Colorectal cancer (CRC) is one of the most common malignant carcinomas. CRC is characterized by asymptomatic onset, and most patients are already in the middle and advanced stages of disease when they are diagnosed. Inflammatory bowel disease (IBD) and the inflammatory-cancer transformation of advanced colorectal adenoma are the main causes of CRC. There is an urgent need for effective prevention and intervention strategies for CRC. In recent years, rapid research progress has increased our understanding of gut microbiota. Meanwhile, with the deepening of research on the pathogenesis of colorectal cancer, gut microbiota has been confirmed to play a direct role in the occurrence and treatment of colorectal cancer. Strategies to regulate the gut microbiota have potential value for application in the prevention and treatment of CRC. Regulation of gut microbiota is one of the important ways for natural products to exert pharmacological effects, especially in the treatment of metabolic diseases and tumours. This review summarizes the role of gut microbiota in colorectal tumorigenesis and the mechanism by which natural products reduce tumorigenesis and improve therapeutic response. We point out that the regulation of gut microbiota by natural products may serve as a potential means of treatment and prevention of CRC.

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New insights into natural products that target the gut microbiota: Effects on the prevention and treatment of colorectal cancer

Targeting the gut microbiota for cancer therapy

Evidence linking Faecalibacterium prausnitzii abundance to nonalcoholic fatty liver disease (NAFLD) is accumulating; however, the causal relationship remains obscure. In this study, 12 F. prausnitzii strains were orally administered to high fat diet fed C57BL/6J mice for 12 weeks to evaluate the protective effects of F. prausnitzii on NAFLD. We found that five F. prausnitzii strains, A2-165, LB8, ZF21, PL45, and LC49, significantly restored serum lipid profiles and ameliorated glucose intolerance, adipose tissue dysfunction, hepatic steatosis, inflammation, and oxidative stress in a mouse model of NAFLD. Moreover, two strains, LC49 and LB8, significantly enhanced short-chain fatty acid (SCFA) production and modulated the gut microbiota. Based on the combined analysis of linear discriminant analysis effect size and microbial communities, the core microbiome related to NAFLD comprised Odoribacter, Roseburia, Erysipelatoclostridium, Tyzzerella, Faecalibaculum, Blautia, and Acetatifactor, and the last five genera can be reversed by treatment with the LC49 and LB8 strains. Additionally, the LC49 and LB8 strains enriched Lactobacillus, Ileibacterium, Faecalibacterium, Dubosiella, and Bifidobacterium and downregulated pathways involving carbohydrate metabolism, amino acid metabolism, and fatty acid biosynthesis. Interestingly, LC49 supplementation also upregulated tryptophan metabolism, glutathione metabolism, and valine, leucine, and isoleucine degradation, which might be related to NAFLD prevention. Collectively, F. prausnitzii LC49 and LB8 exerted considerable anti-NAFLD and microbiota-regulating effects, indicating their potential as probiotic agents for NAFLD treatment.

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Specific Strains of Faecalibacterium prausnitzii Ameliorate Nonalcoholic Fatty Liver Disease in Mice in Association with Gut Microbiota Regulation

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatments over the last 10 years, with even increasing indications in many neoplasms. Non-small cell lung cancer (NSCLC) is considered highly immunogenic, and ICIs have found a wide set of applications in this area, in both early and advanced lines of treatment, significantly changing the prognosis of these patients. Unfortunately, not all patients can benefit from the treatment, and resistance to ICIs can develop at any time. In addition to T lymphocytes, which are the major target, a variety of other cells present in the tumor microenvironment (TME) act in a complex cross-talk between tumor, stromal, and immune cells. An imbalance between activating and inhibitory signals can shift TME from an “anti-” to a “pro-tumorigenic” phenotype and vice versa. Natural killer cells (NKs) are able to recognize cancer cells, based on MHC I (self and non-self) and independently from antigen presentation. They represent an important link between innate and adaptive immune responses. Little data are available about the role of pro-inflammatory NKs in NSCLC and how they can influence the response to ICIs. NKs express several ligands of the checkpoint family, such as PD-1, TIGIT, TIM-3, LAG3, CD96, IL1R8, and NKG2A. We and others have shown that TME can also shape NKs, converting them into a pro-tumoral, pro-angiogenic “nurturing” phenotype through “decidualization.” The features of these NKs include expression of CD56, CD9, CD49a, and CXCR3; low CD16; and poor cytotoxicity. During ICI therapy, tumor-infiltrating or associated NKs can respond to the inhibitors or counteract the effect by acting as pro-inflammatory. There is a growing interest in NKs as a promising therapeutic target, as a basis for adoptive therapy and chimeric antigen receptor (CAR)-NK technology. In this review, we analyzed current evidence on NK function in NSCLC, focusing on their possible influence in response to ICI treatment and resistance development, addressing their prognostic and predictive roles and the rationale for exploiting NKs as a tool to overcome resistance in NSCLC, and envisaging a way to repolarize decidual NK (dNK)-like cells in lung cancer.

https://www.frontiersin.org/articles/10.3389/fonc.2022.886440/pdf

Overcoming Resistance to Checkpoint Inhibitors: Natural Killer Cells in Non-Small Cell Lung Cancer

Abstract Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) proteins transformed the management of advanced cancers. Many tumor-intrinsic factors modulate immunological and clinical responses to such therapies, but ample evidence also implicates the gut microbiome in responses. The gut microbiome, comprising the bacteria, archaea, fungi, and viruses that live in the human digestive tract, is an established determinant of host immunity, but its impact on response to ICI therapy in mice and humans with cancer has only recently been appreciated. Therapeutic interventions to optimize microbiota composition to improve immunotherapy outcomes show promise in mice and humans with cancer. In this review, we discuss the rationale for gut microbiome–based cancer therapies, the results from early-phase clinical trials, and possible future developments.

Facts and Hopes for Gut Microbiota Interventions in Cancer Immunotherapy

The polyphenol castalagin acts as a prebiotic and exerts antitumor activity as well as potentiates anti–PD-1 immune efficacy through a beneficial shift in microbiome composition.

https://aacrjournals.org/cancerdiscovery/article-pdf/12/4/1070/3108049/1070.pdf

A Natural Polyphenol Exerts Antitumor Activity and Circumvents Anti–PD-1 Resistance through Effects on the Gut Microbiota

The commensal bacterium Faecalibacterium prausnitzii has unique anti-inflammatory properties, at least some of which have been attributed to its production of MAM, the Microbial Anti-inflammatory Molecule. Previous phylogenetic studies of F. prausnitzii strains have revealed the existence of various phylogroups. In this work, we address the question of whether MAMs from different phylogroups display distinct anti-inflammatory properties. We first performed wide-scale identification, classification, and phylogenetic analysis of MAM-like proteins encoded in different genomes of F. prausnitzii. When combined with a gene context analysis, this approach distinguished at least 10 distinct clusters of MAMs, providing evidence for functional diversity within this protein. We then selected 11 MAMs from various clusters and evaluated their anti-inflammatory capacities in vitro. A wide range of anti-inflammatory activity was detected. MAM from the M21/2 strain had the highest inhibitory effect (96% inhibition), while MAM from reference strain A2-165 demonstrated only 56% inhibition, and MAM from strain CNCM4541 was almost inactive. These results were confirmed in vivo in murine models of acute and chronic colitis. This study provides insights into the family of MAM proteins and generates clues regarding the choice of F. prausnitzii strains as probiotics for use in targeting chronic inflammatory diseases.

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Oscar Gitton-Quent

Papers

A Natural Polyphenol Exerts Antitumor Activity and Circumvents Anti–PD-1 Resistance through Effects on the Gut Microbiota

Intraspecific Diversity of Microbial Anti-Inflammatory Molecule (MAM) from Faecalibacterium prausnitzii