5 The Gut Microbiome

The Gut Microbiome

The microbiome associated with the human gastrointestinal tract, termed the gut microbiome, may arguably be the most important component of the collective human microbiome. It has been shown to affect numerous other regions of the body and serves a role in many types of diseases throughout it. This is because many of the microbial products are absorbed in the alimentary canal and distributed throughout the body via the cardiovascular system.

Sample procurement to characterize the gut microbiome usually comes in the form of fecal matter, which readily available and less invasive. However, there are novel attempts to characterize gut microbiome constituents by sampling the mucosal-luminal interface (Yan et al., 2020). DNA and other features of interest can then be extracted from the microbes to provide information regarding gut microbiome composition and function.

Composition

The gut microbiome is quite versatile and its composition can vary widely among individuals with different ethnicities, across geographic locations, and with age (Yatsunenko et al., 2012, Gaulke and Sharpton, 2018). The host’s genetics do play a role in the composition of the gut microbiome, as certain members are heritable, while other’s abundances are the causal result of congenital diseases (Xu et al., 2020). Though diet, which is closely related to the aforementioned variables, may be the single strongest influencing factor when it comes to structuring this digestive community and alterations are reflected in both short-term and long-term dietary interventions (David et al., 2014, Xu and Knight, 2015). Indeed, the type of diet, such as a high-fat diet, will have a direct impact on the gut microbiome. More specifically, the unique macromolecules within the gut can modify microbial abundance and predicted functions. For example, a certain oil in the diet could result in higher microbial richness, however, this diversity may not alone be a predictor of better health outcomes (Abulizi et al., 2019). Dietary vitamin content and even receptors required for processing them are in part modulated by the microbiome. For example, vitamin D deficiency and downregulation of its affiliated receptor is associated with pathogenesis of various diseases and their restoration promotes healthy host-microbe homeostasis (Jin et al., 2015). It is also interesting to note that diet usually changes throughout the year as certain food items become available or absent depending on the season. An increased gut prevalence of Bacteroidetes, which can digest complex plant carbohydrates, could be explained by a diet consisting heavily of produce during a harvest season (Davenport et al., 2014). The composition and diversity of the gut microbiome can even be linked to personality traits. Those individuals with larger social networks have a more diverse gut microbiome, and those affected by stress and anxiety show an altered composition with reduced diversity (Johnson, 2020). The connection between the gut microbiome and mental states and behaviors will be discussed more in the section “Mental Health”.

Dysbiosis and Disease

The gastrointestinal mucosal immune system modulates and responds to the gut microbiome, where the resident members aid in its development and transient pathogens cause dysfunction, leading to various diseases (Shi et al., 2017). Inflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, IBD, and ankylosing spondylitis are implicated in the impaired interaction between the intestinal microbiota and mucosal immune system (Arbuckle et al., 2003, Mikuls et al., 2012, Costello et al., 2015). Microbial dysbiosis within these cases are marked by changes in composition and diversity of specific groups of organisms (Shi et al., 2017). So, the gut microbiome can not only serve as an indicator for such diseases, but may also eventually become a target for treatment, with maintaining proper homeostasis a major goal.

Gut microbiome dysbiosis, whether it causes a particular disease or manifests as a result of it, is quickly becoming the focus of many gastrointestinal illnesses. Specific members of the gut microbiome (e.g. bacteriome, mycobiome, virome) can even vary and be affected differently depending on the disease and its severity. For example, while much of the focus is usually on bacteria in the gut, it is important to not discount the contributions of other microorganisms like bacteriophages and fungi. The gut phageome can vary in diversity, complexion, and in so has been shown to contribute to diseases like IBD, malnutrition, and AIDS (Norman et al., 2015, Reyes et al., 2015, Monaco et al., 2016, Shkoporov and Hill, 2019). Similarly, the gut mycobiome has shown to have roles in IBD, colorectal cancer, and even neurological diseases (Forbes et al., 2019, Gu et al., 2019, Qin et al., 2021). Though, it is likely the complex interactions between all members of the gut microbiome with the host undoubtedly play a role in various degrees for the progression of gastrointestinal and other diseases.

Those with Inflammatory Bowel Disease (IBD) experience substantial fluctuations in the gut microbiome, which is implicated due to signs and symptoms of the disease state, diet, as well as increased medication during flare ups (Walters et al., 2014, Halfvarson et al., 2017). IBD is a blanket term for two disorders, ulcerative colitis and Crohn’s disease, which are characterized by chronic inflammation of the gastrointestinal tract and commonly results in frequent diarrhea, abdominal pain, bloody stool, weight loss, and fatigue. It is likely that the gut microbiome plays both a role in the development of these conditions and is affected by the induced changes. The gut virome component responds to disease-induced environmental change of IBD patients by shifting from virulent to temperate bacteriophage core, which subsequently affects the bacteriome and dysbiosis condition (Clooney et al., 2019). A familial study of patients with Crohn’s disease showed an increase in the number of pathogenic bacteria, and a decrease in beneficial bacteria. In particular, three potentially pathogenic biofilm-forming species from both the bacteriome (Serratia marcescens and Escherichia coli) and mycobiome (Candida tropicalis) interact with each other and impact the host immune system by increasing levels of proinflammatory cytokines and mucolytic enzymes which cause oxidative and tissue damage (Hoarau et al., 2016).

Diabetes mellitus is another disease in which its progression is partially in response to gut microbiome dysbiosis. While there are other factors that play into diabetes such as culture, genetics, age, lifestyle, etc., this can be interlinked with an individual’s microbiome. Studies over both type 1 and type 2 diabetes have shown that a change in the gastrointestinal microbial ecology is associated with diabetic subjects as compared with their healthy counterparts (Giongo et al., 2010, Larsen et al., 2010, Musso et al., 2011, Sohail et al., 2017). Type 1 diabetes stems from destruction of pancreatic beta cells, which results in decreased insulin production and elevated blood glucose levels. The gut microbiome may contribute to the disease by dysbiosis-associated immune regulation causing destruction of the beta cells and/or gut leakiness, endotoxemia, and chronic low-grade inflammation associated with certain enteric microbes (Cani et al., 2007, Lee et al., 2011, McDermott and Huffnagle, 2014, Sohail et al., 2017). Type 2 diabetes is characterized by the body’s improper regulation and secretion of insulin and is associated by hyperglycemia. Physiological changes in the GI tract could be induced by dysbiosis in the gut microbiome leading to gut permeability and insulin resistance (Everard and Cani, 2013). In general, the gut microbiota composition is less in terms of diversity and richness for those with type 2 diabetes, though an increase in abundance of certain groups like Bifidobacterium could improve conditions associated with pathogenesis (Cani et al., 2007, Sohail et al., 2017). It seems that an alteration of the microbial gut profile has considerable effects on host metabolism, gastrointestinal physiology, gut fermentation capabilities, and immunity which can have many other downstream implications (Boulange et al., 2016).

Obesity is commonly associated with type 2 diabetes as well as other comorbidities that are linked to gut microbiome dysbiosis. As mentioned earlier, diet strongly affects the composition and function of the gut microbial community and subsequently impacts the host’s metabolic capabilities. In fact, a  high-fat/calorie or improper diet that results in dysbiosis is evident earlier than the signs of the host’s metabolic abnormalities, and so gut microbiome dysbiosis may be the principle ingredient responsible for the progression of obesity and type 2 diabetes (Nagpal et al., 2018). A high-sugar diet seems to promote an abundance of Mollicutes, a class within Firmicutes, which in turn suppresses Bacteroidetes (Turnbaugh et al., 2008), and this higher ratio of Firmicutes/Bacteroidetes has been proposed as a biomarker and hallmark indicator for obesity (de Bandt et al., 2011, Zou et al., 2020). However, it is important to consider other factors such as physical activity and medication that could cause a variation in diversity of the gut microbiome, as this ratio does not always definitively denote obesity (Magne et al., 2020). Though, there are similarities between many of the microbiome-linked contributing factors of pathogenesis progression for diet-induced diseases. For example, a high-fat diet induces increased gut permeability that allows exogenously produced bacterial compounds (e.g. lipopolysaccharides) to diffuse through the intestinal barrier, which then can interact with immune cells and lead to inflammation (Cani et al., 2007, Nagpal and Yadav, 2017). However, diet isn’t the sole factor that can promote gut leakiness, and it seems that obesity in general causes an altered gastrointestinal state (Nagpal et al., 2018).

Chemotherapeutic Intervention and C. diff

Medication and antimicrobial drugs can also have drastic effects on the gut microbiome that invoke risk of secondary infections, allergies, and other diseases like obesity (Becattini et al., 2016). Though many of these prescribed treatments are necessary to combat infectious diseases, the aftermath may have more serious consequences. Not only does antimicrobial therapy disrupt the resident microbiome, but misuse, suboptimal dosing, and patient noncompliance can create conditions conducive to fostering antimicrobial resistance through selective pressure.

Clostridioides difficile (commonly called C. diff) infections are directly associated with antibiotic-induced dysbiosis in the gastrointestinal tract. C. difficile is part of the normal microbiota, however, as an opportunistic pathogen it can invade or colonize empty niches brought about by dysbiosis and cause potentially fatal episodes of pseudomembranous colitis, which is associated with abdominal cramping, pain, sepsis, and bouts of diarrhea (Kho and Lal, 2018). Infection and transmission of this organism has been well known for its prevalence in hospital settings, primarily affecting the elderly and immunocompromised, however, community-associated infections have recently increased in what was once considered low-risk populations (Rouphael et al., 2008, Baker et al., 2010, Hensgens et al., 2012, Benson et al., 2015, Johanesen et al., 2015). It is also alarming that this organism has resistance mechanisms to many commonly prescribed antimicrobials, including β-lactams, aminoglycosides, lincomycin, tetracyclines, and erythromycin (George et al., 1978), and more recently ‘hypervirulent’ strains have developed resistance to fluoroquinolones (He et al., 2013, Johanesen et al., 2015). C. difficile infections have an enrichment of fungi that associate with the bacteriome and perhaps antifungal therapy could help improve treatment success if administered in conjunction with specific antibacterial drugs (Stewart et al., 2019). Though, these infections can have lingering impacts on the gut microbiome, as further antimicrobial therapy that is usually required can perpetuate the situation. The inflammation as a result of the disease induces the production of antimicrobial peptides by epithelial cells and neutrophils which inhibit the growth of the natural resident commensal microbes (Leber et al., 2015).

While many events of gut dysbiosis are directly linked to the chemotherapeutic effects on microbes since they are prescribed to target microbes responsible for the infection, some medications which are meant to address other diseases, like antidepressants for mental health, have undesired effects on the microbiome (Maier and Typas, 2017). In the cases of multi-drug combinations (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, laxatives, proton-pump inhibitors (PPIs), etc.), it is not the number of drugs that affect gut microbiome diversity, but rather the types of drugs (Rogers and Aronoff, 2016). Though these scenarios become complicated as it is difficult to ascertain whether the alterations observed on the microbiome are from the drug’s mechanism of action, a downstream side effect, or originate from the condition that is being treated, and it is likely a complex combination of all factors for each disease and medication (Rogers and Aronoff, 2016, Maier and Typas, 2017, Jackson et al., 2018).

Fecal Microbiota Transplant

Although pharmaceutical drugs are of dire importance to treat various diseases, whether they are infectious in nature or not, other avenues must be pursued for those that may benefit from restoration of the gut microbiome. Probiotics and fecal microbiota transplant (FMT) can serve as viable options for the prevention and treatment of gut microbiome dysbiosis. Probiotics are considered foodstuffs with microorganisms, usually bacteria (many being lactic acid bacteria) and yeast, and their byproducts that have a beneficial effect on human health when introduced into the body. Many probiotics are commercially available to consumers in the forms of products like yogurt, kefir, buttermilk, sauerkraut, pickles, premade vitamin supplements and many others. Specifically, probiotics can be used for the treatment and prevention of many of the aforementioned gut microbiome dysbiosis-associated diseases, especially those induced by antibiotics (Kim et al., 2019). The beneficial microbes outcompete pathogens for resources or prevent them from establishing a niche in which to grow (Ouwehand et al., 1999).

In more extreme cases of gut microbiome dysfunction and disease, like those from C. difficile infection (CDI) in which antibiotics are ineffective and can potentially exacerbate the problem, other measures must be taken. Fecal microbiota transplant therapy takes a stool sample containing the gut microbiome from a healthy donor and relocates it into the infected patient’s colon. The introduced microbiota then helps move the gut microbiome towards homeostasis by restoring the structure of beneficial microbes and metabolites (Fujimoto et al., 2021). This procedure is usually reserved for those patients with recurrent CDI and has shown to be highly successful and is considered safer and more effective than prolonged antibiotic usage (Mattila et al., 2012, Cammarota et al., 2015), though is also being investigated for first-line treatment of CDI (Camacho-Ortiz et al., 2017). FMT has gained traction for its success and is being further considered as a therapeutic option in other treatment protocols, such as those for cancer patients undergoing cancer immunotherapy to help improve response or manage toxicity (McQuade et al., 2020), and individuals undergoing allogenic hematopoietic stem cell transplant for hematological disorders that experience graft-versus-host disease complications from it (Zhang et al., 2021). However, precautions must be taken for FMT, as the donor’s sample could potentially harbor other pathogenic microbes, like multi-drug resistant Escherichia coli, that can result in pathogenesis, further complications, and even death for the recipient (DeFilipp et al., 2019, Martinez-Gili et al., 2020). More comprehensive research and FMT trials must be performed in order to optimize this procedure to better match donors with recipients and to further understand the exact mechanisms of microbiome rehabilitation.

Conclusion

Gut microbiome intervention may be the key to future treatments of diseases associated with dysbiosis like IBD, diabetes, obesity, colorectal cancer, etc., and offers a viable alternative to many traditional pharmaceutical interventions. Though, the gut microbiome is plastic and continually changes with its host’s environment and lifestyle, so stabilization is constant work. Additionally, creating an ideal ‘cocktail’ of microbes that will maintain homeostasis when implemented can be challenge. While there are general members of the gut microbiome that exist at a constant level and show some correlation to normal health, there may not be a true ‘standard’ gut microbiome due to the vast differences between people across the world.  So, this type of therapy may require a more unique and individualized approach that depends on the disease and characteristics of both the host and their microbiome.

References