Beneficial insights into postbiotics against colorectal cancer

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TL;DR

This review examines the potential of postbiotics—non-living microbial preparations and their components—as a safer and more stable alternative to probiotics for colorectal cancer (CRC) prevention and treatment. The authors summarize evidence that postbiotics such as short-chain fatty acids, exopolysaccharides, and cell-free supernatants can inhibit cancer cell proliferation, induce apoptosis, modulate gut microbiota, and exert anti-inflammatory effects through pathways including GPCR, TLR2, and AHR signaling. Despite strong preclinical support, the review highlights a critical gap in clinical trials directly evaluating postbiotics in CRC patients, underscoring the need for large-scale randomized controlled studies.

Full summary

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**Background:** Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related deaths worldwide. Current treatments including surgery, radiotherapy, and chemotherapy are often less effective in late-stage or metastatic disease. Gut microbiota dysbiosis is closely linked to CRC development, with certain species like *Fusobacterium nucleatum* and *Porphyromonas* species promoting carcinogenesis, while others may be protective. Postbiotics—defined by the International Scientific Association of Probiotics and Prebiotics (ISAPP) in 2021 as 'preparation of inanimate microorganisms and/or their components that confers a health benefit on the host'—offer potential advantages over live probiotics in terms of safety, stability, and mechanistic clarity.

**Methods:** This is a narrative review of the literature on postbiotics in CRC. The authors searched PubMed, EMBASE, CNKI, and Wanfang databases up to September 18, 2022, using keywords including 'postbiotics,' 'heat-killed bacterial cells,' 'cell-free supernatant,' 'short chain fatty acids,' 'exopolysaccharides,' and 'cancer.' A total of 538 publications were systematically reviewed, with selected clinical studies analyzed in detail.

**Key Results:** The review categorizes postbiotics into multiple types: (1) Heat-killed bacterial cells (e.g., *Bifidobacterium breve* MG731, *Lactobacillus reuteri* MG5346, *Lactobacillus casei* MG4584) that activate caspase-9-dependent apoptosis in CRC cells; (2) Cell-free supernatants (CFS) from *Lactobacillus* and *Bifidobacterium* species with antimicrobial, antioxidant, and antitumor activity; (3) Cell components including wall teichoic acids (WTAs) and lipoteichoic acids (LTAs) that modulate TLR-2/p38-MAPK/NF-κB pathways, and peptidoglycan (PGN) that induces autophagy and apoptosis via Nod1/CARD/RIP2/NF-κB/MAPK signaling; (4) Exopolysaccharides (EPS) that induce G0/G1 cell cycle arrest and apoptosis in colon cancer cells; (5) Short-chain fatty acids (SCFAs) including butyrate, acetate, propionate, and valerate that interact with GPCR41/43 and GPCR109a, downregulate ERK/MAPK signals, and upregulate cAMP/PKA/CREB/HDAC and Wnt signals; (6) Enzymes such as β-glucuronidase, nitro-reductase, catalase, and superoxide dismutase that suppress chemically induced colon cancer in animal models; (7) Bacteriocins (salivaricin, plantaricin) that modulate MAPK/NF-κB/COX-2 and PI3K/AKT/caspase-3 pathways; (8) Tryptophan metabolites (indole metabolites, kynurenine, serotonin) that interact with aryl hydrocarbon receptor (AHR) to induce Treg differentiation and confine Th17/Th1 responses. In vivo, postbiotics modulate gut microbial composition—for example, heat-killed *Enterococcus faecalis* EC-12 increased *bifidobacteria* and *lactobacilli* while decreasing *Clostridium perfringens* and *Enterobacteriaceae*. *Clostridium butyricum* supernatant decreased pathogenic bacteria including *Desulfovibrio*, *Odoribacter*, and *Helicobacter*. SCFAs protect the mucosal layer by reducing COX-2 expression and prostaglandin E2 levels. Clinical evidence remains limited: only four clinical studies were identified, none directly assessing postbiotics in CRC patients. One randomized double-blind trial (Vreeland et al., 2021) showed that TLPLDC vaccine (yeast cell wall-based) improved 24-month disease-free survival in melanoma patients (62.9% vs. 34.8%, p=0.041). Three trials of heat-killed *Mycobacterium vaccae* SRL172 in lung cancer and mesothelioma showed improved median survival and response rates.

**Clinical Implications:** Postbiotics offer several advantages over probiotics and fecal microbiota transplantation (FMT), including higher stability, defined molecular mechanisms, and better safety profiles—probiotics carry risks of infection and antibiotic resistance gene transfer, while FMT introduces donor-derived uncertainties. However, the clinical translation of postbiotics for CRC faces challenges: limited categories of identified postbiotics, potential unexpected interactions with the host microbiome, risk of disrupting endogenous metabolic feedback loops, and the need for cost-effective commercial production. The authors recommend naming postbiotics by their microbial source and molecular class (e.g., '*Bifidobacterium* sp.-derived cell-free supernatant') and emphasize that large-scale, double-blind, randomized controlled trials are urgently needed to establish clinical efficacy in CRC prevention and treatment.