Plant-derived miRNAs Research Articles

Alfalfa xeno-miR159a regulates bovine mammary epithelial cell proliferation and milk protein synthesis by targeting PTPRF.

Milk protein content is an important index to evaluate the quality and nutrition of milk. Accumulating evidence suggests that microRNAs (miRNAs) play important roles in bovine lactation, but little is known regarding the cross-kingdom regulatory roles of plant-derived exogenous miRNAs (xeno-miRNAs) in milk protein synthesis, particularly the underlying molecular mechanisms. The purpose of this study was to explore the regulatory mechanism of alfalfa-derived xeno-miRNAs on proliferation and milk protein synthesis in bovine mammary epithelial cells (BMECs). Our previous study showed that alfalfa miR159a (mtr-miR159a, xeno-miR159a) was highly expressed in alfalfa, and the abundance of mtr-miR159a was significantly lower in serum and whey from high-protein-milk dairy cows compared with low-protein-milk dairy cows. In this study, mRNA expression was detected by real-time quantitative PCR (qRT-PCR), and casein content was evaluated by enzyme-linked immunosorbent assay (ELISA). Cell proliferation and apoptosis were detected using the cell counting kit 8 (CCK-8) assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, western blot, and flow cytometry. A dual-luciferase reporter assay was used to determine the regulation of Protein Tyrosine Phosphatase Receptor Type F (PTPRF) by xeno-miR159a. We found that xeno-miR159a overexpression inhibited proliferation of BMEC and promoted cell apoptosis. Besides, xeno-miR159a overexpression decreased β-casein abundance, and increased α-casein and κ-casein abundance in BMECs. Dual-luciferase reporter assay result confirmed that PTPRF is a target gene of xeno-miR159a. These results provide new insights into the mechanism by which alfalfa-derived miRNAs regulate BMECs proliferation and milk protein synthesis.

Identification of self- and pathogen-targeted miRNAs from resistant and susceptible Theobroma cacao variety to black pod disease

Cacao (Theobroma cacao) is a highly valuable crop with growing demand in the global market. However, cacao farmers often face challenges posed by black pod disease caused by Phytophthora spp., with P. palmivora being the most dominant. Regulations of various gene expressions influence plant resistance to pathogens. One mechanism involves targeting the mRNA of virulence genes in the invading pathogens, suppressing their infection. However, resistance also could be suppressed by plant-derived miRNAs that target their own defence genes. The objective of this study is to identify differentially expressed miRNAs in black pod-resistant and susceptible cacao varieties and to predict their targets in T. cacao and P. palmivora transcripts. Extracted miRNA from resistant and susceptible varieties of T. Cacao was sequenced, identified, and matched to host and pathogen mRNA. In total, 54 known miRNAs from 40 miRNA families and 67 novel miRNAs were identified. Seventeen miRNAs were differentially expressed in susceptible variety compared to resistant one, with 9 miRNAs upregulated and 8 miRNAs downregulated. In T. cacao transcripts, the upregulated miRNAs were predicted to target several genes, including defence genes. The suppression of these defense genes can lead to a reduction in plant resistance against pathogen infection. In P. palmivora transcripts, the upregulated miRNAs were predicted to target several genes, including P. palmivora effector genes. In the future, limiting expression of miRNAs that target T. cacao’s defence genes and applying miRNAs that target P. palmivora effector genes hold promise for enhancing cacao plant resistance against P. palmivora infection.

Mulberry-derived miR168a downregulates BmMthl1 to promote physical development and fecundity in silkworms

Plant-derived miRNAs and their interactions with host organisms are considered important factors in regulating host physiological processes. In this study, we investigated the interaction between the silkworm, an oligophagous insect, and its primary food source, mulberry, to determine whether mulberry-derived miRNAs can penetrate silkworm cells and regulate their functions. Our results demonstrated that miR168a from mulberry leaves enters the silkworm hemolymph and binds to the silkworm Argonaute1 BmAGO1, which is transported via vesicles secreted by silkworm cells to exert its regulatory functions. In vivo and in vitro functional studies revealed that miR168a targets the mRNA of silkworm G protein-coupled receptor, BmMthl1, thereby inhibiting its expression and activating the JNK-FoxO pathway. This activation reduces oxidative stress responses, prolongs the lifespan of silkworms, and improves their reproductive capacity. These findings highlight the challenges of replacing mulberry leaves with alternative protein sources and provide a foundation for developing silkworm germplasms suitable for factory rearing.

Cross-kingdom regulation by plant-derived miRNAs in mammalian systems.

MicroRNAs (miRNAs) are small noncoding RNA molecules ubiquitously distributed across diverse organisms, serving as pivotal regulators of genetic expression. Notably, plant-derived miRNAs have been demonstrated to have unique bioactivity and certain stability in mammalian systems, thereby facilitating their capacity for cross-kingdom modulation of gene expression. While there is substantial evidence supporting the regulation of mammalian cells by plant-derived miRNAs, several questions remain unanswered. Specifically, a comprehensive investigation of the mechanisms underlying the stability and transport of plant miRNAs and their cross-kingdom regulation of gene expression in mammals remains to be done. In this review, we summarized the origin, processing, and functional mechanisms of plant miRNAs in mammalian tissues and circulation, emphasizing their greater resistance to mammalian digestion and circulation systems compared to animal miRNAs. Additionally, we introduce four well-known plant miRNAs that have been extensively studied for their functions and mechanisms in mammalian systems. By delving into these aspects, we aim to offer a fundamental understanding of this intriguing field and shed light on the complex interactions between plant miRNAs and mammalian biology.

MiR482f and miR482c-5p from edible plant-derived foods inhibit the expression of pro-inflammatory genes in human THP-1 macrophages

BackgroundEdible plants can exert anti-inflammatory activities in humans, being potentially useful in the treatment of inflammatory diseases. Plant-derived microRNAs have emerged as cross-kingdom gene expression regulators and could act as bioactive molecules involved in the beneficial effects of some edible plants. We investigated the role of edible plant-derived microRNAs in the modulation of pro-inflammatory human genes.MethodsMicroRNAs from plant-derived foods were identified by next-generation sequencing. MicroRNAs with inflammatory putative targets were selected, after performing in silico analyses. The expression of candidate plant-derived miRNAs was analyzed by qPCR in edible plant-derived foods and their effects were evaluated in THP-1 monocytes differentiated to macrophages. The bioavailability of candidate plant miRNAs in humans was evaluated in feces and serum samples by qPCR.ResultsmiR482f and miR482c-5p are present in several edible plant-derived foods, such as fruits, vegetables, and cooked legumes and cereals, and fats and oils. Transfections with miR482f and miR482c-5p mimics decreased the gene expression of CLEC7A and NFAM1, and TRL6, respectively, in human THP-1 monocytes differentiated to macrophages, which had an impact on gene expression profile of inflammatory biomarkers. Both microRNAs (miR482f and miR482c-5p) resisted degradation during digestion and were detected in human feces, although not in serum.ConclusionOur findings suggest that miR482f and miR482c-5p can promote an anti-inflammatory gene expression profile in human macrophages in vitro and their bioavailability in humans can be achieved through diet, but eventually restricted at the gut level.

Advances in MicroRNA Therapy for Heart Failure: Clinical Trials, Preclinical Studies, and Controversies.

Heart failure (HF) is a rapidly growing public health issue with more than 37.7 million patients worldwide and an annual healthcare cost of $108 billion. However, HF-related drugs have not changed significantly for decades, and it is essential to find biological drugs to provide better treatment for HF patients. MicroRNAs (miRNAs) are non-coding RNAs (ncRNAs) with a length of approximately 21 nucleotides and play an important role in the onset and progression of cardiovascular diseases. Increasing studies have shown that miRNAs are widely involved in the pathophysiology of HF, and the regulation of miRNAs has promising therapeutic effects. Among them, there is great interest in miRNA-132, since the encouraging success of anti-miRNA-132 therapy in a phase 1b clinical trial in 2020. However, it is worth noting that the multi-target effect of miRNA may produce side effects such as thrombocytopenia, revascularization dysfunction, severe immune response, and even death. Advances in drug delivery modalities, delivery vehicles, chemical modifications, and plant-derived miRNAs are expected to address safety concerns and further improve miRNA therapy. Here, we reviewed the preclinical studies and clinical trials of HF-related miRNAs (especially miRNA-132) in the past 5 years and summarized the controversies of miRNA therapy.

Major roles of the gut microbiota and microRNAs in cardiovascular disease events: a systematic review

Introduction: Gut microbiota (GM) is an essential mediator in the health of GM and has been identified as the origin of several diseases by influencing cell signaling and T cell receptor pathways in the central nervous system. Several microRNAs participate in signaling networks through GM intervention. The interaction between GM and miRNAs plays a crucial role in vascular dysfunction. GM can metabolize L-carnitine, choline, and phosphatidylcholine and produce vascular-toxic metabolites such as trimethylamine-Noxide (TMAO), which is associated with the atherosclerotic process. Nutrology and dietary therapy represent important strategies, especially with the use of plant-derived miRNAs to modify GM. Objective: To carry out a systematic review to highlight the main roles of the gut microbiota and microRNAs in cardiovascular disease events. Methods: The present study followed a concise systematic review model (PRISMA). The literary search process was carried out from March to May 2023 and was developed based on Scopus, PubMed, Science Direct, Scielo, and Google Scholar, using scientific articles from 2002 to 2022. The low quality of evidence was attributed to reports of cases, editorials, and brief communications, according to the GRADE instrument. The risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: The total of 126 studies were found for eligibility analysis, and then 42 of the 64 total studies were selected for this systematic review. According to the GRADE instrument, most studies showed homogeneity in their results, with X2 =88.7%>50%. It was concluded that the gut microbiota can be influenced by diet, genetics, and environmental factors. Changes in the microbial population can lead to multiple diseases, including cardiovascular disease. miRNAs have been known as important regulators of several biological functions, and are also involved in the pathogenesis of cardiovascular diseases. There is evidence that disturbances in the gut microbiota and derived metabolites impair the development of atherosclerotic cardiovascular disease. Studies have shown that YRNAs belonging to extracellular vesicles and their fragments play important roles in the initiation, progression, and diagnosis of atherosclerosis.

Plant-derived cross-kingdom gene regulation benefits human health.

Cross-kingdom gene regulation widely occurs in nature through small (s)RNAs or protein-encoding genes. Examples of plant-derived miRNAs that are advantageous for human health have recently been reported. Mining plant-specialized gene resources for similar cross-kingdom gene communications may lead to the identification of further plant-derived therapeutic agents that can improve human health globally.

Cross-Kingdom Regulation of Plant-Derived miRNAs in Modulating Insect Development.

MicroRNAs (miRNAs), a class of non-coding small RNAs, are crucial regulatory factors in plants and animals at the post-transcriptional level. These tiny molecules suppress gene expression by complementary oligonucleotide binding to sites in the target messenger. Recently, the discovery of plant-derived miRNAs with cross-kingdom abilities to regulate gene expression in insects has promoted exciting discussion, although some controversies exist regarding the modulation of insect development by plant-derived miRNAs. Here, we review current knowledge about the mechanisms of miRNA biogenesis, the roles of miRNAs in coevolution between insects and plants, the regulation of insect development by plant-derived miRNAs, the cross-kingdom transport mechanisms of plant-derived miRNAs, and cross-kingdom regulation. In addition, the controversy regarding the modulation of insect development by plant-derived miRNAs also was discussed. Our review provides new insights for understanding complex plant-insect interactions and discovering new strategies for pest management and even crop genetic improvement.

Small RNA sequencing andidentification ofAndrographis paniculata miRNAs withpotential cross‑kingdom human gene targets.

Cross-species post-transcriptional regulatory potential of plant derived small non-coding microRNAs (miRNAs) has been well documented by plenteous studies. MicroRNAs are transferred to host cells via oral ingestion wherein they play a decisive role in regulation of host genes; thus, miRNAs have evolved as the nascent bioactive molecules imparting pharmacological values to traditionally used medicinal plants. The present study aims to investigate small RNA profiling in order to uncover the potential regulatory role of miRNAs derived from Andrographis paniculata, one of the most widely used herb by tribal communities for liver disorders and document the pharmacological properties of A. paniculata miRNAs. In this study, high-throughput sequencing method was used to generate raw data, ~ 60 million sequences were generated from A. paniculata leaves. Using computational tools and bioinformatics approach, analyses of 3,480,097 clean reads resulted in identification of 3440 known and 51 putative novel miRNAs regulating 1365 and 192 human genes respectively. Remarkably, the identified plausible novel miRNAs apa-miR-5, apa-miR-1, apa-miR-26, and apa-miR-30 are projected to target significant host genes including CDK6, IKBKB, TRAF3, CHD4, MECP2, and ADIPOQ. Subsequent annotations revealed probable involvement of the target genes in various pathways for instance p38-MAPK, AKT, AMPK, NF-Kβ, ERK, WNT signalling, MYD88 dependant cascade, and pathways in cancer. Various diseases such as human papilloma virus infection, Alzheimer's, Non-alcoholic Fatty Liver, Alcoholic liver diseases, HepatoCellular Carcinoma (HCC), and numerous other cancers were predominantly found to be linked with target genes. Our findings postulate novel interpretations regarding modulation of human transcripts by A. paniculata miRNAs and exhibit the regulation of human diseases by plant-derived miRNAs. Though our study elucidates miRNAs as novel therapeutic agents, however, experimental validations for assessment of therapeutic potential of these miRNAs are still warranted.

Inhibition of osteosarcoma by European Mistletoe derived val-miR218

Aim: In recent years, there has been a growing interest in the therapeutic potential of plant-derived miRNAs, which have been considered new bioactive ingredients in medicinal plants. Viscum album L., commonly used as an adjuvant cancer therapy in central Europe, contains a large number of miRNAs associated with human diseases such as cancer, cardiovascular diseases, and neurological disorders. This study aimed to investigate whether mistletoe miRNAs, specifically val-miR218, exert anti-cancer activity against osteosarcoma. Methods: The anti-cancer effects of miRNAs from V. album L. were evaluated. The targets of val-miR218 were identified by RNA-seq. The mRNA and protein expression of the targets was confirmed by RT-qPCR and western blot analyses. The interaction between the val-miR218 and miRNA recognition elements (MREs) was validated by the dual-luciferase assay. The inhibitory effect of val-miR218 against osteosarcoma was investigated in vivo. Results: Among these abundant miRNAs in V. album L., val-miR218 showed high potential anti-cancer effects against osteosarcoma. To clarify its molecular mechanism of action, we sequenced val-miR218 associated RNAs and their down-regulated RNAs. As a result, 61 genes were considered the direct targets of val-miR218. Interestingly, these targets were related to essential cellular functions such as cell cycle, DNA replication, and cell morphology, suggesting that val-miR218 significantly inhibited cell growth and arrested osteosarcoma cells in G0/G1 phase by influencing basic cell activities. Mistletoe extracellular vesicles offered val-miR218 adequate protection and facilitated the uptake of val-miR281 by human cells. Moreover, val-miR218 showed significant anti-tumor effects in vivo. Conclusion: This study demonstrated the significant potential of val-miR218 regarding proliferation inhibition in various tumor cell lines in vitro and for osteosarcoma in vivo. Due to the increasing problems during chemotherapy, new therapeutic approaches are becoming more critical. The significant anti-cancer effects of medicinal plants derived miRNAs indicate a promising therapeutic strategy for treating cancer.

Circulating exosome miRNA, is it the novel nutrient molecule through cross-kingdom regulation mediated by food chain transmission from microalgae to bivalve?

MicroRNAs (miRNAs) can efficiently regulate gene expression at intracellular and extracellular levels. Plant-derived miRNAs are highly enriched in animal haemolymph and regulate mammalian gene expression. However, evidence for food-derived miRNAs in Mollusca species is lacking. In this study, we fed the microalga Nannochloropsis oculata to the pearl oyster Pinctada fucata martensii and detected dietary miRNAs in exosomes isolated from the haemolymph by RNA-seq. In total, 273 endogenous miRNAs were identified in all biological replicates. We identified 23 microalgae-derived miRNAs in the exosomes of pearl oyster haemolymph. Most microalgae-derived miRNAs showed high expression levels in both exosomes and microalgae and exhibited apparent variation among individuals. These food-derived miRNAs were predicted to participate in endocytosis, apoptosis, signal transduction, energy metabolism, and biomineralization by targeting multiple genes. These findings demonstrated the cross-kingdom transport of miRNAs from microalgae to bivalves and provide insights into novel nutrient transmission through the food chain.

Small RNA sequencing and identification of papaya (Carica papaya L.) miRNAs with potential cross-kingdom human gene targets.

Several studies have demonstrated potential role of plant-derived miRNAs in cross-kingdom species relationships by transferring into non-plant host cells to regulate certain host cellular functions. How nutrient-rich plants regulate host cellular functions, which in turn alleviate physiological and disease conditions in the host remains to be explored in detail. This computational study explores the potential targets, putative role, and functional implications of miRNAs derived from Carica papaya L., one of the most cultivated tropical crops in the world and a rich source of phytochemicals and enzymes, in human diet. Using the next-generation sequencing, -Illumina HiSeq2500, ~ 30 million small RNA sequence reads were generated from C. papaya young leaves, resulting in the identification of a total of 1798 known and 49 novel miRNAs. Selected novel C. papaya miRNAs were predicted to regulate certain human targets, and subsequent annotation of gene functions indicated a probable role in various biological processes and pathways, such as MAPK, WNT, and GPCR signaling pathways, and platelet activation. These presumptive target gene in humans were predominantly linked to various diseases, including cancer, diabetes, mental illness, and platelet disorder. The computational finding of this study provides insights into how C. papaya-derived miRNAs may regulate certain conditions of human disease and provide a new perspective on human health. However, the therapeutic potential of C. papaya miRNA can be further explored through experimental studies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00438-022-01904-3.

Identification of potential target genes in Homo sapiens, by miRNA of Triticum aestivum: A cross kingdom computational approach.

Plant-derived miRNAs can be found in the human body after dietary intake, and they can affect post-transcriptional gene regulation in human. It is important to identify targets to determine the possible effects in human genes by using computational approach. In this study, 787 possible mRNAs human targets were predicted by 84 miRNAs of wheat. A total of 14 miRNAs were identified with individual binding to 33 mRNAs associated with schizophrenia, epilepsy, neurodevelopmental disorders, and various cancers, located in the 3′UTR of the mRNA. A functional enrichment was carried out, where the results showed associations to pathways such as dopaminergic synapse (hsa04728), and signaling pathways, significantly associated with the target genes. The prediction of target mRNAs in humans by wheat miRNAs, offer candidates that could facilitate the search and verification, which could be of relevance for future projects and therefor contribute in the therapeutic treatment of various human diseases.

Plant Exosomes As Novel Nanoplatforms for MicroRNA Transfer Stimulate Neural Differentiation of Stem Cells In Vitro and In Vivo.

Differentiation of bone marrow derived mesenchymal stem cells (BMSCs) into functional neural cells has been widely investigated for treating neural diseases. However, the limited neural differentiation of BMSCs remains a big challenge to overcome. Herein, for the first time, ginseng-derived exosomes (G-Exos) were demonstrated to have excellent efficiency in stimulating the neural differentiation of BMSCs by transferring the incorporated miRNAs to BMSCs efficiently. In vivo, a photo-cross-linkable hydrogel with chemokine and G-Exos loaded shows strong efficacy in recruiting and directing the neural differentiation of BMSCs in the program. G-Exos were demonstrated to be promising nanoplatforms in transferring plant-derived miRNAs to mammalian stem cells for neural differentiation both in vitro and in vivo, possessing great potential in neural regenerative medicine.

Diet-derived transmission of MicroRNAs from host plant into honey bee Midgut

BackgroundMicroRNA (miRNA) is a class of small noncoding RNAs, which targets on thousands of mRNA and thus plays important roles in many biological processes. It has been reported that miRNA has cross-species regulation functions between parasitoid-host, or plant-animal, etc. For example, several plant miRNAs enter into the honey bees and regulate gene expression. However, whether cross-species regulation function of miRNAs is a universal mechanism remains a debate question.ResultsWe have evaluated transmission of miRNAs from sunflower and sedr plants into the midgut of honey bee using RNA-Seq analyses complemented with confirmation by RT-qPCR. The results showed that at least 11 plant miRNAs were found in the midgut of honey bee feeding by sunflower and sedr pollen. Among which, nine miRNAs, including miR-30d, miR-143, miR-148a, miR-21, let-7 g, miR-26a, miR-126, miR-27a, and miR-203, were shared between the sunflower- and sedr-fed honey bees, suggesting they might have essential roles in plant-insect interactions. Moreover, existence of these co-shared miRNAs presents a strong evidence to support the successful transmission of miRNAs into the midgut of the insect. In total, 121 honeybee mRNAs were predicted to be the target of these 11 plant-derived miRNAs. Interestingly, a sedr-derived miRNA, miR-206, targets on 53 honeybee genes. Kyoto Encyclopedia of Genes and Genome (KEGG) analyses showed that these target genes are significantly involved in hippo signaling pathway-fly, Wnt signaling pathway, and N-Glycan biosynthesis.ConclusionsIn summary, these results provide evidence of cross-species regulation function of miRNA between honeybee and flowering host plants, extending our understanding of the molecular interactions between plants and animals.

Therapeutic Properties of Edible Mushrooms and Herbal Teas in Gut Microbiota Modulation.

Edible mushrooms are functional foods and valuable but less exploited sources of biologically active compounds. Herbal teas are a range of products widely used due to the therapeutic properties that have been demonstrated by traditional medicine and a supplement in conventional therapies. Their interaction with the human microbiota is an aspect that must be researched, the therapeutic properties depending on the interaction with the microbiota and the consequent fermentative activity. Modulation processes result from the activity of, for example, phenolic acids, which are a major component and which have already demonstrated activity in combating oxidative stress. The aim of this mini-review is to highlight the essential aspects of modulating the microbiota using edible mushrooms and herbal teas. Although the phenolic pattern is different for edible mushrooms and herbal teas, certain non-phenolic compounds (polysaccharides and/or caffeine) are important in alleviating chronic diseases. These specific functional compounds have modulatory properties against oxidative stress, demonstrating health-beneficial effects in vitro and/or In vivo. Moreover, recent advances in improving human health via gut microbiota are presented. Plant-derived miRNAs from mushrooms and herbal teas were highlighted as a potential strategy for new therapeutic effects.

A Timely Review of Cross-Kingdom Regulation of Plant-Derived MicroRNAs.

MicroRNAs (miRNAs) belong to a class of non-coding RNAs that suppress gene expression by complementary oligonucleotide binding to the sites in target messenger RNAs. Numerous studies have demonstrated that miRNAs play crucial role in virtually all cellular processes of both plants and animals, such as cell growth, cell division, differentiation, proliferation and apoptosis. The study of rice MIR168a has demonstrated for the first time that exogenous plant MIR168a influences cholesterol transport in mice by inhibiting low-density lipoprotein receptor adapter protein 1 expression. Inspired by this finding, the cross-kingdom regulation of plant-derived miRNAs has drawn a lot of attention because of its capability to provide novel therapeutic agents in the treatment of miRNA deregulation-related diseases. Notably, unlike mRNA, some plant miRNAs are robust because of their 3′ end modification, high G, C content, and the protection by microvesicles, miRNAs protein cofactors or plant ingredients. The stability of these small molecules guarantees the reliability of plant miRNAs in clinical application. Although the function of endogenous miRNAs has been widely investigated, the cross-kingdom regulation of plant-derived miRNAs is still in its infancy. Herein, this review summarizes the current knowledge regarding the anti-virus, anti-tumor, anti-inflammatory, anti-apoptosis, immune modulation, and intestinal function regulation effects of plant-derived miRNAs in mammals. It is expected that exploring the versatile role of plant-derived miRNAs may lay the foundation for further study and application of these newly recognized, non-toxic, and inexpensive plant active ingredients.

Potential Mechanisms Linking Food-Derived MicroRNAs, Gut Microbiota and Intestinal Barrier Functions in the Context of Nutrition and Human Health.

MicroRNAs (miRNAs) are non-coding single-stranded RNA molecules from 18 to 24 nucleotides that are produced by prokaryote and eukaryote organisms, which play a crucial role in regulating gene expression through binding to their mRNA targets. MiRNAs have acquired special attention for their potential in cross kingdom communication, notably food-derived microRNAs (xenomiRs), which could have an impact on microorganism and mammal physiology. In this review, we mainly aim to deal with new perspectives on: (1) The mechanism by which food-derived xenomiRs (mainly dietary plant xenomiRs) could be incorporated into humans through diet, in a free form, associated with proteins or encapsulated in exosome-like nanoparticles. (2) The impact of dietary plant-derived miRNAs in modulating gut microbiota composition, which in turn, could regulate intestinal barrier permeability and therefore, affect dietary metabolite, postbiotics or food-derived miRNAs uptake efficiency. Individual gut microbiota signature/composition could be also involved in xenomiR uptake efficiency through several mechanisms such us increasing the bioavailability of exosome-like nanoparticles miRNAs. (3) Gut microbiota dysbiosis has been proposed to contribute to disease development by affecting gut epithelial barrier permeability. For his reason, the availability and uptake of dietary plant xenomiRs might depend, among other factors, on this microbiota-related permeability of the intestine. We hypothesize and critically review that xenomiRs-microbiota interaction, which has been scarcely explored yet, could contribute to explain, at least in part, the current disparity of evidences found dealing with dietary miRNA uptake and function in humans. Furthermore, dietary plant xenomiRs could be involved in the establishment of the multiple gut microenvironments, in which microorganism would adapt in order to optimize the resources and thrive in them. Additionally, a particular xenomiR could preferentially accumulate in a specific region of the gastrointestinal tract and participate in the selection and functions of specific gut microbial communities.

Plant-derived xenomiRs and cancer: Cross-kingdom gene regulation.

Exosomal microRNAs (miRNAs) critically regulate several major intracellular and metabolic activities, including cancer evolution. Currently, increasing evidence indicates that exosome harbor and transport these miRNAs from donor cells to neighboring and distantly related recipient cells, often in a cross-species manner. Several studies have reported that plant-based miRNAs can be absorbed into the serum of humans, where they hinder the expression of human disease-related genes. Moreover, few recent studies have demonstrated the role of these xenomiRs in cancer development and progression. However, the cross-kingdom gene regulation hypothesis remains highly debatable, and many follow up studies fail to reproduce the same. There are reports that show no effect of plant-derived miRNAs on mammalian cancers. The foremost cause of this controversy remains the lack of reproducibility of the results. Here, we reassess the latest developments in the field of cross-kingdom transference of miRNAs, emphasizing on the role of the diet-based xenomiRs on cancer progression.