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The bacteria, fungi, and viruses that reside in and on our bodies, collectively known as the microbiome, play vital roles in metabolic health, gene expression, and healthy aging. On the flipside, these microbial communities can also influence disease development and progression.
Indeed, not only has the composition of the gut microbiome been associated with the onset of various pathologies including cancer, but it also influences the efficacy of treatments like immunotherapeutics. For this reason, the gut microbiome has become a major research focus in the field of oncology over the past few years.
The labile nature of the gut microbiome makes it a good target for modulation via approaches such as dietary manipulation, prebiotics, probiotics, and fecal matter transplants (FMTs). However, given the sheer number of species and strains of bacteria present in the gut and the complexities underlying their interactions, the primary roadblock to therapeutic microbiome modulation is understanding exactly which bacteria to support and which to select against.
The roughly 100 trillion bacteria present in the gut create thousands of metabolites that can directly interact with our tissues and modulate their functions. The two major phyla of bacteria present in adults are Firmicutes and Bacteroidetes.
The microbiome likely begins developing in utero upon exposure to the maternal microbiome. After birth, the consumption of breast milk, which is rich in prebiotic molecules known as human milk oligosaccharides (HMOs), greatly boosts microbial density in the gut. Specifically, these HMOs support the growth of Bifidobacteria which help to establish immunity in the neonate.
Over time, the microbial composition shifts towards that observed in adults, which possess relatively stable microbiomes. However, diet, exposures to antibiotics and other drugs, changes in environment, physical activity levels and other factors greatly influence the quality and stability of the microbiome.
Figure 1. Changes in microbial alpha and beta diversity over the course of a life time and the factors that influence these changes [1]
One important feature of the microbiome is diversity. There are two primary types of diversity that researchers reference when assessing the microbiome: alpha diversity and beta diversity.
Alpha diversity is the diversity of species present within one individuals, whereas beta diversity is the diversity of species between individuals. Various disease states are closely associated with low diversity including cardiovascular disease, autoimmunity, obesity, diabetes, and neurological conditions. Generally, a state of low diversity, low stability, and overrepresentation of harmful bacteria is referred to as dysbiosis. Dysbiosis can result in unfavorable immune modulation that can drive inflammation both locally and throughout the body.
Among the diseases whose development is directly linked to the microbiome are cancers of the gastrointestinal system and liver, with colorectal cancer (CRC) being the most significant. As the third most common type of cancer, CRC is widely prevalent and has a high mortality rate. Research suggests that processed food consumption coupled with low intake of fiber in the form of fruits and vegetables is a primary risk factor for the development of CRC.
There are a few species of bacteria whose levels closely correspond to disease progression. Namely, populations of the bacterium Fusobacterium nucleatum increase as CRC progresses into more advanced stages [2]. Interestingly, F. nucleatum has not only been shown to enhance tumor cell proliferation, but also renders tumor cells more resistant to chemotherapy [2]. In fact, clinical research has shown that the abundance of F. nucleatum corresponds to reduced overall survival.
Furthermore, levels of Atopobium parvulum and Actinomyces ondontolyticus also appear to track with disease severity, and increases in the sizes of their populations are only detectable in individuals with multifocal tumors, not solitary tumors [2]. Thus, these bacteria may also be useful clinical biomarkers to assess the extent of CRC progression in diagnosed patients.
Changes in the populations of other bacteria may also serve as early warning signs of increased CRC risk. Among these are bacteria associated with gut mucosal integrity. The mucus layer of the gut lies at the interface of the gut microbiome and the body, and helps to regulate intestinal permeability to ensure that harmful microbes and toxic metabolites cannot enter into the bloodstream. Thus, a healthy mucosal layer is essential for preventing both local and systemic inflammatory responses. For example, levels of Akkermansia muciniphila—a species that resides in the mucus layer of the gut—are closely associated with enhanced gut barrier integrity and decreased permeability, and higher levels of these microbes are associated with improved outcomes in multiple types of cancers and enhanced efficacy of some immunotherapeutic treatments like immune checkpoint inhibitors (ICIs) [3].
In addition to the direct impact of the microbiome of the efficacy of treatments like immunotherapies, the use of certain drugs also has a strong effect on whether a treatment will be effective. For example, multiple clinical studies have shown that the use of antibiotics negatively impacts treatment efficacy in patients receiving ICIs for lung cancer, kidney cancer, and skin cancer [4]. Antibiotic use prior to ICI administration resulted in lower alpha diversity, which was a biomarker of overall survival in patients who were not exposed to antibiotics prior to treatment [4].
Other drugs also exert harmful effects on the gut microbiome. Perhaps the most widely used and well-studied of these are proton pump inhibitors (PPIs). PPIs are drugs prescribed to individuals with acid reflux or similar conditions, and their long-term use is closely correlated to increased rates of gastric cancers. Research suggests that PPI use corresponds with increased levels of Streptococcacae and Micrococcaceae but the precise roles these bacteria play in disease pathogenesis is unclear [5]. However, clinical studies indicate that PPI use may reduce the efficacy of ICI treatment for melanoma by half, as well as decreasing rates of overall survival [5].
Another class of drugs that appears to impart harmful effects on the microbiome and ICI efficacy are corticosteroids. Corticosteroids are prescribed for a range of inflammatory conditions as they exert both anti-inflammatory and immunosuppressive effects. In the setting of cancer, daily corticosteroid use reduced both ICI efficacy and overall survival [6]. Additionally, their use appears to create significant changes in gut microbial composition; however, most of these data are from animal models. Thus, clinical studies are required to assess the effect of this class of drugs on the human microbiome.
The microbiome possesses various self-regulatory mechanisms to help maintain a healthy homeostasis. These include the production of metabolites and peptides that inhibit the growth of harmful pathogens, as well as the production of short chain fatty acids (SCFAs) from the fermentation of indigestible carbohydrates (e.g., fibers, polyphenols, HMOs).
Not only do these SCFAs serve as important energy sources for colon cells, but they also appear to selectively inhibit the growth of cancerous cells in the gut. In this way, microbiome optimization geared towards enhanced production of SCFAs is emerging as an important strategy in the treatment and prevention of CRC.
Therapeutic microbiome modulation is an emerging area of study that is geared towards identifying either beneficial or harmful bacterial populations and enhancing or inhibiting their growth, respectively.
For example, the consumption of HMO prebiotics is known to bolster levels of Bifidobacteria in the gut, which can help fight irritable bowel syndrome, and modulate the immune system to reduce inflammation at the level of both the gut and whole body.
Meanwhile, certain species of Lactobacillus can outcompete pathogens like H. pyloriand in doing so prevent pathogen colonization of the gut. In this way, understanding the specific roles of key bacteria in the gut ecosystem is of primary importance as we make dietary recommendations and design drugs and nutraceuticals geared towards creating specific shifts in microbiome composition.
Figure 2. Methods of microbiome modulation and assessment for clinical use [1]
The lability of the gut microbiome and its strong influence over immune function, metabolism, gene expression and more makes it an attractive target for both health optimization and disease treatment.
Indeed, a strong link has been observed between microbiome composition and obesity, autoimmunity, diabetes, and certain cancers, namely colorectal cancer. In the case of colorectal cancer, research implicates the gut microbiome not only in disease severity and rate of progression, but also in treatment efficacy.
Moreover, the use of drugs that negatively impact the microbiome, such as antibiotics, proton pump inhibitors, and corticosteroids, are also associated with decreased treatment response and reduced overall survival in patients with multiple cancer types.
Moving forward, the targeted modulation of the gut microbiome through the use of key prebiotics, probiotics, nutritional strategies, and fecal matter transplants can be leveraged to modulate gut microbial composition for improved clinical outcomes and disease prevention.
Written By:
Alexis Cowan, Ph.D.
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