Williams Cancer Institute

Role of the gut microbiota in anticancer therapy

How the human microbiota interacts with cancer is the question Lin-Yong Zhao et. al. wanted to answer in their review article whose purpose is to summarize initial insights into the molecular mechanisms that underlie the interplay between gut microbiota and cancer development. It also aims to highlight how gut microbes can influence the outcomes of various cancer treatments, including immunotherapy, chemotherapy, radiation therapy, and surgery.

We know that the human microbiota is composed of nearly 40 trillion microorganisms with 3000 species, including bacteria, fungi, and viruses, exhibiting variable richness among microbes and diverse constituents among individuals; most of these microbes are in the gastrointestinal tract, more specifically in the colon; this “gut microbiome” is known to have a lot of physiological functions as immune system development, and synthesis of the nutrients. Normal gut microbiota plays a crucial role in the development of the host’s immune system. The absence of a healthy gut microbiota can lead to structural and functional impairments in the immune system, which may be linked to the initiation of cancer. The gut microbiota influences the immune system in two fundamental ways:

  1. a) Promoting Maturation of Lymphoid Organs:The microbiota contributes to the maturation of lymphoid organs, which are essential for the development of B- and T-lymphocytes. These central lymphoid organs include the bone marrow and thymus.
  2. b) Differentiation of Immune Cells: Microorganisms also influence the differentiation of immune cells, which is crucial for the functioning of the immune system. This aspect reflects how microorganisms impact the function of the immune system.

In addition to microorganisms within the digestive tract, the intratumoral microbiota has also drawn increasing since microbes colonizing the tumor microenvironment (TME) may be one of the causes leading to the cancer progression and the discrepancies in the efficacy of cancer therapies among patients. The TME, due to its angiogenic nature, immune privilege, and the immunosuppressive effects of microbes, provides an environment that is well-suited for the invasion and proliferation of microbes within tumors. This has implications for understanding the complex interactions between the microbiota and cancer development. Evidence from animal experiments has shown that microbes can facilitate the initiation and progression of various types of cancer including gastric cancer, colorectal cancer, hepatocellular carcinoma, breast cancer, and pancreatic ductal adenocarcinoma. poor response after receiving cancer treatment, including chemotherapy, radiotherapy, surgery, and immunotherapy, can be partially ascribed to some microbes, which was also confirmed in mice.

Mechanism of microbes in tumorigenesis:

Cancer-promoting bacteria may participate in the process of oncogenesis through a variety of different molecular pathways:

  1. DNA damage and epigenetics alterations.
  2. Interference with the DNA damage response (DDR)
  3. Abnormal signaling pathways; and
  4. Immune suppression.

Also, Insulin resistance has the potential to stimulate the growth of cancer via mTOR activation and it leads to metabolic changes that promote cancer growth. Thus, it is possible that gut microbiota dysfunction that induces insulin resistance may contribute to tumor development.

Additionally, microbes may be involved in cancer development via epigenetic mechanisms like the methylation of DNA, the posttranslational modification of histones, chromatin remodeling and regulation by noncoding RNAs, of which the methylation of DNA.

In this review, they explain the various ways in which the gut microbiota can interact with cancer development, both directly and indirectly:

  • Contact-Dependent Interactions:
  1. a) Gut microbes can interact directly with the gastrointestinal tract mucosal surface, leading to various effects such as genotoxic effects, epithelial cell proliferation, loss of cellular polarity, and the development of intestinal metaplasia.
  2. b) Microbiota can stimulate hematopoiesis in the thymus and bone marrow through signaling pathways, especially after hematopoietic stem cell transplant (HSCT), potentially providing radio-protective effects in radiotherapy.
  3. c) Gut microbes and their products can interact with gut-associated lymphoid tissues (GALT), lymph nodes (LN), and the spleen. They influence the regulation of T cells and dendritic cells, affecting various immune responses, such as enhancing TH17 responses, interferon (IFN) production, antigen presentation, and signaling involving IFN-1, IL-12, and Toll-like receptor 4 (TLR4).
  • Contact-Independent Interactions:
  1. a) Microbes in the gut and tumor can influence the tumor microenvironment (TME) through immunostimulatory and immunosuppressive effects. This includes presenting microbial-specific antigens to T cells and regulating the balance between regulatory T cells and tumor-infiltrating lymphocytes (TILs).
  2. c) Microbiome-secreted metabolites and outer membrane vesicles (OMVs) can impact the TME by modulating the innate immune response, including the recruitment and activation of innate immune cells like neutrophils, which produce tumor necrosis factor α (TNFα) and reactive oxygen species (ROS) to combat tumorigenesis. They can also influence the adaptive immune response by co-stimulating T cells.

Mechanisms of microbes in tumor suppression:

while some bacterial toxins can contribute to cancer development, others have shown promise as direct anticancer agents. These toxins have the potential to be used in the development of novel chemotherapy agents, for example:

Clostridium perfringens enterotoxin (CPE): CPE is a virulence factor associated with food poisoning caused by Clostridium perfringens type A. Interestingly, CPE can also target cancer cells. It does so by binding to transmembrane tight junction proteins known as claudin-3 and claudin-4, which are often highly expressed in various human cancers, including breast, prostate, and colon cancer. When CPE interacts with claudins, it triggers the formation of a pore complex in the cell’s plasma membrane. This disrupts the osmotic equilibrium between the inside and outside of the cell, ultimately leading to cell death.

Other Bacterial Toxins: Several other bacteria, including Pseudomonas aeruginosa, Salmonella typhimurium, and Clostridium difficile, produce toxins that have demonstrated anticancer activity. These toxins can potentially be harnessed for their anticancer properties.

Bifidobacterium pseudolongum, Olsenella, and Lactobacillus johnsonii: its effects are attributed to the presence of the metabolite inosine: Inosine is considered an immunotherapy-promoting metabolite. Experimental evidence has shown that inosine can influence various types of cancer, including colon cancer, bladder cancer, and melanoma. is thought to trigger the activation of Th1 cells by regulating T-cell-specific A2AR signaling. This mechanism plays a role in enhancing the effectiveness of immune checkpoint inhibitors (ICIs). Suggesting that the development of adjuvant therapies based on inosine may enhance the efficacy of ICIs in cancer treatment.

B-vitamins: Vitamin B plays a significant role in DNA and protein synthesis and is involved in one-carbon metabolism. Gut bacteria have the capability to synthesize various B vitamins, including B1, B2, B3, B5, B6, B7, B9, and B12, which are essential for human health. B vitamins, including those synthesized by gut bacteria, can impact tumorigenesis through the ser-gly one-carbon (SGOC) pathway.

Development of Chemotherapy Agents: There is potential for the development of new chemotherapy agents derived from these microbial toxins or their modified, less toxic derivatives. Genetic engineering techniques may be employed to modify virulence factors to reduce their toxicity to normal cells while retaining their anticancer properties.

The carcinogenic and anti-cancer mechanisms of microbes are extremely intricate. Human microbiota can be modified to boost the host response to the existing anti-cancer therapies and minimize the corresponding adverse toxicities and reduce drug resistance in immunotherapy, chemotherapy, cancer surgery, and radiation therapy, and specific interventions targeting the microbiota include diet-based interventions, prebiotics, probiotics, postbiotics, targeted antibiotic approaches, and fecal microbiota transplantation.

  • Immunotherapy: The gut microbiota is emerging as a significant factor that can influence the effectiveness of cancer immunotherapy, particularly immune checkpoint inhibitors. The composition of gut microbes appears to influence how the immune system responds to immunotherapy. t is suggested that the response to ICIs can be predicted based on the composition of gut microbes. The gut microbiota can indirectly affect the response of cancer patients to ICIs by modulating host immunity. As an example, active enterococci can secrete SagA, a molecule that enhances host immunity by binding to the NOD2 pattern recognition receptor. This interaction activates multiple pathways that may ultimately enhance the antitumor efficacy of anti–PD-L1 immunotherapy.
  • Chemotherapy: Understanding how specific gut microbes influence chemotherapy response is essential for improving treatment outcomes and developing personalized cancer therapies. The variations in how cancer patients respond to identical chemotherapy drugs may be attributed, at least in part, to differences in the composition of their gut microbiota. For example, butyrate, a product of dietary fiber fermented by gut microbes, could increase the anticancer effects of oxaliplatin by regulating the function of CD8 + T cells in the TME through IL-12 signaling. Another example, the side effects of irinotecan can also be alleviated by taking certain probiotics like E. coli strain Nissle 1917, which could regulate gut barrier epithelial function, alleviate gut dysbiosis, and ultimately reduce intestinal complications caused by irinotecan.
  • Radiotherapy: the basic principles of radiotherapy include two aspects: on the one hand, the DNA of cancer cells is destroyed by ionizing radiation directly to kill cancer cells; on the other hand, RT indirectly kills cancer cells by causing reactive oxygen species-dependent damage to DNA. the presence of some commensal microbes is critical for improving the efficacy of radiotherapy and moderating RT-related adverse events. Fungi have also been found to be associated with the response to radiation therapy, which suggests that other types of secondary microbes in the gut microbiota can also influence the efficacy of radiotherapy.
  • Gut microbiota and therapy-related side effects: It has been noted that the gut microbiome is associated with the toxicity of traditional anticancer therapies and that modulating the components of the gut microbiome may alleviate related toxicity. As an example, Immune checkpoint therapy can cause severe inflammatory side effects, and one of its most serious adverse events is colitis. Some researchers have found that in patients with severe ICI-related colitis, the abundance of Lactobacillus in the gut decreased obviously, and subsequent studies confirmed that the ICI-related colitis could be moderated via oral administration of this probiotic.
  • Fecal microbial transplantation (FMT): refers to the transplantation of the functional flora of healthy donors into the intestinal tract of recipients for the purpose of treating diseases. Following FMT, the abundance of favorable microorganisms, including Ruminococcus and Bifidobacteriaceae, in the recipient’s gut significantly increased, which is associated with improved clinical responses. FMT can improve the anticancer efficacy of ICIs by modifying the recipient’s gut microbial composition and then improving host immunity. In addition to improving the efficacy of anticancer therapy, available evidence has confirmed that FMT could cure adverse events occurring during cancer treatment.

Normal gut microbiota plays a vital role in supporting the development and function of the host’s immune system, which has implications for cancer prevention and immune responses. Understanding the relationship between the gut microbiota and the immune system is essential for exploring potential immunoregulatory mechanisms in cancer prevention and therapy.

Reference: Wenyu Li,Tingtao Chen, 01 Sept 2022, An Insight into the Clinical Application of Gut Microbiota during Anticancer Therapy, https://www.hindawi.com/journals/agmr/2022/8183993/

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