Original Research Long-­Term Dietary Patterns Are Associated with Pro-­ Gut: First Published As 10.1136/Gutjnl-2020-322670 on 2 April 2021

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Original Research Long-­Term Dietary Patterns Are Associated with Pro-­ Gut: First Published As 10.1136/Gutjnl-2020-322670 on 2 April 2021 Gut microbiota Original research Long- term dietary patterns are associated with pro- Gut: first published as 10.1136/gutjnl-2020-322670 on 2 April 2021. Downloaded from inflammatory and anti- inflammatory features of the gut microbiome Laura A Bolte ,1,2 Arnau Vich Vila ,1,2 Floris Imhann,1,2 Valerie Collij,1,2 Ranko Gacesa,1,2 Vera Peters,1 Cisca Wijmenga,2 Alexander Kurilshikov,2 Marjo J E Campmans-K uijpers,1 Jingyuan Fu,2,3 Gerard Dijkstra,1 Alexandra Zhernakova,2 Rinse K Weersma 1 ► Additional material is ABSTRACT Significance of this study published online only. To view, Objective The microbiome directly affects the balance please visit the journal online of pro-inflammatory and anti-inflammatory responses (http:// dx. doi. org/ 10. 1136/ What is already known on this subject? gutjnl- 2020- 322670). in the gut. As microbes thrive on dietary substrates, ► Western diet and low- grade intestinal 1 the question arises whether we can nourish an anti- Department of inflammation are implicated in a growing Gastroenterology and inflammatory gut ecosystem. We aim to unravel number of immune- mediated inflammatory Hepatology, University of interactions between diet, gut microbiota and their Groningen and University functional ability to induce intestinal inflammation. diseases. Medical Centre Groningen, Design We investigated the relation between 173 ► Diet quantity, content and timing play a major Groningen, The Netherlands role in shaping gut microbial composition and 2 dietary factors and the microbiome of 1425 individuals Department of Genetics, function. University of Groningen and spanning four cohorts: Crohn’s disease, ulcerative colitis, University Medical Centre irritable bowel syndrome and the general population. ► Dysbiosis, shifts in metabolites and Groningen, Groningen, The Shotgun metagenomic sequencing was performed translocation of microbial products contribute Netherlands to profile gut microbial composition and function. to immune activation. 3Department of Pediatrics, Dietary intake was assessed through food frequency ► Research has been focused on anti- University of Groningen and inflammatory properties of isolated compounds, University Medical Centre questionnaires. We performed unsupervised clustering Groningen, Groningen, The to identify dietary patterns and microbial clusters. with limited efficacy. http://gut.bmj.com/ Netherlands Associations between diet and microbial features were What are the new findings? explored per cohort, followed by a meta- analysis and ► Diet- gut microbiome associations are consistent Correspondence to heterogeneity estimation. Prof Dr Rinse K Weersma, across patients with intestinal disease (Crohn’s Department of Gastroenterology Results We identified 38 associations between dietary disease, UC, IBS) and the general population. patterns and microbial clusters. Moreover, 61 individual and Hepatology, University ► Higher intake of animal foods, processed of Groningen and University foods and nutrients were associated with 61 species foods, alcohol and sugar, corresponds to a on September 30, 2021 by guest. Protected copyright. Medical Centre Groningen, P.O. and 249 metabolic pathways in the meta- analysis across microbial environment that is characteristic of Box 30.001, Groningen 9700 healthy individuals and patients with IBS, Crohn’s disease RB, The Netherlands; inflammation, and is associated with higher r. k. weersma@ umcg. nl and UC (false discovery rate<0.05). Processed foods and levels of intestinal inflammatory markers. animal- derived foods were consistently associated with ► Plant- based foods are linked to short- chain LAB and AVV are joint first higher abundances of Firmicutes, Ruminococcus species authors. fatty acid (SCFA)- producers, microbial of the Blautia genus and endotoxin synthesis pathways. metabolism of polysaccharides and a lower Received 28 July 2020 The opposite was found for plant foods and fish, abundance of pathobionts. Revised 13 February 2021 which were positively associated with short- chain fatty Accepted 15 February 2021 acid- producing commensals and pathways of nutrient metabolism. Conclusion We identified dietary patterns that in the intestine. Microbial competition for nutri- consistently correlate with groups of bacteria with shared ents plays a key role in controlling this balance.1 functional roles in both, health and disease. Moreover, Inflammatory bowel disease (IBD) is the archetyp- specific foods and nutrients were associated with species ical disease in which the homoeostasis between the known to infer mucosal protection and anti-inflammatory gut microbiota and the intestinal immune system is © Author(s) (or their lost. Beyond the local immune responses, the gut employer(s)) 2021. Re- use effects. We propose microbial mechanisms through which permitted under CC BY. the diet affects inflammatory responses in the gut as a microbiota also affect systemic immune compo- Published by BMJ. rationale for future intervention studies. nents and are implicated in a growing number of immune- mediated inflammatory diseases (IMIDs), To cite: Bolte LA, Vich Vila A, ranging from diabetes to arthritis and systemic Imhann F, et al. Gut Epub 2 ahead of print: [please lupus erythematosus. Gut dysbiosis and associated include Day Month Year]. INTRODUCTION inflammation have also been implicated in cancer doi:10.1136/ The gut microbiome directly affects the balance of and cardiometabolic disorders.3 4 Epidemiological gutjnl-2020-322670 pro- inflammatory and anti- inflammatory responses studies uncovered several dietary factors associated Bolte LA, et al. Gut 2021;0:1–12. doi:10.1136/gutjnl-2020-322670 1 Gut microbiota replicability of diet-microbiome associations in different disease Significance of this study contexts. We propose pro- inflammatory and anti- inflammatory mechanisms through which specific foods and dietary patterns Gut: first published as 10.1136/gutjnl-2020-322670 on 2 April 2021. Downloaded from How might it impact on clinical practice in the foreseeable could affect inflammatory responses in the gut as a rational basis future? for designing dietary interventions. ► Modulation of gut microbiota through diets enriched in vegetables, legumes, grains, nuts and fish and a higher MATERIALS AND METHODS intake of plant over animal foods, has a potential to prevent Study design and cohort description intestinal inflammatory processes at the core of many chronic We associated the diet to the gut microbiome composition and diseases. function of 1425 individuals from the general population and Whole food- based dietary patterns could increase the anti- ► patients with intestinal diseases, using two independent cohorts inflammatory capacity of nutrients through synergistic effects from the northern Netherlands. Cohort 1 consists of 331 on the gut microbiome. patients with IBD from the 1000IBD cohort of the University Sources of n-3 PUFAs (omega-3 polyunsaturated fatty acids) 20 ► Medical Center Groningen (UMCG). Patients were diagnosed and polyphenols may be used to potentiate the abundance of by their treating physician based on accepted radiological, endo- SCFA- producers. scopic and histopathological evaluation and were classified as Replacement of animal protein by plant protein has a ► either Crohn’s disease or ulcerative colitis. Cohort 2 consists potential to reduce intestinal inflammatory processes by of 1094 individuals from the Dutch general- population-based targeting microbial pathways involved. 21 cohort LifeLines DEEP. The LifeLines DEEP cohort comprises 223 individuals with irritable bowel syndrome (IBS) according to a symptom questionnaire based on Rome- III criteria. Due with the onset of these diseases. However, the mechanisms to known differences in the gut microbiome composition and underlying this relationship remain largely unknown. dietary preferences between healthy individuals and patients As microbes rely on dietary substrates in the intestine, the gut with IBD and IBS, participants were divided into four sub- microbiome is often proposed as a mediator through which foods cohorts, namely Crohn’s disease (CD, n=205), ulcerative colitis exert their pro- inflammatory and anti- inflammatory effects. For (UC, n=126), IBS (n=223) and healthy controls (HC, n=871) example, animal experiments demonstrated that foods containing (table 1).22–25 To explore consistency and heterogeneity across 5 6 7 8 high levels of saturated fats, dietary heme, sugar, salt and low these different contexts, all analyses were performed separately 1 levels of fibre induce inflammation and autoimmunity through per cohort, followed by a meta-analysis. microbial mechanisms such as induction of T- helper 17 (TH17) cells. Other studies in mice and humans implicated that ingredi- Fecal sample collection and processing ents added during food processing including dietary emulsifiers,9 For each participant one stool sample was collected. Participants antimicrobial additives10 and artificial sweeteners,11 promote gut were asked to collect and immediately freeze their sample at permeability and intestinal inflammation through an increase in http://gut.bmj.com/ home. Samples were then picked up, transported on dry ice and mucolytic bacteria and endotoxins. In contrast, a high intake of stored at –80°C. All samples were processed according to the tryptophan12 and fibre13 generally leads to immune states associ- same pipeline in one laboratory (UMCG, Groningen). Intestinal ated with colonic health. inflammatory markers were measured in the same sample. The The
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