The Microbiome in Inflammatory Bowel Disease

Abstract

The management of patients with inflammatory bowel disease (IBD) aims to control inflammation through the use of immunosuppressive treatments that target various points in the inflammatory cascade. However, the efficacy of these therapies in the long term is limited, and they often are associated with severe side effects. Although the pathophysiology of the disease is not completely understood, IBD is regarded as a multifactorial disease that occurs due to an inappropriate immune response in genetically susceptible individuals. The gut microbiome is considered one of the main actors in the development of IBD. Gut dysbiosis, characterised by significant changes in the composition and functionality of the gut microbiota, often leads to a reduction in bacterial diversity and anti-inflammatory anaerobic bacteria. At the same time, bacteria with pro-inflammatory potential increase. Although changes in microbiome composition upon biological agent usage have been observed, their role as biomarkers is still unclear. While most studies on IBD focus on the intestinal bacterial population, recent studies have highlighted the importance of other microbial populations, such as viruses and fungi, in gut dysbiosis. In order to modulate the aberrant immune response in patients with IBD, researchers have developed therapies that target different players in the gut microbiome. These innovative approaches hold promise for the future of IBD treatment, although safety concerns are the main limitations, as their effects on humans remain unknown.

Keywords: Crohn’s disease; biofilm; biomarker; dysbiosis; microbiota; ulcerative colitis.

Figure 1

Schematic representation of the human intestinal microbiome. The microbiota is a broad concept that includes microorganisms (the microbiota), the genes and gene products of the microbiota, and the microenvironment. Most nutrients are digested and absorbed in the small intestine. However, dietary fibre remains intact until it reaches the colon. In the colon, a fermentation process is performed by enzymes produced by gut bacteria, resulting in short-chain fatty acid (SCFA) production, including acetate, propionate, and butyrate. These metabolites participate in various cellular and immunological processes. They stimulate the production of mucins, reduce the intestinal permeability, and promote anti-inflammatory pathways. Among the SCFAs, butyrate is the main energy source for the intestinal epithelial cells and has modulator functions that lead to a decreased concentration of oxygen in the intestinal lumen. As a result, the number of obligate anaerobic bacteria, including those of the phylum Firmicutes, which produce butyrate, increases. Bile acids (BAs) are the end products of cholesterol catabolism and are released into the small intestine through the ampulla of Vater. They form micelles with lipid molecules and facilitate their absorption in the small bowel through the enterohepatic circulation. However, there is a small proportion of BAs that remain in the gut and is metabolised by the gut bacteria [11]. Tryptophan is an essential amino acid that should be ingested with the diet. Gut bacteria convert it into tryptamine and other products. These products can function as endogenous ligands for the aryl hydrocarbon receptor (AhR), an essential signalling pathway in the maintenance of gut homeostasis [12].

Figure 2

Overview of the intestinal mucosal barrier. The human gut is a vast surface of contact with the environment that is colonised by trillions of gut microbes. The intestinal barrier comprises a thick layer of mucus, a single layer of epithelial cells, and the inner lamina propria hosting innate and adaptive immune cells. The intestinal epithelium, along with the mucus layer that covers it, acts as a physical barrier.

Figure 3

Multi-omics for the study of the human gut microbiome in inflammatory bowel disease. Metagenomics involves identifying the bacterial composition and diversity using techniques such as 16S rRNA gene amplicon or shotgun sequencing. This method provides information on the presence or absence of specific genes in the microbiome. Metatranscriptomics focuses on assessing the functionality of the microbiome by analysing gene expression over time using RNA sequencing techniques. Proteomics studies the entire set of proteins that a genome can express in a cell, known as the proteome. Combining metagenomic and metaproteomic data, it is possible to characterise signalling proteins and pathways. Metabolomics explores the metabolome, which consists of metabolites derived from both the host and microorganisms.