Chemotherapy is one of the cancer treatment methods, but some anticancer agents appear to
influence the occurrence and progression of cachexia. Chemotherapy-Induced Cachexia
refers to symptoms such as appetite loss, weight loss, muscle mass reduction, and fatigue
caused by chemotherapy. While anticancer agents are used to eliminate or suppress tumor
cells, most are administered intravenously, potentially causing damage not only to tumor
cells but also to healthy cells and tissues. Cyclophosphamide, 5-fluorouracil (5-FU), and
cisplatin induce negative nitrogen balance leading to weight loss, while cisplatin,
irinotecan, adriamycin, and etoposide can cause muscle wasting through NF-κB activation.
Additionally, muscle loss due to combination chemotherapy like FOLFIRI (5-fluorouracil,
irinotecan, cisplatin) is associated with extracellular signal-regulated kinase 1/2
(ERK1/2) and p38 mitogen-activated protein kinase activation. Furthermore, research
approached from a metabolic perspective has shown clear differences between
cancer-induced cachexia and chemotherapy-induced cachexia, highlighting the need to
differentiate and study cachexia induced by anticancer agents separately from cancer
cachexia. In conclusion, while anticancer agents are essential for the demise of cancer
cells and the inhibition of tumor growth, the occurrence of cachexia due to
chemotherapy-induced damage to normal cells through prolonged administration poses a
challenge that needs to be addressed to maintain the overall health of patients.
On the other hand, the microbiome refers to the total sum of all microorganisms present
in a specific environment, and the human microbiome specifically refers to the collection
of commensal, symbiotic, and pathogenic microorganisms coexisting with the human body.
Approximately 95% of all microbes reside in the gastrointestinal tract, including the
colon, and they are also widely distributed in the respiratory, reproductive, oral, and
skin systems. The gut microbiome is known to play a crucial role in nutrient absorption,
immune system regulation, and prevention of infectious diseases within the body.
Several studies suggest that changes in the composition and function of the gut
microbiome may contribute to the development and progression of cachexia in cancer
patients undergoing chemotherapy. In experiments where gut microbiota from mice treated
with chemotherapy were transplanted into germ-free mice, an increase in
inflammation-related C-X-C motif chemokine ligand 1 (CXCL1) was observed in the germ-free
mice, accompanied by a significant decrease in their movement and physical activity. This
result indicates that chemotherapy induces changes in the gut microbiota, which in turn
can impact the entire body.
Chemotherapy can induce dysbiosis, an imbalance in the microbial community structure,
leading to a reduction in beneficial bacteria and overgrowth of harmful bacteria, which
can trigger inflammation and impair intestinal barrier function. Ultimately, this can
promote inflammatory responses, exacerbating muscle loss and weight loss in cancer
patients. Moreover, it can also affect nutrient absorption and metabolism, leading to
malnutrition and energy imbalance.
Additionally, gut microbial communities produce various metabolites, such as short-chain
fatty acids (SCFAs), which play important roles in host metabolism and immune function
regulation. Dysbiosis may affect intestinal protein synthesis and energy metabolism.
Overall, the profound involvement of the gut microbiome and metabolites in
chemotherapy-induced cachexia symptoms suggests that microbiome-based therapies could be
an interesting development target for alleviating or treating chemotherapy-induced
cachexia.
Probiotics are generally known to improve gastrointestinal conditions such as
constipation and diarrhea, inhibit harmful bacteria in the gut, and prevent diseases
through their regulatory effects on intestinal function. They are also known to have
effects such as immune enhancement, improvement of vaginal health, and alleviation of
allergies. In particular, there is ongoing global research aimed at developing probiotics
as therapeutic agents for the microbiome, which constitutes the total microorganisms in
the gut. Recently, with the FDA approval of microbiome therapy for clostridiosis
difficile infection, research in this area has been increasing.
The test strain of Lactobacillus reuteri ATG-F4 used in this study has been confirmed to
be safe based on preclinical research results. When administered to mice transplanted
with tumors and then treated with anticancer agents, it was observed to improve weight
loss, muscle mass reduction, and muscle strength decline. Additionally, it helped
alleviate diarrhea symptoms and normalize gut microbiota. These effects were found to be
associated with the suppression of inflammatory responses induced by anticancer agents.
Based on previous studies, this trial was planned to analyze the impact of the
investigational product LT-002 (Lactobacillus reuteri ATG-F4) on the safety and
improvement of anticancer agent side effects in cancer patients.