Gut microbiota-immune-brain interactions in chemotherapy-associated behavioral comorbidities

Abstract

Increasing scientific attention is focused on the gut-brain axis, including the ability of the gastrointestinal (GI) tract to modulate central nervous system function. Changes in the intestinal microbiome can influence affective-like behavior, cognitive performance, fatigue, and sleep in rodents and humans. Cancer patients receiving chemotherapy experience similar negative behavioral changes and concurrent GI symptoms. These chemotherapy comorbidities can be long-lasting and reduce patients' quality of life and motivation to comply with treatment. This review summarizes the clinical and preclinical evidence supporting a role for the intestinal microbiome in mediating behavioral comorbidities through peripheral immune activation in cancer patients undergoing chemotherapy. In addition, evidence suggesting that targeted modification of the intestinal microbiome during cancer treatment could ameliorate associated behavioral comorbidities is reviewed.

Introduction

Cancer patients are often treated with chemotherapy, which targets cellular division mechanisms in order to impair cancer cell proliferation. Most chemotherapies lack the specificity to solely target cancer cells, and as a consequence, result in negative side effects throughout the body including behavioral and gastrointestinal (GI)-related comorbidities. As cancer survival rates continue to increase,¹ understanding the pathophysiology underlying these comorbidities will inform treatment options, thereby improving many lives.

While the ability of the central nervous system (CNS) to affect GI function has a long history in physiology and medicine, the ability for intestinal microbiota (the natural community of bacteria, archaea, fungi, other single-celled eukaryotes, and viruses populating the GI tract) to influence CNS function and behavior is relatively novel.² Altered composition of the GI microbiota has been observed in CNS diseases such as autism, Parkinson's disease, schizophrenia, and affective disorders.²

The intestinal microbiota is hypothesized to influence the brain through multiple pathways simultaneously.² One such pathway is the peripheral immune system. The behavioral and cognitive problems that have been linked to either altered intestinal bacterial community structure or changes in peripheral inflammation in other disease models are similar to those observed after chemotherapy treatment. However, the relationship between the CNS and GI tract (especially those mediated by the immune system) remains to be determined in the context of cancer treatment. In this review, clinical and preclinical evidence supporting a role for the gut-immune-brain axis in chemotherapy-associated comorbidities is summarized. We also consider targeting GI symptoms through the use of microbial interventions as a cost-effective alternative for ameliorating the behavioral comorbidities associated with chemotherapy.

1. Chemotherapeutic consequences on behavior and the GI tract

1.1 Chemotherapy and behavior in cancer patients

Cancer patients who have received chemotherapy during their course of treatment often present with symptoms of anxiety, depression, cognitive impairment, fatigue and sleep disturbances.^3-6 Prevalence of depression in these patients varies with reports ranging from 3 to 53%.^{3, 7, 8} Depressive symptoms are also associated with anxiety, which is reported in 20-33% of chemotherapy-treated patients.³ Traditional antidepressant treatment of these symptoms are often overlooked and ineffective.⁹ Cognitive performance is reduced by 40% on average after chemotherapy treatment in domains including: executive function, learning and memory, visuospatial skills, attention, language, and concentration.^{4, 10} Symptoms of fatigue increase during chemotherapy treatment, ranging from 28-90%,⁵ and about one-third of cancer patients report sleep disturbances (inability to fall/stay asleep, daytime dysfunction, and reduced sleep quality), which ar exacerbated by chemotherapy treatments.⁶

Subjective and objective behavioral symptoms may be influenced by factors outside of chemotherapy treatment, such as tumor location, tumor stage, and patient demographics.^{11, 12} For example, symptoms of fatigue and sleep disturbances may precede and be exacerbated by chemotherapy treatments.^{6, 12} Due to the treatment heterogeneity of cancer populations in clinical studies, there often is not enough statistical power to delineate the specific effects of most chemotherapeutic drugs on behavior. However, taxane-based chemotherapies, in particular, are associated with increased severity and duration of psychological symptoms after cancer treatment.¹³

While these behavioral symptoms may be most severe during treatment, they can last well over 5 years,¹⁴ and are associated with poor quality of life.⁹ In addition, these comorbidities decrease efficiency of completing simple or work-related tasks, reduce compliance with treatments, and ultimately increase mortality.⁹ Therefore, novel strategies to reduce them are necessary.

1.2 Chemotherapy, behavior, and the brain in rodent models

Mice treated with chemotherapeutic agents (e.g., taxanes, antimetabolites, alkylating agents) mirror behaviors hypothesized to be homologous to anxiety, depression,^{15, 16} and cognitive impairments observed in cancer patients.^{17, 18} Most rodent studies report increases in these negative behaviors, although the duration and magnitude of behavioral changes vary.¹⁹ The effects of specific chemotherapeutic drugs on cognition and, to a lesser extent, affective-like behaviors in rodents have been summarized previously.¹⁹

Fewer studies have used rodent models to measure fatigue and sleep disturbances after chemotherapy. Treatment with a combination of alkylating and antimetabolite chemotherapies as well as taxanes chronically decreases both motivated (wheel running) and passive (horizontal movement) activity in mice.^{20, 21} In another study, chemotherapy treatment acutely increases sleep during the dark phase when mice are most active; however, these sleep bouts are fragmented and low-quality.²² Although different chemotherapeutic agents, including those that supposedly do not cross the blood-brain barrier, impair various aspects of cell proliferation, they induce similar changes in behavior.¹⁹

These behavioral parallels to cancer patients observed in animal models allow researchers to systematically investigate the underlying physiological changes within the CNS after chemotherapy treatment. Decreases in neurogenesis and general brain cell proliferation are reported after treatment with nearly all chemotherapeutic drugs.^{18, 19} In addition, some drugs (alkaloids, alkylating agents, and taxanes) alter neurotransmission and cause oxidative stress in the brain, resulting in cellular dysfunction within the CNS.²³ Finally, numerous chemotherapies (alkaloids, taxanes, antimetabolites, and topoisomerase inhibitors) increase markers of inflammation within the CNS.^{18, 19} For example, treatment with an alkylating chemotherapy activates astrocytes and microglia, the resident innate immune cell of the CNS, in a mouse model of chemotherapy-associated neuropathy.²⁴ Furthermore, expression of pro-inflammatory cytokines, such as IL-6 and TNFα, is acutely increased in the CNS after chemotherapy treatment.²⁵ However, not all studies report increases in microgliosis and local cytokine production, likely due to differences in the markers and chemotherapeutic drugs used and in the durations between treatment and analyses.²⁶ While behavioral deficits may be caused by changes in several neurophysiological mechanisms simultaneously, for the purpose of this review, we focus on neuroinflammation as the most relevant to the gut-immune-brain axis in the context of chemotherapy.

1.3 Chemotherapy and the GI tract in cancer patients

In addition to CNS symptoms, cancer patients receiving various chemotherapies experience debilitating GI side effects (diarrhea, nausea, abdominal cramping, and anorexia)²⁷ that are described as worse than those of cancer. Much like behavioral comorbidities, GI symptoms lead to delays in and poor adherence to cancer treatments, extreme hospital costs, and occasionally death.²⁷ These chemotherapy-induced GI symptoms are attributed to disruption of the natural intestinal microbiota as well as inflammation and ulceration of the intestinal mucosal cell lining (mucositis).²⁸

The GI tract is host to a complex community of symbiotic microorganisms, increasing in density from the proximal to distal regions. These microbes help to maintain the intestinal epithelial barrier, regulate host immunity and metabolism, and modulate brain function.² Few studies have investigated the effects of chemotherapy on fecal microbial composition and are limited by low sample size as well as heterogeneous tumor types and chemotherapeutics. Consequently, the conclusions remain broad: acute chemotherapy reduces bacterial diversity, marked by decreased Lactobacillus, Enterococcus, and Bifidobacterium, but increased Escherichia and Staphylococcus.^29-32 Conflicting effects on Bacteroides are reported. Notably, a drastic decrease in known butyrate-producing genera, Faecalibacterium and Roseburia, is observed in one study.²⁹ Butyrate is an anti-inflammatory agent of microbial origin discussed in section 3.1 immune pathways from the GI tract. In addition to receiving chemotherapy, cancer patients may receive radiation therapy and additional drugs (e.g., antibiotics) to treat side effects of cancer treatment and reduce the risk of infection. These additional treatments surely play a role in further altering intestinal microbial composition.³³

Chemotherapy-induced alterations in fecal bacterial structure are associated with the development of mucositis.²⁸ Indeed, up to 80% of chemotherapy-treated patients are diagnosed with mucositis, the number one dose-limiting side effect of chemotherapeutic agents.³⁴ Chemotherapy also profoundly affects the intestinal barrier, which functions to keep resident bacteria from triggering an innate immune response.^35-37 Disturbances in the mucus layer, tight junctions, and overall tissue integrity result in translocation of bacterial products (e.g., lipopolysaccharide leading to endotoxemia)³⁵ or whole bacteria (leading to bacteremia)³⁷ and general inflammatory responses. While alterations in fecal microbiota after chemotherapy have been linked to the development of mucositis as well as cancer-related cachexia,^{28, 35} the extent to which these alterations are associated with behavioral outcomes has yet to be reported.

1.4 Chemotherapy and the GI in rodent models

The composition of the GI microbiome in rodents differs from that of humans; however, rodent models of chemotherapy treatment can be useful for understanding the associated intestinal inflammation. For example, similar to in human cancer patients, chemotherapy treatment in mice decreases bacterial diversity and intestinal barrier function.^{38, 39} In mice, the most typically abundant Bacteroides spp. are decreased, while low-abundance Bacteroides spp. are increased 1,000-fold (up to 8% relative abundance),³⁹ which may explain the aforementioned conflicting Bacteroides results in chemotherapy-treated patients. Shifts in bacterial community structure are likely a multifactorial effect of individual species' susceptibility to chemotherapeutics as well as their ability to directly metabolize them. Indeed, culture-dependent analyses have revealed that the majority of retrievable bacterial colonies from the small and large intestine are directly resistant to treatments with an antimetabolite chemotherapy.⁴⁰ With respect to the ability for specific species to metabolize chemotherapeutic drugs, chemotherapy treatment increases β-glucuronidase-producing bacteria, which can reactivate glucuronidated (biologically inactivated) chemotherapeutics in the GI tract, contributing to intestinal toxicity, mucositis, and diarrhea.⁴¹

Furthermore, treatment of germ-free mice (GF; lacking any detectable bacteria) with an anthracycline chemotherapy demonstrates the necessity of enteric bacteria in chemotherapy-induced reductions in the depth and number of intestinal crypts, structures important for the maintenance and renewal of epithelial cells in the intestine.⁴² This field would benefit from further research characterizing the effects of chemotherapeutic drugs on the intestinal microbiota and determining how chemotherapy-associated microbial changes alter the structure and function of the intestines and CNS.

2. Gut-brain axis influences behavior

2.1 Gut-brain axis influences behavior in rodents

The intestinal microbiome modulates rodent brain development and function throughout all stages of life.² Although hypothesized mechanisms have not yet been adequately delineated, mounting evidence demonstrates associations between the intestinal microbiome and mood and cognition, and, to a lesser extent, fatigue and sleep disruptions.² For example, GF mice and adult mice aggressively treated with antibiotics (eliminating much of the intestinal microbiota) display increases in anxiolytic-like exploratory behaviors (e.g. using open field, elevated plus maze, and light-dark box tests) and impaired memory in a novel object recognition test.^{43, 44}

Furthermore, such manipulations of the gut microbiota modulate neurophysiological changes in the brain regions that regulate these behaviors. For example, mice lacking intestinal microbiota display increased neurogenesis and impaired microglia maturation and activation in response to systemic immune challenges (lipopolysaccharide treatment).^{45, 46} Although conflicting trends in some behavioral changes are observed in GF and antibiotic-treated rodents compared to chemotherapy models, taken together these lines of research support the notion that various alterations in the intestinal microbiome can affect these behaviors and neurophysiological mechanisms. Basic science studies investigating the ability of chemotherapy-induced alterations in the intestinal microbiome to influence behavior and neurophysiology are warranted.

2.2 Gut-brain axis influences behavior in humans

Alterations in microbial communities are also associated with affective disorders in humans.^47-49 For example, fecal bacterial communities from patients with major depressive disorder (MDD) are distinct from healthy subjects, with MDD patients having increased relative abundance of Actinobacteria and decreased Bacteroidetes.⁴⁸ Furthermore, the severity of depressive symptoms is negatively correlated with abundance of butyrate-producing Faecalibacterium spp.⁴⁹ In parallel, the use of probiotics (defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host) is associated with decreased depressive symptoms in healthy adults as well as patients diagnosed with MDD.^{50, 51}

Outside of affective disorders, a role for the intestinal microbiome in cognition and fatigue in humans is still being established; therefore, evidence is limited. Patients diagnosed with disorders associated with large shifts in intestinal and fecal microbial taxa and systemic inflammation, such as irritable bowel syndrome and liver cirrhosis, report measurable differences in cognition.^{52, 53} For example, increases in fecal Alcaligenaceae and Porphyromonadaceae families are correlated with poor cognitive performance in patients with liver cirrhosis.⁵³ Altered fecal microbiomes are also found in patients diagnosed with chronic fatigue syndrome (CFS).^54-56 In one study, reduced fecal Faecalibacterium is positively correlated with emotional well-being scores in patients diagnosed with CFS.⁵⁵ In another study, antibiotic treatment that successfully reduced fecal Streptococcus abundance in CFS patients is associated with improved sleep and increased vigor.⁵⁶ Additional clinical studies characterizing the intestinal microbiome in patient populations characterized by fatigue and cognitive impairments, such as cancer patients and survivors treated with chemotherapy are necessary to strengthen the connection between the intestinal microbiome and these behaviors in humans.

3. Gut-immune-brain axis

The intestinal microbiome is capable of altering brain function through multiple pathways simultaneously,² which is likely the case during chemotherapy treatment. The mechanisms by which endocrine and neural pathways mediate signals from the GI tract have been thoroughly reviewed elsewhere.² For this review, we hypothesize that the most relevant pathway between the GI tract and the brain during chemotherapy treatment is the peripheral immune system. This hypothesis is represented in Figure 1.

Figure 1. Gut-Immune-Brain Axis After Chemotherapy.

Chemotherapy alters the composition of the intestinal microbial structure, reducing alpha diversity and species associated with anti-inflammatory activities, while increasing intestinal inflammation and permeability. Simultaneously, chemotherapy results in increased peripheral inflammation, neuroinflammation, and impaired CNS function. Alteration of the intestinal microbial community may result in and exacerbate neuroinflammation and behavioral comorbidities after chemotherapy. While the brain and the gut can communicate bi-directionally through multiple pathways, including through neuroendocrine pathways and the autonomic nervous system, we hypothesize that in the context of chemotherapy, the peripheral immune system is the most relevant mediator between the gut and the brain.

3.1 Immune pathways from the GI tract

It has long been recognized that the intestinal microbiota plays a crucial role in the development and maintenance of the immune system.⁵⁷ GF mice exhibit an overall underdeveloped immune system, which can be rescued by conventional microbial colonization from healthy mouse donors.⁵⁸ However, re-colonization with only select species fails to fully recuperate these deficits, implying that normal immune function is the culmination of complex activities of the commensal microbiota as a whole.⁵⁸

The intestinal microbiota can influence circulating immunity positively and negatively through direct production of multiple products within the intestinal lumen, influencing infiltration of peripheral immune cells in the intestine. For example, butyrate is a short-chain fatty acid (SCFA) product of microbial fermentation, which is intimately related to intestinal inflammation and immunomodulation via its ability to reduce pro-inflammatory cytokines.⁵⁹ Clinically, decreased luminal concentrations of butyrate and butyrate-producing microbes have been implicated in the development of inflammatory bowel disease.^{60, 61} Butyrate therapy has been investigated for the amelioration of a variety of systemic inflammatory processes, including the reduction of chemotherapy-induced mucositis.⁶² Furthermore, butyrate and other SCFAs can promote the migration of leukocytes, although much of this work has been conducted in vitro.^{63, 64} It should be noted that these anti-inflammatory actions of butyrate may be physiologically isolated to the intestine, given that butyrate concentrations are drastically reduced beyond the portal vein,⁶⁵ although this may differ during illness. Relevant to chemotherapy, enteric infections (and resultant inflammation and reduction in barrier function) can increase butyrate concentrations in the circulation.⁶⁶

As previously discussed, chemotherapy causes intestinal mucositis and alterations in GI microbial communities, both of which can result in systemic inflammation. For example, chemotherapy-induced diarrhea in cancer patients is associated with increased concentrations of matrix metalloproteinases and NF-κB, IL-1β, and TNFα in circulation.³¹ The microbiota has been implicated in the pathogenesis of mucositis during chemotherapy through its ability to regulate local inflammation and by decreasing intestinal barrier function.^{28, 41} In fact, bacteria that have translocated out of the intestines are commonly found in the circulation of cancer patients after chemotherapy treatment.⁶⁷

Commensal and probiotic Lactobacillus species are broadly investigated for their immunomodulatory potential and native species are consistently reduced by chemotherapy treatment.⁶⁸ Of these species, Lactobacillus reuteri strains (a commensal human species) in particular reduce inflammation through the production of histamine and indole-3-aldehyde.⁶⁹

3.2 Inflammation and behavior

Based on basic science research, peripheral inflammation can be transduced into neuroinflammation through both neural and humoral pathways.⁷⁰ Neuroinflammation induces a wide range of neurophysiological processes involved in mood regulation, cognition, fatigue, and sleep.⁷¹ The neurophysiological cascades triggered by neuroinflammation (e.g., apoptosis) are similarly altered after chemotherapy treatments,^{18, 19, 23, 72} and neuroinflammation is regarded as one of the primary mechanisms underlying chemotherapy-associated behavioral comorbidities.⁷³

Direct evidence supporting a role for neuroinflammation in behavioral disorders in humans stems from brain necropsies from successful suicides by MDD patients, which are characterized by increased cytokine expression as well as increased microglial activation in brain regions associated with mood regulation and cognition.^{74, 75} Indeed, elevated cytokines and cytokine-based treatment in humans has been linked to the development of behavioral disorders.^76,77 For example, cancer patients treated with interferon alpha (IFN-α) and IL-2 develop symptoms of depression and anxiety, cognitive dysfunction, and fatigue.^{78, 79} Furthermore, the development of depression, anxiety, and impaired memory after low dose endotoxin treatment correlates with increases in circulating TNFα expression.⁸⁰

Several studies have demonstrated the ability for chemotherapeutic drugs, in particular taxanes, to stimulate immune function⁸¹ and increase circulating expression of inflammatory cytokines in cancer patients.^82-84 Furthermore, behavioral comorbidities in cancer patients and survivors correlate with these increases in peripheral inflammation.^{12, 85-87} For example, cognitive impairments in breast cancer survivors are associated with increased peripheral inflammatory markers, such as IL-6 and TNFα.^{86, 87} Likewise, persistent fatigue in breast cancer survivors is accompanied by increased expression of IL-6,^{8, 88, 89} as well as altered gene expression in leukocytes suggesting enhanced pro-inflammatory NF-κB signaling and decreased anti-inflammatory glucocorticoid signaling.⁹⁰ Finally, the use of pharmaceutical and mindfulness-based interventions that inhibit or reduce inflammation have been successful in reducing cancer/chemotherapy-associated symptoms of fatigue and depression.^91-95

3.3 Gut-immune-brain

The intestinal microbiota may increase neuroinflammation and affective behaviors during disease or in response to disease treatments by activating a peripheral immune response. However, few studies have thoroughly investigated the connection between the intestinal microbiota, immune, and brain systems to date and much of the current data rely on correlational observations. Outside of the cancer context, increased neuroinflammation and altered behavior are concurrent with shifts in intestinal microbiota, intestinal inflammation, and systemic inflammation in mouse models of obesity and colitis.^{96, 97} Similarly, probiotic treatment with Lactobacillus rhamnosus simultaneously ameliorates behavioral changes and reduces systemic inflammation in a model of chronic social stress.⁹⁸ Finally, the inhibitory effects of antibiotics on neurogenesis in rodents is mediated by circulating Ly6C^hi monocytes.⁴⁵ However, additional experiments elucidating causal mechanisms underlying the gut-immune-brain axis are warranted.

Within the context of cancer, chemotherapy treatment is associated with increased peripheral and central inflammation, behavioral and cognitive disorders, as well as shifts in fecal bacterial diversity and community structure. While a role for the gut-immune-brain axis has been implicated in chemotherapy-induced pain in mice,⁹⁹ the extent to which changes in affective disorders, cognition, and fatigue are influenced by chemotherapy-associated alterations in fecal bacterial community structure remains undetermined. Larger clinical studies characterizing shifts in microbial compositional, metagenomics, and metabolomics profiles after chemotherapy treatments, and investigating how these alterations correlate with altered peripheral inflammation, and changes in neuroimaging and/or behavior are warranted. In addition, using rodent models treated systematically with specific chemotherapy drugs or combinations of drugs to determine mechanistically how changes to the intestinal microbiome and intestinal integrity contribute to peripheral and central inflammation and affect behavior would expand our understanding of the gut-immune-brain axis during disease.

4. Potential interventions

Understanding how, and the extent to which, chemotherapy-induced alterations in the GI microbiome contribute to behavioral comorbidities could transform the manner in which the debilitating side effects that cancer patients experience are treated. Specifically, innovative treatment of GI illness using probiotics, prebiotics (defined as non-digestible ingredients that support beneficial bacterial growth), and/or fecal microbiota transplantation (FMT) may reduce behavioral comorbidities, the risk of peripheral infections, and GI symptoms simultaneously, all of which currently interrupt cancer treatment and reduce quality of life.

For example, pairing chemotherapy treatment with probiotic supplementation is a promising co-therapy that reduces GI symptoms, intestinal inflammation, intestinal permeability, and the risk of infection, while concurrently increasing bacterial diversity in cancer patients.^100-102 Supplementation of probiotics (particularly specific Lactobacillus spp.) is relatively well-investigated for amelioration of behavioral, microbial, and inflammatory morbidities in other patient populations, as discussed throughout this review. While implementing probiotic interventions to ameliorate psychiatric disorders is a relatively novel approach, most available clinical trials report reduced symptoms of depression and anxiety.^{50, 103} For example, consumption of a mixture of Lactobacillus casei, Lactobacillus acidophilus, and Bifidobacterium bifidum by patients with MDD reduces symptoms of depression.⁵¹ This same mixture of probiotics also increases cognitive function in patients diagnosed with Alzheimer's disease.¹⁰⁴

Similarly, the vast majority of clinical studies focused on probiotic use specifically in cancer patients are limited to GI-related outcomes. Only one study demonstrates the ability of Lactobacillus rhamnosus and Lactobacillus acidophilus treatment to reduce symptoms of depression, anxiety, and fatigue (notably in tandem with reduced GI symptoms) in chemotherapy-treated colorectal cancer survivors, indicating that additional studies are needed to determine efficacy of these treatments on behavioral comorbidities in cancer patients.¹⁰⁵ Current clinical trials involving probiotics are further limited by small sample sizes and differing combinations of probiotic strains and dosages implemented, making meaningful comparisons among studies difficult.

Prebiotic supplementation is less-studied compared to probiotics, but is also an emerging intestinal microbiota-targeted therapy for attenuating behavioral disorders. This is exemplified by a small number of rodent and human studies. Prebiotic supplementation of rat diets with galactooligosaccharides, polydextrose, and bioactive milk fractions improves sleep quality.¹⁰⁶ In addition, galactooligosaccharides and fructooligosaccharides have a neurotropic effect, increasing expression of brain-derived neurotropic factor (BDNF) and NMDA subunits, while concurrently increasing levels of fecal Lactobacillus rhamnosus CFU and bacterial alpha diversity in rodents.^{106, 107} In healthy humans, consumption of galacto-oligosaccharides alters neuroendocrine responses and emotional processing,¹⁰⁸ indicating that prebiotics may be a relevant GI-focused treatment of fatigue and mood issues associated with chemotherapy. Beyond supplementation with prebiotics or probiotics, a more general alteration in diet (particularly in terms of fiber and macronutrient composition) rapidly affects the composition of the intestinal microbiome¹⁰⁹ and therefore might influence behavior.

While the health benefits of some microbial therapies are localized to the intestine or immune system, a limited number of probiotics (e.g. B. infantis and L. rhamnosus) and prebiotics (e.g. galactooligosaccharides) potentially alleviate symptoms of psychiatric illness¹¹⁰. These novel probiotics, which have been termed psychobiotics, represent an emerging subset of probiotics that require further investigation, especially in human populations.

Fecal microbiota transplant is an additional potential treatment for behavioral comorbidities. Clinical FMT from healthy individuals to patients with Clostridium difficile infection is exceptionally successful in restoring a diverse intestinal microbiota and alleviating devastating GI symptoms.¹¹¹ In mice, FMT drastically modifies the resident intestinal microbial composition, as well as transfers behavioral attributes of the fecal donor.^{96, 112} For example, FMT from obese to lean mice transfers both the obese intestinal microbial profile (e.g., low Akkermansia muciniphila) and the associated cognitive deficits to the lean recipients.⁹⁶ To the best of our knowledge, only a single study has examined the safety and efficacy of FMT in cancer patients after chemotherapy.¹¹³ However, while the study reported success in treating Clostridium difficile infections, the extent to which treatment altered peripheral inflammation and behavior was not reported. While FMT is a potential new strategy for ameliorating behavioral comorbidities following chemotherapy, FMT in humans does not always succeed in altering fecal microbiota composition or in conveying the intended benefit (e.g. resolving C. difficile infections).¹¹⁴ Further research using preclinical animal models to increase safety and efficacy is required before this technique should be applied to cancer populations.

5. Conclusion

Chemotherapy remains one of the harshest, but most common, systemic clinical treatments for cancer. Therefore, the development of new and innovative treatment strategies to alleviate the associated behavioral and GI comorbidities is essential. The extent to which GI dysfunction influences behavior in chemotherapy-treated patients has yet to be elucidated. However, the ability of the intestinal microbiota to modify immune activity, behavior, and its underlying neurophysiological processes suggests a potential role for the gut-immune-brain axis in chemotherapy-associated comorbidities. Indeed, supporting evidence from both clinical and animal chemotherapy studies demonstrates significant alterations to the composition of intestinal microbiota, increased intestinal inflammation, and reduced GI barrier function. Often, measures of peripheral inflammation are correlated with behavioral deficits in chemotherapy-treated cancer patients and survivors. Much-needed prospective, longitudinal clinical studies in chemotherapy-treated patients would inform basic science work to identify the mechanisms underlying communication between the intestinal microbiome and the brain during specific cancer treatments and the extent to which this communication is mediated by the peripheral immune system. In addition, clinical and preclinical testing of innovative and non-invasive interventions targeting the intestinal microbiota and/or their byproducts is warranted. This work has the potential to improve the health and quality of life for millions of cancer survivors by reducing the prevalence of chemotherapy-associated behavioral comorbidities.