To investigate, the team studied adult male rats fed either a standard chow diet or a rotating cafeteria diet made up of high-fat, high-sugar foods for seven and a half weeks. Half of the animals in each group were given access to a running wheel. This setup allowed the researchers to distinguish the separate and combined influences of diet quality and physical activity on the brain and behavior.

Novel Mechanisms Connecting Exercise and Mood

The findings showed that voluntary running produced an antidepressant-like effect even when the rats consumed an unhealthy diet, suggesting that regular physical activity could benefit people who eat Western-style foods.

Using a comprehensive metabolomic approach, Professor Nolan and her colleagues examined the caecal contents of the animals and found that the cafeteria diet profoundly altered gut metabolism. Out of 175 metabolites analyzed in sedentary rats, 100 were significantly affected. Exercise influenced a smaller subset of these, partially restoring the balance. Three metabolites known to play a role in mood regulation -- anserine, indole-3-carboxylate, and deoxyinosine -- were reduced by the cafeteria diet but rebounded with exercise.

Behavioral tests assessing learning, memory, and emotional responses revealed further insights. The cafeteria diet alone did not greatly impair spatial learning or recognition memory, but exercise slightly improved navigation skills. The researchers also found mild anti-anxiety effects from exercise that occurred regardless of diet type.

What are caecal contents?

The term caecal contents refers to the material found inside the caecum, a pouch located at the beginning of the large intestine. In animals such as rats, this area is rich in gut microbes that help break down food and produce a wide variety of chemical compounds called metabolites. Scientists often analyze caecal contents to understand how diet, exercise, or medication affect gut health and metabolism.

Hormonal Pathways in the Diet-Exercise Relationship

Analysis of blood samples revealed strong hormonal changes that mirrored the behavioral outcomes. Sedentary rats on the cafeteria diet had sharply higher insulin and leptin levels, but these elevations were significantly reduced in those that exercised. According to Dr. Minke Nota, the study's first author, this hormonal rebalancing may help explain how exercise protects against the behavioral effects of poor diet.

The team also identified intricate interactions between diet and exercise involving other hormones that regulate metabolism. In animals eating standard chow, exercise boosted glucagon-like peptide 1 (GLP-1) levels, but this response was weakened in those on the cafeteria diet. In contrast, exercise increased peptide YY (PYY) levels only in the cafeteria-fed rats, suggesting that compensatory hormonal mechanisms help stabilize metabolism when diet quality is low.

Levels of fibroblast growth factor 21 (FGF-21) rose substantially in response to the cafeteria diet regardless of physical activity, while glucagon levels declined. Together, these findings reveal a complex hormonal network through which diet and exercise interact to influence metabolism and brain function.

Implications for Understanding Diet-Brain Relationships

Perhaps most intriguingly, the study found that the cafeteria diet prevented the typical exercise-induced increase in adult hippocampal neurogenesis (formation of new neurons), as measured by doublecortin-positive cells in the dentate gyrus. In standard chow-fed animals, exercise robustly increased neurogenesis throughout the hippocampus, a brain region involved in emotion and memory. This finding suggests that diet quality may fundamentally alter the brain's capacity to benefit from physical activity at the cellular level.

The research team conducted correlation analyses to identify relationships between specific metabolites and behavioral outcomes. Several caecal metabolites including aminoadipic acid and 5-hydroxyindole-3-acetic acid showed negative associations with cognitive performance. These correlations were independent of experimental condition, suggesting fundamental relationships between gut metabolite profiles and brain function.

An accompanying editorial by Professor Julio Licinio and colleagues emphasizes the clinical relevance of these findings, noting that "exercise has an antidepressant-like effect in the wrong dietary context, which is good news for those who have trouble changing their diet." The editorial highlights how this research provides a biological framework for understanding why exercise remains beneficial even when dietary improvements prove challenging to implement.

Future Directions and Clinical Translation

The study raises important questions about optimal sequencing of lifestyle interventions. The findings suggest that while exercise can provide mood benefits regardless of diet quality, achieving full neuroplastic benefits may require attention to nutritional status. This has implications for designing interventions that maximize both feasibility and biological impact.

Several limitations warrant consideration. The study was conducted exclusively in male rats, and sex differences in metabolic and neurogenic responses to diet and exercise are well-documented. Additionally, the seven-week intervention period may not capture longer-term adaptations that could emerge with chronic exposure. Future studies incorporating female animals, longer intervention periods, and dose-response designs will help refine understanding of these complex interactions.

The research also opens new avenues for investigating specific metabolites as potential therapeutic targets. The protective effects of exercise on anserine, indole-3-carboxylate, and deoxyinosine levels suggest these compounds may serve as biomarkers or even therapeutic agents for mood disorders. The strong correlations between specific gut metabolites and behavioral measures support growing interest in the microbiota-gut-brain axis as a target for mental health interventions.

This peer-reviewed research represents a significant advance in understanding the biological mechanisms linking diet, exercise, and mental health, offering new insights into how lifestyle factors interact at molecular and cellular levels to influence brain function. The findings challenge existing paradigms about the relationship between metabolic and mental health by demonstrating that exercise can provide antidepressant-like effects even in the context of poor dietary choices. By employing innovative metabolomic approaches combined with comprehensive behavioral and neurobiological assessments, the research team has generated data that not only advances fundamental knowledge but also suggests practical applications for addressing the mental health challenges associated with modern dietary patterns. The reproducibility and validation of these findings through the peer-review process ensures their reliability and positions them as a foundation for future investigations. This work exemplifies how cutting-edge research can bridge the gap between basic science and translational applications, potentially impacting individuals struggling with mood disorders in the coming years.

Published in Nature Medicine, the Phase III AMPLITUDE trial tested whether adding niraparib, a targeted cancer therapy known as a PARP inhibitor¹, could enhance the effectiveness of the current standard treatment, abiraterone acetate and prednisone (AAP).²

Targeting Genetic Weaknesses in Prostate Cancer

The study focused on men with advanced prostate cancer that had spread to other parts of the body and who were beginning treatment for the first time. All participants had mutations in genes involved in homologous recombination repair (HRR), a key system that helps repair damaged DNA.

When these DNA repair genes malfunction, cancer cells can multiply and spread more rapidly. About one in four men with advanced prostate cancer at this stage have mutations in HRR-related genes, including BRCA1, BRCA2, CHEK2, and PALB2.

How the Study Was Conducted

Currently, the standard treatment for advanced prostate cancer is AAP (or similar drugs). Roughly one in five patients also receive docetaxel chemotherapy. However, patients with HRR gene mutations typically experience faster disease progression and shorter survival under standard care.

The AMPLITUDE trial, led by Professor Gerhardt Attard of the UCL Cancer Institute, involved 696 men across 32 countries, with a median age of 68. Half received the combination of niraparib and AAP, while the other half received standard AAP treatment with a placebo. More than half of the participants (55.6%) carried mutations in BRCA1 or BRCA2.

The trial was double-blind, meaning neither the patients nor their doctors knew who received the active treatment.

Key Findings from the AMPLITUDE Trial

After a median follow-up period of just over two and a half years (30.8 months), researchers found notable benefits from the drug combination:

• Reduced progression risk: Niraparib lowered the risk of cancer growth by 37% in all participants, and by 48% in those with BRCA1 or BRCA2 mutations.
• Slower symptom worsening: The time until symptoms worsened was about twice as long for those receiving niraparib. Only 16% of these patients experienced significant symptom progression, compared to 34% in the placebo group.
• Potential survival benefit: A trend toward improved overall survival was seen in the niraparib group, though a longer follow-up period is needed to confirm whether it extends life expectancy.

Expert Perspective

Professor Attard said: "Although current standard treatments are very effective for the majority of patients with advanced prostate cancer, a small but very significant proportion of patients have limited benefit. We now know that prostate cancers with alterations in HRR genes account for a significant group of patients whose disease recurs quickly and has an aggressive course. By combining with niraparib we can delay the cancer returning and hopefully significantly prolonging life expectancy.

"These findings are striking because they support widespread genomic testing at diagnosis with use of a targeted treatment for patients who stand to derive the greatest benefit.

"For cancers with a mutation in one of the eligible HRR genes, where niraparib has been approved, a doctor should consider a discussion that balances the risks of side effects against the clear benefit to delaying disease growth and worsening symptoms." ³

Side Effects and Safety

While the treatment was generally well tolerated, side effects were more common in the niraparib group. Significantly more cases of anemia and high blood pressure were reported with niraparib, and 25% of patients required blood transfusions. Treatment-related deaths were also higher in the niraparib group (14 versus 7), though overall discontinuation rates remained low.

The study's authors note that while the results are promising, further research is needed to confirm long-term survival benefits and to explore the impact of newer imaging techniques and broader genetic testing.

Prostate Cancer: Key Statistics

Globally, an estimated 1.5 million men are diagnosed with prostate cancer each year. In the UK prostate cancer is the most common cancer in men, with more than 56,000 men diagnosed every year, and around 12,000 men die from the disease each year.

The AMPLITUDE trial was sponsored by Janssen Research & Development, part of Johnson & Johnson.

Notes

1. PARP inhibitors, such as niraparib, are a type of targeted therapy that work by blocking the PARP protein, which is involved in repairing damaged DNA in cancer cells. By inhibiting PARP, the cancer cells are unable to repair the DNA damage, leading to their death.
2. Abiraterone acetate and prednisone (APP) are both hormone therapies. This combination blocks androgen production in the testes, adrenal glands, and the tumor itself, slowing cancer growth by reducing the available testosterone for the cancer cells.
3. In the UK, Niraparib is approved to treat some types of cancer but has not yet been approved for prostate cancer. The National Institute for Clinical Excellence has said it waiting for further information, before it can make a decision. https://www.nice.org.uk/guidance/ta1032^[1]