The Gut Microbiome and Inflammatory Bowel Disease

By Dr. Priyom Bose, Ph.D.Reviewed by Megan Craig, M.Sc.

Inflammatory bowel disease (IBD) is associated with chronic inflammation in the intestine. IBD has been categorized into two subtypes, i.e., ulcerative colitis (UC) and Crohn’s disease (CD), which are prevalent globally. The incidence of IBD is impacted by multiple factors, such as genetic susceptibility, immune factors, and gut microbiota. This article focuses on the impact of the gut microbiome on IBD.

The Beneficial Roles of Human Gut Microbiota

The human microbiota is composed of 10 to 100 trillion microorganisms, that include bacteria, fungi, protozoa, and viruses. However, bacteria are more frequently found compared to other microbes with a density of 10¹¹–10¹² cells/ml. In a healthy human gut, 99% of the bacteria belong to the phyla Bacteroides, Actinomycetes, Firmicutes, and Proteus.

Bacteria present in the gastrointestinal tract play an important role in host homeostasis, which includes metabolism, nutrition, immunity, and defense against harmful pathogens. Gut microbes take part in the process of food digestion, where it decomposes carbohydrates and indigestible oligosaccharides in food. In addition, many gut bacteria synthesize short-chain fatty acids (SCFAs), such as acetate, propionic acid, and butyric acid, which supply energy to the intestinal epithelium. 

The gut microbiome also plays an immunosuppressive role by regulating host immune cells. Gut microbiome dysbiosis, or the presence of harmful bacteria, can induce inflammatory cytokines through immune cell interactions or synthesis of specific bacterial metabolites, which can promote intestinal damage.

The Effect of Gut Microbiota on IBD

The gut microbiome influences the manifestation of IBD in multiple ways. Some of the key factors are mentioned below:

Composition of Gut Microbiota in IBD Patients

The composition of gut microbiota in IBD patients is considerably different from healthy individuals. It has been noted that gut microbial composition changes in the early stages of IBD. The degree of microbial dysbiosis in CD patients is significantly more compared to patients with UC. 

The abundance of beneficial microbes, such as Bifidobacterium longum, Faecalibacterium prausnitzii, Roseburia intestinalis, and Eubacterium rectale, are reduced considerably in IBD patients. Instead, increased levels of harmful bacteria, such as Bacteroides fragilis have been found.

At the onset of CD and UC, an increased level of Ruminococcus torques was consistently observed. In addition, some bacterial strains, such as Clostridium hathewayi, Ruminococcus gnavus, and Clostridium bolteae, were found at a higher frequency in IBD patients compared to healthy individuals. In patients with CD, higher levels of Coriobacteriaceae sp., Escherichia coli, Actinomyces sp., Veillonella sp., and Christensenellaceae, and lower frequency of Clostridium leptum, were found. In UC patients, a decreased abundance of Akkermansia muciniphila and Eubacterium rectum, and increased levels of E. coli were observed.

Intestinal Epithelial Barrier

The intestinal barrier comprises chemical, immune, mechanical, and microbial barriers. A unique intestinal microbial community is linked with the development of IBD through intestinal barrier damage by immune cells. Increased intestinal permeability plays a crucial role in IBD pathogenesis. IBD leads to gut microbial dysbiosis, which causes an imbalance between beneficial and harmful bacteria taxa that ultimately damages the intestinal microbial barrier.

An increased frequency of Enterotoxigenic E. coli (ETEC) promotes the secretion of high levels of enterotoxin that enhances intestinal epithelium permeability and inhibits ascorbic acid uptake through the NF-κB pathway. In a stable environment, secretory immunoglobulin A (IgA) plays an important role in dynamic balance within the gut microbiota.

When pathogens produce immunosuppressive protein, it damages the intestinal immune barrier. In IBD patients, IgA-coated bacteria invade the mucus layer, enhancing the frequency of harmful bacteria, such as Helicobacter, and Prevotellaceae.

Gut Microbial Metabolite

More than 2700 bacterial metabolites have been identified associated with the altered microbial abundance in IBD. Generally, an imbalance in bile acids, tryptophan, and SCFA is found in IBD patients. Upregulation in bile acid and sphingolipids production and reduced synthesis of tetrapyrrole and triacylglycerol have also been found in IBD patients.

Gut microbiota synthesizes various metabolites that inhibit the invasion of harmful bacteria and support intestinal homeostasis. The mucus secreted by the gut microbiome acts as a chemical barrier to the intestinal tract. F. prausnitzii produce butyrate that has an anti-inflammatory property. Mechanistically, this metabolite blocks the IL-6/signal transducer and activator of the transcription 3 (STAT3)/IL-17 pathway and activates forkhead box protein P3 (Foxp3), promoting anti-inflammatory activity.

SCFAs regulate mucosal immunity by influencing the synthesis of B cells and differentiation of regulatory T cells, which may activate the production of inflammatory cytokines. A decrease in SCFAs has been found in IBD patients, which enhances intestinal inflammatory cells.

Intestinal bacteria also regulate host immunity through the modulation of bile acids. Modified bile acids activate Tregs and effector helper T cells, particularly Th17, which regulates immune response by promoting or inhibiting inflammation. In IBD patients, the tryptophan metabolism level has been associated with disease severity. Dietary tryptophan is typically metabolized via microbial pathways (indole pathway) and host pathways, i.e., serotonin and casein pathways.

An enhancement in Proteus and a reduction in Bacteroides levels have been associated with producing N-acylethanolamine in IBD patients. This metabolite could be targeted to ameliorate IBD-related gut microbiota disorders.

IBD Treatment Targeting Gut Microbiome

The association between gut microbial dysbiosis and the development of IBD is extremely complex. Fecal microbiota transplantation (FMT) and probiotics supplementation, particularly with butyrate-producing bacteria, are used for IBD treatment. E. coli Nissle 1917 is a probiotic that can inhibit the growth of pathogenic bacteria, such as Salmonella. A clinical trial assessment revealed that E. coli Nissle 1917 could effectively prevent the remission of UC.

FMT can improve severe IBD complications due to recurrent or refractory Clostridium difficile infection. This treatment effectively restores the intestinal ecological imbalance related to reduced Bacteroidetes species in UC patients. Anti-tumor necrosis factor (anti-TNF) agents, such as infliximab, etanercept, golimumab, and certolizumab, prevent inflammation by blocking TNF activity. IBD patients treated with anti-TNF agents exhibited enhancement in bacteria-producing SCFAs and reduction in pathogenic bacteria.

Biotherapy products, such as Gut-103 and Gut-108, have been used to rectify gut microbial dysbiosis in IBD patients. Notably, diet also plays an important role in reshaping the gut microbial population. 

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