Impact of red and processed meat and fibre intake on treatment outcomes among patients with chronic inflammatory diseases: protocol for a prospective cohort study of prognostic factors and personalised medicine

Abstract

Introduction: Chronic inflammatory diseases (CIDs) are frequently treated with biological medications, specifically tumour necrosis factor inhibitors (TNFi)). These medications inhibit the pro-inflammatory molecule TNF alpha, which has been strongly implicated in the aetiology of these diseases. Up to one-third of patients do not, however, respond to biologics, and lifestyle factors are assumed to affect treatment outcomes. Little is known about the effects of dietary lifestyle as a prognostic factor that may enable personalised medicine. The primary outcome of this multidisciplinary collaborative study will be to identify dietary lifestyle factors that support optimal treatment outcomes.

Methods and analysis: This prospective cohort study will enrol 320 patients with CID who are prescribed a TNFi between June 2017 and March 2019. Included among the patients with CID will be patients with inflammatory bowel disease (Crohn's disease and ulcerative colitis), rheumatic disorders (rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis), inflammatory skin diseases (psoriasis, hidradenitis suppurativa) and non-infectious uveitis. At baseline (pretreatment), patient characteristics will be assessed using patient-reported outcome measures, clinical assessments of disease activity, quality of life and lifestyle, in addition to registry data on comorbidity and concomitant medication(s). In accordance with current Danish standards, follow-up will be conducted 14-16 weeks after treatment initiation. For each disease, evaluation of successful treatment response will be based on established primary and secondary endpoints, including disease-specific core outcome sets. The major outcome of the analyses will be to detect variability in treatment effectiveness between patients with different lifestyle characteristics.

Ethics and dissemination: The principle goal of this project is to improve the quality of life of patients suffering from CID by providing evidence to support dietary and other lifestyle recommendations that may improve clinical outcomes. The study is approved by the Ethics Committee (S-20160124) and the Danish Data Protecting Agency (2008-58-035). Study findings will be disseminated through peer-reviewed journals, patient associations and presentations at international conferences.

Trial registration number: NCT03173144; Pre-results.

Keywords: biomarker and lifestyle; lifestyle and chronic inflammatory disease; patient related outcome measures; personalized medicine; treatment outcome; western style diet.

Conflict of interest statement

Competing interests: All authors declare no conflict of interest. However, the following authors declare: B. Heitmann has received funding from ‘MatPrat’, the information office for Norwegian egg and meat; L. Hvid is on the advisory board for Abbvie A/S; J. Fallingborg is on the advisory boards for AbbVie A/S, MSD Denmark, Takeda Pharma A/S, and Ferring Pharmaceuticals A/S; V. Andersen receives compensation for consultancy and for being a member of the advisory board for MSD Denmark (Merck) and Janssen A/S. The funding sponsors had no role in the design of the study; in the collection, analysis, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1

Hypothesis for effects of diet in relation to treatment effect. (Left) Low levels of fibre intake may promote microbial metabolism of mucus as the main energy source. This will lead to decrease of the mucus layer. Further, degradation of mucus releases free sulfate, which would then become available for use by sulfate-reducing bacteria (eg, Bilophila wadsworthia) for microbial produced hydrogen sulfide. In addition, high intake of food containing organic sulfur and sulfate additives, such as meat and processed meat, may increase the amount of sulfate for microbial produced hydrogen sulfide. The resultant hydrogen sulfide from low intake of fibre and high intake of meat may reduce the disulfide bonds in the mucus network rendering the mucus layer penetrable to, for example, bacteria. Then, MAMPs from microbes or contained in the diet may reach the epithelium and activate the pattern recognition receptors such as TLRs on the enterocytes (IEC) and next activate NFkB, type I interferon and other inflammatory pathways. This leads to production of pro-inflammatory (TNF, IL-1β, IL-6, IFN, IL-17, etc), and anti-inflammatory (primarily IL-10) cytokines and chemokines that will next activate innate lymphocytic cells and other immune cells and the immune system in general. There is some support for such a mechanism in chronic inflammatory disease, including findings of high amounts of sulfate-reducing bacteria in patients with UC; an association between the highest tertile of carbohydrate-restricted diet and RA, in a nested case–control study among 386 individuals who developed RA and 1886 matched controls from the Swedish Västerbotten Intervention Program cohort with prospectively sampled dietary survey; association of high-fibre intake with low risk of Crohn’s disease among 170 776 participants from the prospective Nurses’ Health Study I; association of high intake of red meat and total protein and risk of developing inflammatory polyarthritis in the population-based prospective cohort of 25 630 participants from the European Prospective Investigation of Cancer in Norfolk. Finally, a prospective study of 191 patients with UC in remission found that high consumption of meat, particularly red and processed meat, protein and alcohol was associated with risk of relapse, and that high sulfur or sulfate intakes may offer an explanation for the observed findings. Additionally, support of the notation that diet may affect systemic immune response is provided by the finding that intake of low glycaemic index diet was found to lower secretion of TNF and IL-6 from stimulated peripheral blood mononuclear cells from obese humans. (Right) Intake of high fibre and low meat may promote an effective mucosal barrier and support the effects of outcome after drug targeting the pro-inflammatory molecule TNF (TNF inhibitors). Intake of soluble plant fibre has been found to block bacterial adhesion to gut enterocytes in animal and cell studies. The genetic architecture of the individual may also impact the influence of lifestyle factors. Hence, to provide lifestyle recommendations, we need to understand the effects of lifestyle on the immune system and how lifestyle may improve the therapeutic outcome and reduce the need of medical treatment in the individual person. Information on diet and non-diet lifestyle exposures may be collected by using, for example, questionnaires and lifestyle-associated biomarkers or a combination of these methods. Evidence-based biomarkers for lifestyle assessment are scarce and mostly used for studies on healthy individuals. IEC, intestinal epithelial cells; IL, interleukin; MAMPS, microbial-associated molecular patterns; NFkB, nuclear factor kappa B; RA, rheumatoid arthritis; TLR, Toll-like receptors; TNF, tumour necrosis factor; UC, ulcerative colitis.

Figure 2

Organisation and patient research partners. IBD, inflammatory bowel disease.