Chemotherapy-induced gut microbiome disruption, inflammation, and cognitive decline in female patients with breast cancer.

Chemotherapy is notorious for causing behavioral side effects (e.g., cognitive decline). Notably, the gut microbiome has recently been reported to communicate with the brain to affect behavior, including cognition. Thus, the aim of this clinical longitudinal observational study was to determine whether chemotherapy-induced disruption of the gut microbial community structure relates to cognitive decline and circulating inflammatory signals. Fecal samples, blood, and cognitive measures were collected from 77 patients with breast cancer before, during, and after chemotherapy. Chemotherapy altered the gut microbiome community structure and increased circulating TNF-α. Both the chemotherapy-induced changes in microbial relative abundance and decreased microbial diversity were related to elevated circulating pro-inflammatory cytokines TNF-α and IL-6. Participants reported subjective cognitive decline during chemotherapy, which was not related to changes in the gut microbiome or inflammatory markers. In contrast, a decrease in overall objective cognition was related to a decrease in microbial diversity, independent of circulating cytokines. Stratification of subjects, via a reliable change index based on 4 objective cognitive tests, identified objective cognitive decline in 35% of the subjects. Based on a differential microbial abundance analysis, those characterized by cognitive decline had unique taxonomic shifts (Faecalibacterium, Bacteroides, Fusicatenibacter, Erysipelotrichaceae UCG-003, and Subdoligranulum) over chemotherapy treatment compared to those without cognitive decline. Taken together, gut microbiome change was associated with cognitive decline during chemotherapy, independent of chemotherapy-induced inflammation. These results suggest that microbiome-related strategies may be useful for predicting and preventing behavioral side effects of chemotherapy.

Manipulations of the gut microbiome alter chemotherapy-induced inflammation and behavioral side effects in female mice.

Chemotherapy treatment is associated with acute behavioral side effects (fatigue, anorexia) that significantly reduce patient quality of life and are dose-limiting, thereby increasing mortality (Kidwell et al., 2014). Disruptions to gut homeostasis (diarrhea, constipation, microbial dysbiosis) are also observed in patients receiving chemotherapy. In non-oncological patients, facets of mental health (fatigue, anxiety, depression) correlate with alterations in the gut microbiome, suggestive of a contribution of the gut in CNS disease etiology. The potential gut-to-brain pathway is poorly understood in patients receiving chemotherapy. Our prior studies have demonstrated a correlation between chemotherapy treatment, gut changes, peripheral and central inflammation, and behavioral symptoms in mice. Here we aimed to determine the extent to which chemotherapy-associated gut manipulations modulate the behavioral and biological consequences of chemotherapy. We measured sickness behaviors, peripheral and central inflammatory mediators, and anxiety in conventional or germ-free female mice: 1) cohabitating with mice of the opposite treatment group, 2) pre-treated with broad-spectrum antibiotics, or 3) given an intra-gastric gavage of gut content from chemotherapy-treated mice. In cohabitation studies, presumed coprophagia promoted body mass recovery, however strong associations with inflammation and behavior were not observed. Reduction of gut microbial alpha diversity via antibiotics did not prevent chemotherapy-associated side effects, however the relative abundances of the genera Tyzzerella, Romboutsia, and Turicibacter correlated with circulating inflammatory (IL-1ß) and behavioral outcomes (lethargy, anxiety-like behavior). A gut microbiota transplant from chemotherapy-treated mice decreased central locomotion in open field testing, increased circulating CXCL1, and increased hippocampal Il6 and Tnfa in germ-free mice compared to germ-free mice that received a transplant from vehicle-treated mice. Taken together, these data provide further evidence that the gut microbiota likely contributes to the development of chemotherapy-associated side effects. This work has significant implications in the future treatment of anxiety in patients, and warrants future studies using microbe-based treatment options.

Chemotherapy-induced neuroinflammation is associated with disrupted colonic and bacterial homeostasis in female mice.

Chemotherapy treatment negatively affects the nervous and immune systems and alters gastrointestinal function and microbial composition. Outside of the cancer field, alterations in commensal bacteria and immune function have been implicated in behavioral deficits; however, the extent to which intestinal changes are related to chemotherapy-associated behavioral comorbidities is not yet known. Thus, this study identified concurrent changes in behavior, central and peripheral immune activation, colon histology, and bacterial community structure in mice treated with paclitaxel chemotherapy. In paclitaxel-treated mice, increased fatigue and decreased cognitive performance occurred in parallel with reduced microglia immunoreactivity, increased circulating chemokine expression (CXCL1), as well as transient increases in pro-inflammatory cytokine/chemokine (Il-1ß, Tnfα, Il-6, and Cxcl1) gene expression in the brain. Furthermore, mice treated with paclitaxel had altered colonic bacterial community composition and increased crypt depth. Relative abundances of multiple bacterial taxa were associated with paclitaxel-induced increases in colon mass, spleen mass, and microglia activation. Although microbial community composition was not directly related to available brain or behavioral measures, structural differences in colonic tissue were strongly related to microglia activation in the dentate gyrus and the prefrontal cortex. These data indicate that the chemotherapeutic paclitaxel concurrently affects the gut microbiome, colonic tissue integrity, microglia activation, and fatigue in female mice, thus identifying a novel relationship between colonic tissue integrity and behavioral responses that is not often assessed in studies of the brain-gut-microbiota axis.