Leah M. Pyter

In the United States, over 300,000 people are diagnosed with breast cancer every year, and chemotherapy is one of the most common treatments.1 Chemotherapy treatment (a regimen of anti-cancer chemo...

Background/Objectives: Nutrition and the gut microbiota influence treatment tolerance and recovery in patients with colon cancer receiving chemotherapy. This pilot study examined changes in diet quality and fecal microbiota over 6 months of chemotherapy and evaluated longitudinal associations between diet quality and gut microbiota diversity and taxa. Methods: 48 adults with stage II–III colon cancer receiving 5-fluorouracil-based chemotherapy were assessed at baseline and 6 months post-initiation. Diet quality was measured using 3-day dietary recalls to calculate Healthy Eating Index (HEI) scores. Stool samples underwent 16S rRNA sequencing to assess Shannon diversity, Beta and taxonomic composition. Pre–post changes were analyzed using paired tests, and associations between HEI and microbiota measures were evaluated using multivariable linear regression adjusting for demographic and clinical covariates. Results: Diet quality declined during chemotherapy, with reduced intake of fiber, fruits and vegetables, and whole grains. Gut microbial alpha diversity decreased over time. At the phylum level, Actinobacteriota decreased, while Bacteroidota and Proteobacteria increased. At the genus level, only Streptococcus (decreased) and Escherichia (increased) remained significantly altered after multiple testing correction. Higher baseline diet quality and improvements over time were associated with greater microbial diversity and lower Proteobacteria abundance. Diet quality was inversely associated with Streptococcus and Escherichia and positively associated with short-chain fatty acid-producing, fiber-responsive genera (Faecalibacterium, Mediterraneibacter, Ruminococcus_E, Fusicatenibacter). Baseline gut microbiota did not significantly associate with changes in diet quality. Conclusions: Chemotherapy was associated with declines in diet quality, gut microbial alpha diversity, along with shifts in beta diversity and microbial taxa. Higher diet quality appeared protective against microbial disruption, supporting a bidirectional relationship between diet and the gut microbiome during chemotherapy. Nutritional and microbiota-focused approaches warrant further investigation in the context of chemotherapy.

Background/Objectives: Nutritional status and the gut microbiome play key roles in supporting treatment tolerance and recovery among patients with colon cancer receiving chemotherapy. This pilot study examined (1) changes in diet quality and fecal microbiome profiles during 6-month chemotherapy and (2) associations between diet quality and microbiome diversity and composition over time. Methods: A longitudinal study of 48 adults with stage II–III colon cancer receiving 5-Fluouracil (FU)–based chemotherapy assessed diet quality and the gut microbiome at baseline and 6 months post-chemotherapy initiation. Diet quality was measured using 3-day dietary recalls to compute Healthy Eating Index (HEI) scores. Stool samples collected at both timepoints underwent 16S rRNA sequencing to quantify Shannon diversity and taxonomic composition. Pre–post differences were examined using paired tests, and associations between HEI and microbiome indicators were evaluated with multivariable linear regressions adjusting for demographic and clinical covariates. Results: Diet quality declined during chemotherapy (HEI 62.4→54.2, p=0.015). Shannon diversity also decreased (1.20→1.05, p=0.011). Microbiome composition shifted, with declines in Short-Chain Fatty Acids (the result of fiber fermentation)-producing taxa (Agathobacter, Bifidobacterium, and Prevotella), and increases in Bacteroides and Proteobacteria. Higher baseline HEI was linked to greater microbial diversity, higher levels of beneficial Firmicutes, and lower Proteobacteria. Changes in HEI were significantly aligned with changes in fecal microbiome profiles. Conclusions: Chemotherapy worsens diet quality and gut microbial health. Higher baseline diet quality appeared protective against microbial disruption, supporting a bidirectional diet–microbiome relationship. Early nutritional and microbiome-supportive strategies may help preserve gut resilience during chemotherapy.

Cancer patients experience circadian rhythm disruptions during and after chemotherapy that can contribute to debilitating side effects. It is unknown how chemotherapy mediates circadian disruptions and specifically the extent to which these disruptions occur at the level of the principal clock, the suprachiasmatic nuclei (SCN) of the hypothalamus. In the present study, we assessed how the commonly used chemotherapeutic, paclitaxel, impacts the SCN molecular clock and SCN-dependent behavioral adaptations to circadian challenges in female mice. Following a repeated chemotherapy regimen, we measured rhythmic SCN expression of molecular clock and circadian-associated transcripts. Paclitaxel chemotherapy disrupted the SCN molecular clock through abolished rhythmicity (Bmal1, Nr1d2) and damped rhythmic transcription (Ciart, Dbp, Nr1d1, Per2) of key molecular clock genes. We further determined chemotherapy-induced changes to SCN function by measuring circadian wheel running adaptations to a jet lag phase-delay or phase-advance paradigm and by generating a phase response curve (PRC). Chemotherapy did not alter re-entrainment to a 6 h phase-advance, but after a 6 h phase-delay, chemotherapy-treated mice had a more stable and robust circadian rhythm than vehicle-treated mice, possibly indicative of a weakened or decoupled SCN. In the PRC, chemotherapy blunted light-induced phase-shift delays during subjective night compared with vehicle controls, also indicative of disrupted SCN-dependent entrainment. Together, this work demonstrates that paclitaxel chemotherapy disrupts both the molecular clock and functional re-entrainment of the SCN that could cause or contribute to observed circadian rhythm disruptions after treatment. This research could help guide application of circadian-mediated therapies to mitigate side effects of chemotherapy.

Chemotherapy can cause debilitating behavioral side effects (e.g., fatigue, depression, cognitive decline); however, having an intimate partner can buffer these effects. The California mouse (Peromyscus californicus) is a rare monogamous mouse species that offers a novel opportunity to model human intimate partnership to identify the neurobiological mechanisms by which mate bonding reduces chemotherapy-associated behavioral side effects. As a first step toward this goal, this pilot study aimed to develop the first chemotherapy model, to our knowledge, in adult male and female California mice. Following a repeated paclitaxel chemotherapy regimen, well characterized in laboratory mice (Mus musculus), gross sickness physiology was first assessed after various doses. The 20 mg/kg paclitaxel dose, injected six times every other day, was the highest tolerable, clinically relevant dose and was characterized by moderate body mass loss and increased spleen mass. Thus, further investigation of the effects of this chemotherapy paradigm on peripheral and neural inflammatory gene expression, based on previous reports in laboratory mice, was undertaken; results were mixed. Consistent across the spleen, hippocampus, and hypothalamus, some proinflammatory genes were unexpectedly decreased with chemotherapy (Il1β, Tnf), whereas one gene was increased (Icam1). Chemotherapy also increased fatigue and sociability, but not anxiety-like behavior or cognition. Taken together, this pilot study characterized a translational model of chemotherapy in California mice with clinically relevant gross physiological changes and modest changes in neuroinflammation and behavioral side effects. This work also highlights the need for comparative studies and the growth of research tools for this socially relevant mouse species.

Background: Cancer-related cognitive impairment (CRCI) is one of the most frequently reported symptoms by breast cancer patients. However, it remains unclear precisely what contributing factors are present among chemotherapy-naïve breast cancer patients that contribute to CRCI. Thus, it is essential to identify potential factors related to CRCI that may occur before chemotherapy so that interventions can be employed to help prevent the worsening of CRCI. Objective: This study examined the association between intolerance of uncertainty (IU) and cognitive function among breast cancer patients before chemotherapy and explored whether anxiety mediates this association. Methods: A total of 58 females diagnosed with stage I-III breast cancer and scheduled for chemotherapy were included in this study. Data on cognitive function, IU, anxiety, and other relevant information were analyzed. Results: We found that higher IU was associated with higher anxiety and such higher anxiety was subsequently associated with lower cognitive function being reported by breast cancer patients who were scheduled for chemotherapy. The association between IU and cognitive function was largely mediated through anxiety with standardized β = −0.19 (SE = 0.07) for the indirect association via anxiety and β = −0.2 (SE = 0.12) for the total association. Conclusions: IU shows an impact on cognitive function. Therefore, it is necessary to assess IU before chemotherapy, which may help detect patient risk for cognitive impairment early.