SLC6A4 DNA Methylation Levels and Serum Kynurenine/Tryptophan Ratio in Eating Disorders: A Possible Link with Psychopathological Traits?

Abstract

Background: The incidence of eating disorders (EDs), serious mental and physical conditions characterized by a disturbance in eating or eating-related behaviors, has increased steadily. The present study aims to develop insights into the pathophysiology of EDs, spanning over biochemical, epigenetic, psychopathological, and clinical data. In particular, we focused our attention on the relationship between (i) DNA methylation profiles at promoter-associated CpG sites of the SCL6A4 gene, (ii) serum kynurenine/tryptophan levels and ratio (Kyn/Trp), and (iii) psychopathological traits in a cohort of ED patients. Among these, 45 patients were affected by restricting anorexia nervosa (AN0), 21 by purging AN (AN1), 21 by bulimia (BN), 31 by binge eating disorders (BED), 23 by unspecified feeding or eating disorders (UFED), and finally 14 by other specified eating disorders (OSFED) were compared to 34 healthy controls (CTRs). Results: Kyn level was higher in BED, UFED, and OSFED compared to CTRs (p ≤ 0.001). On the other hand, AN0, AN1, and BN patients showed significatively lower Kyn levels compared to the other three ED groups but were closed to CTRs. Trp was significantly higher in AN0, AN1, and BN in comparison to other ED groups. Moreover, AN1 and BN showed more relevant Trp levels than CTRs (p <0.001). BED patients showed a lower Trp as compared with CTRs (p ≤ 0.001). In addition, Kyn/Trp ratio was lower in the AN1 subtype but higher in BED, UFED, and OSFED patients than in CTRs (p ≤ 0.001). SCL6A4 DNA methylation level at CpG5 was lower in AN0 compared to BED (p = 0.021), and the CpG6 methylation was also significantly lower in AN0 in comparison to CTRs (p = 0.025). The mean methylation levels of the six CpGs analyzed were lower only in the AN0 subgroup compared to CTRs (p = 0.008). Relevant psychological trait EDI-3 subscales were correlated with biochemical and epigenetic data. Conclusions: These findings underline the complexity of psychological and pathophysiological components of EDs.

Epigenetic alterations in patients with anorexia nervosa—a systematic review

“…However, altered methylation profiles in AN compared to healthy controls were identified for only ten genes. These genes are related to mood regulation and neurotransmitter release (serotonin, dopamine, alpha-synuclein) [57,58,[66][67][68], social attachment (oxytocin) [62,69], appetite regulation (leptin, ghrelin) [53,68,70], lipid metabolism and energy homeostasis (NR1H3) [45,49,54,61], extracellular matrix organization (TNXB) [45,49,54,61] and regulation of gene expression (HDAC4) [49,71]. Intriguingly, all genes except for leptin and, more recently, serotonin showed an increased methylation level in patients with AN compared to healthy controls [53,66].…”

“…Altered methylation patterns in patients with AN were identified for the following ten genes: SLC6A4, SLC6A3/DAT, OXTR, DRD2, LEP/LEPR, NR1H3, GHSR1a, TNXB, HDAC4, and SNCA. Interestingly, except for the leptin gene (LEP), which was identified in the only longitudinal candidate study [53], and recently the serotonin receptor gene (SLC6A4) [66], all other genes showed hypermethylation in patients with AN compared to healthy controls (Table 2). The serotonergic system has been proposed to have a distinct impact on the pathophysiology of AN, given its pivotal role in regulating appetite, satiety, and mood [38,99].…”

“…However, candidate gene studies have thus far produced inconclusive or even contradictory results for epigenetic changes in different genes in patients with AN compared to healthy controls (Table 1C) [66,67], or the results could not be reproduced in subsequent studies [49,71]. This could be due to the small sample sizes; furthermore, some of the participants studied were a mix of acutely ill and recovered patients, which can lead to heterogeneity in the obtained results.…”

Solute Carrier Family 26 Member 4 (SLC26A4), A Potential Therapeutic Target for Asthma

“…It plays a crucial role in the reuptake of serotonin from the synaptic cleft into presynaptic neurons, terminating neurotransmission and regulating serotonin signaling. Dysfunction or dysregulation of SLC6A4 can lead to alterations in serotonin levels and signaling, which have been implicated in various neuropsychiatric disorders, including depression, anxiety disorders, schizophrenia, and obsessive-compulsive disorder (OCD) [ 10 , 33 , 35 , 36 ]. Antiporters transport two different molecules in opposite directions (one substrate moves into the cell, another moves out) across the membrane (e.g., SLC4A1/AE1).…”

New Perspective on Anorexia Nervosa: Tryptophan-Kynurenine Pathway Hypothesis

“…Anorectic and bulimic patients did not manifest changes in L-kynurenine levels compared to controls. There was a small but significant increase in the TRP level among purging AN, as well as a small decrease in the L-kynurenine/TRP ratio [ 54 ]. Excessive physical activity in both groups of patients with AN resulted in a lower L-kynurenine level and higher TRP compared to non-exercising patients [ 54 ].…”