Role of gut microbiota in inflammatory diseases: IBD and obesity

By Kai Yee Eng

To find an area with the greatest population of microorganisms covered in or on our body, we only need look to our gut. Our gut microbiota comprises bacteria, archaea, virus and other microorganisms. Unsurprisingly, none can find another person with the same gut microbiota composition. Given gut microbiota is unique in every individual, the role of gut microbiota and how the composition evolves with ageing, diet changes and other factors has been the interest of researchers. We now know that the gut microbiota plays a crucial role in the human body, to an extent that it is symbolized as the “invisible organ”. (Li et al., 2020) Dysbiosis, a disruption or shift in the composition of gut microbiota, has been found to have correlation with several diseases such as inflammatory bowel disease and obesity, which has been classified as a disease of low-grade inflammation. (Clemente, Manasson and Scher, 2018) Therefore, studies have been carried out to investigate the role of gut microbiota and inflammation. 

Inflammation is one of the most important mechanisms of the innate immune system to fight against pathogens. When the immune cells detect the antigen and recognise it as a threat, they will release signals to induce a state of inflammation. When inflammation occurs, more white blood cells are recruited to the site of inflammation. This will result in local redness, pain and swelling due to the increased blood flow. (Chen et al., 2018) However, to trigger inflammation in the gut ecosystem, this process becomes more complex: the commensal flora which occupy the gut are foreign substances which do not present self-antigen and can therefore be judged as “threat”. As an adaptation to this condition, dendritic cells located at Peyer’s patches in the gut wall and M cells sample antigens and deduce if homeostasis has been disrupted. If homeostasis is maintained, there will be no reaction mediated and enters a condition known as immune anergy. (Wu and Wu, 2012) Intestinal epithelial cells form a physical barrier to separate the gut environment from other tissue (Takiishi, Fenero and Câmara, 2017), but if the microbes cross the barrier, they will be pathogenic and induce inflammation. With these protective mechanisms, commensal bacteria colonise in the gut and without initiating an immune response. 

With some adaptation, the gut microbiota does not trigger unwanted inflammatory signals. However, as mentioned in the above, this can only be achieved if homeostasis is maintained. Studies have found out that in inflammatory diseases, the gut microbiota composition differs from those of healthy individuals. In inflammatory bowel diseases – namely Crohn’s disease and ulcerative colitis – stool samples from patients have shown reductions in several specific bacteria, which are Faecalibacterium prausnitzii, Leuconostocaceae, Odoribacter splanchnius, Phascolarctobacterium, and Roseburia. (Clemente, Manasson and Scher, 2018; Wang, Chen and Wang, 2020) Of these bacteria, reduced colonisation of  Faecalibacterium prausnitzii, is correlated with inflammatory bowel disease. (Lobionda et al., 2019) Faecalibacterium prausnitzii is a fermenter producing the by-product butyrate, a short chain fatty acid. Butyrate has been found to activate acetate and facilitate the regeneration of colon epithelial cells. At the same time, butyrate interacts with regulatory T cells (Tregs), a type of immune cell that contributes to homeostasis. Butyrate is widely known for its role in inhibiting histone deacetylases, changing the epigenetics and regulate gene expression. (Furusawa et al., 2013) Butyrate is thus thought to change the epigenetics of T cells in the gut and later affect their transcription.  In a germ-free mouse model, this hypothesis is supported as the experiment shown increased of H3 histone acetylation via the upregulation of Foxp3 gene, which a transcription factor responsible for Treg differentiation and proliferation. The balance in this epigenetic change which induces Treg differentiation is critical for regulating inflammation. (Lobionda et al., 2019) 

In patients with obesity, it is observed that there is less diversity in the microbiota composition, with a shift to fewer Bacteroidetes and more Firmicutes. (Wang, Chen and Wang, 2020) Facultative anaerobes – Lactobacillus, and Enterococcus – increase. (Abenavoli et al., 2019) Gut microbial dysbiosis can influence metabolism and immune dysregulation, which are closely related in the case of obesity. Fat accumulation and lipotoxicity can result in cytokine activation to induce inflammation due to high calorie intake. (Boulangé et al., 2016a) Short chain fatty acids produced via fermentation can be taken up by immune cells such as B cells and serve as the energy source to undergo differentiation. Acetate was found to increase the activity of inflammasome by reducing IL-18 and increasing IL-1β. (Xu et al., 2019; Kim, 2021) The ligands of the short chain fatty acids – GPR41, GPR43 and GPR109A – have been shown to activate the immune system. The shift of microbiota diversity in obese patients diminishes the protective effect of gut microbiota, as there are more microbes associated with anti-inflammatory status. (Boulangé et al., 2016b) Lipopolysaccharides released by bacteria can cross the mucosal layer or enter the adipose tissue and trigger a signal to the immune system, releasing TNF-α and other cytokines to start inflammation. (Wang, Chen and Wang, 2020)

While this article focuses on the role of gut microbiota in immune system, the function of gut microbiota is mainly mediated via fermentation of non-digestible substance to synthesis short chain fatty acids: butyrate, acetate, and propionate.(Valdes et al., 2018) These short chain fatty acids are essential player in the metabolism, controlling satiety, energy homeostasis and many more indirect interactions with the host, and correlates with diseases for instance autism spectrum disorder and Alzheimer’s disease. (Morais, Schreiber and Mazmanian, 2021) With the advancement of technology, scientists are excited to dive deeper into gut microbiota and more exciting research to discover the mechanism of microbiota and the host cell interaction to reveal the secrets of “invisible organ”.

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