Gut Inflammation Induced by Finasteride Withdrawal: Therapeutic Effect of Allopregnanolone in Adult Male Rats

Diviccaro, Silvia; Giatti, Silvia; Cioffi, Lucia; Falvo, Eva; Herian, Monika; Caruso, Donatella; Melcangi, Roberto Cosimo

doi:10.3390/biom12111567

Cited by 6 publications

(2 citation statements)

References 73 publications

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“…Nevertheless, recent evidence on the impact of sex-specific gut steroids on the gut microbiome in rats supports our findings in humans. Diviccaro et al demonstrated that Roseburia were inversely associated with allopregnanolone, pregnenolone, isoallopregnanolone, progesterone, dihydroprogesterone and testosterone (Diviccaro et al, 2022). Additionally, it appears likely that etifoxine elevated these gut steroids, presumably through the enteric nervous system (Giatti et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Short-term effects of etifoxine on human gut microbiome in healthy men

Manook,

Baghai,

Riebel

et al. 2023

Front. Neurosci.

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BackgroundNeurosteroids have recently gained in interest as a treatment strategy for affective disorders. Etifoxine is known for its dual mode of action, one of which is to stimulate endogenous neurosteroid synthesis. The gut microbiome has been studied in affective disorders, but it has not been investigated in the context of human etifoxine or neurosteroid interventions.MethodsWe performed a crossover study with 36 healthy male volunteers who received etifoxine versus alprazolam and placebo in a balanced Williams design. Participants were randomized into six sequences and went through three 5-day treatments followed by wash-out phases of 9 days. Bacterial compositions in stool samples were determined by high-throughput 16S rRNA amplicon sequencing.ResultsGut microbiome analyses revealed no relevant effects between treatments with respect to alpha and beta diversity. Differential abundance analyses yielded etifoxine treatment as the only effect related to changes in microbial features with reductions of Faecalibacterium duncaniae, Roseburia hominis and Lactobacillus rogosae (i.e., Bacteroides galacturonicus).ConclusionHere we report on the first human investigation of the gut microbiome with short-term etifoxine intervention. Differences in diversity and compositional structure of the microbiome were more likely due to between- subject effects rather than medication. However, five-day treatment with etifoxine reduced the abundance of a few bacterial species. These species are currently seen as beneficial components of a healthy intestinal microbiome. This reduction in abundances may be related to elevated endogenous neurosteroids.

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Section: Discussionmentioning

confidence: 99%

Short-term effects of etifoxine on human gut microbiome in healthy men

Manook,

Baghai,

Riebel

et al. 2023

Front. Neurosci.

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“…Synthetic progestins frequently disturb the gut microbiota, resulting in gut dysbiosis. This disruption contributes to impaired bidirectional communication between the gut microbiome and the brain, impacting brain functions, though the precise mechanisms remain largely elusive [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Exposure to Progestin 17-OHPC Induces Gastrointestinal Dysfunction through Claudin-1 Suppression in Female Mice with Increased Anxiety-Like Behaviors

Zeng,

Zhang,

Shen

et al. 2024

Neuroendocrinology

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Introduction: Progestin, commonly used in oral contraception and preventing preterm birth, elicits various off-target side effects on brain and gastrointestinal (GI) functions, yet the precise mechanisms remain elusive. This study aims to probe progestin's impact on GI function and anxiety-like behaviors in female mice. Methods: Colon stem cells were utilized to explore the mechanism underlying progestin 17-hydroxyprogesterone caproate (17-OHPC)-mediated suppression of claudin-1 (CLDN1), crucial for epithelial integrity. Chromatin immunoprecipitation and luciferase assays identified potential progestin-response elements on the CLDN1 promoter, with subsequent assessment of oxidative stress and pro-inflammatory cytokine release. Manipulation of vitamin D receptor (VDR) or estrogen receptor β (ERβ) expression elucidated their roles in 17-OHPC-mediated effects. Intestine-specific VDR deficient mice were generated to evaluate 17-OHPC's impact on GI dysfunction and anxiety-like behaviors in female mice. Additionally, gene expression was analyzed in various brain regions, including the amygdala, hypothalamus, and hippocampus. Results: Exposure to 17-OHPC suppressed CLDN1 expression via epigenetic modifications and VDR dissociation from the CLDN1 promoter. Furthermore, 17-OHPC intensified oxidative stress and proinflammatory cytokine release. VDR knockdown partly mimicked, while overexpression of either VDR or ERβ partly restored 17-OHPC-mediated effects. Intestinal VDR deficiency partly mirrored 17-OHPC-induced GI dysfunction, with minimal impact on 17-OHPC-mediated anxiety-like behaviors. Conclusions: 17-OHPC suppresses CLDN1 expression through VDR, contributing to GI dysfunction in female mice, distinct from 17-OHPC-induced anxiety-like behaviors. This study reveals a new mechanism and potential negative impact of progestin exposure on the gastrointestinal tract, alongside inducing anxiety-like behaviors in female mice.

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Analysis of the finasteride treatment and its withdrawal in the rat hypothalamus and hippocampus at whole-transcriptome level

Giatti,

Cioffi,

Diviccaro

et al. 2024

J Endocrinol Invest

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Purpose As reported in patients treated for androgenetic alopecia with finasteride (i.e., a blocker of the enzyme 5 alpha-reductase) and in an animal model, side effects affecting sexual, psychiatric, neurological, and physical domains, may occur during the treatment and persist with drug suspension. The etiopathogenesis of these side effects has been poorly explored. Therefore, we performed a genome-wide analysis of finasteride effects in the brain of adult male rat. Methods Animals were treated (i.e., for 20 days) with finasteride (1mg/rat/day). 24 h after the last treatment and 1 month after drug suspension, RNA sequencing analysis was performed in hypothalamus and hippocampus. Data were analyzed by differential expression analysis and Gene-Set Enrichment Analyses (GSEA). Results Data obtained after finasteride treatment showed that 186 genes (i.e., 171 up- and 15 downregulated) and 19 (i.e., 17 up- and 2 downregulated) were differentially expressed in the hypothalamus and hippocampus, respectively. Differential expression analysis at the drug withdrawal failed to identify dysregulated genes. Several gene-sets were enriched in these brain areas at both time points. Conclusion Some of the genes reported to be differentially expressed (i.e., TTR, DIO2, CLDN1, CLDN2, SLC4A5, KCNE2, CROT, HCRT, MARCKSL1, VGF, IRF2BPL) and GSEA, suggest a potential link with specific side effects previously observed in patients and in the animal model, such as depression, anxiety, disturbance in memory and attention, and sleep disturbance. These data may provide an important background for future experiments aimed at confirming the pathological role of these genes.

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Gut Inflammation Induced by Finasteride Withdrawal: Therapeutic Effect of Allopregnanolone in Adult Male Rats

Cited by 6 publications

References 73 publications

Short-term effects of etifoxine on human gut microbiome in healthy men

Short-term effects of etifoxine on human gut microbiome in healthy men

Exposure to Progestin 17-OHPC Induces Gastrointestinal Dysfunction through Claudin-1 Suppression in Female Mice with Increased Anxiety-Like Behaviors

Analysis of the finasteride treatment and its withdrawal in the rat hypothalamus and hippocampus at whole-transcriptome level

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