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. 2022 Mar 31;14(1):47.
doi: 10.1186/s13148-022-01264-0.

Regulation of oxytocin receptor gene expression in obsessive-compulsive disorder: a possible role for the microbiota-host epigenetic axis

Claudio D'Addario  1   2   3 , Mariangela Pucci  4 , Fabio Bellia  4 , Antonio Girella  4 , Annalaura Sabatucci  4 , Federico Fanti  4 , Matteo Vismara  5 , Beatrice Benatti  5 , Luca Ferrara  5 , Federica Fasciana  5 , Laura Celebre  5 , Caterina Viganò  5 , Luca Elli  5 , Manuel Sergi  4 , Mauro Maccarrone  6   7 , Valeria Buzzelli  8 , Viviana Trezza  8 , Bernardo Dell'Osso  9   10
Affiliations

Regulation of oxytocin receptor gene expression in obsessive-compulsive disorder: a possible role for the microbiota-host epigenetic axis

Claudio D'Addario et al. Clin Epigenetics. .

Abstract

Background: Obsessive-compulsive disorder (OCD) is a prevalent and severe clinical condition. Robust evidence suggests a gene-environment interplay in its etiopathogenesis, yet the underlying molecular clues remain only partially understood. In order to further deepen our understanding of OCD, it is essential to ascertain how genes interact with environmental risk factors, a cross-talk that is thought to be mediated by epigenetic mechanisms. The human microbiota may be a key player, because bacterial metabolites can act as epigenetic modulators. We analyzed, in the blood and saliva of OCD subjects and healthy controls, the transcriptional regulation of the oxytocin receptor gene and, in saliva, also the different levels of major phyla. We also investigated the same molecular mechanisms in specific brain regions of socially isolated rats showing stereotyped behaviors reminiscent of OCD as well as short chain fatty acid levels in the feces of rats.

Results: Higher levels of oxytocin receptor gene DNA methylation, inversely correlated with gene expression, were observed in the blood as well as saliva of OCD subjects when compared to controls. Moreover, Actinobacteria also resulted higher in OCD and directly correlated with oxytocin receptor gene epigenetic alterations. The same pattern of changes was present in the prefrontal cortex of socially-isolated rats, where also altered levels of fecal butyrate were observed at the beginning of the isolation procedure.

Conclusions: This is the first demonstration of an interplay between microbiota modulation and epigenetic regulation of gene expression in OCD, opening new avenues for the understanding of disease trajectories and for the development of new therapeutic strategies.

Keywords: DNA methylation; Gene expression; Microbiota; Obsessive–compulsive disorder; Oxytocin receptor; Saliva.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schematic representation of the experimental design that was used to investigate the effects of social isolation in rats. Behavioral and molecular analysis was conducted at the indicated time points
Fig. 2
Fig. 2
Transcriptional regulation of OXTR gene in PBMCs of OCD and control (CTRL) subjects. a Schematic representation of human OXTR gene. Translation start codon (ATG), exons and introns are depicted. Coding regions of exons are shown darker. Sequence of the CpG island under study is also reported. Bold text indicates the 4 CpG sites analyzed; b OXTR mRNA levels in PBMCs from patients diagnosed with OCD and CTRL subjects. Scattered plots represent 2 (−DDCt) values calculated by the DDCt method [****p < 0.001]; c OXTR exon III DNA methylation levels in PBMCs of OCD and CTRL subjects represented as scattered plot for individual CpG sites under study as well as of the average (AVE) of the 4 CpG sites [*p < 0.05]; d correlation between OXTR gene expression and % change of DNA methylation in the overall human population under study. Data were compared by Spearman's rank correlation coefficient
Fig. 3
Fig. 3
Transcriptional regulation of OXTR gene in saliva of OCD and control (CTRL) subjects. a DNA methylation levels of OXTR exon III in human saliva samples of OCD and CTRL subjects represented as scattered plot for individual CpG sites under study as well as of the average (AVE) of the 4 CpG sites [*p < 0.05]; b Spearman correlation analysis between AVE of DNA methylation from PBMCs (x-axis) and from saliva (y-axis)
Fig. 4
Fig. 4
Relative abundance of the bacterial phyla (a Actinobacteria, b Bacteroidetes, c Firmicutes, d Proteobacteria, e Fusobacteria) quantified in the saliva of OCD and CTRL groups. Scattered plots represent 2(−DDCt) values; f Spearman correlation analysis between DNA methylation AVE levels of the 4 CpG sites under study in saliva (y-axis) and relative abundance of Actinobacteria (x-axis). ****p < 0.0001, *p < 0.05 vs CTRL
Fig. 5
Fig. 5
Behavioral and molecular analysis in ISO rats. a ISO rats (n = 8) housed individually for five weeks (from PND 21 to PND 54, ISO) showed an anxious-like phenotype in the open field test, as they spent less time in the center of the arena compared to CTRL animals (n = 8). Moreover, ISO rats showed stereotypic behaviors as they displayed a higher frequency of wall rearing (b) and more head dippings in the hole-board test (c); d–g Oxtr relative gene expression in the AM, PFC, HYP and DStr of ISO and CTRL rats. Scattered plots represent 2 (−DDCt) values calculated by the DDCt method [** p < 0.01]; h–j correlations between Oxtr expression and behavioral outcomes. Data were compared by Spearman's rank correlation coefficient
Fig. 6
Fig. 6
Relative abundance of the bacterial phyla (a Actinobacteria, b Bacteroidetes, c Firmicutes, d Proteobacteria) quantified in the feces of ISO (n = 8) and CTRL (n = 8) rats collected at social isolation time point T1. Scattered plots represent 2 (−DDCt) values calculated by the DDCt method. Concentration of fecal total SCFA (e) and butyrate (f) quantified using fecal samples collected at social isolation time point T1. ***p < 0.001, **p < 0.01, *p < 0.05 vs CTRL group
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