Antitumor effects of fecal microbiota transplantation: Implications for microbiome modulation in cancer treatment

Abstract

Fecal microbiome transplantation (FMT) from healthy donors is one of the techniques for restoration of the dysbiotic gut, which is increasingly being used to treat various diseases. Notably, mounting evidence in recent years revealed that FMT has made a breakthrough in the oncology treatment area, especially by improving immunotherapy efficacy to achieve antitumor effects. However, the mechanism of FMT in enhancing antitumor effects of immune checkpoint blockers (ICBs) has not yet been fully elucidated. This review systematically summarizes the role of microbes and their metabolites in the regulation of tumor immunity. We highlight the mechanism of action of FMT in the treatment of refractory tumors as well as in improving the efficacy of immunotherapy. Furthermore, we summarize ongoing clinical trials combining FMT with immunotherapy and further focus on refined protocols for the practice of FMT in cancer treatment, which could guide future directions and priorities of FMT scientific development.

Keywords: FMT; cancer; fecal microbiota transplantation; gut microbiota; immunotherapy.

Figure 1

Gut-microbiome-mediated mechanisms of oncogenesis and progression. Factors such as the host genetics, unhealthy dietary components, medication, and aging cause gut dysbiosis. Inflammatory markers such as TNF-α and interleukins such as IL-17 are activated by the corresponding pathogenic microbial strains via the NF-κB or STAT3 pathways thereby inducing cell proliferation. Microbial strains such as Segmented filamentous bacteria (SFB) are effective inducers of Th17 cells in the SILP. E. coli induces DNA damage and thus promotes tumorigenesis through the release of virulent substances such as coliphage. Clostridium nucleatum activates the differentiation of myeloid-derived suppressor cells (MDSCs) and further induces reactive oxygen species (ROS), leading to MutL homolog 1 (MLH-1) methylation and microsatellite instability (MSI), leading to tumor progression. Activated MDSCs also inhibit T cell differentiation and promote tumor progression through activation of Arg1 and NOS2-mediated antitumor immunity (adapted from 16). F, nucleatum also stimulates cell proliferation through activation of the Wnt/β-linked protein pathway. Many components of our daily diet are metabolized by bacteria in the digestive tract and produce the corresponding metabolites such as secondary bile acids, which promote carcinogenesis. Furthermore, intestinal microbiota, microbial metabolites, immune cells and cytokines can also produce carcinogenic effects at different sites in the distal part of the body through blood circulation. (The figure was created with Biorender.com).

Figure 2

Local effects of the gut microbiota on CRC development. Clostridium nucleatum promotes tumor development through multiple mechanisms. Its production of the virulence factor FadA can lead to increased expression of membrane-linked protein A1 via E-calmodulin, which in turn activates Wnt/β-linked protein signaling. The wnt ligand, a secreted glycoprotein, can bind to coiled-coil receptors and form larger cell surface complexes with lipoprotein receptor-associated protein (LRP). Displacement of the multifunctional kinase GSK-3β from the regulatory APC/Axin/GSK-3β complex is triggered by the activated Wnt receptor complex. The stable β-linked protein translocates to the nucleus, displaces the co-inhibitor upon binding to LEF/TCF transcription factors, and recruits the coactivator. Lipopolysaccharide (LPS) in F. nucleatum causes the activation of the nuclear factor κ light chain enhancer (NF-κB) signaling pathway in activated B cells. The conventional signaling pathway is that NF-κB/Rel proteins bind to and are inhibited by IκB proteins. Lipopolysaccharide (LPS) activates IKK complexes (IKKβ, IKKα, and IKKγ) via toll-like receptors (TLR) to phosphorylate IκB proteins. IκB phosphorylation leads to its ubiquitination and proteasomal degradation followed by release of NF-κB/Rel complexes. The active NF-κB/Rel complex is further translocated into the nucleus and induces target gene expression. Another important signaling pathway that activates cytokines is the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. When STAT is phosphorylated, it polymerizes into an activated form of transcriptional activator and enters the nucleus to bind to target genes and promote their transcription.

Figure 3

Various approaches for modification of the dysbiotic gut. Dietary modifications such as increasing dietary fiber, antibiotic treatment for pathogenic bacteria, probiotics to increase the colonization of beneficial bacteria in the gut, and fecal microbiome transplantation (FMT) are all options for regulating intestinal flora imbalance (adapted from 16). (The figure was created with Biorender.com).

Figure 4

Fecal microbiome transplantation (FMT) from a healthy donor improves the process of dysbiosis and various disorders in patients. FMT can treat many diseases including Clostridioides Difficile infections (CDIs), colonized with multidrug-resistant organisms (MDROs), inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and neurological disorders including multiple sclerosis (MS), hepatic encephalopathy (HE), Parkinson’s disease, diabetic neuropathy and so on. On the one hand, FMT may improve the gut microbiological environment in patients with insignificant therapeutic efficacy or severe side effects. On the other hand, FMT has antitumor effects and/or reduces the occurrence of associated toxic events (combination FMT with immunotherapy, chemotherapy or radiotherapy). (The figure was created with Biorender.com).