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

ABSTRACT: 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-1β) 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.

SUBMITTER: Grant CV

PROVIDER: S-EPMC8461613 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Sucralose is a non-nutritive artificial sweetener (NNS) used in foods or beverages to control blood glucose levels and body weight gain. The consumption of NNS has increased in recent years over the world, and many researches have indicated long-term sucralose administration altered the gut microbiome composition of mice. These studies all focus on the US Food and Drug Administration (FDA) defined acceptable daily intake (ADI), approximately 5 mg/kg BW/day for human. In our study, mice were given with T1-4 (0.0003, 0.003, 0.03, and 0.3 mg/mL) of sucralose, respectively, Control group mice were given normal water. In particular, 0.3 mg/mL of sucralose was equal to the ADI (5 mg/kg BW/day). After 16 weeks, all mice were weighted and sacrificed, the liver of each mouse was isolated and weighed, segments of jejunum, ileum and colon were collected for H&E-stained. The contents of jejunum, ileum, cecum and colon were collected for 16S rRNA gene sequencing. The results showed sucralose administration affects the intestinal barrier function evidenced by distinct lymphocyte aggregation in ileum and colon while not change the mice body weight. The 16S rRNA gene sequencing of the mice gut microbiome suggested sucralose administration significantly changed the composition of gut microbiota, especially in T1 and T4 group. For example, a reduction of probiotics abundance (Lachnoclostridium and Lachnospiraceae) was found in cecum of T4 group mice compared with Control group. On the other hand, Allobaculum, which was reported positively correlated with diabetes, was increased in the T1 and T4 group. In addition, the potential pathogens, including Tenacibaculum, Ruegeria, Staphylococcus were also increased in jejunum, ileum and colon by sucralose administration in T1 and T4 group. These new findings indicate that low dose of sucralose (T1) alter gut microbiome in mice, and these adverse health effects are equal to ADI level (T4). Overall, our study provides guidance and suggestions for the use of sucralose in foods and beverages.

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

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