Introduction:

As a team of researchers in basic medical science, we strive to uncover the underlying mechanisms behind cancer-related complications and explore potential therapeutic strategies. During our interactions with clinicians, a recurring concern emerged—cognitive impairment in hepatocellular carcinoma (HCC) patients, known as cancer-related cognitive impairment (CRCI). CRCI is a significant challenge in clinical oncology, affecting the cognitive function and quality of life of cancer patients. The current understanding of CRCI is limited, and effective interventions are lacking. While the impact of cancer and its treatments on the brain have been acknowledged, the role of the gut microbiota in this context has emerged as a novel and promising area of investigation.

Study Design and Methodology:

In this study, our primary objective was to investigate the influence of HCC growth on the composition of the gut microbiota and its subsequent impact on hippocampus-related cognitive functions. We assembled a multidisciplinary team comprising cancer immunologists and neural scientists that enabled us to conduct a comprehensive exploration of the tumor-gut-immune-brain axis, unveiling the relationship between cancer and cognitive impairment.
We began our study by establishing a murine orthotopic HCC model that mimics the complex tumor microenvironment observed in patients. Additionally, we designed and implemented rigorous assessments of hippocampal function and cognitive plasticity. Specifically, we employed well-recognized models of hippocampal memory functions, including long-term potentiation (LTP) and synaptic tagging/capture (STC), to assess the impact of tumor growth on cognitive plasticity.

Impaired Cognitive Plasticity in HCC Tumor-Bearing Mice

Our findings revealed impaired STC in the hippocampus of tumor-bearing mice, suggesting a deficit in associative plasticity. These observations were consistent with the clinical reports of cognitive impairment in HCC patients and provided a solid foundation for our subsequent investigations.

Gut Microbiota Alterations in HCC Tumor-Bearing Mice

Simultaneously, we conducted a comprehensive analysis of the gut microbiota composition in our HCC tumor-bearing mice and compared it to that of control mice. This analysis revealed significant alterations in the gut microbiota of tumor-bearing mice, characterized by a decrease in beneficial bacteria, such as Lactobacillus, and an increase in potentially harmful bacteria, including Bacteroides. Importantly, these observations mirrored findings from clinical studies, highlighting the relevance and significance of our research.

Association between Microbiota Alteration and Cognitive Impairment

Building upon these initial observations, we investigated the potential association between gut microbiota alteration and STC impairment in the HCC tumor-bearing mice. Remarkably, we observed that sterilization of the gut microbiota restored the STC in the hippocampus of the tumor-bearing mice, suggesting a strong association between microbiota alteration and STC impairment. We further investigated the underlying mechanisms driving the observed cognitive impairment. Our analysis revealed elevated levels of interleukin-1β (IL-1β), a critical pro-inflammatory cytokine, in both the serum and hippocampus of tumor-bearing mice. IL-1β, a critical pro-inflammatory cytokine, has been implicated in various neuroinflammatory processes. In our study, we found that IL-1β played a pivotal role in disrupting hippocampal synaptic plasticity, a key mechanism underlying learning and memory formation.
Based on these compelling findings, we proposed potential therapeutic interventions for CRCI. Firstly, we explored the use of fecal transplantation, a procedure that involves the transfer of fecal contents from healthy donor mice to tumor-bearing mice. This approach aimed to restore the normal microbiota composition and promote cognitive recovery. Remarkably, fecal transplantation significantly rescued the STC in the tumor-bearing mice, suggesting its potential as a therapeutic strategy for CRCI.

Therapeutic Interventions for CRCI

Additionally, given the crucial role of IL-1β in hippocampal dysfunction, we investigated the possibility of neutralizing IL-1β as a therapeutic intervention. Using neutralizing antibodies, we successfully restored the STC in the HCC tumor-bearing mice, further supporting the critical role of IL-1β in hippocampal cognitive dysfunction. These findings open up new avenues for the development of targeted immune therapies to mitigate CRCI and improve patient outcomes.
The implications of our findings are far-reaching in terms of clinical applications. Our research highlights the significance of the gut microbiota and its interaction with the immune system in cancer-related cognitive impairment. It provides novel insights into the underlying mechanisms and offers potential therapeutic targets for intervention. 

Conclusion:

In conclusion, our study revealed the role of tumor-induced gut microbiota alterations in cancer-related cognitive impairment. Through a multidisciplinary approach and close collaborations, we have shed light on the relationships among cancer,  gut microbiota, and cognitive functions. Our findings provide compelling evidence for the liver/tumor-gut-immune-brain axis and highlight the therapeutic potential of targeting gut microbiota and/or IL-1β signaling in alleviating cognitive dysfunction. These discoveries pave the way for further research and the development of personalized treatment strategies to improve the quality of life for cancer patients.