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The Marvels, Functions, and Promises of the Gut Microbiome

There are approximately 100 trillion bacteria, viruses, and fungi representing the thousands of species of microorganisms that are residing within our digestive systems. Some of them are beneficial - or even essential - to our bodies, whilst others could be harmful to our health. Regardless of their role, this enormous community of microorganisms as a whole is known as the gut microbiome.

To put things into perspective, there are ten times more microorganisms living inside and on humans compared to all somatic and germ cells combined!

Figure 1: A diagram showcasing the human gut and where the gut microbiome is found (in the small and large intestines).

On that note, since there are so many organisms living within us as well as in the environment surrounding us, it would be naïve to believe they don’t affect our health in some way. Hence, the Human Microbiome Project, an extension of the Human Genome Project, was launched in 2007 in an attempt to find a connection between the gut microbiome and human health.

The Human Microbiome Project


The Human Microbiome Project was a compilation of projects organized by the National Institute of Health (NIH) with an aim to understand how microbiomes contribute to human physiology and disease. This project was carried out in different parts of the globe including the United States, Europe and Asia.


Following the first part of the Human Microbiome Project, a second phase called The Integrative Human Microbiome Project was launched in 2014. This study placed a focus on the gut microbiota profiles of individuals under three medical conditions:

  • Pregnancy or preterm birth

  • Inflammatory bowel diseases

  • Stressors in pre-diabetic individuals

Over time, the data obtained from both phases of the project proved to be invaluable in establishing links between the gut microbiome and a wide range of medical conditions such as cancer, heart disease, obesity, and even autism. In addition to this, they have also shown great variation in bacterial lineages between individuals.


Let’s take a look at some examples of how the gut microbiome is being manipulated to improve our health.

The gut microbiome and immune homeostasis


The gut microbiota plays a significant role in maintaining a balance in our immune system-they do this by finding a middle ground between eliminating pathogens and avoiding autoimmunity, where the immune system of an individual attacks other harmless cells in the body.


This role has been proven in experiments where altering the gut microbiota has had adverse implications on human health, and many autoimmune diseases such as type 1 diabetes, lupus, and multiple sclerosis can now be linked to poor and unhealthy gut microbiomes. Furthermore, the gut is also thought to be capable of triggering or halting inflammatory responses.


Since the gut is in contact with multiple species of microbes (both benign and hostile), as well as different environmental factors, immune tolerance is very significant. Infections and certain foods have long been thought to trigger and exaggerate autoimmune diseases. These have lately become more focused on the microbiome of the gut as the main culprit.

In some case studies, it has been shown that specific cells can be affected by dysbiosis of the gut microbiome. These include nerve cells in multiple sclerosis and pancreatic beta cells in type 1 diabetes, but also includes cells involved in lupus, where the affected cells are not located in one specific part of the body but are spread across multiple organs. Patrizia Casaccia from the City University of New York notes that she believes metabolites could communicate with the brain through the vagus nerve, because bacteria have been found in affected organs in patients with autoimmune diseases. An example of this is that specific bacteria has been found in the pancreas in patients with type-1 diabetes.


One specific case study demonstrating the potential significance of the gut microbiome was carried out in 2017 and compared the gut microbiome of multiple sclerosis patients against healthy individuals. The researchers discovered a very different number of certain microorganisms between both groups. Additionally, when they transferred microbes from multiple sclerosis patients to healthy mice, they saw a significant decrease in the health of the mice.

Figure 2: A study carried out in 2017 where healthy and multiple sclerosis individuals were screened for particular microorganisms in their gut. Multiple sclerosis patients have substantially reduced the amount of some microorganisms. When these were transferred to mice, mice suffered a significant decrease in health.


The researchers also took two species of bacteria from the patients with multiple sclerosis, and after incubating them in human blood in vitro, they discovered the inflammatory responses had suddenly spiked. This indicates that these led to differences in their immune response.


Isn’t that interesting? A disease that seems to have no apparent connection with the intestinal tract can be in fact strongly influenced by it. This response also clearly corresponds to the findings of numerous scientists around the world.

How can our gut microbiota help treat cancer?


What about cancer? This is a question asked by millions in regard to millions of different treatments. Dysbiosis of the microbiome is caused by factors such as smoking, antibiotics, hormones and diet (to name a few), some of which are also commonly linked to the development of cancer and tumours in our bodies (just look at the label on a cigarette pack).

As explained previously, inflammatory states in the body due to dysbiosis in the gut can have an impact on our mental states through the gut-brain-axis, but dysbiosis also supports carcinogenesis or the development and initiation of cancer formation in the body. As written by Laurence Zitvogel and colleagues, “Abrogating or specifically altering the composition of the gut microbiota influences the incidence and progression of colorectal carcinoma in both genetic and carcinogen-induced models of tumorigenesis.”


One group of cells which are targeted by various by-products of the gut microbiome are

intestinal epithelial cells (IECs), which mediate and may even suppress the onset of cancer development in the body by suppressing tumorigenesis, or the initial development of tumours, as stated by Zitvogel. This puts into perspective just how a single region of the body we often do not consider can impact such a large variety of matters in our bodies and it cannot be ignored.

Making the most of the gut microbiome


As of 2020, although we have some understanding of the relationships between drugs taken and their effects on the body, there is still not sufficient research to fully understand the extent of these impacts. Being able to understand these relationships would help us develop new treatments and push the medical industry to rethink the prescription of medicines and create a more personalised solution.

Researchers are currently biosynthesising individual microorganism species to deliver treatments as well as to monitor different conditions. At the same time, ecologists are studying individual colonies and communities to understand their behaviour.

Biosynthesis and engineering of microbes, also known as live therapeutics, is a hot topic of study and has proven to potentially be used for the treatment of numerous conditions. For instance, experiments conducted on mice have shown that when engineering a bacterium to secrete an enzyme found in vegetables, it reduces the size and recurrence of colon cancer. Other experiments have proven that bacteria can be engineered to ‘detect’ a disease and produce molecules to fight against the disease by segregating therapeutic substances or by sending signals to different cells.


An example of this is the works written by Lu and Anantha Chandrakasan at MIT’s School of Engineering. They have designed sensors added to bacteria to detect a molecule responsible for signalling called AHL, which is a marker for gastrointestinal diseases and infections.

Figure 3: Representation of experiments to genetically modify gut microbiome to fit a specific purpose, such as the production of an enzyme.

Nonetheless, these have yet to be tested in humans. Researchers are particularly concerned with how these engineering bacteria would behave outside of the closed laboratory environment, as the human gut comprises thousands of other microorganisms which could interact with the engineered bacterium in harmful ways. Another major concern of this practice is deciding if the use of these bacteria is safe. Bacteria can easily transfer DNA to other bacteria and move outside of the desired environment. To avoid this problem, researchers are looking into adding “kill switches” to the engineering bacteria, which would lead to apoptosis - cell death - if they leave the desired environment.

As previously mentioned, synthetic ecologists are taking a different approach to study the gut microbiome: they are investigating communities of microorganisms rather than focusing on a particular species. They believe that the interaction between different microorganisms is key to understand the gut microbiome as a whole. Just like in any other ecosystem, members of the gut microbiome have to compete for survival, interact and communicate with one another.

To study this, ecologists are creating synthetic ecosystems, groups of different microorganisms, both naturally occurring or genetically engineered using computer modelling. Research has shown that if faeces could be separated to only the necessary microorganisms needed to treat a patient, the microbe combination could be recreated in a laboratory to create a standardized therapeutic procedure for patients suffering from recurrent Clostridium difficile colitis. Colitis refers to the inflammation of the colon.

It is the disruption of the microbiota that allows C. difficile to establish an infection, and recurrent C. difficile colitis is characterised not only by fever, abdominal cramping and diarrhoea, but also the inability of antibiotic treatments to completely clear the infection. When this is the case, there is an alternative solution: bacteriotherapy, also known as faecal microbiota transplantation (FMT).

Faecal transplantation involves the transplant of faeces from a donor into the gastrointestinal tract of a patient. The processed good bacteria from the faeces can also be turned into pills that can be ingested. This is mainly done to replenish the gut with benign bacteria that can target a specific pathogenic organism. Nonetheless, finding a suitable donor can be challenging. Having a standardised therapeutic procedure would take away the hustle of finding a suitable donor, avoid pathogenic microbes and ensure only the useful microbes are transferred.


Figure 4: Representation of faecal microbiota transplantation. Donor stool is collected and processed to select desired microbiomes for the implant. Microbiomes can be delivered orally through pills or through transplants with colonoscopies.

Both of the aforementioned approaches - individually engineering microbes and creating microbe communities - could be combined to find a more efficient therapeutic option. By combining both approaches, researchers could split different tasks between bacteria and make them work together as a community, making sure that if one species dies, there won’t be an extremely detrimental effect in the whole community.

These principles, amongst others, can be applied to creating drugs from the contents of the gut microbiome.

What does the brain have to do with the gut?


The gut microbiome reaches areas of our bodies we would least expect. Gut health and function is not only evidenced to impact gastrointestinal diseases and dysfunction, but also has a significant impact on diseases outside this part of the body, according to a research group led by Megan Clappp in their publication of ‘The Gut-Brain Axis’. An upset stomach or a malfunctioning gut is correlated with upset mindsets, but this goes beyond that.

Anxiety and depression are among those mental illnesses that have been linked to gut dysbiosis. The vagus nerve, an important component of the central nervous system, connects your brain to the gut, among other necessary parts of the body. Direct messages between the colon and the brain show the vitality of the gut in the development of not only mental but also physical illnesses humanity suffers.

John Cryan from the University College Cork in Ireland was one of the first to investigate the relationship between microbes in the gut and behaviour in mice and found a clear correlation. Germ-free mice tended to avoid social interaction more than those with a developed and diverse set of bacteria in the gut. This has been widely studied among neurodevelopmental scientists.

More and more studies have since then been carried out to further this evidence to investigate what effect the gut-brain-axis has on the endocrine, neural and immune pathways of our bodies. Could probiotics really serve as a treatment for mental illnesses of the likes of anxiety and depression? It is not immediately clear to us that there may be a connection, but the gut microbiome is more important than we think.

The regulation of digestive processes is controlled by the brain. If unnecessary or atypical stresses are placed on the vagus nerve, this then translates back to the brain and consequently its ability to respond effectively to inflammation becomes impaired. The inflammation in the gut that arises due to this can contribute to the development of mental illnesses such as depression, which can lead to a vicious cycle as it has been evidenced that depression may also cause inflammation itself. The richness of diverse, healthy bacteria in the gut reduces this inflammation, thus reducing the symptoms of anxiety and depression. This shows the importance of a varied diet in not only physical health but also mental health.

A little about the gut: gut bacteria break down fibres in food eaten and transform these into metabolites such as short-chain fatty acids (SCFA). Fibre is one of the most important components in maintaining the gut bacteria in their healthy state by being a source of energy. As stated by AtlasBioMed, “Probiotics help to support human health by keeping the gut ecosystem balanced and preventing dysbiosis. By doing so, beneficial bacteria can thrive and contribute to your health and butyrate production.” Some call these probiotics ‘psychobiotics’ due to their favourable impact on mental illnesses as explained above.

How can we restore or improve our gut microbiome?


According to Harvard Health, in order to have a healthy gut microbiome, there are a few different kinds of nutrients and supplements we can consume:


  • Fermented foods: these are key because they allow for an optimal growth environment for microorganisms as well as contributing to their diversification.

  • Probiotic supplements: these contain live microorganisms that are beneficial for the gut, as first introduced in the above section.

  • Prebiotic foods: prebiotics are naturally occurring substances in carbohydrates such as fibre or resistant starch that are not digested by us, but are essential for healthy bacterial growth in the gut.

  • Fibre-rich products such as fruits and vegetables. Even though fibre is not digested by our body, certain bacteria can absorb it for growth.

  • Polyphenol-rich foods such as broccoli, blueberries, green tea, red wine, almonds and onions. Polyphenol is a plant compound that, just like fibre, is not easily digested by humans but can be digested by microbes and allow their growth.

What’s the takeaway message?


As mentioned in the introduction, there are more than 100 trillion microorganisms living within each of us. Whether good or bad, they play a role in the workings of our body. The more we learn about these organisms inhabiting us, the more we will ultimately know about ourselves.

The study of the gut microbiome is a promising field of research that looks to revolutionise the way therapies are thought of and the significance of a balanced diet. Having a healthy, well-balanced gut microbiome has been linked to improvements in immune responses, cancer treatment, and neurological disorders, amongst others. Similarly, having an unhealthy gut bacterium can lead to many conditions of different significance. This area still requires a lot of research, particularly due to challenges such as the wide diversity of microbes it comprises, and the little research carried on humans.

Many more discoveries are to be made, and many connections are yet to be found. Until we know the full extent of the gut microbiome’s power, we should aim to maintain a healthy lifestyle to support its growth.

Author


Covadonga Piquero Lanciego

BSc Biological and Biomedical Sciences

University of Dundee

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