Gut bacteria derived bacteriocins — novel anti-tumor agents

(Eductional article)

Cancer remains one of the leading causes of mortality worldwide, even despite significant advancements in diagnostics (early detection) and treatment options like immunotherapy. Traditional therapies, such as chemotherapy, often lack specificity, resulting in collateral damage to healthy cells. There is an urgent need for the development of new, safer, and more effective cancer treatments with less off target effects and more precision.

However, we might not need to look outside of ourselves for these powerful therapeutic agents.

Some lactic acid and spore-forming bacteria are known for their ability to produce bacteriocins — HU58 (bacillus subtilus) and lactobacillus Reuteri are a few well known producers of bacteriocines. If you’ve been reading the EDU patreon articles and engaging with my instagram Q/A’s, you’ve probably heard me talk about these a few times.

Bacteriocins are antimicrobial peptides that inhibit the growth of pathogenic micro-organisms, particularly in the gut. They play a crucial role in competition among bacterial species and help to establish dominance in particular ecological niches with the gut micro-environment. This makes them particularly powerful tools for modifying the microbiome towards less pathogenic and more beneficial species. You can think of them as targeted antibiotics that don’t negatively impact the good flora in your gut

Bacterocinines aren’t just powerful anti-microbials. They’re also being actively studied as novel anti-tumor agents.

Lactic acid bacteria

LAB are a group of beneficial bacteria commonly found in fermented foods and the human gut microbiome. LAB-derived bacteriocins have gained a fair bit of attention in microbiological research for their potential anti-cancer properties. LAB-derived bacteriocins appear to effectively target cancer cells while sparing healthy cells. For instance, studies have identified specific bacteriocins, such as Lactacin B and Lactacin F, that exhibit strong binding affinities to cancer-related genes, demonstrating some plausible mechanisms through which they may inhibit cancer cell proliferation and inducing apoptosis in malignant cells without affecting normal tissues.

The mechanisms by which LAB bacteriocins exert their anti-cancer effects are still being studied, but various pathways have been proposed

For example, bacteriocins may interfere with critical signaling pathways involved in cancer progression, such as the Wnt signaling pathway. experimental evidence has shown that certain LAB bacteriocins can bind to key proteins like CTNNB1 and LRP5, which are involved in the regulation of colon cancer growrh

Bacteriocins can also trigger programmed cell death in cancer cells, reducing tumor size and preventing distant metastasis. The selective induction of apoptosis in cancer cells is a significant advantage over conventional therapies. LAB and their many metabolites, including bacteriocins and lactic acid, also enhance the immune system's ability to recognize and destroy cancer cells, providing a dual mechanism of action. You can think of bacterial derived metabolites almost as signaling molecules that act very similar to oncotherapies that aim to ‘work with’ the body like immunotherapy

In silico analyses have been employed to predict the efficacy of different bacteriocins (there are many produced by different bacteria) against specific cancer types, particularly colon cancer, where they appear to have the biggest, direct impact. However, gut bacteria derived bacteriocins have also been implicated in the success treatment of brain tumors as well as breast and prostate cancer.

Here’s a list of some bacterocines that have been researched for different cancers:

1. Nisin

Nisin is a well-studied bacteriocin produced by lactococcus lactis. It has anti-tumor potential especially in head and neck cancers. Nisin's mechanism involves inducing apoptosis (aka programmed cell death) in cancer cells, which can be particularly beneficial in treating tumors that are resistant to conventional therapies like chemo. it can also enhance the sensitivity of cancer to chemotherapy, making it a promising adjuvant.

2. Pediocin

Pediocin, along with Nisin, has been found to activate immune cells such as natural killer cells and macrophages. By enhancing the immune response, bacteriocins help the body recognize and eliminate cancer cells more effectively. This immunomodulatory effect opens new avenues for combining bacteriocins with immunotherapy. This is part of the reason why a healthy gut is such a critical linchpin in cancer immunotherapy success.

3. Enterocin AS-48

Enterocin AS-48 is a bacteriocin that disrupts the cell membrane of cancer cells. This membrane-disrupting ability allows it to induce cell death in malignant cells. Its unique mechanism makes it a potential candidate for targeted cancer therapies, particularly in overcoming the limitations of traditional treatments that may not effectively penetrate certain tumors. It appears to have widespread action against a variety of cancer cell types

4. Lactocin 27 and enterocin CRL35

Both Lactocin 27 and Enterocin CRL35 have the ability to hinder angiogenesis, which is the process of new blood vessel formation that tumors rely on to grow and metastasize. By inhibiting angiogenesis, bacteriocins can directly starve tumors of the nutrients and oxygen they need.

5. P28

P28 is a cell-penetrating peptide derived from azurin, a redox-active bacteriocin. Cell-penetrating peptides (PNC-27 being the most well-known CPP studied for cancer ) have the unique ability to cross the blood-brain barrier as well as cell membranes (hence the name), where they can disrupt the metabolism of cancer cells. Many short chain bio-regulator peptides like Vilon are also CPP’s. Think of P28 and other bacteriocins as specialized ‘Trojan horse’ bio-regulators that target and cripple malignant cells

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The ‘leaky gut’ mechanism

chemotherapy opens up the intestinal barrier. Aka "leaky gut". Usually not a good thing, right? However, if you have healthy intestinal micro flora (good bacteria in your gut) some of these bacteria migrate out of the gut (through the leaky barrier) into the lymph nodes and even directly to tumor sites. They act locally at the tumor (almost like a homing beacon) telling the immune system what it needs to attack. This could also be another mechanism through which bacterocines themlseves are able to migrate out of the gut and into tumors. Another possible explanation for the observed tumor-modifying properties of gut-derived bacteria is the local release of these bacterocines directly into the tumor micro-environment.

In the future, it’s possible we could use agents that transiently promote intestinal permeability in order to improve treatment outcomes without as many side effects. Currently, standard of care (chemotherapy and radiation) comes with many downsides and odd target effects to healthy cells. However, it’s becoming increasingly common to see some of these synergistic pairings in the literature (conventional treatment plus nutacuticals) aimed at improving the efficacy of standard oncotherapies while mitigating the downsides.

Next generation medicine shouldn’t kick conventional therapies to the curb — it should seek to intergrate with them.

So, how can you turn your gut into a cancer fighting, bacteriocin producing factory?

1. You can supplement with spore-forming bacteria found in probiotics like Just Thrive and and MegaSpore

2. You can reintroduce known strains of keystone bacteria like lactobacillus Reuteri in particular as well as lactis. Using these as a starter culture for yogurt (YouTube ‘SIBO yogurt’ for culture guides and instructions ), along with some other well-known bacterocine producing strains like pediococcus acidilactici (common in some fermented vegetables and yogurts) is best.

https://www.nutrimaxcity.com/product-page/nutrilots-plant-based-probiotic-lemon

https://www.oxiceutics.com/pages/myreuteri?srsltid=AfmBOoq0O1fEfKGsbIDuDpEC_gYFIx1nuB-op7tgPisquGikte2JifKN