The gut microbiota – the collection of micro-organisms in the gut – can best be viewed as a newly discovered organ, defined as a group of adjacent cells with a function. The gut microbiota, in fact, fulfils a number of important functions: it digests our food, synthesizes amino acids, trains our immune system, and helps resist gastrointestinal infections. The composition and functions of the gut microbiota can therefore have a large impact on our health.
In this thesis the role of the gut microbiota in intestinal disorders is systematically analysed using DNA sequencing techniques. The intestinal disease we focus on most is inflammatory bowel disease (IBD), a recurrent remittent inflammatory disease of the gut that comprises Crohn’s disease and ulcerative colitis. However, irritable bowel syndrome (IBS), traditionally characterized as a functional disorder consisting of a combination of gut complaints, and bacterial gastroenteritis, a bacterial infection often leading to diarrhoea, were also investigated.
One of the most important discoveries of this thesis is the relationship between use of proton pump inhibitors (PPIs), one of most prescribed drugs in Europe and the United States, and the gut microbiota. PPIs work by reducing stomach acid, normally an important barrier to bacteria entering the intestinal tract, and we observed that bacteria normally found in the mouth were now present in the gut of PPI users. PPI users also have a more pro-inflammatory gut microbiota, showing a decrease in favourable butyrate-producing bacteria and an increase in the Enterobacteriaceae that can produce toxin. As a consequence, PPI users are more susceptible to both bacterial gastroenteritis, e.g. that caused by Salmonella spp, and to Clostridium difficile infections. After these results were published in 2016, government officials began to question whether PPIs should remain available as over-the-counter drugs in grocery stores, and this debate was still ongoing as of the writing of this thesis. This discovery received a lot of media attention in the written press: De Telegraaf, Reuters and Scientific American, on the radio: RTV Noord and BNR Nieuwsradio and on the television show Kassa.

Another important discovery, the gut metagenomes of IBD and IBS are compared to those of population controls and are described in great detail using the metagenomic sequencing technique. With this technique, we were able to both determine the composition of the gut microbiome and infer its function, strain diversity, the level of virulence and the level of antibiotic resistance, leading to thousands of new results. We also present a computer algorithm that uses gut metagenomes to reliably distinguish IBD from IBS (AUC=0.93), performing much better than faecal calprotectin, which is currently used as a marker to distinguish between the two conditions. In the future, a gut microbiome-based test could reduce the number of painful and costly colonoscopies. This discovery was published in the renowned journal Science Translation Medicine and the Dutch television programme Editie NL on RTL4 discussed its importance for patients with irritable bowel syndrome.

The results of this thesis allow us to better understand intestinal disesases and to work towards microbiota-based diagnostics and therapeutics.