Environmental triggers is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, novel technologies, precision medicine and pragmatic clinical research. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the environmental triggers section is focused on the main research gaps in elucidating causality of environmental factors in IBD. Research gaps were identified in: 1) epidemiology of exposures; 2) identification of signatures of biological response to exposures; and 3) mechanisms of how environmental exposures drive IBD. To address these gaps, the implementation of longitudinal prospective studies to determine disease evolution and identify sub-clinical changes in response to exposures is proposed. This can help define critical windows of vulnerability and risk prediction. In addition, systems biology analysis and in silico modeling were proposed as approaches to integrate the IBD exposome for the identification of biological signatures of response to exposures, and to develop prediction models of the effects of environmental factors in driving disease activity and response to therapy. This research could lead to identification of biomarkers of exposures and new modalities for therapeutic intervention. Finally, hypothesis-driven mechanistic studies to understand gene-environment interactions and to validate causality of priority factors should be performed to determine how environment influences clinical outcomes.

/pdf/challenges-in-ibd-research-environmental-triggers-4fup2p777z.pdf

Challenges in IBD Research: Environmental Triggers.

Infectious agents are known causes of human cancers. Schistosoma japonicum and Schistosoma mansoni cause a percentage of colorectal cancers in countries where the respective Schistosoma species are prevalent. Colorectal cancer is a complication of ulcerative colitis and colonic Crohn’s disease, the two main forms of idiopathic inflammatory bowel disease (IIBD). Mycobacterium avium subspecies paratuberculosis (MAP), the cause of a chronic intestinal disease in domestic and wild ruminants, is one suspected cause of IIBD. MAP may therefore be involved in the pathogenesis of IIBD-associated colorectal cancer as well as colorectal cancer in individuals without IIBD (sporadic colorectal cancer) in countries where MAP infection of domestic livestock is prevalent and MAP’s presence in soil and water is extensive. MAP organisms have been identified in the intestines of patients with sporadic colorectal cancer and IIBD when high magnification, oil immersion light microscopy (×1000 total magnification rather than the usual ×400 total magnification) is used. Research has demonstrated MAP’s ability to invade intestinal goblet cells and cause acute and chronic goblet cell hyperplasia. Goblet cell hyperplasia is the little-recognized initial pathologic lesion of sporadic colorectal cancer, referred to as transitional mucosa, aberrant crypt foci, goblet cell hyperplastic polyps or transitional polyps. It is the even lesser-recognized initial pathologic feature of IIBD, referred to as hypermucinous mucosa, hyperplastic-like mucosal change, serrated epithelial changes, flat serrated changes, goblet cell rich mucosa or epithelial hyperplasia. Goblet cell hyperplasia is the precursor lesion of adenomas and dysplasia in the classical colorectal cancer pathway, of sessile serrated adenomas and serrated dysplasia in the serrated colorectal cancer pathway, and of flat and elevated dysplasia and dysplasia-associated lesions or masses in IIBD-associated intestinal cancers. MAP’s invasion of intestinal goblet cells may result in the initial pathologic lesion of IIBD and sporadic colorectal cancer. MAP’s persistence in infected intestines may result in the eventual development of both IIBD-associated and sporadic colorectal cancer.

/pdf/could-mycobacterium-avium-subspecies-paratuberculosis-cause-41n3phmouz.pdf

Could Mycobacterium avium subspecies paratuberculosis cause Crohn’s disease, ulcerative colitis…and colorectal cancer?

Bovine paratuberculosis is a chronic infectious disease of cattle caused by Mycobacterium avium subspecies paratuberculosis (MAP). This is the first in a two-part review of the epidemiology and control of paratuberculosis in dairy herds. Paratuberculosis was originally described in 1895 and is now considered endemic among farmed cattle worldwide. MAP has been isolated from a wide range of non-ruminant wildlife as well as humans and non-human primates. In dairy herds, MAP is assumed to be introduced predominantly through the purchase of infected stock with additional factors modulating the risk of persistence or fade-out once an infected animal is introduced. Faecal shedding may vary widely between individuals and recent modelling work has shed some light on the role of super-shedding animals in the transmission of MAP within herds. Recent experimental work has revisited many of the assumptions around age susceptibility, faecal shedding in calves and calf-to-calf transmission. Further efforts to elucidate the relative contributions of different transmission routes to the dissemination of infection in endemic herds will aid in the prioritisation of efforts for control on farm.

/pdf/a-review-of-paratuberculosis-in-dairy-herds-part-1-yq67ksh1g1.pdf

A review of paratuberculosis in dairy herds - Part 1: Epidemiology.

Nilotinib, a tyrosine kinase inhibitor, has been studied extensively in various tumor models; however, no information exists about the pharmacological action of nilotinib in bacterial infections. Mycobacterium bovis (M. bovis) and Mycobacterium avium subspecies paratuberculosis (MAP) are the etiological agents of bovine tuberculosis and Johne’s disease, respectively. Although M. bovis and MAP cause distinct tissue tropism, both of them infect, reside, and replicate in mononuclear phagocytic cells of the infected host. Autophagy is an innate immune defense mechanism for the control of intracellular bacteria, regulated by diverse signaling pathways. Here we demonstrated that nilotinib significantly inhibited the intracellular survival and growth of M. bovis and MAP in macrophages by modulating host immune responses. We showed that nilotinib induced autophagic degradation of intracellular mycobacterium occurred via the inhibition of PI3k/Akt/mTOR axis mediated by abelson (c-ABL) tyrosine kinase. In addition, we observed that nilotinib promoted ubiquitin accumulation around M. bovis through activation of E3 ubiquitin ligase parkin. From in-vivo experiments, we found that nilotinib effectively controlled M. bovis growth and survival through enhanced parkin activity in infected mice. Altogether, our data showed that nilotinib regulates protective innate immune responses against intracellular mycobacterium, both in-vitro and in-vivo, and can be exploited as a novel therapeutic remedy for the control of M. bovis and MAP infections.

https://www.mdpi.com/2073-4409/8/5/506/pdf

Nilotinib: A Tyrosine Kinase Inhibitor Mediates Resistance to Intracellular Mycobacterium Via Regulating Autophagy.

Johne’s disease (JD) caused by Mycobacterium avium subsp. paratuberculosis (M. paratuberculosis) is a chronic infection characterized by the development of granulomatous enteritis in wild and domesticated ruminants. It is one of the most significant livestock diseases not only in the USA but also globally, accounting for USD 200–500 million losses annually for the USA alone with potential link to cases of Crohn’s disease in humans. Developing safe and protective vaccines is of a paramount importance for JD control in dairy cows. The current study evaluated the safety, immunity and protective efficacy of a novel live attenuated vaccine (LAV) candidate with and without an adjuvant in comparison to an inactivated vaccine. Results indicated that the LAV, irrespective of the adjuvant presence, induced robust T cell immune responses indicated by proinflammatory cytokine production such as IFN-γ, IFN-α, TNF-α and IL-17 as well as strong response to intradermal skin test against M. paratuberculosis antigens. Furthermore, the LAV was safe with minimal tissue pathology. Finally, calves vaccinated with adjuvanted LAV did not shed M. paratuberculosis post-challenge, a much-desired characteristic of an effective vaccine against JD. Together, this data suggests a strong potential of testing LAV in field trials to curb JD in dairy herds.

https://www.mdpi.com/2076-2607/8/9/1427/pdf

A Protective Vaccine against Johne's Disease in Cattle.

On March 24 and 25, 2017 researchers and clinicians from around the world met at Temple University in Philadelphia to discuss the current knowledge of Mycobacterium avium ssp. paratuberculosis (MAP) and its relationship to human disease. The conference was held because of shared concern that MAP is a zoonotic bacterium that poses a threat not only to animal health but also human health. In order to further study this problem, the conferees discussed ways to improve MAP diagnostic tests and discussed potential future anti-MAP clinical trials. The conference proceedings may be viewed on the www.Humanpara.org website. A summary of the salient work in this field is followed by recommendations from a majority of the conferees.

/pdf/the-consensus-from-the-mycobacterium-avium-ssp-13jowgn6pe.pdf

The Consensus from the Mycobacterium avium ssp. paratuberculosis (MAP) Conference 2017

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The Consensus from the Mycobacterium avium ssp. paratuberculosis (MAP) Conference 2017