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Modulation of fecal miRNA highlights the preventive effects of a Mediterranean Low-Inflammatory Dietary Intervention in patients with Familial Adenomatous Polyposis (RNA-Seq)

ABSTRACT: Diet can regulate gene and microRNA (miRNA) expression and various biological processes in the gut. Dietary interventions have been proposed as therapeutic approaches for several diseases, including cancer. In a pilot study, we showed that a low-inflammatory Mediterranean diet reduced markers of local and systemic inflammation in patients with Familial Adenomatous Polyposis (FAP). We evaluated the changes induced by a low-inflammatory Mediterranean dietary intervention on fecal miRNome and intestinal tissue transcriptome in FAP subjects and assessed whether these changes could be associated with the beneficial effects observed in the pilot study. The diet modulated 41 fecal miRNAs, and this modulation remained for three months after the intervention. miR-5092-5p, miR-4527, and miR-3612-3p were positively correlated with adherence to the Mediterranean diet, while miR-6867-5p and miR-760-5p were negatively correlated with serum calprotectin levels. The altered miRNAs target genes mainly related to inflammatory pathways, DNA repair, metabolism, and cytoskeleton organization. Seventy genes were differentially expressed between adenoma and normal tissue. Most were different before the dietary intervention, but reached similar levels after the diet. Functional enrichment analysis identified the proinflammatory ERK1/2, cell cycle regulation and nutrient response pathways as commonly regulated by differentially expressed miRNAs and genes. These findings suggest that fecal miRNAs modulated by the diet reflect an epigenetic regulation occurring in tissues that seems to influence inflammatory pathways. miRNAs and genes with oncogenic and tumor suppressor functions are also regulated, highlighting the potential cancer-preventive effect of the low-inflammatory Mediterranean diet.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222298 | GEO | 2024/01/12

REPOSITORIES: GEO

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Project description:We tested the hypothesis that a panel of placental mammal-specific miRNAs and their targets play important to establish receptivity to implantation and their dysregulated expression may be a feature in women with early pregnancy loss. Relative expression levels of miR-340-5p, −542-3p, and −671-5p all increased following treatment of Ishikawa cells with progesterone (10 μg/ml) for 24 hrs (p < 0.05). RNA sequencing of these P4-treated cells identified co-ordinate changes to 6,367 transcripts of which 1713 were predicted targets of miR-340-5p, 670 of miR-542-3p, and 618 of miR-671-5p. Quantitative proteomic analysis of Ishikawa cells transfected with mimic or inhibitor (48 hrs: n=3 biological replicates) for each of the P4-regulated miRNAs was carried out to identify targets of these miRNAs. Excluding off target effects, mir-340-5p mimic altered 1,369 proteins while inhibition changed expression of 376 proteins (p < 0.05) of which, 72 were common to both treatments. A total of 280 proteins were identified between predicted (mirDB) and confirmed (in vitro) targets. In total, 171 proteins predicted to be targets by mirDB were altered in vitro by treatment with miR-340-5p mimic or inhibitor and were also altered by treatment of endometrial epithelial cells with P4. In vitro targets of miR-542-3p identified 1,378 proteins altered by mimic while inhibition altered 975 a core of 200 proteins were changed by both. 100 protein targets were predicted and only 46 proteins were P4 regulated. miR-671-mimic altered 1,252 proteins with inhibition changing 492 proteins of which 97 were common to both, 95 were miDB predicted targets and 46 were also P4-regulated. All miRNAs were detected in endometrial biopsies taken from patients during the luteal phase of their cycle, irrespective of prior or future pregnancy outcomes Expression of mir-340-5p showed an overall increase in patients who had previously suffered a miscarriage and had a subsequent miscarriage, as compared to those who had infertility or previous miscarriage and subsequently went on to have a life birth outcome. The regulation of these miRNAs and their protein targets regulate the function of transport and secretion, and adhesion of the endometrial epithelia required for successful implantation in humans. Dysfunction of these miRNAs (and therefore the targets they regulate) may contribute to endometrial-derived recurrent pregnancy loss in women.

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Modulation of fecal miRNA highlights the preventive effects of a Mediterranean Low-Inflammatory Dietary Intervention in patients with Familial Adenomatous Polyposis (RNA-Seq)

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