Gut Bacteria Make Chemotherapy More Effective

A new study shows how gut microbiota increases the sensitivity of colorectal cancer cells to chemotherapy. Reducing cancer proliferation and promoting cell death.

July 28, 2022

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Colorectal cancer (CRC) is the third most common cancer that causes death worldwide. It is of particular concern in the developed world where risk factors such as an increasingly sedentary lifestyle, a diet high in processed food and fats but low in fiber, along with increasing levels of obesity all raise the individual and societal risk for CRC.[1] From a mortality and morbidity perspective, a critical obstacle to the treatment of CRC is the recurrence of the disease post-treatment which has a significant negative impact on long-term survival rates. Worse still, these recurrent tumors often show increased resistance to chemotherapy drugs, often resulting in the death of the patient. Existing chemotherapy drugs suffer from toxicity, and side effects that worsen as doses are increased to combat chemo-insensitive, recurrent CRC, worsening the patient’s quality of life until further treatment is no longer viable and must be replaced with palliative care. There is clearly a need for therapeutic strategies in addressing CRC that increase the sensitivity of the tumor cells to chemotherapy compounds, allowing reduced dosing, minimizing side effects, and enabling effective therapy to continue.

 

Treatment of colorectal cancer

 

The most widely used, front-line chemotherapy drug in the treatment of CRC is 5-fluorouracil (5-FU), however over time recurrent CRC tumors will tend to develop resistance to 5-FU, and negative side effects for the patient place an upper limit on dosing to address this. On top of this, 5-FU resistant CRC cells have been shown to exhibit an aggressive phenotype with increased cell invasion and metastasis.

 

The role of butyrate in colorectal cancer

 

Butyrate is a short-chain fatty acid (SCFA) derived from dietary fiber by bacterial fermentation in the colon and is an important mediator of colonic cell homeostasis. Butyrate is efficiently absorbed by colonic epithelial cells and provides the primary energy source for the cells of the colon. Furthermore, butyrate is detrimental to cancerous cells due to the Warburg effect, a well-documented phenomenon common to most cancers wherein the cancerous cells can only derive energy from simple sugars via aerobic glycolysis, or fermentation. The inability to utilize butyrate leads to a buildup inside the CRC cells, particularly within the nucleus where it acts as a histone deacetylase inhibitor and works to suppress CRC cell proliferation while promoting apoptosis.

 

Gut microbiota work to destroy cancer cells

 

The gut microbiota provides a beneficial therapeutic effect by targeting cancer cells through several anti-cancer pathways. Among these beneficial bacteria, Lactobacillus plantarum[2]  has been shown to contribute significantly to the health of its human host and previous studies have confirmed its effectiveness in the treatment of CRC.

 

In a recent study Kim et al., demonstrated the role and mode of action of the beneficial gut bacteria L.plantarum in increasing the sensitivity of 5-FU resistant CRC cells to chemotherapy, as well as reducing proliferation, and inducing apoptosis in the cancerous cells. [2] The authors showed that the acquisition of butyrate resistance in a common strain of 5-FU resistant CRC cells (HCT116/5FU) was strongly correlated with the inhibition of the expression and function of the SMCT1 gene, which encodes a major transporter protein used to transfer butyrate across the cell membrane and into colonic epithelial cells. It is this gene that becomes silenced in butyrate insensitive CRC cells, a conclusion that is further supported by previously published studies showing a positive correlation between SMCT1 expression levels in CRC cells with remission and patient survival.

 

The authors utilized cultured L. plantarum cells to generate a cell-free supernatant that could be used in experiments on cultured HCT116/5FU cells to determine levels of apoptosis, and cellular activity under a range of different conditions including treatment with butyrate and chemotherapy drugs both alone and in combination. Critical to the success of the experiments is the ability to produce a consistent L. plantarum supernatant that can be used in the experiments. L. plantarum cultures were prepared, and 4 mL samples taken at 6, 12, 24, and 48 hours corresponding to different points in the growth phase of the bacteria. Sample concentrations were assayed, and samples centrifuged and filtered ready for use. The authors selected AcrodiscÒ 0.2 mm membrane filters for the critical filtration step, these filters are designed for the filtration of samples up to 10 mL with an effective filtration area of 1.0 cm2 providing high flow rates and resistance to filter clogging from suspended particulate matter. The filters are also HPLC compatible, with certified low levels of extractables ensuring the finished cell-free supernatant was usable for downstream HPLC which made up part of the experimental protocol.

 

Using this high purity cell-free supernatant, the authors were able to demonstrate that L. plantarum was able to restore the functional expression of SMCT1 in HCT116/5FU cells with a resultant butyrate-induced antiproliferative effect and apoptosis. This work further supports the potential to leverage the microbiota of cancer patients, in particular L. plantarum, as a potential chemosensitizer to address CRC resistance to 5-FU and butyrate in patients. An important step forward in understanding and addressing the critical obstacle of recurrence after treatment in CRC patients.

 

You can find out more about the Acrodisc filters used in this study as well as the other application-specific Acrodisc products on the Pall website.

 

 

References

 

 

 

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