Gut out of here! How the gut microbiome can enhance the immune response

Inflammatory bowel disease, or IBD,  encompasses several gut illnesses – such as ulcerative colitis and Crohn’s disease. These and other IBD diseases induce chronic, irritating inflammation in the human digestive tract. As a result, sufferers of IBD often experience a litany of painful, inconvenient, and often embarrassing ailments: diarrhea, abdominal cramps, and rectal bleeding, to name a few.  

The onset of IBD is often rooted in the perturbation of gut homeostasis, which is dependent on a complex interplay of genetics, diet, and perhaps most importantly, the synergistic, well-oiled communication between the gut microbiome and the host’s immune system. 

The gut, its microbiome, & the immune system 

The gut is an incredibly complicated and interesting organ – it is also one of the main entry points for microbes, or microscopic organisms. Some microbes are disease-causing – or pathogenic (think viruses and bacteria like Salmonella). Because of this power to make us ill, microbes tend to have a notorious reputation. But,  “good”, non-pathogenic microbes do exist, and they are not only beneficial, but absolutely vital, to human health. These “good” microbes – also known as commensal microbes – have colonized several niches in the human body, including our gut, and can help protect against harmful diseases.

You might be surprised to learn that our gut houses one of the most vibrant and diverse ecosystems in the world, comprised of several species of  commensal, microscopic fauna. Also known as the gut microbiome, this ecosystem performs functions integral to the health and function of the gastrointestinal (GI) tract, such as synthesizing important  compounds and serving as a key player in the arena of gut immunity. 

This synergy between the gut microbiome and the human immune system has become a burgeoning field of research, especially in the context of disease. In fact, the pathology of many gastrointestinal diseases is often rooted in the disruption of this vital relationship. In, IBD and other diseases, for example, it is thought that imbalances in the gut microbiome might contribute to immune system dysfunction upon pathogen encounter, often leading to chronic inflammation, or swelling, of the intestines and other unpleasant GI symptoms.  

In studying gut microbiome-immune system crosstalk, scientists aim to develop therapies to combat diseases like IBD. To this end, a study of out of Oxford elegantly explores the interface between commensal bacteria’s contributions to host metabolism and host immunity. The group discovered that the short chain fatty acid (SCFA) butyrate, produced by commensal gut bacteria, enhances the anti-bactericidal properties of relevant immune cells.

Butyrate increases bacterial destruction by macrophages

So what is an SCFA? SCFAs are derived from the fiber present in the fruits, vegetables, and grains that you consume. This dietary fiber is subsequently fermented in your gut’s colon by resident, commensal gut bacteria. The byproducts of this fermentation process are SCFAs, such as propionate, acetate, and butyrate (Figure 1). Interestingly, sufferers of IBD and related diseases often have a dearth of these SCFA producing commensal bacteria in the gut.

Figure 1: Short chain fatty acids. SCFAs, including butyrate, are derived from dietary fibers that are fermented by members of the gut microbiome.

Curious about the role of SCFAs in gut immunity and disease, the Oxford scientists investigated their impact on macrophages, a type of innate immune cell. The authors were particularly interested in macrophages because these are often the first line of defense in clearing bacterial infections in the gut.  Essentially, a macrophage scavenges for and kills foreign substances like pathogens, mainly by swallowing the invader and digesting it with specialized enzymes in a process called phagocytosis

To evaluate the antimicrobial power of SCFAs on  macrophages, the authors grew these cells in the presence or absence of SCFAs and then  exposed them to various strains of pathogenic bacteria. After incubation, the macrophages were burst open, or lysed, to release the cells’ contents – including surviving bacteria that were not digested and killed by the macrophages. 

Interestingly, for all tested strains of bacteria, the bacterial survival rates were significantly higher in the control macrophages as compared to the macrophages grown with SCFAs, and most robustly, butyrate. Thus, butyrate appeared to be pivotal in optimizing the anti-bacterial properties of macrophages. 

Butyrate macrophages strongly express anti-microbial genes 

These butyrate-treated  macrophages seem to be killing machines – but what exactly makes them so effective? What is butyrate doing to enhance the killing activity of these macrophages? 

To answer this question, the scientists investigated the activity of genes inside the gut macrophages. Genes are segments of DNA that provide the instructions for making proteins, which are the molecules that do work in our cells to allow our bodies to function. 

Notably, when the group contrasted the gene activity profiles of the control macrophages with the butyrate macrophages, they found  that butyrate macrophages had high activity in genes associated with microbicidal activity.

But how? 

Delving deeper, the authors were curious about exactly how butyrate was specifically amplifying the activity of these highly desirable, anti-microbial genes. 

The answer lies in the efficient packaging of DNA. 

Our DNA is composed of hundreds of thousands of genes. If you unraveled the DNA in a single cell, the average length of the strand would be the equivalent of two meters. How can one cell, unseeable by the naked human eye, accommodate that much DNA? 

Thus, in all cells, including these macrophages, DNA is tightly and efficiently coiled. Like sewing string around a spool, DNA is wound around protein complexes called histones. This condensed DNA-protein structure is collectively known as chromatin (Figure 2). 

Figure 1: Butyrate impacts the immune response to pathogens. Upon phagocytosis, macrophages destroy pathogens by degrading them with anti-microbial proteins. Butyrate facilitates the production of these proteins by inhibiting HDACs. This inhibition prevents the removal of acetyl groups from chromatin to allow for the loosening of chromatin structure and the increased activity of antimicrobial genes.

As you can imagine, different cell types will express, or turn on,  different genes, and not express, or silence, others, depending on their individual needs. For example, a cell in the heart expresses different genes from one in the lung, according to their different functions. In order for genes to be expressed, your DNA needs to be “unspooled” – i.e. the chromatin needs to be unwound so that pertinent genes can be accessed by the appropriate cellular machinery necessary for protein production (Figure 2).

How does butyrate figure into all of this? It turns out that butyrate can critically influence chromatin architecture within these macrophages. Small compounds called acetyl groups facilitate the “loosening” of chromatin so that your genes can be read. Proteins called histone deacetylases (or HDACs), as their name suggests, remove these acetyl groups so that DNA is in its dense, inaccessible, “chromatin” state. 

 Butyrate can inhibit these HDACs, and in so doing, it prevents the removal of acetyl groups from histones. This, in turn, results in the loosening of chromatin structure, freeing up access to certain genes (such as those encoding for antimicrobial proteins) and facilitating their activity and downstream antimicrobial protein synthesis (Figure 2). 

Thus, in these macrophages, butyrate causes antimicrobial protein production  essential to killing foreign invaders. 

Therapeutic potential  

Ultimately, butyrate has powerful therapeutic potential – indeed, the study effectively “piloted” butyrate treatment in mice by orally administering the SCFA for seven days. Mice were then infected with common pathogenic bacterial strains, such as Salmonella, and the bacterial dissemination beyond the GI tract to peripheral organs was evaluated. The bacterial burden and dissemination was much lower in butyrate treated mice, strongly attesting butyrate’s critical role in enhancing the antimicrobial efficacy of intestinal macrophages and mitigating infection. 

Current treatments for IBD encompass immunosuppressants to modulate long-term immune-mediated inflammation, antibiotics and anti-diarrheal medications, vitamin supplements, and even surgery, depending on severity. 

Again, it has been shown that IBD patients lack commensal butyrate-producing bacteria in the gut. Through this study, the authors present a potential, non-invasive therapy for IBD patients, in which supplemented butyrate could theoretically restore microbicidal function to intestinal macrophages and ameliorate symptoms. Though more research needs to be done before butyrate can seriously be considered as a treatment option, this study shows promise for its use in the future. 

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Cover image: “IBM and MIT Help Scientists Study Connection Between Bacteria and Autoimmune Diseases” by IBM Research is licensed under CC BY-ND 2.0 

 Primary research article: Schulthess, J., Pandey, S., Capitani, M., Rue-Albrecht, K. C., Arnold, I., Franchini, F., Chomka, A., Ilott, N. E., Johnston, D. G., Pires, E., et al.(2019). The Short Chain Fatty Acid Butyrate Imprints an Antimicrobial Program in Macrophages. Immunity 50.

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