Unraveling the Microbial Symphony: Flaxseed, Gut Microbiota and Mammary miRNAs in the Battle Against Breast Cancer

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The human gut microbiota, a complex community of trillions of microorganisms, plays a pivotal role in influencing host health by metabolizing dietary components into bioavailable compounds. This intricate relationship extends beyond the gut, impacting distal organs and contributing to various physiological processes (1).

In this article, we delve into the fascinating connection between the gut microbiota and the mammary gland, with a particular focus on the role of flaxseed (FS) and its components in modulating this interaction.

Flaxseed and Enterolignans

Flaxseed, recognized as the richest dietary source of the lignan secoisolariciresinol diglucoside (SDG), is at the forefront of research investigating the gut-breast axis (2). The gut microbiota plays a crucial role in converting SDG into enterolignans, including enterodiol (ED) and enterolactone (EL).

This conversion is orchestrated by bacterial species such as Bacteroides, Clostridium, Eubacteriaceae, Peptostreptococcus, Eggerthella, and Enterobacter (3). Notably, in mice, certain taxa, such as Lactobacillus and Coriobacteriaceae, have shown positive correlations with serum ED and EL levels (4).

Human studies have reinforced the connection between dietary lignans and microbial taxa, revealing that interventions with lignans result in increased urinary enterolignan excretion and a positive association with taxa like Ruminococcus, Roseburia, and Lachnospiraceae (5). The presence of high concentrations of circulating lignans has been linked to reduced mortality from breast cancer in postmenopausal women (6–9).

Moreover, ED and EL, being phytoestrogens, are believed to exert protective effects in postmenopausal breast cancer, influencing key biomarkers and c-erbB2 expression in clinical trials (10). Urinary EL has also demonstrated an inverse association with proteins involved in pro-proliferative and apoptotic pathways, such as the PI3k-Akt pathway (11).

Microbiota Metabolic Activity and Lignan Processing

Interestingly, the metabolic activity of the gut microbiota, even in non-lignan metabolizers, has been identified as crucial for lignan processing (4). This observation aligns with the emerging concept that the gut microbiota could be a viable target to enhance the efficacy of breast antitumor drugs (12).

Beyond Lignans: Flaxseed as a Whole Food

Flaxseed is not only a source of lignans but also provides fiber, protein, and oil (FSO). Studies have demonstrated that both FS fiber and oil can influence gut microbiota composition (13, 14). Notably, FSO stands out as one of the highest plant-based sources of alpha-linolenic acid (ALA), exhibiting properties that delay mammary tumor onset, reduce tumor growth, and inhibit tumor proliferation (15–17). Therefore, the anticancer properties of FS may arise from the combined action of its diverse components, raising the question of whether these components act synergistically or independently.

MicroRNA Responses and Breast Cancer

Intriguingly, FS, FSO, and SDG, when provided in equal amounts as in FS, elicit specific microRNA (miRNA) responses in the mammary gland (18). MicroRNAs, short non-coding RNAs, act as epigenetic regulators of transcription and translation, potentially influencing up to 90% of all genes by targeting the 3′ untranslated region of mRNAs (19, 20). Modulating miRNA expression is considered a mechanism through which hosts respond to metabolic signals, including those generated by microbial metabolites.

Exploring the Relationship

The focus of recent research has shifted towards determining the relationship between the mammary gland miRNome (miRNA repertoire) and the gut microbiota, investigating how dietary FS modifies this relationship, and discerning if FS-associated miRNAs are altered in human breast cancer (21). This exploration aims to unravel the intricate interplay between gut microbiota, dietary components, and miRNA regulation in the context of breast cancer.

Discussion: Unraveling the Complex Interplay Between Flaxseed, Gut Microbiota, and Mammary miRNAs in Breast Cancer Prevention

The findings presented in this study shed light on the intricate relationship between flaxseed (FS), gut microbiota, mammary gland miRNAs, and their potential implications in breast cancer prevention. The study primarily focused on the conversion of flaxseed compounds, such as secoisolariciresinol diglucoside (SDG), by the gut microbiota and their subsequent impact on mammary gland miRNAs.

Microbial-MiRNA Relationships and FS Diet Modification

The study successfully established a link between the cecal microbiota and mammary gland miRNAs, demonstrating for the first time that an FS diet can modify this relationship. The alterations observed in microbiota-miRNA connections were particularly noteworthy, as they targeted pathways associated with the PI3K-Akt-mTOR pathway and genes implicated in breast cancer. This pathway, activated during puberty and dysregulated in breast cancer, has been linked to increased ductal branching and potential implications for cancer risk later in life.

Genetic Players in the PI3K-Akt-mTOR Pathway

The study delved into the genetic players involved in the enrichment of the PI3K-Akt-mTOR pathway, revealing the downregulation of Runx2 and Skp2 in response to the FS diet. Runx2, a transcription factor crucial for mammary gland development, was significantly decreased, suggesting a potential contribution to cancer-protective effects. Likewise, miR-137 and miR-340-5p, which target Runx2 and Skp2, were significantly increased in the FS diet, aligning with potential downregulation of these genes. Interestingly, miR-137 associated with Lachnospiraceae and miR-340-5p with Lactobacillus, both enriched in the FS diet, hinting at the involvement of specific microbial taxa in miRNA modulation.

Implications for Breast Cancer

Comparisons with human breast cancer samples reinforced the relevance of these findings, with increased Runx2 and Skp2 and decreased miR-137 and miR-340 mirroring the FS diet effects. The study highlighted the complex interplay between microbiota, miRNAs, and genetic targets, with alterations in miRNA-gene correlations potentially influencing breast cancer pathways.

FSO and SDG: Divergent Roles in FS as a Whole Food

A significant revelation emerged regarding the divergent roles of flaxseed oil (FSO) and SDG within FS. While both components contributed to enriched pathways, particularly related to extracellular matrix and collagen regulation, the study identified unique correlations altered by FSO, suggesting distinct mechanisms of action. The study emphasized that FS, as a whole food, offers maximum benefits, emphasizing collagen’s potential role in both pubertal mammary gland development and cancer progression.

Unraveling FS-Specific Taxa-miRNA Relationships

Distinct FS-specific taxa-miRNA relationships were identified, reinforcing the unique impact of FS on microbial modulation compared to its individual components. The PI3K-Akt-mTOR pathway exhibited consistent correlations across diets, suggesting an FS-specific taxa-miRNA change. Notably, the study hinted at potential differences in fiber, protein, and lignan processing between FS and SDG, urging further investigation into these components’ distinct roles.

Foundation for Future Research and Functional Food Interventions

In conclusion, this study provides a comprehensive foundation for mechanistic investigations into how FS, mediated by the gut microbiota, modulates mammary miRNA expression. The identification of specific microbial taxa and their association with miRNAs opens avenues for targeted dietary interventions, potentially aiding in breast cancer prevention. The study’s nuanced approach to dissecting FS components, especially the divergent roles of FSO and SDG, underscores the complexity of whole-food interactions. Moving forward, this knowledge holds the potential to inform the design of tailored dietary strategies, including the provision of fiber or FS-based synbiotics, to optimize mammary gland health and reduce breast cancer risk.


reference link : https://journals.asm.org/doi/10.1128/spectrum.02290-23

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