Profilo microbiomico e metabolomico in soggetti con anoressia nervosa prima e dopo recupero di peso: un approccio multi-omico

Although the etiopathogenesis of Anorexia Nervosa (AN) is not yet completely known, alterations in the feeding regulatory systems have been proposed as possible pathogenetic mechanisms. Recently, the gut microbiota has been indicated as an important contributor to the mechanisms regulating host appetite and body weight as well as brain functions that may have a role in the pathophysiology of AN. Thus, an emerging idea is that the intestinal microbiota could contribute to the development of this disorder. Moreover, although metabolomics studies are recently spreading and have allowed the characterization of putative biomarkers in many mental diseases, they are relatively scanty in AN. Aim of this study was to analyse fecal microbiome profiles of AN women before and after weight restoration and to combine them with fecal metabolomic profiles according to a multi-omics approach. The clinical sample was composed by 24 women who met the criteria of the Diagnostic and Statistical Manual for Mental Disorders-5th edition (DSM-5) for AN as assessed by the Structured Clinical Interview for DSM-5, Clinician Version (SCID-5- CV). The gut microbiome of participants was sequenced in both the underweight phase (T0) and after short-term weight restoration (T1) and compared to that of 20 healthy women (CTRL) regularly menstruating and in good physical and mental health, as assessed by physical examination, routine medical interview and the MiniInternational Neuropsychiatric Interview. According to a multi-omics approach, microbiome data were correlated with relevant fecal metabolites characterized in participants by an untargeted metabolomic procedure. AN subjects showed a decreased intra-individual bacterial richness, an increased Bacteroidetes-to-Firmicutes abundance ratio and significant changes in the relative abundances of several bacteria at different order levels in both the underweight and weight-restored condition compared to healthy women. The untargeted metabolomic procedure allowed the characterization of 224 metabolites involved in energy, lipid and amino acid metabolism. Fourteen metabolities able to separate the 3 subject groups were identified and statistically significant differences in some fecal compounds emerged among the 3 groups. Moreover, a genetic algorithm identified 49 relevant metabolites clustered in 3 separated groups: one with lower concentrations in healthy controls, one with lower concentrations in underweight patients and one with lower concentrations in weight-restored patients. The relationships among these fecal metabolites and bacteria genera showed different frameworks in the 3 groups. In particular, healthy subjects showed a complex net of relationships between bacteria and metabolites as showed by several clustering nodes for both the features. AN women at T0, instead, showed a very simple context according to the lower number of principal clustering nodes while at T1 they showed an intermediate situation. Finally, in acute AN 70% of those correlations showed a negative sign suggesting a prevalent metabolites consummation by gut microbiota. In the present study we analyzed fecal microbiome profiles of women with AN before and after weight restoration and combined them with fecal metabolomes. We found the occurrence of gut dysbiosis in acutely ill AN subjects that did not normalize after short-term weight restoration. Moreover, we have provided the evidence that in AN patients gut bacteria are significantly connected with several fecal metabolites differently with respect to normal controls, and that some of these relationships have a divergent direction in the acute phase with respect to the weight restored phase of AN. These data should prompt further studies aiming to investigate whether correction of gut dysbiosis and dysmetabolism may have therapeutic effects in AN. [edited by Author]