Lactobacillus plantarum-derived metabolites sensitize the tumor-suppressive effects of butyrate by regulating the functional expression of SMCT1 in 5-FU-resistant colorectal cancer cells

Kim, Hyeju; An, JaeJin; Ha, Eun-Mi

doi:10.1007/s12275-022-1533-1

Cited by 28 publications

(20 citation statements)

References 81 publications

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“…Additionally, we hypothesized that, if higher fecal SCFA would re ect higher production, it would be associated with better tumor response. This was expected based on the earlier described anticarcinogenic effects of particularly butyrate (11,49), but also valerate and propionate (44). While butyrate is the preferred energy substrate for normal colonocytes, cancer cells preferably consume glucose.…”

Section: Discussionmentioning

confidence: 67%

“…For instance, Encarnação et al observed anti-proliferative effects of butyrate and a synergistic effect of irinotecan and butyrate in different colon cancer cell lines (10). Very recently, Kim et al described anti-carcinogenic effects of butyrate in colon cancer cell lines, which could be potentiated by the addition of a growth medium from Lactiplantibacillus plantarum in butyrate-resistant cells (11). Furthermore, SCFA might reduce (gastrointestinal) side effects of the chemotherapy, which are commonly caused by intestinal barrier disruption and in ammation (12).…”

Section: Introductionmentioning

confidence: 99%

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Fecal levels of SCFA and BCFA during capecitabine in patients with metastatic or unresectable colorectal cancer

Ziemons

Aarnoutse

Heuft

et al. 2023

Preprint

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Background Short-chain fatty acids (SCFA) and branched-chain fatty acids (BCFA) are produced by the gut microbiota and are considered to fulfill crucial physiological roles. Previous pre-clinical studies also indicated bi-directional interactions between gut bacteria and the chemotherapeutic capecitabine or its metabolite 5-FU. However, evidence from clinical studies in this field of research is scarce. This study investigated the effect of three cycles of capecitabine on fecal SCFA and BCFA levels and their associations with tumor response, nutritional status, physical performance, chemotherapy-induced toxicity, systemic inflammation, and bacterial abundances in patients with colorectal cancer (CRC). Methods Forty-four patients with metastatic or unresectable CRC, scheduled for treatment with capecitabine (± bevacizumab), were prospectively enrolled in a multicentre cohort study. Patients collected a fecal sample and completed a questionnaire before (T1), during (T2), and after (T3) three cycles of capecitabine. Tumor response (based on CT/MRI scans), nutritional status (MUST score), physical performance (Karnofsky Performance Score), and chemotherapy-induced toxicity (CTCAE) were recorded. Additional data on clinical characteristics, treatment regimen, medical history, and blood inflammatory parameters were collected. Fecal SCFA and BCFA concentrations were determined by gas chromatography-mass spectrometry (GC-MS). Gut microbiota composition was assessed using 16S rRNA amplicon sequencing. Results Fecal levels of the SCFA valerate and caproate decreased significantly during three cycles of capecitabine in our patient population. Furthermore, baseline levels of the BCFA iso-butyrate were associated with tumor response. Nutritional status, physical performance, and chemotherapy-induced toxicity were not statistically significantly associated with SCFA or BCFA. Baseline SCFA correlated positively with blood neutrophil counts. At the three sampling timepoints, we identified associations between SCFA and BCFA and the relative abundance of bacterial taxa on family level. Conclusions The present study provided the first indications for a role of SCFA and BCFA during treatment with capecitabine as well as implications and recommendations for further research. More knowledge in this field will contribute to the evidence-based design of interventions targeting the gut microbiota and/or SCFA/BCFA production to optimize chemotherapy efficacy. Trial registration The current study was registered in the Dutch Trial Register (NTR6957) on 17/01/2018 and can be consulted via the International Clinical Trial Registry Platform (ICTRP).

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Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Fecal levels of SCFA and BCFA during capecitabine in patients with metastatic or unresectable colorectal cancer

Ziemons

Aarnoutse

Heuft

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…CRC cells that are 5-FU-resistant show cancer stem-cell-like properties and can induce early tumor recurrence or metastasis [ 51 , 52 ]. Therefore, novel therapeutic strategies are needed to overcome chemoresistance and increase the efficacy of anticancer drugs [ 53 , 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

“…L. plantarum and its metabolites have an inhibitory effect on chemoresistant CRC cells, especially 5-FU-resistant CRC cells [ 32 , 51 , 53 , 54 ]. L. plantarum can exhibit anticancer effects by increasing the cytotoxicity and death of CRC cells or reducing NLRP3 and ERK phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…Altered glycolysis increases glucose uptake and lactate production [ 42 ] and can promote acidic conditions, one of the hallmarks of cancer as well as chemoresistance [ 45 , 65 , 66 , 67 , 68 ]. However, L. plantarum metabolites can reverse altered glycolysis mechanisms, thereby decreasing cancer cell proliferation, increasing apoptosis, and decreasing chemoresistance [ 53 , 54 ]. Thus, L. plantarum metabolites can induce therapeutic effects and prevent cancer recurrence.…”

Section: Discussionmentioning

confidence: 99%

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Lactobacillus plantarum Metabolites Elicit Anticancer Effects by Inhibiting Autophagy-Related Responses

et al. 2023

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Lactobacillus plantarum (L. plantarum) is a probiotic that has emerged as novel therapeutic agents for managing various diseases, such as cancer, atopic dermatitis, inflammatory bowel disease, and infections. In this study, we investigated the potential mechanisms underlying the anticancer effect of the metabolites of L. plantarum. We cultured L. plantarum cells to obtain their metabolites, created several dilutions, and used these solutions to treat human colonic Caco-2 cells. Our results showed a 10% dilution of L. plantarum metabolites decreased cell viability and reduced the expression of autophagy-related proteins. Moreover, we found co-treatment with L. plantarum metabolites and chloroquine, a known autophagy inhibitor, had a synergistic effect on cytotoxicity and downregulation of autophagy-related protein expression. In conclusion, we showed the metabolites from the probiotic, L. plantarum, work synergistically with chloroquine in killing Caco-2 cells and downregulating the expression of autophagy-related proteins, suggesting the involvement of autophagy, rather than apoptosis, in their cytotoxic effect. Hence, this study provides new insights into new therapeutic methods via inhibiting autophagy.

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A Review of Gut Microbiota‐Derived Metabolites in Tumor Progression and Cancer Therapy

et al. 2023

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Gut microbiota‐derived metabolites are key hubs connecting the gut microbiome and cancer progression, primarily by remodeling the tumor microenvironment and regulating key signaling pathways in cancer cells and multiple immune cells. The use of microbial metabolites in radiotherapy and chemotherapy mitigates the severe side effects from treatment and improves the efficacy of treatment. Immunotherapy combined with microbial metabolites effectively activates the immune system to kill tumors and overcomes drug resistance. Consequently, various novel strategies have been developed to modulate microbial metabolites. Manipulation of genes involved in microbial metabolism using synthetic biology approaches directly affects levels of microbial metabolites, while fecal microbial transplantation and phage strategies affect levels of microbial metabolites by altering the composition of the microbiome. However, some microbial metabolites harbor paradoxical functions depending on the context (e.g., type of cancer). Furthermore, the metabolic effects of microorganisms on certain anticancer drugs such as irinotecan and gemcitabine, render the drugs ineffective or exacerbate their adverse effects. Therefore, a personalized and comprehensive consideration of the patient's condition is required when employing microbial metabolites to treat cancer. The purpose of this review is to summarize the correlation between gut microbiota‐derived metabolites and cancer, and to provide fresh ideas for future scientific research.

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Lactobacillus plantarum-derived metabolites sensitize the tumor-suppressive effects of butyrate by regulating the functional expression of SMCT1 in 5-FU-resistant colorectal cancer cells

Cited by 28 publications

References 81 publications

Fecal levels of SCFA and BCFA during capecitabine in patients with metastatic or unresectable colorectal cancer

Fecal levels of SCFA and BCFA during capecitabine in patients with metastatic or unresectable colorectal cancer

Lactobacillus plantarum Metabolites Elicit Anticancer Effects by Inhibiting Autophagy-Related Responses

A Review of Gut Microbiota‐Derived Metabolites in Tumor Progression and Cancer Therapy

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