Integrating multi-omics biomarkers and postprandial metabolism to develop personalized treatment for anorexia nervosa

Abstract

Background Anorexia nervosa (AN) is a serious mental illness characterized by emaciation, an intense fear of gaining weight despite being underweight, and distorted body image. Few treatments reverse the core symptoms in AN such as profound aversion to food and food avoidance. Consequently, AN has a chronic and relapsing course and the highest mortality rate of any psychiatric illness. A more complete understanding of the disease pathogenesis is needed in order to develop better treatments and improve AN outcome. The pathogenesis and psychopathophysiology of AN can be better elucidated by combining longitudinal phenotyping with multiple “omics” techniques, including exon sequencing, proteomics, lipidomic, and metabolomics. Design This paper summarizes the key findings of a series of interrelated studies including new experimental data and previously published data, and describes our current initiatives and future directions. Results Exon sequencing data was analyzed in 1205 AN and 1948 controls. Targeted metabolomics, lipidomics, and proteomics data were collected in two independent convenience samples consisting of 75 subjects with eating disorders and 61 age-matched healthy controls. Study participants were female and the mean age was 22.9 (4.9 [SD]) years. Epoxide hydrolase 2 (EPHX2) genetic variations were significantly associated with AN and that activity of epoxide hydrolase (sEH) was elevated in AN compared to controls. The polyunsaturated fatty acid (PUFA) and eicosanoids data revealed that Cytochromes P450 pathway was implicated in AN, and AN displayed a dysregulated postprandial metabolism of PUFAs and sEH-dependent eicosanoids. Implication and current Initiatives Collectively, our data suggest that dietary factors may contribute to the burden of EPHX2-associated AN susceptibility and affect disease outcome. We are implementing new investigations using a longitudinal study design in order to validate and develop an EPHX2 multi-omics biomarker system. We will test whether sEH-associated postprandial metabolism increases AN risk and affects treatment outcome through an ω-6 rich breakfast challenge. Participants will include 100 ill AN patients, 100 recovered AN patients, and 100 age- and race-matched healthy women. These data will allow us to investigate 1) how genetic and dietary factors independently and synergistically contribute to AN risk and progression, and 2) if clinical severity and treatment response in AN are affected by sEH activity and eicosanoid dysregulation. Results of our study will 1) identify clinically relevant biomarkers, 2) unravel mechanistic functions of sEH, and 3) delineate contributory roles of dietary PUFAs and Cytochrome P450 pathway eicosanoids for the purpose of developing novel AN treatments and improving disease prognosis.

Personalized polyunsaturated fatty acids as a potential adjunctive treatment for anorexia nervosa

“…Muller et al also identified similar clinical benefits of celecoxib as adjunctive treatment during the middle of the treatment course, and demonstrated the activation of the type-1 immune response coupling to down-regulation of the type-2 immune response mediated by celecoxib as a potential mechanism of action [98]. Our eicosanoid data which showed AN had a hyper postprandial responsiveness to ARA compared to healthy controls suggests that food-associated inflammatory processes may increase anxiety and pain, contributing to psychopathological eating behavior in AN [16]. In light of the aberrant PUFAs identified in AN (Table 1), a better understanding of how PUFAs interact with host factors (e.g., genetic variation) to modulate eicosanoid-induced inflammation in AN can provide much-needed knowledge to develop optimum PUFA formulation to improve AN symptoms and treatment outcomes.…”

“…Our multi-omics studies in AN [15,16] demonstrated for the first time that similar to cancer [77,78], PUFA and PUFA-associated eicosanoids play a role not only in AN risk but may also effect comorbid psychopathology [15] and postprandial metabolism dysregulation [79]. The increased activity of soluble epoxide hydrolase (sEH) observed in both ill and recovered AN patients compared to controls [15,16] implicates cellular inflammation as a key risk factor or disease modulator for AN.…”

“…The increased activity of soluble epoxide hydrolase (sEH) observed in both ill and recovered AN patients compared to controls [15,16] implicates cellular inflammation as a key risk factor or disease modulator for AN. In effect, the sEH converts epoxyeicosatrienoic acids, which are anti-inflammatory, to corresponding diols that lessen anti-inflammation function and induce a shift to inflammation [80].…”

“…While a small number of studies suggest a potential for n-3 PUFAs to improve AN symptoms, the association between AN and specific PUFA is inconsistent, and the mechanisms by which PUFAs could benefit AN remain untested. We recently demonstrated that AN patients not only showed a significantly different pattern of PUFA concentration when compared with healthy controls [15], dysregulation in PUFA-derived eicosanoids were associated with AN risk [15] and comorbid psychopathology [16]. Of special interest is the finding that AN demonstrated a differential postprandial metabolism compared to healthy controls with n-6 ARA but not with n-3 PUFAs [16] (raw data in Table 1 of Ref 17)[17].…”

“…We recently demonstrated that AN patients not only showed a significantly different pattern of PUFA concentration when compared with healthy controls [15], dysregulation in PUFA-derived eicosanoids were associated with AN risk [15] and comorbid psychopathology [16]. Of special interest is the finding that AN demonstrated a differential postprandial metabolism compared to healthy controls with n-6 ARA but not with n-3 PUFAs [16] (raw data in Table 1 of Ref 17)[17]. Our work to date highlights the possibility that the metabolism of PUFAs leading to increased production of proinflammatory bioactive lipid mediators may be a key mechanism underlying the profound food aversion in AN.…”