Impact van voedingsbestanddelen en voedselverwerking op de pathofysiologie van inflammatoire darmaandoeningen & impact van de SARS-CoV-2 pandemie op inflammatoire darmaandoeningen.

Inflammatory bowel diseases (IBD), with its two main entities: Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastro-intestinal tract. Where IBD used to predominantly be Western diseases, we can now increasingly find cases all over the world, including Asia, India, and South America. IBD are thought to develop in susceptible individuals on the background of the complex interplay between genetics, the immune system, and the gut microbiota. Due to the rapid and global increase in prevalence, environmental factors are increasingly appreciated to play an important role in triggering IBD. Examples of human exposures throughout their lives include smoking, physical exercise, air pollution, diet, and urban living. Out of those, the diet is especially intriguing as patients often report foods to have an impact on their symptoms and their disease course. In addition, the site of inflammation in IBD is the gut, where food and food components meet the gut microbiota and the intestinal epithelium. A typical Western diet that is high in fat and sugar, and low in fiber, and often contains large amounts of ultra-processed foods (UPFs). UPFs are produced with the help of industrialized manufacturing processes and usually contain food additives such as colorants, preservatives, and emulsifiers (Chapter I). To investigate the effect of UPF intake on human health, we performed an umbrella review as well as an update of existing meta-analyses. In doing so, we assessed the current evidence on the association between UPF intake and various health outcomes. We reported a convincing and positive association between UPF intake and renal function decline and wheezing in children and adolescents, and highly suggestive associations with diabetes mellitus, overweight, obesity, depression, and common mental disorders. Although the evidence was weaker, we also found associations between the intake of UPFs and IBD. Importantly, not a single study reported an association between UPF intake and a beneficial health outcome (Chapter III). To get a more granular picture on the association between UPF intake and IBD alone, we performed a cross-sectional and prospective cohort study in 187,854 individuals included in the UK Biobank. Using data collected through 24-hour dietary recall questionnaires we found that UPF consumption in IBD patients was significantly higher compared to controls. In addition, in individuals with a pre-existing diagnosis of IBD, increased UPF consumption was associated with an increased need for IBD-related surgery. In the prospective part of the study, higher intakes of UPFs were associated with an increased incidence of CD, but not UC (Chapter IV). To assess the overall inflammatory properties of a given diet, others have designed dietary inflammatory indices, including the empirical dietary inflammatory pattern (EDIP) based on food groups and dietary inflammatory index (DII) based on nutrients. These scores have been previously associated with an increased risk of IBD, although with inconsistent findings. Again, using the UK Biobank cohort, we conducted a prospective study to validate these dietary inflammation indices and their relationship with IBD incidence and IBD-related clinical outcomes. However, for both inflammatory indices, we found a null association. Given the results derived from Chapter IV, our results challenge the use of these dietary inflammatory scores and highlight the possible importance of food processing in the inflammatory potential of a diet (Chapter V). UPFs can be defined by their degree and extent of processing. However, many different aspects in their industrial processing could be responsible for any of the cited adverse health outcomes, such as a lower nutritional quality, the use of food additives, and the use of packaging materials. Another aspect that might explain the findings from Chapter III, is the cooking method we use to prepare our food. Cooking methods that make use of high temperatures for a long time in dry circumstances, such as grilling and baking, generate higher levels of advanced glycation end-products (AGEs), which have previously been associated with adverse metabolic and inflammatory outcomes. In a pilot randomized cross-over trial in healthy volunteers in which all participants consumed a diet that was cooked using high-AGE producing and low-AGE producing cooking methods consecutively, this had an impact on serum AGEs levels, as well as on human and gut microbial metabolism. More specifically, we found that a diet low in AGEs beneficially alters the lipid profile of healthy volunteers and increases the protein 4E-BP1, which is implicated in tumour biology, insulin resistance and is associated with increasing life span. We also report an increase in faecal butyrate production after a diet high in AGEs which challenges the previous reports that a diet high in AGEs promotes intestinal inflammation (Chapter VI). Lastly, we investigated the role of emulsifiers in inflammation, cardiometabolic and gut health in healthy volunteers. Emulsifiers are a type of food additive that is used to improve texture, shelf-life and mouthfeel in many foods. After conducting a pilot double blind randomized study in healthy volunteers, we report that a sustained emulsifier-free diet was able to improve faecal calprotecin levels and increase stool short chain fatty acids, whereas carrageenan supplementation increased small bowel transcellular permeability (Chapter VII). We showed that an emulsifier-free diet was feasible and acceptable with high adherence rates in healthy volunteers. In addition, while following the emulsifier-free diet together with a decreased consumption of emulsifiers, an inadvertent and stable decrease in ultra-processed food intake was seen (Chapter VIII). This concludes the first part of my PhD research. The flip side of this booklet was not originally planned, yet was driven by SARS-CoV-2. SARS-CoV-2, a coronavirus that was first detected in December 2019 caused a global outbreak around the start of my doctoral research. This virus is the cause of COVID-19, an infectious respiratory disease that leads to few or mild symptoms in the majority of infected individuals. However, it may cause severe and lethal respiratory disease in others. As many of the current therapies that are used in IBD modulate the immune system, it was unclear whether these treatments could lead to a higher risk of contracting COVID-19 or developing a more severe disease course. With the advent of this novel virus, there was a clear need to better understand the immunological response to SARS-CoV-2 infection in IBD patients. Therefore, we compared the humoral immunity of 55 IBD patient treated with infliximab, infliximab and thiopurines, or vedolizumab to otherwise healthy volunteers. Using different techniques, we found that all IBD patients showed a significantly reduced IgG antibody response for all SARS-CoV-2 antigens, as well as a lower neutralizing antibody response. Importantly, the greatest reduction was observed in individuals treated with infliximab/thiopurine combination therapy (Chapter XI). A second question that arose because of the ongoing pandemic, related to the effect of social distancing behaviors and geography on the risk of COVID-19. To provide answers, 2,303 IBD patients were recruited to our observational cohort study in seven countries in Europe, North America, and Asia. After measuring anti-Spike (anti-S) and anti-Nucleocapsid (anti-N) antibodies to SARS-CoV-2, we found that seroprevalence rates between countries ranged from 0% in Hong Kong to 81.2% in Chandigarh, India, signifying geographical differences in risk of infection. After multivariable analysis, country, as well as male sex and diabetes remained significantly associated with a higher seropositivity rate. On the other hand, a lower seroprevalence rate was linked to the use of biological therapies. Interestingly, after multiple linear regression, treatment was associated with the anti-S and anti-N levels, but not country, which corroborates the findings from Chapter XI in that IBD medication can influence humoral immunity (Chapter XII). Lastly, when the first vaccines to combat COVID-19 were rolled out, IBD patients were not included in any of the registration trials. Therefore, the effectiveness of the vaccine in this patient population remained uncertain, which could potentially affect the uptake of the vaccine by IBD patients. Therefore, we assessed the uptake of the COVID-19 vaccine at three different timepoints, including primary vaccination and uptake of boosters at the infusion centers in Oxford and London. We reported a decrease in COVID-19 vaccination uptake over time in our IBD population, which mirrored findings from the general population. Regarding vaccination hesitancy, we identified age, type of therapy, ethnicity and deprivation as significant contributors to lower vaccination uptake, which could inform which patients to increase overall vaccination rates in future vaccination campaigns in IBD (Chapter XIII). Taken together, this PhD dissertation tried to answer a common clinical question from IBD patients: 'Doctor, what should I eat'. We focused on the role of UPFs in human health (Chapter III) and zoomed in on its association with IBD incidence and IBD-related outcomes (Chapter IV). Next, we questioned the utility of dietary inflammatory indices to estimate the inflammatory potential of a diet, related to IBD (Chapter V). Lastly, we focused on selected aspects of UPFs, namely cooking methods and the use of dietary emulsifiers and their role on metabolic and gut health in healthy volunteers in a clinical trial setting (Chapter VI-VIII). This PhD dissertation also investigated the seroprevalence (Chapter XII) and the humoral response to SARS-CoV-2 infection (Chapter XI) in IBD patients, as well as their attitudes towards and uptake of the SARS