1. Introduction

The gastrointestinal (GI) tract harbors a complex community of bacteria, fungi, viruses, archaea, and their genomes, which affect human health and disease [1]. Dysbiosis, or a disruption of the gut microbiota, refers to adverse changes in the microbiota associated with disturbed homeostasis and disease [2]. Gut dysbiosis has been associated with behavioral changes and impaired immune function characterized by increased proinflammatory biomarkers in both humans and rodents [3,4,5]. Cancer treatments, notably chemotherapy, while lifesaving, have been associated with gut microbial dysbiosis [6,7,8]. Moreover, gut microbial associated changes in psychological and cognitive function following chemotherapy treatment have also been found [6,9,10]. Notably, while some of the studies discussed herein used techniques such as PICRUSt to infer the metabolic capacity of the microbiome, we focused our discussion of the findings from these studies on the taxonomic characterization of the microbiota using 16S rRNA sequencing, and, therefore, refer to microbiota throughout the manuscript as opposed

1.1. Chemotherapy Impacts the Gut Microbiota

The microbiota–gut–brain axis facilitates crosstalk between the microbiota and brain via neural, endocrine, immune and metabolic pathways [1,11], which are susceptible to chemotherapy-related toxicities. In a pre-clinical study with adult female mice, 6 cycles (i.e., one treatment per every other day) of paclitaxel chemotherapy altered gut microbiota composition, which was associated with changes in taxonomic relative abundance, colonic tissue integrity, and microglial activation [12]. In clinical studies, chemotherapy treatment has been shown to alter the gut microbiota. In a sample of 36 pediatric patients with acute lymphoblastic leukemia, stool samples collected at baseline and days 3 (mid-treatment) and 7 (immediately post-chemotherapy) showed that high-dose methotrexate chemotherapy significantly reduced the overall taxonomic abundance of the gut microbiota during treatment and relative to healthy controls [7]. Another study found that chemotherapy decreased abundance of microbes belonging to the Firmicutes phylum [8]. Moreover, chemotherapy-induced mucositis, a common GI symptom in patients undergoing chemotherapy, is associated with increased symptoms of pain, anxiety, and depression [13].

1.2. Chemotherapy Compromises the GI Tract

The microbiota–gut–brain axis influences immune function and behavior [14]. The epithelial layer that lines the GI tract is a fine-tuned interface between the host and the external environment. The epithelia’s paracellular permeability under healthy physiological conditions is tightly regulated by tight junction proteins that prevent passage of macromolecules [15]. Chemotherapy may compromise the protective epithelial layer in the gut [12]. Compromising this layer can lead to increased intestinal permeability (i.e., “leaky gut”), which will provide easy passage of bacteria and their byproducts, such as lipopolysaccharide (LPS), a bacterial endotoxin component of the cell wall of Gram-negative bacteria, from the gut lumen into the bloodstream [9,12,16]. A compromised gut can lead to an immune response, characterized by the expression of sickness behaviors (e.g., lethargy, anxiety, cognitive dysfunction)[17]. Chemotherapy has thus been implicated in increased intestinal wall permeability, mucositis, sickness behaviors, and changes in the gut microbiota [6,7,8,9,12]. However, it is unclear whether these adverse changes persist in the longer term after treatment has ended.

1.3. Chemotherapy Impacts Psychosocial Health

Chemotherapy is associated with acute and chronic adverse changes in psychosocial health, but potential underlying mechanisms require elucidation. Mental health, a dimension of psychosocial health (i.e., psychological, behavioral, emotional, and social factors), in this context, refers to one’s emotional, psychological, and social well-being [18]. A growing body of research implicates the gut microbiota in symptoms of anxiety and depression [16,19,20], post-traumatic stress disorder (PTSD) [21], fatigue [22,23], cognitive and social function, pain [1,24,25], and GI disturbance [26,27,28]. Moreover, changes in the gut microbiota have been associated with anxiety and depressive behaviors in animals and humans [16,29,30,31,32].Chemotherapy has been associated with cognitive and psychological impairments [9,33,34]. Many survivors of cancer have been treated with toxic anti-cancer therapies and face chronic physical and psychosocial challenges because of cancer and its treatments. During and after chemotherapy treatment, cognitive impairments (e.g., attention, concentration, processing speed) are reported [33]. Survivors also tend to report higher incidence of anxiety, depression, cancer-related fatigue, and other psychosocial symptoms compared to healthy peers [35,36]. However, potential underlying mechanisms that may contribute to the maintenance of psychosocial symptoms require clarification.

Although many cancer survivors face post-treatment challenges regardless of their age, young adults may face additional challenges and unmet needs [37,38]. Young adults may be particularly susceptible to psychosocial issues following a cancer experience due to the added stress of developmental challenges (e.g., finding a long-term partner, fertility concerns, career development, gaining financial stability) compared to older survivors [38,39]. Understanding potential chronic effects of cancer treatments on the gut microbiota, GI, and psychosocial outcomes, and how these factors may relate, is needed to improve cancer survivors’ wellbeing.