Whole-blood transcriptome profiling reveals signatures of metformin and its therapeutic response

Ustinova, Monta; Ansone, Laura; Silamiķelis, Ivars; Rovīte, Vita; Elbere, Ilze; Silamiķele, Laila; Kalniņa, Ineta; Fridmanis, Dāvids; Sokolovska, Jeļizaveta; Konrāde, Ilze; Pīrāgs, Valdis; Kloviņš, Jānis

doi:10.1371/journal.pone.0237400

Cited by 20 publications

(12 citation statements)

References 59 publications

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“…10,11). It has been shown that metformin exerts its effects on the microbiome already in the first 24 hours ( 10 )⁠ and that the alterations in the gut microbiome could be related to the metformin-induced immune response ( 13 )⁠.…”

Section: Introductionmentioning

confidence: 99%

Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes

et al. 2021

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Effects of metformin, the first-line drug for type 2 diabetes therapy, on gut microbiome composition in type 2 diabetes have been described in various studies both in human subjects and animals. However, the details of the molecular mechanisms of metformin action have not been fully understood. Moreover, there is a significant lack of information on how metformin affects gut microbiome composition in female mouse models, depending on sex and metabolic status in well controlled experimental setting. Our study aimed to examine metformin-induced alterations in gut microbiome diversity, composition, and functional implications of high-fat diet-induced type 2 diabetes mouse model, using, for the first time in mice study, the shotgun metagenomic sequencing that allows estimation of microorganisms at species level. We also employed a randomized block, factorial study design, and including 24 experimental units allocated to 8 treatment groups to systematically evaluate the effect of sex and metabolic status on metformin interaction with microbiome. We used DNA obtained from fecal samples representing gut microbiome before and after ten weeks-long metformin treatment. We identified 100 metformin-related differentially abundant species in high-fat diet-fed mice before and after the treatment, with most of the species relative abundances increased. In contrast, no significant changes were observed in control diet-fed mice. Functional analysis targeted to carbohydrate, lipid, and amino acid metabolism pathways revealed 14 significantly altered hierarchies. We also observed sex-specific differences in response to metformin treatment. Males experienced more pronounced changes in metabolic markers, while in females the extent of changes in gut microbiome representatives was more marked, indicated by 53 differentially abundant species with more remarkable Log fold changes compared to the combined-sex analysis. The same pattern manifested regarding the functional analysis, where we discovered 5 significantly affected hierarchies in female groups but not in males. Our results suggest that both sexes of animals should be included in future studies focusing on metformin effects on the gut microbiome.

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Section: Introductionmentioning

confidence: 99%

Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes

et al. 2021

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“…To ensure that the observed transcriptomic changes are a faithful representation of the DCS state, care was taken to minimize interindividual differences amongst the divers selected for this study. The peripheral blood transcriptome is known to broadly reflect the combined effects of pharmacotherapy, chronic disease, and environmental exposures such as smoking ( Lampe et al, 2004 ; Liu Y. et al, 2015 ; Beretta et al, 2020 ; Ustinova et al, 2020 ). While these factors are integral components of many human studies, they can cause confounding in gene expression experiments.…”

Section: Discussionmentioning

confidence: 99%

Acute Effects on the Human Peripheral Blood Transcriptome of Decompression Sickness Secondary to Scuba Diving

et al. 2021

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Decompression sickness (DCS) develops due to inert gas bubble formation in bodily tissues and in the circulation, leading to a wide range of potentially serious clinical manifestations. Its pathophysiology remains incompletely understood. In this study, we aim to explore changes in the human leukocyte transcriptome in divers with DCS compared to closely matched unaffected controls after uneventful diving. Cases (n = 7) were divers developing the typical cutis marmorata rash after diving with a confirmed clinical diagnosis of DCS. Controls (n = 6) were healthy divers who surfaced from a ≥25 msw dive without decompression violation or evidence of DCS. Blood was sampled at two separate time points—within 8 h of dive completion and 40–44 h later. Transcriptome analysis by RNA-Sequencing followed by bioinformatic analysis was carried out to identify differentially expressed genes and relate their function to biological pathways. In DCS cases, we identified enrichment of transcripts involved in acute inflammation, activation of innate immunity and free radical scavenging pathways, with specific upregulation of transcripts related to neutrophil function and degranulation. DCS-induced transcriptomic events were reversed at the second time point following exposure to hyperbaric oxygen. The observed changes are consistent with findings from animal models of DCS and highlight a continuum between the responses elicited by uneventful diving and diving complicated by DCS. This study sheds light on the inflammatory pathophysiology of DCS and the associated immune response. Such data may potentially be valuable in the search for novel treatments targeting this disease.

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“…The study of the transcriptome finds great application in studies aimed at searching for new molecular markers and therapeutic targets. They involve numerous human diseases, including neurological disorders such as chronic pain [19], multiple sclerosis [20], diabetes [21], cardiovascular disease [22], cancers, and their response to treatment [23]. Microarrays and high-throughput RNA sequencing are of great importance, as they rapidly provide a huge amount of data on the processes or organisms under study [24].…”

Section: Multiomics Strategiesmentioning

confidence: 99%

Recent Multiomics Approaches in Endometrial Cancer

Boroń¹,

Zmarzły²,

Wierzbik-Strońska³

et al. 2022

IJMS

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Endometrial cancer is the most common gynecological cancers in developed countries. Many of the mechanisms involved in its initiation and progression remain unclear. Analysis providing comprehensive data on the genome, transcriptome, proteome, and epigenome could help in selecting molecular markers and targets in endometrial cancer. Multiomics approaches can reveal disturbances in multiple biological systems, giving a broader picture of the problem. However, they provide a large amount of data that require processing and further integration prior to analysis. There are several repositories of multiomics datasets, including endometrial cancer data, as well as portals allowing multiomics data analysis and visualization, including Oncomine, UALCAN, LinkedOmics, and miRDB. Multiomics approaches have also been applied in endometrial cancer research in order to identify novel molecular markers and therapeutic targets. This review describes in detail the latest findings on multiomics approaches in endometrial cancer.

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Whole-blood transcriptome profiling reveals signatures of metformin and its therapeutic response

Cited by 20 publications

References 59 publications

Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes

Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes

Acute Effects on the Human Peripheral Blood Transcriptome of Decompression Sickness Secondary to Scuba Diving

Recent Multiomics Approaches in Endometrial Cancer

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