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Although many may be familiar with the fact that the human body contains more bacterial cells than human cells, the implications of our microbial collaborations are less frequently considered. The reality is that the microbiome, namely that of the gut, is a vast ecosystem of bacteria, fungi, and viruses engaged in symbiotic interactions with each other and with our tissues.
Although technological advances continue to provide us with further insights into the extent to which these microbes influence the function of the body in both health and disease, there is still no consensus as to what exactly a “healthy” microbiome looks like.
On the flipside, research has helped the scientific community to understand the microbial signatures associated with dysbiosis, or an unhealthy microbiome. Through these research endeavors, we have unearthed features of the microbiome associated with the onset and progression of various disease states including cancer.
Although classically cancer has been largely viewed as a disease driven by gene mutations, it is becoming increasingly clear that factors such as diet, lifestyle, age, and microbiome composition can each influence the number of tumor-promoting mutations that accumulate. Moreover, a healthy immune system is extremely effective at identifying and eradicating malignant (i.e., cancerous) cells. Therefore, factors that influence immune health and functionality will indirectly diminish one’s risk of developing cancer. It is now well-established that the gut microbiome plays a crucial role in the development of the immune system in infancy as well as the maintenance of proper immune function throughout adolescence and adulthood [1]. Research exploring the link between cancer and the microbiome indicates that the microbial composition of the gut can both directly affect cancer cell metabolism and gene expression, and also modulate the immune system’s ability to surveil for cancer cells [1].
An inextricable link exists between the microbiome and both the innate and adaptive arms of the immune system.
The innate immune systemis inherent to each individuals and is the foremost defense against pathogens that enter the body. It consists of both physical defense, in the form of the skin and mucosal barriers, as well as cellular defense in the form of immune cells that create an inflammatory response in an attempt to neutralize the pathogen [2].
Conversely, the adaptive immune system is developed by an individual over the course of their lifetime. Adaptive immunity responds to a pathogen by first identifying the invader, and then creating a response that is targeted specifically to that invader. The body then remembers this response so that subsequent exposures to the pathogen can be dealt with swiftly [2].
Early animal research in the field showed that mice without a microbiome exhibited deficits in immune function including a lack of mucosal barriers, under-developed lymph nodes, and changes in immune cell markers [3]. Importantly, all of these defects were ameliorated by giving the mice a microbiota transplant from normal healthy mice [3]. These experiments illuminated the importance of the microbiome in the maturation and education of immune cells in the body.
Subsequent experiments showed that the microbiome is absolutely essential for the differentiation of naïve lymphocytes (i.e. white blood cells) into various the subtypes needed to mount an effective immune response. Specifically, the researchers found that wild mice and adult humans both possessed all of the lymphocyte subtypes within the gut lamina propria, whereas laboratory mice and newborn humans lack these immune cell populations. Furthermore, unlike the laboratory mice, the wild mice showed resistance to influenza infection, and cohousing the wild mice with the laboratory mice resulted in microbial transfer to the laboratory mice, which then conferred protection against infection.
Indeed, research has demonstrated that the microbes within the gut directly influence the differentiation of naïve immune cells into specific lineages. For example, the microbiota influences the development of specific lymphocytes called Th9 cells that play a crucial role in anti-tumor immunity. Strikingly, animal studies show that antibiotic treatment leads to depletion of Th9 cell populations [4].
Studies also show that Clostridia and Bacteroides fragilispopulations can ameliorate colitis by inducing the differentiation of a specific type of T cell called Foxp3+ Tregs (i.e. regulatory T cells) in the colon [5]. Regulatory T cells are critical for maintaining balance in the immune system and preventing the development of autoimmunity. B. fragilis has also been shown to increase the levels of CD4+ T cells in the spleen, which also serve a regulatory role like Tregs [6].
Researchers believe that metabolites produced by the microbes in the gut are largely responsible for the effects on immune system function and maturation. For example, the short chain fatty acid (SCFA) butyrate produced by certain bacteria has been shown to be essential for CD8 T cell memory and survival [7]. CD8 T cells are crucial for the elimination of viruses and virus-infected cells in the body. Both butyrate and propionate, another short chain fatty acid, can lead to the induction of Tregs.
A large body of human studies also exists that supports the extensive crosstalk between the immune system and the microbiome. For example, the gut microbiome of neonates delivered via cesarean versus vaginally differs dramatically. Infants born via cesarean possess gut microbiomes similar to that present on the mother’s skin, whereas the gut microbes within vaginally-born infants correspond to the mother’s vaginal microbiome [8]. These differences in microbial composition can still be detected seven years after birth, with higher levels of butyrate-producing Clostridia species in the vaginally-born children [8].
As a result, children born via cesarean have a dramatically increased likelihood of developing infections during the first year of life, as well as increased risk of developing inflammatory and autoimmune diseases later in life including inflammatory bowel disease (IBD), food allergies, diabetes, asthma, and arthritis [9]. By the same mechanism, early exposure to antibiotics also increases a child’s risk of developing IBD, cancers, and obesity as they age [1].
Breastfeeding, which is instrumental in the cultivation of a healthy infant microbiome, is also associated with decreased risks of developing autoimmunity and inflammatory conditions [1]. Thus, the microbiome-immune interactions during and immediately following birth profoundly shape the health of the child over his or her lifetime.
With respect to cancer, there are two primary mechanisms by which the immune system is believed to influence cancer onset and progression.
- antigens are molecules that are recognizable by the immune system
- antigens present on bacteria can mimic antigens present on tumor cells, thereby improving the anti-tumor immune response
- commensal viruses can also express antigens that mimic tumor antigens
- direct: the secretion of a factor that can cause a cell to become cancerous (e.g., the production of the small molecule colibactin by certain strains of E. coli can induce DNA damage and incite colorectal cancer)
- indirect: modulation of cancer immunosurveillance, immune cell function, and cytokine production (e.g. microbially-produced SCFAs modulate immune cell gene expression and control the inflammatory response)
Although many of the mechanistic details of the interactions between tumors and both the local microbiome within the tumor microenvironment as well as the gut microbiome remain elusive, the impact of microbes on cancer progression and prevention is becoming increasingly more clear.
Importantly, not only does the microbiome influence the immune system itself, it also impacts the efficacy of immunotherapies in the treatment of cancer, namely immune checkpoint inhibitors (ICIs). For example, in lung cancer patients, the use of antibiotics greatly decreased both disease-free survival and overall survival, suggesting strong impairment of treatment efficacy [1]. Moreover, analysis of stool samples from patients who responded to the ICI treatment revealed that responders possessed significantly higher levels of Akkermansia muciniphila compared to non-responders [1]. A. muciniphila plays a critical role in the maintenance of gut barrier integrity and metabolic health. In addition to A. muciniphila, Bifidobacterium longum, Collinsella aerofaciens, Enterococcus faecium, and Ruminococcaceaealso showed a positive association with response to ICI therapy [1].
The gut microbiome’s influence over the establishment and maturation of immunity is critical beginning at the day of birth. Exposures that compromise the nascent microbiome of the neonate can result in lifelong changes to immunity and increased risk of developing health issues including food allergies, asthma, autoimmunity, and diabetes. Moreover, the microbes within the gut can either positively or negatively impact the immunosurveillance mechanisms that are responsible for finding and eliminating cancer cells in the body before tumor formation. Additionally, pathogens within the gut ecosystem can create metabolites that directly promote cancer onset and progression, while symbionts can create metabolites that can counter these damaging effects. Identification of the roles specific species of bacteria play in the gut-immune axis will facilitate the development and implementation of targeted dietary, supplemental, and pharmaceutical strategies to selectively bolster or inhibit key microbes to achieve meaningful clinical outcomes in immunology, oncology, endocrinology, and beyond.
Author:
Dr. Alexis Cowan, a Princeton-trained PhD specializing in the metabolic physiology of nutritional and exercise interventions.
Follow Dr. Cowan on Instagram: @dralexisjazmyn
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