The National Cancer Institute in 2014 estimates that 1.66 million people in the United States were diagnosed with cancer in 2013 and as many in 2014.1 These individuals likely received multiple therapies, either curative or palliative, to combat or manage their disease. Although such treatments may serve to prolong life, many lead to distressing symptoms. Symptoms often co-occur and have been hypothesized to share biological underpinnings such as epigenetic changes and immune dysregulation.2 Symptoms present across multiple cancer populations include pain, depression, fatigue, sleep disturbance, and cognitive issues and have been collectively termed “psychoneurologic symptoms” (PNSs).2 Cancer, depending on type and stage, have other reported symptoms such as nausea, vomiting, and bloating associated with many gastrointestinal (GI) cancers.3
The relationship between symptoms and markers of inflammation has been shown in multiple studies4; however, the results have not been entirely consistent, particularly in those with human participants. Other potential biological mechanisms have been implicated, including the possible relationship of symptoms and alterations in the gut microbiome.5 Understanding mechanisms involved in the genesis and persistence of symptoms is an important step in developing strategies to combat the manifestation and progression of symptoms. In this article, we discuss the emerging evidence that points to a possible role of the microbiome in cancer symptoms. This review details examples from extant research for the emerging role of the microbiome in cancer research and focuses on the relationship between the microbiome and symptoms often reported by individuals with cancer.
The relationship between humans and microorganisms has been evolving over millennia and is theorized to play a key role in health and illness.6 Recently, this relationship has become a burgeoning area of inquiry. Technological advances such as metagenomics and next-generation sequencing permit the study of the various microbiota of the human body at a previously unseen scale.7 A “healthy” microbiota is defined by high diversity, optimal quantities of beneficial microbes, and an ability to resist change under physiological stress; in contrast, microbiota associated with disease is defined by lower species diversity, fewer beneficial microbes, and/or the presence of pathobionts.6
Microbes colonize many niches of the human body. For example, 100 trillion bacteria inhabit the distal gut,8 and microbes living on and within the human body far outnumber human cells. This colonization is initiated at birth and is altered throughout the life span.6 The symbiotic relationship between human and microbe is also dynamic; in fact, when in homeostasis, this relationship is mutualistic, but when the balance of organisms is disrupted, “dysbiosis” occurs. Dysbiosis is defined as a “state of altered microbial community that disrupts the symbiotic relationship and causes or contributes to disease/dysfunction.”9 In such a case, invading pathogens may overwhelm the immune system or replace “normal” flora. When dysbiosis persists, disease is imminent, and the outcome may range from an upset stomach to other diseases such as irritable bowel syndrome, diabetes, and cancer.6,8 It is becoming evident that this “forgotten organ,” the microbiome, is shaped by a delicate balance of bacteria, fungi, and archaea that are critical to human health.
The species and amount of microbes vary from individual to individual, yet studies have demonstrated there is some commonality among the microbiota of humans. The largest numbers of microbes dwell within the human gut, and the gut microbial count increases descending the GI tract. There is approximately a 1010 concentration of microorganisms per gram of stool living in the human colon that consists of 1000 or more bacterial species. Mutualism, 2 organisms of different species that exist in a relationship in which each benefits from the activity of the other, is maintained in the gut by 3 key mechanisms: (1) the microbes (by releasing nutrients from foods and creating a barrier against pathogens), (2) the gut epithelium (by initially detecting invading pathogens), and (3) immune cells in the gut wall (by launching an inflammatory response).6 In addition to immune cells responding to invading pathogens via inflammatory response, normal flora contain organisms that may induce inflammation.8 However, both the innate and adaptive immune systems have “learned” to tolerate commensal or mutualistic microbes and are able to identify and eliminate microbes that may disrupt homeostasis.6 Generally, most interaction between the human immune system and microbes occurs within the GI system. Within this system, microbes have learned to fend off disease by competing for space and nutrients as well as initiating immune response.6
Microbiota and Cancer
The exact mechanism(s) by which the gut microbiota contributes to cancer is not fully known; however, the gut microbiota may play an important role via several paths.10 First, there may be differences in the gut microbial content that promote carcinogenesis. For example, human microbiome studies have revealed significant differences in the relative abundance of certain microbes in cancer cases compared with control subjects.11 Second, there is a well-known association between gut microbiota and inflammation and metabolism, which are 2 characteristics of cancer.12 In this path, the gut microbiota metabolizes plant-derived foods into biologically active compounds that may be carcinogenic.12
Research in this area has focused on the relationship between gut microbiota and colorectal cancer (CRC), and studies have shown that alterations in gut bacteria have been associated with the development of CRC. Indeed, a study by Arthur et al13 found that the gut microbiota of mice infected with colitis or CRC clustered apart from the control subjects. In addition, infected mice had a decreased number of microbes and microbial diversity compared with uninfected mice; however, no difference was noted between mice with colitis and CRC. This indicates there may be a difference in the gut microbiota between sick and healthy individuals, and there may be a link between colitis and CRC. Similarly, after analyzing stool samples in human patients, researchers found alterations in the gut microbiota (enrichment in some species, whereas a depletion in others) were strongly associated with adenomas and carcinomas.14 Recently, Schwabe and Jobin15 found CRC risk was associated with decreased bacterial diversity in feces; depletion of gram-positive, fiber-fermenting clostridia; and increased presence of gram-negative, proinflammatory genera Fusobacterium and Porphyromonas. This finding suggests inflammation may be responsible for microbial “shifts” in the gut.
In addition to CRC, other cancers, such as pancreatic, laryngeal, and gallbladder, and cancer-related conditions, are being explored in relationship to the gut microbiota.16,17 For example, a study by Farrell et al18 found individuals with pancreatic cancer had significantly decreased abundance of Neisseria elongata and Streptococcus mitis compared with individuals without pancreatic cancer. As a result, researchers indicated that these microbes may be potential biomarkers of pancreatic cancer. Similarly, Salmonella has been identified as an important factor for gallbladder cancer due to Salmonella’s influence on secondary bile acid, which has been linked to tumor promotion.19 Finally, graft-versus-host disease, a major complication that can occur after bone marrow transplantation, has been associated with shifts in the gut microbiota.16 Indeed, Jenq et al16 found patterns in humans similar to those of murine models following transplantation. This study noted that Lactobacillus abundance mediated graft-versus-host disease.16 In summary, although evidence is emerging in this area, more research is necessary to elucidate the role of the gut microbiota in cancers other than CRC.
Because of the prevalence of digestive problems in patients with cancer, researchers examining gut microbiota have focused on symptoms such as abdominal pain and eating disturbances.5 Researchers have also started to examine the role of the gut microbiota in cancer cachexia—a condition that involves metabolic dysregulation leading to unintentional weight loss, loss of functioning, and decreased quality of life. Treatment is often delayed or even halted secondary to cachexia, which may increase levels of cortisol and inflammatory cytokines.20 Dysbiosis is speculated to be involved in the metabolic disruption of cachexia, but more research is needed in this area, particularly in humans. Indeed, in a murine study of cachexia, oral supplementation with Lactobacillus reuteri and Lactobacillus gasseri reduced the levels of cytokines interleukin 4 (IL-4), IL-6, and monocyte chemoattractant protein 1.20 Nutrition is a major concern for individuals with cancer, and the gut microbiota plays a role in linking malnutrition to outcomes such as diarrhea, inflammation, and weight loss.21 Comorbidity exists between stress-related symptoms and GI disorders.5 These symptoms include the constellation of PNSs of cancer.
Gut-Brain Connection and Symptoms
The discovery of the bidirectional signaling between the brain and the gut microbiome has resulted in new research on central nervous system disorders, including autism, depression, anxiety, and persistent pain.22 Significantly, research has found that tryptophan and the 5-HT system are involved at every level of the brain-gut-microbiome axis.23 In addition, animal models have revealed that gut microorganisms can activate the vagus nerve, which mediates brain and behavior, and that alterations in gut microbial composition are associated with marked changes in behaviors relevant to mood, pain, and cognition.24 This evidence suggests that the bidirectional pathway of communication between the microbiota and the brain is a critical component in the development of health and disease.5 As this line of research is emerging, evidence is accumulating to support relationships among “gut-brain” biological mechanisms (Figure).
Recent studies with human participants support the relationship between gut-brain interactions, mood, and behavior. Through activation of hormone and immune system responses, the status of the gut microbiome influences mechanisms of the hypothalamic-pituitary-adrenal axis such as inflammation activation, which may affect symptoms such as sleep quality and reactivity to stress.25 The constellation of PNSs has established links to inflammation across various cancer populations, including both solid tumor cancers and hematologic cancers.2,26
Because of the influence of the gut microbiota on regulation of stress hormones and the immune system, alterations in gut microbiota may play an important role in symptoms experienced by people with cancer. Stress increases gut permeability, which allows bacteria to migrate across the intestinal mucosa and affect the immune and neuronal cells of the enteric nervous system.27 Microbiota may influence the central nervous system via the immune system as a result of this increased permeability.27 Research has shown that site-specific symptoms of cancer may be related to the origin of malignancy and that a constellation of PNSs, including depression, fatigue, pain, and cognitive dysfunction, may affect individuals with a variety of cancers. In addition to being prominent across cancer populations, PNSs are reported by individuals many months to years after the cessation of cancer treatments. Therefore, examining potential biological markers suspect in the development and/or persistence of PNSs is of importance.
Depression is a multifactorial disorder influenced by a combination of factors. Depression may represent a maladaptive response or an exacerbated immune response.28 One study by Naseribafrouei et al29 found a significant relationship between human fecal microbes (a surrogate for the gut microbiota) and depression in humans. Other studies have shown that higher levels of Bacteroidetes and lower levels of Lachnospiraceae were significantly related to depression. Furthermore, Gareau et al30 found that germ-free mice also exhibited impaired memory and cognitive abilities. Anxiety and depressive behaviors have been associated with alterations in microbiota in multiple animal models.31–33 This may occur because of alterations in microbiota, which modulate plasticity-related, serotonergic, and GABAergic signaling systems in the central nervous system.27
In addition to depression, fatigue affects approximately 80% of individuals with cancer who receive either radiation or chemotherapy.34 This symptom can be severe and generally occurs with other PNSs. Emerging evidence suggests that microbiota may be associated with exercise capacity and fatigue.35 For example, a study of gnobiotic mice colonized with Bacteroides fragilis demonstrated enhanced exercise capacity compared with germ-free mice.35 In a double-blind, randomized controlled trial, individuals with chronic fatigue syndrome had reduced plasma levels of C-reactive protein and inflammatory cytokines (tumor necrosis factor and IL-6) after receiving Bifidobacterium infantis supplements.36 Although the association between inflammation and fatigue was not reported in this study, it is well established in the literature. Thus, replication of this study would inform how well B infantis reduces fatigue. This could provide useful evidence to develop and test targeted interventions to mitigate fatigue.
Similar to depression and fatigue, gut microbiota alterations have been associated with the level and perception of pain.37 For example, recent literature implicates dysbiosis of the gut microbiome as a key player in central sensitization leading to chronic pain conditions as well as cancer-related pain.38 Other studies have shown administration of Lactobacillus strains contributed to reduction of pain perception in rodents.39 Also, germ-free mice have demonstrated lower sensitivity to inflammatory stimuli than that of conventional mice, thereby indicating the necessity of commensal microbes for hypernocioception.39 Thus, understanding the relationship between the gut microbiota and pain has clinically significant implications for symptom management in patients with cancer.
In animal studies, gut microbial colonization with specific bacteria has also been linked to cognition, motor control, and behavior. For example, in a mouse model, infection with Citrobacter rodentium caused stress-induced memory dysfunction in mice at 10 and 30 days after infection, and probiotics administered before and during the infection prevented memory dysfunction.30 Similarly, other studies have shown that probiotics administration considerably improved the impaired spatial memory in diabetic animals. In fact, probiotics supplementation in diabetic rats recovered the declined basic synaptic transmission and further restored the hippocampal long-term potentiation.40 With respect to humans, emerging literature in humans suggests an association between the microbiome and cognitive outcomes in individuals with chronic illnesses. For example, specific bacterial families (eg, Alcaligeneceae, Porphyromonadaceae, Enterobacteriaceae) are strongly associated with cognition and inflammation in hepatic encepelopathy.41 Future studies are necessary to draw conclusion about these associations and to determine these relationships in individuals across the cancer spectrum.
Understanding the mechanisms influencing dysbiosis and the relationships between the gut microbiota and symptoms in animal and human models informs decision regarding targeted, individualized interventions to mitigate the effects of dysbiosis. Of the biological milieu, the gut microbiome is most directly affected by lifestyle elements, including dietary intake, which contribute to the composition and metabolism of the gut microbiome.42,43 The 3 main phyla of bacteria inhabiting the large intestine (Bacteroidetes, Firmicutes, and Actinobacteria) have enzymes that degrade complex dietary substrates.43 Degradation of macronutrients (carbohydrates, protein, and fats) initiates fermentation, which produces weak acids such as acetate.43 This acid lowers intestinal pH, which impacts microbial composition and affects host health.43 Diet has a major influence on microbial metabolites of the gut microbiota. In addition to microbial metabolites, diet also influences the amount and types of bacteria present in the gut.33 Evidence supports the possibility of symptom mitigation by increasing the amount and diversity of beneficial bacteria. Individuals whose diets are higher in fiber from fruits, vegetables, and whole grains are more likely to have more diverse and numerous microbes than individuals whose diets include more processed foods.42
Several novel interventions may directly affect the microbiome, although further research is needed to confirm these results from animal and human trials in individuals with cancer. One diet-related modality that theoretically affects the microbiome is intermittent calorie restriction (ICR). Research from animal models and humans support the beneficial effects of ICR on multiple outcomes including increased survival, reduced incidence of tumors and other diseases, and delayed onset of these diseases to later ages in laboratory rodents.44 Although the mechanisms for the salutary effects of ICR on disease onset, including cancer, are not yet clear, 1 pathway of increasing interest is the mechanistic target of rapamycin (mTOR) signaling pathway.45 Formerly known as mammalian target of rapamycin, mTOR is a protein that contributes to a large number of human diseases, including cancer, obesity, type 2 diabetes mellitus, and neurodegeneration.46 Although it was first thought that the effects of ICR on tumor progression were a secondary response to decreased cell growth, it is now recognized that this process actually impinges on key intracellular signaling pathways, particularly that of the mTOR complex 1 (mTORC1).47 Fecal microbiota transplantation is another intervention that may have potential beneficial effects on inflammation and outcomes including psychological conditions.48 Although research to date is not extensive, there are small studies supporting that fecal microbiota transplantation has had dramatic effects on obesity and metabolic parameters; thus, further study in individuals with cancer is needed to examine the effects on cancer disease and patient-related outcomes.49
Conventional nutritional interventions that include a diet high in fruits, vegetables, and whole grains to stabilize gut microbiota may improve health outcomes in individuals with cancer.43 However, proper diet and nutrition are a challenge for many individuals with cancer because of depression, anxiety, changes in taste, lack of appetite, and nausea.50 Because of the adverse effects of cancer treatment, nutritional supplementation may help individuals acquire nutrients that they do not receive from their regular diets. Nutraceuticals are supplements that include prebiotics (to aid the growth of beneficial bacteria in the GI tract) and probiotics (to increase the number of live, beneficial bacteria in the GI tract). Supplementation with prebiotics may be useful in maintaining microbial diversity.43 In addition, studies have demonstrated that probiotic treatment improves depressive behavior in mice.30,51 Another study, which tested stress response in germ-free, specific pathogen–free, and gnotobiotic mice, found that administration of B infantis mitigated the exaggerated stress response of germ-free mice.52 A recent study in rats showed administration of Lactobacillus farciminis prior to restraint (which induces a stress response) reduced intestinal permeability and prevented hyperactivity of the hypothalamic-pituitary-adrenal axis.53 Another study by Gareau et al54 found that the administration of the same probiotic normalized basal stress hormone levels of rat pups stressed by maternal separation. It remains uncertain if this would be the case in humans and warrants exploration.
A new term, “psychobiotics,” encompasses the possibility of psychological/behavioral effects of prebiotics/probiotics. It is hypothesized that probiotic strains act as preclinical delivery vehicles for neuroactive compounds and decrease proinflammatory cytokines and reduce hypothalamic-pituitary-adrenal axis activity. Such a profile is far broader than that of a simple anti-inflammatory molecule.55
Other targeted interventions aimed at reducing inflammation and stress may also mitigate dysbiosis via the bidirectional feedback loop of the gut-brain axis. These may include interventions such as mindfulness interventions and acupuncture. Mindfulness interventions include modalities such as mindfulness-based stress reduction and mindfulness-based cognitive therapy.56 These modalities include self-management strategies. Similarly, acupuncture is a traditional Chinese medical modality believed to correct imbalances in the flow of energy (qi) through channels known as meridians.57 Acupuncture has been shown to decrease levels of proinflammatory cytokines and increase opioid peptides.57 Thus, future research should explore how reducing stress and inflammation may impact the gut microbiota, influence the biofeedback of the gut-brain axis, and improve health outcomes.
The possible relationship between the microbiome and cancer-related symptoms raises several important research questions. First, is there a relationship between gut microbiota and cancer symptoms? Second, could interventions that aim to enhance nutrition and reduce stress mitigate dysbiosis? Third, could mitigating dysbiosis prior to cancer therapy ameliorate distressing symptoms during and following treatment? Answers to these questions would help develop interventions that may increase the quality of life for individuals with cancer. Nurses are first responders to patients, families, and caregivers and play a central role in symptom management. Understanding the relationship between the microbiome and cancer will enable nurses to implement low-cost, effective therapies that help individuals with cancer achieve optimal quality of life.
The mechanism(s) by which gut microbiota may be associated with cancer and its symptoms is a promising area of biobehavioral nursing scientific inquiry. A growing body of research supports the associations between the gut microbiome and GI symptoms as well as the presence of a “gut-brain” connection and PNSs. However, further study is needed to develop the associations at the preclinical level in human descriptive studies, as well as in theoretically based interventions that alter gut microbiota to mitigate microbial dysbiosis. This review described examples of extant research that supports the emerging role for the microbiome in oncology nursing science.
The authors would like to thank Debra McDonald for her editorial support on this article.
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