive subjects: a systematic review

Background: Increases in physical activity ameliorate low-grade systemic inflammation in disease populations such as type 2 diabetes mellitus and coronary artery disease. The effects of aerobic and resistance training (RT) on inflammatory biomarker profiles in non-disease, physically inactive individuals are unknown. Methods: A systematic review of randomized controlled trials measuring the effect of aerobic and resistance exercise on pro-inflammatory biomarkers in healthy, inactive adult populations was conducted. The available peer-reviewed literature was searched from January 1990 to June 2016 using the electronic databases PubMed and Scopus. A narrative synthesis of review findings was constructed with discussion of the impact of aerobic, resistance and combined training on C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8, interleukin-1β and tumour necrosis factor-α. Results: The initial search revealed 1596 potentially relevant studies. Application of the study eligibility criteria led to the full-text review of 54 articles with 11 studies deemed suitable for inclusion. Review of related articles and the reference lists of the 54 full-text articles led to the inclusion of 2 additional studies. The review revealed inconsistent findings relating to the effect of aerobic training and RT on CRP and IL-6. Studies of older-aged adults (>65 years old) demonstrated the greatest and most consistent reduction in inflammatory biomarkers post-training intervention. Conclusions: A paucity of evidence exists relating to the effect of exercise training on inflammatory markers in non-disease, physically inactive adults. The available evidence suggests potential for the greatest benefit to be seen in older populations and with higher intensity aerobic exercise

Mechanisms of Action of Probiotics in Intestinal Diseases

Intestinal microbiota is a positive health asset that exerts a conditioning effect on intestinal homeostasis. Resident bacteria deliver regulatory signals to the epithelium and instruct mucosal immune responses. Recent research has revealed a potential therapeutic role for the manipulation of the microbiota and exploitation of host-microbial signalling pathways in the maintenance of human health and treatment of various mucosal disorders. A variety of pharmabiotic strategies, such as the use of specific members of the microbiota, their surface components, or metabolites, as well as genetically modified commensal bacteria, are being investigated for their ability to enhance the beneficial components of the microbiota. It is clear that engagement with host cells is central to pharmabiotic action, and several strain-specific mechanisms of action have been elucidated. However, the molecular details underpinning these mechanisms remain almost entirely unknown. Understanding how pharmabiotics exert their beneficial effects is critical for the establishment of definitive selection criteria for certain pharmabiotic strategies for specific clinical conditions. Scientifically accredited evidence of efficacy and studies to elucidate the molecular mechanisms of host-microbiota interactions are needed to lend credence to the use of pharmabiotic strategies in clinical medicine

Exercise and the microbiota

The authors are supported in part by research grants from Science Foundation Ireland including a centre grant (Alimentary Pharmabiotic Centre; Grant Numbers SFI/12/RC/2273 and 12/RC/2273). Dr. Orla O’Sullivan is funded by a Starting Investigator Research Grant from Science Foundation Ireland (Grant number 13/SIRG/2160). Dr. Paul Cotter is funded by a Principal Investigator Award from Science Foundation Ireland P.D.C are supported by a SFI PI award (Grant number 11/PI/1137).peer-reviewedSedentary lifestyle is linked with poor health, most commonly obesity and associated disorders, the corollary being that exercise offers a preventive strategy. However, the scope of exercise biology extends well beyond energy expenditure and has emerged as a great ‘polypill’, which is safe, reliable and cost-effective not only in disease prevention but also treatment. Biological mechanisms by which exercise influences homeostasis are becoming clearer and involve multi-organ systemic adaptations. Most of the elements of a modern lifestyle influence the indigenous microbiota but few studies have explored the effect of increased physical activity. While dietary responses to exercise obscure the influence of exercise alone on gut microbiota, professional athletes operating at the extremes of performance provide informative data. We assessed the relationship between extreme levels of exercise, associated dietary habits and gut microbiota composition, and discuss potential mechanisms by which exercise may exert a direct or indirect influence on gut microbiota.The authors are supported in part by research grants from Science Foundation Ireland including a centre grant (Alimentary Pharmabiotic Centre; Grant Numbers SFI/12/RC/2273 and 12/RC/2273). Dr. Orla O’Sullivan is funded by a Starting Investigator Research Grant from Science Foundation Ireland (Grant number 13/SIRG/2160). Dr. Paul Cotter is funded by a Principal Investigator Award from Science Foundation Ireland P.D.C are supported by a SFI PI award (Grant number 11/PI/1137)

Targeting the Microbiota to Address Diet-Induced Obesity: A Time Dependent Challenge

peer-reviewedLinks between the gut microbiota and host metabolism have provided new perspectives on obesity. We previously showed that the link between the microbiota and fat deposition is age- and time-dependent subject to microbial adaptation to diet over time. We also demonstrated reduced weight gain in diet-induced obese (DIO) mice through manipulation of the gut microbiota with vancomycin or with the bacteriocin-producing probiotic Lactobacillus salivarius UCC118 (Bac+), with metabolic improvement achieved in DIO mice in receipt of vancomycin. However, two phases of weight gain were observed with effects most marked early in the intervention phase. Here, we compare the gut microbial populations at the early relative to the late stages of intervention using a high throughput sequencing-based analysis to understand the temporal relationship between the gut microbiota and obesity. This reveals several differences in microbiota composition over the intervening period. Vancomycin dramatically altered the gut microbiota composition, relative to controls, at the early stages of intervention after which time some recovery was evident. It was also revealed that Bac+ treatment initially resulted in the presence of significantly higher proportions of Peptococcaceae and significantly lower proportions of Rikenellaceae and Porphyromonadaceae relative to the gut microbiota of L. salivarius UCC118 bacteriocin negative (Bac-) administered controls. These differences were no longer evident at the later time. The results highlight the resilience of the gut microbiota and suggest that interventions may need to be monitored and continually adjusted to ensure sustained modification of the gut microbiota.The authors are supported in part by Teagasc, Science Foundation Ireland (in the form of a research centre grant to the Alimentary Pharmabiotic Centre and PI awards to PWOT and PC) and by Alimentary Health Ltd

Fas ligand expression in human and mouse cancer cell lines; a caveat on over-reliance on mRNA data

BACKGROUND: During carcinogenesis, tumors develop multiple mechanisms for evading the immune response, including upregulation of Fas ligand (FasL/CD95L) expression. Expression of FasL may help to maintain tumor cells in a state of immune privilege by inducing apoptosis of anti-tumor immune effector cells. Recently this idea has been challenged by studies reporting that tumor cells of varying origin do not express FasL. In the present study, we aimed to comprehensively characterize FasL expression in tumors of both murine and human origin over a 72 hour time period. METHODS: RNA and protein was extracted from six human (SW620, HT29, SW480, KM12SM, HCT116, Jurkat) and three mouse (CMT93, CT26, B16F10) cancer cell lines at regular time intervals over a 72 hour time period. FasL expression was detected at the mRNA level by RT-PCR, using intron spanning primers, and at the protein level by Western Blotting and immunofluorescence, using a polyclonal FasL- specific antibody. RESULTS: Expression of FasL mRNA and protein was observed in all cell lines analysed. However, expression of FasL mRNA varied dramatically over time, with cells negative for FasL mRNA at many time points. In contrast, 8 of the 9 cell lines constitutively expressed FasL protein. Thus, cells can abundantly express FasL protein at times when FasL mRNA is absent. CONCLUSION: These findings demonstrate the importance of complete analysis of FasL expression by tumor cells in order to fully characterize its biological function and may help to resolve the discrepancies present in the literature regarding FasL expression and tumor immune privilege

The effect of a probiotic blend on gastrointestinal symptoms in constipated patients: A double blind, randomised, placebo controlled 2-week trial

Selected strains of lactobacilli and bifidobacteria are known to ameliorate constipation-related symptoms and have previously shown efficacy on digestive health. In this clinical trial, the safety and effectiveness of a probiotic blend containing lactobacilli and bifidobacteria were evaluated in adults with self-reported bloating and functional constipation. Constipation was diagnosed by the Rome III criteria. A total of 156 adults were randomised into this double-blind and placebo-controlled trial. Participants consumed the combination of Lactobacillus acidophilus NCFM (1010 cfu), Lactobacillus paracasei Lpc-37 (2.5×109 cfu), Bifidobacterium animalis subsp. lactis strains Bl-04 (2.5×109 cfu), Bi-07 (2.5×109 cfu) and HN019 (1010 cfu) (n=78), or placebo (microcrystalline cellulose) (n=78) for two weeks. After treatment the following were measured: primary outcome of bloating and secondary outcomes of colonic transit time, bowel movement frequency, stool consistency, other gastrointestinal symptoms (flatulence, abdominal pain, and burbling), constipation-related questionnaires (PAC-SYM and PAC-QoL) and product satisfaction. Faecal recovery of consumed strains was determined. The enrolled population was defined as constipated, however, the initial bloating severity was lower than in previous similar studies. No clinically significant observations related to the safety of the product were reported. Product efficacy was not shown in the primary analysis for bloating nor for the secondary efficacy analyses. The placebo functioned similarly as the probiotic product. In post-hoc analysis, a statistically significant decrease in flatulence in favour of the probiotic group was observed; day 7 (intention-to-treat (ITT): P=0.0313; per-protocol (PP): 0.0253) and on day 14 (ITT: P=0.0116; PP: P=0.0102) as measured by area under the curve (AUC) analysis. The mean AUC of all symptoms decreased in favour of the probiotic group, indicating less digestive discomfort. The study was registered at the ISRCTN registry (ISRCTN41607808)