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Anorexia nervosa and familial risk factors: a systematic review of the literature

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• Published: 25 August 2022
• Volume 42 , pages 25476–25484, ( 2023 )

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• Antonio Del Casale   ORCID: orcid.org/0000-0003-2427-6944 1 ,
• Barbara Adriani 2 ,
• Martina Nicole Modesti 2 ,
• Serena Virzì 2 ,
• Giovanna Parmigiani 1 ,
• Alessandro Emiliano Vento 1 &
• Anna Maria Speranza 1  

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Anorexia Nervosa (AN) is a psychological disorder involving body manipulation, self-inflicted hunger, and fear of gaining weight.We performed an overview of the existing literature in the field of AN, highlighting the main intrafamilial risk factors for anorexia. We searched the PubMed database by using keywords such as “anorexia” and “risk factors” and “family”. After appropriate selection, 16 scientific articles were identified. The main intrafamilial risk factors for AN identified include: increased family food intake, higher parental demands, emotional reactivity, sexual family taboos, low familial involvement, family discord, negative family history for Eating Disorders (ED), family history of psychiatric disorders, alcohol and drug abuse, having a sibling with AN, relational trauma. Some other risk factors identified relate to the mother: lack of maternal caresses, dysfunctional interaction during feeding (for IA), attachment insecurity, dependence. Further studies are needed, to identify better personalized intervention strategies for patients suffering from AN.

Highlights:

This systematic review aims at identifying the main intrafamilial risk factors for anorexia nervosa, including maternal ones.

Intrafamilial risk factors identified mostly regard family environment and relational issues, as well as family history of psychiatric diseases.

Family risk factors identified may interact with genetic, environmental, and personal risk factors.

These findings may help develop tailored diagnostic procedures and therapeutic interventions.

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Introduction

Eating behavior encompasses all responses associated with the act of eating and is influenced by social conditions, individual perception, previous experiences, and nutritional status. Additional influencing factors include mass media and idealization of thinness. Anorexia nervosa (AN) is a psychological disorder concerning body manipulation, including fear of becoming fat and self-inflicted hunger. This disorder is interpreted as a response to the social context and a woman’s rejection of fat to deny mature sexuality (Gonçalves et al., 2013 ; Korb, 1994 ) and it was once supposed to have “hysterical” causes (Valente, 2016 ). The current definition of AN provided by the DSM-5 describes it as “a restriction of energy intake relative to requirements such as to lead to a significantly low body weight […]; intense fear of gaining weight or becoming fat, or persistence in behaviors that interfere with weight gain […]; alteration in the way weight or body shape are experienced […]” (Cuzzolaro, 2014 ). The lifetime prevalence of AN is estimated being of 1.4% (0.1–3.6%) in women and 0.2% (0-0.3%) in men (Galmiche et al., 2019 ). The lifetime prevalence rates of anorexia nervosa might be up to 4% among females and 0.3% among males (Van Eeden et al., 2021 ). AN finds its roots in biological, psychological, social, and familial risk factors.

More precisely, heritable risk factors for AN can be found in 48–74% of cases (Baker et al., 2017 ): for example, it has a higher prevalence in female relatives of individuals with AN (Bulik et al., 2019 ). The presence of genetic correlations between AN and metabolic and anthropometric traits may explain why people with AN achieve very low BMIs and may even maintain and relapse to low body weight despite clinical improvement (Bulik et al., 2019 ). On the other hand, psychological risk factors include excessive concerns about weight and figure, low self-esteem, and depression; while social risk factors are related to peer diet, peer criticism, and poor social support (Haynos et al., 2016 ). As far as family is concerned, it has been observed that anorexic girls’ families are often characterized by poor communication with one another, overprotection, conflicts, and hostility (Emanuelli et al., 2003 ; Horesh et al., 2015 ; Sim et al., 2009 ).

Overall, the puzzle of AN risk factors is still obscure and needs deeper investigations as far as some predisposing aspects are concerned, such as intrafamilial risk factors, which have been extensively analyzed but not properly clarified for clinical applications. Because of the multifactorial etiology of AN, intrafamilial risk factors identification can help to establish preventive interventions in at-risk individuals, and to provide tailored treatments from the earliest stages of the disorder. Our main hypothesis is that intrafamilial as well as maternal risk factors play an essential role in the development of the disease.

Therefore, the main objective of this work is to provide a scientific review of the existing literature about familial relational risk factors involved in the development of AN, with the aim of improving: prevention, establishment of an early diagnosis, and development of a tailored treatment.

Methodology

On February the 16th, 2022, a first research was conducted on PubMed with the title/abstract filter, using the terms “anorexia AND risk factors AND family” in the search bar. For eligibility, we included only randomized controlled studies and case-control studies focused on the issue, as well as case-control studies with at least 50 participants. We excluded reviews, single case studies, case reports, other types of articles and other studies that did not focus on the main topic. The system provided 76 articles, of which 24 were ignored for low relevance. Hence, 52 were assessed for eligibility, from which 26 articles were excluded for not respecting the inclusion criteria, and 12 were excluded for not analyzing the research subject specifically. To the remaining 14 articles, 2 were added from citation search.

In the PRISMA diagram below (Fig.  1 ), the articles identified for the review (76) are reported schematically: screened (76), assessed for eligibility (52) and included (16).

PRISMA diagram of the study

The main results of the studies analyzed are summarized in Table  1 .

Despite anorexia having been usually considered an expression of age-specific conflicts intensified by constrictive cultural ideas and certain kinds of familial constellations (Bemporad et al., 1988 ), having our review included studies from 1990 to 2021 and conducted across many countries (i.e. US, Japan, Poland, UK, etc.) we can hypothesize that such a condition just evolves with culture and time, still maintaining certain background issues that we are aiming to emphasize in order to recognize certain red flags.

Eating disorders mark deficits in the ability to be nourished and to symbolize embodied experience. Psychoanalytic theories suggest that mothers who are insufficiently developed leave the child either austerely avoiding intrusion or struggling to digest maternal provisions without becoming lost in them. (Charles, 2021 ). Infantile Anorexia (IA) has been defined as a child’s refusal of food for more than 1 month, between 6 months and 3 years of age; acute and/or chronic malnutrition; parental concern about the child’s eating; mother-child conflict, talk, and distraction during mealtime (Chatoor et al., 1998 ). Maternal risk factors for (IA) we have identified across the review can confirm this widely accepted theory, specifically lack of maternal caresses (Mangweth et al., 2005 ), dysfunctional interaction during feeding in IA (Ammaniti et al., 2010 ), and attachment insecurity (Chatoor et al., 2000 ). Regarding maternal history of psychiatric diseases, it has been noted that maternal depression has an influence on the development of conflicts during mother-child interaction in younger children, while maternal psychoticism predicts mother-child conflict during feeding in older children (Ammaniti et al., 2010 ). This means that depressed mothers engage in less positive interactions with their infants while breastfeeding, with difficulties in empathically recognizing their infant’s affective states at mealtimes (Ammaniti, Ambruzzi et al., 2004 ; Feldman et al., 2004 ).

In addition to the relational risk factors, maternal diet seems to play a role in the development of AN (Haynos et al., 2016 ). This mechanism seems to find its roots early during childhood, since the infant’s weight appears to be inversely related to the mother’s degree of concern about her body shape (Ammaniti, Lucarelli et al., 2004 ). The “modelling theory of AN” (Pike & Rodin, 1991 ) argues that adolescent girls begin the diet by mimicking their dieting mothers. It seems that family concerns about weight and appearance are directly linked to the development of low satisfaction with one’s body, and therefore directly or indirectly related to eating problems (Leung et al., 1996 ).

Maternal risk factors are synthesized in Table  2 .

Enlarging our highlight from the mother to the whole family nucleus, the onset and maintenance of AN seems to be closely related to familial risk factors, and knowing them is crucial to identify the best therapeutic approach in order to target the unhealthy family environment as well as the needs of the patient. In addition, being aware of the familiar background may help in strengthening the hypothesis of genetic correlates within Eating Disorders (ED). Intrafamilial risk factors for the development of ED seem to have a greater impact when they occur early in adolescence (Field et al., 2008 ), but most of them are chronic in time and one can suppose they can be found in a family at any time during the life of the patient.

The major intrafamilial risk factors identified in this review are summarized in the following Table  3 .

Increased food intake in the family (Hilbert et al., 2014 ) seems to play a role in the development of ED. This seems counterintuitive, but the discrepancy between one’s family food intake and peer and media influences on body ideals may contribute to triggering a subtle mechanism by which diet represents a way to affirm oneself in front of the family and reestablish social acceptance.

Perfectionism (Hilbert et al., 2014 ; Pike et al., 2008 , 2021 ) is widely recognized as a familiar risk factor across many studies, and it can be assimilated to higher parental demands (Pike et al., 2008 ). It surely contributes to creating a tense family environment in which the development of oneself is more difficult, therefore inhibiting progressive differentiation of self from other (Charles, 2021 ). Perfectionism itself will become a personal risk factor for the outcome and severity of disease (Longo, Aloi et al., 2021 ) in a way that could be mimicking the family environment.

In general, unhealthy family functioning is predictive of adolescence problems (Lyke & Matsen, 2013 ). General family malfunction is predictive for AD onset during adolescence, and the level of affective expression of the family seems to be relate to ED risk during adolescence (Felker & Stivers, 1994 ), but our review has highlighted that all those features of what could be described as a “toxic” family environment in the common sense play a role in the development of AN. Emotional reactivity (Lyke & Matsen, 2013 ), as well as family taboos regarding nudity and sexuality (Mangweth et al., 2005 ), low familial involvement (Haynos et al., 2016 ), negative affectivity (Pike et al., 2008 , 2021 ), and family discord (Pike et al., 2008 ) may lie in the background in the lives of a future AN patient, and should be recognized as environmental risk factors in order to develop a tailored psychotherapeutic intervention that may involve the family as well as the patient, since it seems clear that the quality of family functioning influences the development (McGrane & Carr, 2002 ) and maintenance of EDs (North et al., 1997 ; Strober et al., 1997 ; Wewetzer et al., 1996 ).

As far as the presence of other disorders in family members is concerned, our review established that a familiar history of almost any psychiatric disorder (Longo, Marzola et al., 2021 ; Pike et al., 2021 ), including depression (Lyon et al., 1997 ), affective disorders (Steinhausen et al., 2015 ), alcohol and drug abuse (Lyon et al., 1997 ) plays a role in the development of AN. Nevertheless, having a sibling with AN increases the risk of developing AN (Machado et al., 2014 ; Steinhausen et al., 2015 ). We can hypothesize that the role of genetics in this mechanism is crucial yet still obscure, and nevertheless, talking about the presence of these diseases in members of the family nucleus, having to cope and live with the difficulties of others’ conditions is what can predispose to AN. In addition, the opposite may happen as well: there is an increased risk for relatives of patients with AN and BN to develop subclinical forms of ED, major depressive disorder, obsessive-compulsive disorder, and anxiety disorders (Lilenfeld et al., 1998 ). What is curious to note is that, on the one hand, having a sibling with AN predisposes to the development of AN (Felker & Stivers, 1994 ; Machado et al., 2014 ; Steinhausen et al., 2015 ), probably because of shared intrafamilial risk factors, therefore underlining the importance of the aim of this review; but, on the other hand, negative family history for ED predicts poor outcome (Ackard et al., 2014 ), probably because of the familiar unpreparedness to cope with such a difficult condition and the discrepancy created between the healthy members and the patient, which remains alone and uncapable of sharing certain issues with the others, so close yet so far from them.

Another risk factor identified is having suffered a relational trauma (Longo, Marzola et al., 2021 ). In general, individuals who have suffered from traumatic events (physical violence, being threatened with a weapon, sexual violence, being a victim of robbery) more frequently develop maladaptive eating behaviors (Field et al., 2008 ). Some evidence also suggests an increase of severe life events in the year preceding the onset of AN (Råstam & Gillberg, 1991 ). Children of mothers who have experienced the loss of a vital member of their family (i.e. older child or partner) in the six months prior to pregnancy have a higher risk of ED than children and infants who have not been exposed to this risk factor (Su et al., 2015 ). Further confirming the possible role of relational trauma as a red flag not only in the development of AN, but also in determining the severity of the disease, patients with AN and comorbid Post Traumatic Stress Disorder (PTSD) show more severe concerns about body shape and weight (Field et al., 2008 ). Having suffered physical and sexual abuse during childhood appears to be related to the onset of psychiatric pathologies in general, and not specifically to the onset of EDs in the young adult (Bruch, 1977 ; McGrane & Carr, 2002 ; Smith et al., 1995 ): therefore, this risk factor needs further investigation to confirm its specific role in the development of AN.

Strength and limits

The strength of this work lies in the comparison between different studies regarding AN showing high level of evidence and providing a complete picture of the constellation of intrafamilial risk factors of anorexia nervosa. There main limit of this study is that few articles from those included are from the very last years, while many other studies were conducted and published earlier (1990–2014), underlining the need of further investigations.

Conclusions

The main intrafamilial risk factors for AN identified from this study are: increased food intake in the family, perfectionism, higher parental demands, emotional reactivity, family taboos regarding nudity and sexuality, low familial involvement, negative affectivity, family discord, dependence, negative family history for ED (as a predictor of poor outcome), family history of depression, positive family history for psychiatric disorders, affective disorders in family members, alcohol and drug abuse, having a sibling with AN, relational trauma. Some other risk factors identified may relate to the role of the mother during childhood especially, and are as follows: lack of maternal caresses, dysfunctional interaction during feeding (for IA), attachment insecurity, dependence, maternal diet.

Complex interactions occur between intrafamilial risk factors and other personal aspects and symptoms, including perfectionism, individual body image issues, social concerns, excessive preoccupation with weight control, stress and adjustment problems, lack of close friends, social prejudice.

In conclusion, further studies are needed to understand more clearly how intrafamilial risk factors for AN interact with other environmental, personal and genetic ones, in order to connect the dots that can lead to an improvement of diagnostic and therapeutic procedures, and to the development of tailored intervention strategies that may target multiple issues in the life of the patient, including intrafamilial mechanisms that may be identified precociously and addressed through familial therapy, for the sake of the whole family nucleus.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Antonio Del Casale, Giovanna Parmigiani, Alessandro Emiliano Vento & Anna Maria Speranza

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Conceptualization: ADC, SV; Data curation ADC, GP; Investigation: SV, BA, MNM, AV, GP; Methodology: ADC; MNM; Supervision: ADC, AMS; Roles/Writing - original draft: ADC, SV, BA, MNM; Writing - review & editing: ADC, MNM.

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Del Casale, A., Adriani, B., Modesti, M.N. et al. Anorexia nervosa and familial risk factors: a systematic review of the literature. Curr Psychol 42 , 25476–25484 (2023). https://doi.org/10.1007/s12144-022-03563-4

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Received : 09 May 2022

Revised : 09 May 2022

Accepted : 24 July 2022

Published : 25 August 2022

Issue Date : October 2023

DOI : https://doi.org/10.1007/s12144-022-03563-4

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• Published: 29 April 2024

Inclusion of the severe and enduring anorexia nervosa phenotype in genetics research: a scoping review

• Sarah Ramsay 1 ,
• Kendra Allison 2 ,
• Heide S. Temples 2 ,
• Luigi Boccuto 1 &
• Sara M. Sarasua 1  

Journal of Eating Disorders volume  12 , Article number:  53 ( 2024 ) Cite this article

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Anorexia nervosa has one of the highest mortality rates of all mental illnesses. For those who survive, less than 70% fully recover, with many going on to develop a more severe and enduring phenotype. Research now suggests that genetics plays a role in the development and persistence of anorexia nervosa. Inclusion of participants with more severe and enduring illness in genetics studies of anorexia nervosa is critical.

The primary goal of this review was to assess the inclusion of participants meeting the criteria for the severe enduring anorexia nervosa phenotype in genetics research by (1) identifying the most widely used defining criteria for severe enduring anorexia nervosa and (2) performing a review of the genetics literature to assess the inclusion of participants meeting the identified criteria.

Searches of the genetics literature from 2012 to 2023 were performed in the PubMed, PsycINFO, and Web of Science databases. Publications were selected per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). The criteria used to define the severe and enduring anorexia nervosa phenotype were derived by how often they were used in the literature since 2017. The publications identified through the literature search were then assessed for inclusion of participants meeting these criteria.

most prevalent criteria used to define severe enduring anorexia nervosa in the literature were an illness duration of ≥ 7 years, lack of positive response to at least two previous evidence-based treatments, a body mass index meeting the Diagnostic and Statistical Manual of Mental Disorders-5 for extreme anorexia nervosa, and an assessment of psychological and/or behavioral severity indicating a significant impact on quality of life. There was a lack of consistent identification and inclusion of those meeting the criteria for severe enduring anorexia nervosa in the genetics literature.

This lack of consistent identification and inclusion of patients with severe enduring anorexia nervosa in genetics research has the potential to hamper the isolation of risk loci and the development of new, more effective treatment options for patients with anorexia nervosa.

Plain English Summary

Anorexia nervosa (AN) is a serious illness with a high death rate. Many of those with AN do not recover and have continuing severe psychological and physical symptoms that greatly impact their quality of life. Research has shown that genetics plays an important role, along with environment, in the development and persistence of AN. This review highlights the continued lack of consensus on defining criteria for severe and enduring AN in the literature and the continued focus on younger females with shorter illness durations in AN genetics research. Greater efforts are needed to include older participants with severe AN of longer duration in genetics research in hopes of developing more effective treatments for this underrepresented group.

Anorexia nervosa (AN) is a devastating illness with a high mortality rate. The standardized mortality ratio (SMR) calculates whether those in a given study population are equally, more or less likely to die compared to a reference population [ 1 ]. With an estimated SMR between 5.9 and 15.9 (i.e., 6–16 times excess mortality), AN is considered one of the deadliest mental disorders [ 2 , 3 ].

Studies indicate that the overall incidence rate for AN has remained relatively stable (4% female lifetime-0.3% male lifetime) since the 1970s [ 2 , 4 ]. The symptomology and presentation of AN have evolved along cultural lines; however, it is not simply a manifestation of modern cultural and social pressures. Accounts of deliberate self-starvation date back to the beginning of written history [ 5 ].

Although the exact etiology of AN is still unclear, a substantial body of evidence indicates that genetics plays a considerable role [ 6 , 7 ]. Genetic studies dating from the late 20th century have shown that AN is highly familial. The lifetime risk of developing AN for female relatives of individuals with AN is 11 times greater than that for female relatives of individuals without AN [ 8 ]. Heritability (h 2 twin ) estimates from twin studies range from ∼ 48–74% [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. The large range in estimates may be due to the use of broader participant inclusion criteria in AN studies to increase study group size. Broadening the inclusion criteria results in a more heterogeneous sample and decreased heritability estimates, while narrowing the definition of AN yields higher and more consistent estimates [ 17 ].

Although recovery from AN is possible, for approximately 20% of affected individuals the condition takes on a more intractable phenotype [ 18 , 19 ]. While AN symptoms vary from person to person, it has been suggested that a unique severe and enduring anorexia nervosa (SE-AN) subtype exists; however, aligning on clear defining criteria has proved challenging [ 20 ].

Since the 1980s, a small number of literature reviews of varying breadth and depth have been conducted in attempts to better define SE-AN. The most comprehensive to date, a 2017 review by Broomfield and colleagues identified illness duration and previous unsuccessful treatment as the criteria most often used in the literature to define AN severity [ 21 ]. A 2018 editorial by Hay and Touz, which referenced the Broomfield review, expanded the suggested criterion to include significantly diminished quality of life and narrowed the duration criterion to a minimum of three years and the therapeutic intervention exposure criterion to at least two previous evidence-based treatments [ 22 ]. In a 2021 follow-up review, with the aim of defining a neuropsychological profile for SE-AN, Bloomfield et al. identified intelligence, set-shifting and decision-making as features warranting further attention and noted that additional data are needed to align on defining severity criteria [ 23 ]. In short, there continues to be a lack of consensus on how to best define SE-AN.

Psychiatric illness is often diagnosed in a binary manner; an individual is assessed as either having the illness or not. In reality, due to their complex nature, psychiatric illnesses are better defined on a continuum [ 24 , 25 ]. Genome-wide association studies (GWAS) often use a binary case-control design. However, as Yang et al. [ 26 ] noted, with an equal population sample size, a quantitative trait (for example, symptom severity) association study will have greater power than a case-control association study. The difference is because in a case-control study, an individual with mild symptoms is not differentiated from one with severe symptoms. Relating this to AN, there would be no differentiation between an individual who met the DSM-5 criteria for mild illness, of short duration and who was responsive to first-line treatment, and an individual who met the extreme illness criteria, with a duration of over a decade and lack of positive response to multiple treatment modalities. Delineating participants based on illness severity when performing genetic data analysis of those with AN may improve the chances of identifying significant variants.

The potential value of defining more phenotypically similar groups based on quantitative phenotypes and comorbidities in genetic studies of psychiatric illness has been demonstrated in major depressive disorder (MDD), schizophrenia, autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) [ 27 , 28 , 29 , 30 ]. Individuals with more severe MDD symptoms have been found to have increased genetic risk for other psychiatric disorders [ 29 ], and polygenic risk scores (PRS) for schizophrenia correlate with symptom severity [ 28 ]. Genetic risk score (GRS), PRS and polygenic score (PGS) are the terms most often used in the literature when referring to values estimating an individual’s lifetime risk of developing a phenotype (disorder) based only on their genetics [ 31 ]. The scores are generated by combining the number of risk alleles at all the risk variants in an individual’s genome. Disease-associated risk variants are based on the latest and most comprehensive GWAS for the disorder at the time of the analysis.

Studies delineating and comparing subgroups of individuals with AN based on defined quantitative criteria may result in the discovery of rare variants associated with symptom severity, and individuals manifesting a more severe phenotype may be more likely to show higher heritability estimates and thus represent a subgroup of patients for which genetics findings may be beneficial. However, this hypothesis cannot be adequately tested to the rigorous standards required without a more precise definition of what constitutes a severe and enduring phenotype, and greater attention given to specifically identifying and including this group in genetic studies [ 32 ].

The aim of this review is to first, as an extension of the Broomfield et al. review [ 21 ], identify the criteria most widely used to describe the phenotypic severity of AN by including articles published since 2017 and, second, evaluate the genetics literature for inclusion of individuals meeting these criteria.

Delineating criteria for the severe and enduring anorexia nervosa phenotype

To better identify and delineate research participants manifesting a severe and enduring phenotype in the genetics literature, it was necessary to discern the most often used defining criteria for this subgroup of AN. The terms Anorexia Nervosa AND severe AND (Enduring OR Chronic) were used, with no year limit, to search titles and abstracts in PubMed, PsycINFO, and Web of Science. Articles were also limited to human subjects.

One of the articles identified was an extensive review by Broomfield et al. of how the literature labeled and defined AN severity up to 2017 [ 21 ]. The current search was limited to articles published after the Broomfield 2017 review to focus on the most recent literature. The references were not required to be attempting to empirically define a severe or enduring anorexia nervosa phenotype. The goal was to determine how those with a longer lasting and more severe clinical presentation are currently referred to in the literature. After removing commentaries on other references, clarifications, and updates from previous studies with the same authors and criteria, redundant references, and those not referring to a severe or enduring anorexia nervosa phenotype, 37 publications remained. Of these 37 publications, there were 22 research papers (6 clinical trials, 16 studies), 4 case reports, 6 expert panel/position papers/or opinion/editorial papers, 2 literature reviews and 3 general reviews. These references are listed in Table  1 , along with a book chapter [ 33 ] identified through reviewing the references of the selected papers, that was not included in the Broomfield 2017 review, bringing the total publications included to 38. The mean age, mean BMI, duration of illness in years, and history of previous treatment, as well as any other measures of illness severity, were extracted from the articles and are shown in Table  1 . A second reviewer, using the RANBETWEEN function in Microsoft Excel, selected 10% of the articles at random from Table  1 . to review for meeting inclusion criteria and accuracy of the data extracted.

Articles were reviewed to determine which criteria are used most often in the literature in regard to the severe enduring phenotype. Specifically, articles with a central purpose of better defining a severe and or enduring/chronic AN phenotype or the need for better treatment options (for example [ 34 , 35 ]), and articles including case studies or participants in one or more study groups defined as having a severe and or enduring/chronic AN phenotype (for example [ 36 , 37 ]) were included. The tabulation from the Broomfield review was combined with the current total. Given that the four Dalton articles referenced the same data, they were counted as only one reference. The results are outlined in Fig.  1 .

Number of references from Table  1 representing the specific duration of illness, number of previous unsuccessful treatments and body mass index (BMI) subgroups indicated either in defining severe and enduring anorexia nervosa or as inclusion criteria for participants. The totals indicated include both the references from the 2017 Broomfield review [ 21 ] and the current work

Literature review: inclusion of participants meeting the severe and enduring AN phenotype in genetics research

The search outlined in this section followed the process depicted in the PRISMA flow diagram [ 38 ] in Fig.  2 , which captures the literature selection flow. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist was utilized [ 39 ]. The goal was to assess whether participants meeting the criteria identified as the most widely used to define a severe and enduring phenotype are being included in genetics research, and, if included, whether these participants were assessed as an independent group.

PRISMA flow diagram for the literature search

The terms Anorexia Nervosa AND (genetic OR gene OR hereditary) in titles and abstracts were used for the following searches. Articles were limited to human subjects, and review articles were excluded. The goal was to be as inclusive as possible in the initial searches of each database. The search was limited to the last decade of published literature to assess current practices in genetics research. This span of time encompasses the five years leading up to and following the identification of the first genome wide significant locus for AN [ 40 ] and the publication of Broomfield et al., both of which were published in 2017. The inclusion dates were as follows: PubMed, 1-Jan-2012 to 6-Oct-2023 (date of search); PsycINFO, 1-Jan-2012 to 10-Oct-2023 (date of search); and Web of Science, 1-Jan-2012 to 12-Oct-2023 (date of search).

Searches of PubMed, PsycINFO and Web of Science conducted with the search criteria resulted in 240, 206 and 235 hits, respectively. Titles and keywords were reviewed, and 277 articles were eliminated for redundancy (see “identification” in Fig.  2 ). During the first screening, the abstracts for the remaining 404 were reviewed, and 211 were eliminated for the reasons depicted in the PRISMA diagram (“Records selected for Review 1”). The remaining 193 publications progressed to the second screening.

In the second screening, noted as “Records selected for Review 2” in the PRISMA diagram, the methods sections of the remaining 193 articles were reviewed for details on age, psychological assessments, anorexia subtype, duration of illness, prior treatment history, and other indications of disease severity. Studies did not need to specifically call out a subgroup of participants as being severe and or enduring; however, those not including participant data for at least three of the following four criteria were eliminated because they did not provide adequate information for the assessment of participant phenotype severity and intractability: (1) duration of illness; (2) body mass index (BMI); (3) prior treatment history; and (4) severity as measured by one or more clinical, social, or psychological scales. This resulted in the elimination of an additional 115 articles. A total of 78 articles were ultimately included in the information extraction process; the results are presented in Table  2 .

The data were extracted by reviewing both the methods and results sections of each paper for the following participant data: (1) mean duration of illness in years; (2) mean BMI in kg/m 2 ; (3) prior treatment history; (4) and severity as measured by one or more clinical, social, or psychological scales. Participant gender, mean age, and groups of eating disorders included in the studies (i.e., AN-restricting, AN-binge purge, bulimia, binge eating) were also extracted. A second reviewer, using the RANBETWEEN function in Microsoft Excel, selected 10% of the articles at random from Table  2 to review for meeting inclusion criteria and accuracy of the data extracted.

Defining severe enduring anorexia nervosa in the research literature

A review of the literature revealed that the terms severe, chronic, and enduring identified by Broomfield et al., in 2017 [ 21 ] continue to be widely used to label the more intractable AN phenotype. How these labels are defined in the literature, when they are defined, continues to vary greatly. The age of study participants, BMI, duration of illness, and previous treatment history were extracted from each reference and are recorded in Table  1 .

The primary inclusion criteria presented in the articles reviewed were as follows:

The Broomfield review [ 21 ] identified duration as the primary criterion used to define the severe and enduring AN phenotype, and this continues to be true. Several articles reviewed included duration of illness as a criterion for inclusion in their study or clearly delineated a subgroup using duration as one criterion. The stringency of how duration was measured varied.

In their audit of care received by patients with “early stage” versus “severe and enduring” AN, Ambwani et al. [ 36 ] defined a duration of < 3 years for early stage and ≥7 years for severe and enduring AN, as recommended by Robinson et al. and Touyz et al. [ 41 , 42 ]. This was also the case for Calugi et al. [ 43 ], who used ≥7 years in their study of cognitive behavioral therapy effectiveness. The patient described in the case study by Voderholzer et al. [ 44 ] had AN for seven years. In the four papers by Dalton et al. studying the impact of transcranial magnetic stimulation on severe and enduring AN, the duration inclusion criterion for study participation was ≥3 years of AN symptoms [ 45 , 46 , 47 , 48 ]. Whereas Knyahnytska et al. [ 49 ] included a duration of > 5 years as a criterion for treatment resistance in their insula H-coil transcranial stimulation therapy study. In the selection of a subset of participants from the Anorexia Nervosa Genetics Initiative (ANGI) to include in their assessment of the polygenic association of severity and long-term outcome in AN, Johansson et al. [ 50 ] included in their criteria for the severe enduring subtype a ≥ 5 year follow-up time, defined by the authors as years between initial registration and ANGI recruitment. Finally, in two of the three studies evaluating the effectiveness of deep brain stimulation, an illness duration of ≥ 10 years was required for participant inclusion [ 51 , 52 ], with the third requiring > 7 years [ 53 ]. Case study, clinical trial and study participants included in groups indicated as manifesting a severe and enduring phenotype tended to have illness of longer duration. For example, participants in the Calugi et al. [ 43 ] study had a mean duration of 12.3(4.7 SD) years, and the three case study subjects had illness durations of 7 [ 44 ], 11 [ 54 ], 25 [ 55 ], and 26 [ 37 ] years.

Position papers, commentaries, and reviews also varied greatly in defining duration requirements. For example, in their German language case study on palliative care for severe AN, Westermair et al. [ 56 ] proposed a long duration of illness, e.g., 10 years, as a criterion, whereas Hay and Touyz [ 22 ] and Herpetz-Dahlmann [ 57 ] used a duration of > 3 years. Other authors fell between the two extremes; Bianchi et al. [ 58 ] defined severe and enduring AN participants as those who had the disorder for six years or more, and Marzola et al. [ 59 ] used a seven-year demarcation. However, these two papers also proposed that duration should not be used alone when defining AN severity. The usefulness of duration as a criterion was also questioned by Wildes et al. [ 60 ]. In an attempt to define the severe and enduring phenotype empirically, Wildes found no evidence for a chronic subgroup of AN, instead proposing that this group may be better classified on the basis of impact on quality of life and severity of injurious behaviors. As indicated in Fig.  1 , a duration of 7 or more years was used most frequently, followed by 10 years.

Body mass index (BMI):

The DSM-5 defines four levels of AN severity: mild, BMI greater than 17 kg/m 2 ; moderate, BMI of 16–16.99 kg/m 2 ; severe, BMI of 15–15.99 kg/m 2 ; and extreme, BMI of less than 15 kg/m 2 [ 61 ]. Once again, the literature indicates a wide range of BMIs in articles attempting to define severe and enduring AN and/or for participation in studies targeting this group of individuals. The two studies of deep brain stimulation with duration criteria of ≥ 10 years for participation also had BMI requirements falling into the DSM extreme category [ 51 , 52 ]. Deep brain stimulation involves a high degree of risk, and the authors delineated that only individuals with the most severe cases should be included. Similar to duration of illness, participants included in groups indicated as manifesting a severe and enduring phenotype in case studies, clinical trials and studies, tended to have substantially lower BMIs than required per the inclusion criteria. For example, participants in the Bemer et al. bone mineral density (BMD) study had a mean BMI of 12.60 ± 1.60 kg/m 2 , which was well below the < 16 kg/m 2 criteria [ 62 ].

Notably, several studies included a low weight cutoff for participation. For example, in their transcranial magnetic stimulation studies, Dalton et al. [ 45 , 46 , 47 , 48 ] required a BMI > 14 kg/m 2 for participation. The reason provided in the study protocol for the low weight cutoff was “safety precaution” [ 63 ]. The deep brain stimulation studies conducted by Park et al. [ 64 ] required that participants be severely underweight but with a low-weight BMI criterion of > 13 kg/m 2 . Although reasons were not given for the low weight cutoff, they stated that participants needed to have a BMI > 13 kg/m 2 for surgery, which is understandable given its invasive nature.

Again, as with duration of illness, the literature suggests that BMI should not be used as the sole determinant of severity in AN. In their editorial on the challenges of defining severe and enduring AN, Hay and Touyz [ 22 ] recognized the utility of the DSM-5 BMI severity categories but also noted that for those with unremitting AN for a decade or more, having a BMI above the DSM severe range is still associated with marked morbidity.

Psychological assessment:

All the studies reviewed included an assessment of symptoms such as psychological stress, disordered eating, depression, anxiety, obsessiveness, and quality of life. For example, Wildes et al. [ 60 ], used the Research and Development Corporation (RAND) 36-Item Health Survey 1.0 (SF-36) to measure health-related quality of life, and found that these scores better classified AN subgroups than BMI and duration of illness. A score of ≤45 on the Global Assessment of Functioning (GAF) found in the DSM-4, which assesses the severity of mental illness [ 65 ], was used by Oudijn et al. [ 51 ] for inclusion in their deep brain stimulation studies. A plethora of tools was used in assessing eating disorder pathology, with the Eating Disorder Examination Questionnaire (EDE-Q) [ 66 ] and/or various iterations of the EDE-Q being the most prevalent.

Treatment response:

Lack of positive response to prior treatment, variously described as treatment resistance, treatment refractoriness, and failure to respond, was also included in assessing AN severity in several of the articles. The number and type of previous treatments required for inclusion in studies varied. For inclusion in deep brain stimulation studies, Park et al. [ 67 ] required a lack of positive response to ≥2 “typical modes” of treatment, as did Oudijn et al. [ 51 ]. The participant inclusion criteria used by Dalton et al. [ 48 ] for transcranial stimulation studies included the need to have completed at least one “previous course of National Institute for Health and Care Excellence” recommended “specialist psychotherapy or specialist day-patient or inpatient treatment”. The clearest classification criterion for treatment resistance was proposed by Hay and Touyz et al. [ 68 ]: “exposure to at least two evidence-based treatments delivered by an appropriate clinician or treatment facility together with a diagnostic assessment and formulation that incorporates an assessment of the person’s eating disorder health literacy with an assessment of the person’s stage of change”, which was referenced in the reviews of treatment options for those with severe enduring AN by Zhu et al. and Wonderlich et al. [ 20 , 69 ]. In contrast, Smith and Woodside [ 70 ] defined treatment resistance as “patients with two or more incomplete inpatient admissions and no complete admissions”. Emphasis was placed on patients failing to complete treatment rather than the treatment failing to help patients, although the authors did note that approximately 10% of patients treated at their inpatient facility were “unable to benefit”. As indicated in Fig.  1 , the criterion of two or more treatment attempts was most frequently used.

In summary, the literature indicates that a combination of assessments and criteria, including an illness duration of ≥ 7 years, lack of positive response to at least two previous evidence-based treatments, a BMI meeting the DSM-5 for extreme AN, and an assessment of psychological and/or behavioral severity indicating a significant impact on quality of life, were the most prevalent means of defining the severe and enduring AN phenotype. As the DSM-5 includes clear definitions of severe and extreme BMI (15–15.99 kg/m 2 and < 15 kg/m 2 , respectively), the criteria for severe BMI were also used in assessing the genetics literature in the following section.

Inclusion of participants meeting severe enduring anorexia nervosa-defining criteria in studies of anorexia nervosa genetics

The 78 articles identified as meeting the search criteria defined in the methods section were assessed for whether the following inclusion criteria were used and how they were defined:

Duration of illness,

Prior treatment history,

Severity as measured by one or more clinical, social, or psychological scales.

As mentioned previously, neither the statistical strength of the studies nor the study outcomes were assessed, as the purpose was to determine whether genetic studies included those meeting the severe and enduring phenotype criteria defined in the first aim through assessing prevalence of use in the literature. The studies consisted of Genome-Wide Association Studies (GWAS) as well as analyses of polymorphisms, expression, and gene methylation, including but not limited to the leptin ( LEP ) and the leptin receptor ( LEPR ) genes, the fat mass and obesity-associated gene ( FTO ), and the oxytocin receptor ( OXTR ) gene [ 16 , 71 , 72 , 73 ]. The gender of the study participants was also recorded where reported (Table  2 ).

Most of the 78 articles, including those specifically stating that the study was of severe AN, did not include criteria defined in the first aim. Most notably, only one article specifically stated that participants included had at least one prior treatment attempt [ 50 ].

Of the 71 studies reporting mean BMI, the mean BMI for all groups was 15.73 kg/m 2 (SD 1.48). For 15 studies (21%), the mean BMI was > 17 kg/m 2 (mild DSM-5). Sixteen studies (22%) had a mean BMI of 16–16.99 kg/m 2 (moderate DSM-5). Twenty-three studies (32%) had a mean BMI of ≤15.99 kg/m 2 (severe DSM-5), and 17 studies (21.8%) included at least one group with a mean BMI of ≤15 kg/m 2 , required to meet the DSM-5 definition of extreme AN. Only one study included a lifetime minimum BMI of ≤15 kg/m 2 as an inclusion criterion [ 74 ].

The duration of illness and or minimum duration required for inclusion in studies were reported for 23 (29%) of the 78 articles. Of those 23 studies, 3 (13%) had participants with a mean duration of illness ≤ 3 years, 12 (52%) had a mean of 3.1–6.99 years, and 6 (26%) had a mean of ≥ 7 years. Five of the 23 studies required a duration of illness ≥3 years as a participant inclusion criterion. None of the articles identified required duration of illness ≥7 years as an inclusion criterion.

Assessment of psychological stress, disordered eating, depression, anxiety, obsessiveness, and quality of life was another facet of defining the severity of AN in the studies evaluated. Across the 54 studies identifying defined assessment modalities, 38 different tools, checklists and guidelines were used in various combinations, including the following: Hamilton Anxiety Rating Scale (HARS), Clinical Global Impression anxiety scale (CGI), State-Trait Anxiety Inventory form (STAI); depression: Beck Depression Inventory (BDI), Children’s Depression Inventory (CDI), Montgomery-Asberg Depression Rating Scale (MADRS); alexithymia: Toronto Alexithymia Score (TAS); obsessive-compulsive and impulsive symptoms: Young-Brown Obsessive-Compulsive Symptoms (YBC-EDS), Leyton Obsessional Inventory-Child Version (LOI-CV); Barratt Impulsiveness Scale (BIS); and perfectionism: Child and Adolescent Perfectionism Scale (CAPS). Numerous eating disorder assessment tools, including the Eating Disorders Inventory (EDI), Eating Disorder Examination Questionnaire (EDE-Q), Eating Attitudes Test (EAT), and the Structured Interview for Anorexia and Bulimia Nervosa (SIAB) were also used. Table  3 shows a list of tools and how often they were used.

Historically, the focus of AN research has been on teens and young adults. The current assessment found that, of the 71 studies in which the mean age was reported or could be calculated, the mean of the mean ages reported for study participants was 20.9 (4.26 SD) years. Furthermore, the reported mean age of study participants in 36 (51%) of the 71 studies was ≤19.9 years, 21 (30%) had a mean age of 20-24.9 years, 14 (20%) had a mean age of 25-29.9 years, and only one study had an overall group mean age of ≥ 30 years, although eight studies included individual groups with means ≥ 30 years. Figure  3 provides a summary of the BMI, age and duration findings discussed above.

Number of articles in Table  1 representing the body mass index (BMI), age and duration subgroups indicated. NR = Not reported. A. BMI: 71 of the 78 articles reported BMI (kg/m 2 ), 17 of those 71 had participant mean BMI ≤ 15; Age: 72 of the 78 articles reported age, of those 72, one had a mean participant age over 30 years; Duration: 23 of the 78 articles included duration, of those 23, 6 had participant mean illness duration of ≥ 7 years

Incidence rates for AN are reported to be ten times lower in males, although this is considered an underestimation due to underreporting and underdetection [ 2 ]. Only 16 (20%) of the 78 studies included male participants.

Based on the min/max and standard deviations of the mean provided for duration of illness and BMI, it was clear that many of the articles included subsets of individuals meeting the criteria noted herein for severe and enduring AN. However, as data for those specific individuals were often not delineated, it was not possible to determine how the study conclusions may have differed for said subgroups. For example, the mean duration of illness reported by Hernández et al. [ 75 ] for the AN restricting type (AN-R) subgroup was 4.03 (4.44 SD) years, indicating that at least some of the participants met the duration criteria.

Nevertheless, there were examples of results being assessed against some measures of severity, including duration. The Booij et al. study [ 76 ] AN-R group participant duration of illness was 54.9 (30 SD) months; range: 12–84. They specifically assessed methylation against the cumulative duration of illness and observed associations between duration and methylation levels at 142 probes. The mean duration of illness in the AN-R group in the Steiger et al. study [ 77 ] was 96.00 ± 98.91 (12–456) months. They also assessed duration and found an association between chronicity of illness and methylation status at 64 probes mapping to 55 genes.

Other authors evaluated genetic correlation with the severity of various psychological assessments including quality of life, depression, food behaviors, anxiety, and obsessiveness [ 75 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 ]. For example, Acevedo and colleagues found a correlation between specific single nucleotide polymorphisms (SNPs) of the oxytocin receptor gene ( OXTR ), and increased severity of eating disorder symptoms in those with AN [ 78 ]. A polymorphism in the promotor region of the serotonin transporter gene ( 5-HTTLPR ), previously associated with stress and depression [ 91 ], may impact depression and long-term outcomes in those with AN [ 79 ]. Research also suggests a possible correlation between specific haplotypes of the DHEA-producing enzyme cytochrome P450 CYP17A [ 81 ] and the C861 allele of the serotonin receptor 1Dβ gene ( HTR1B ) and severity of anxiety in those with AN.

An example of potential utility in assessing the severe and enduring AN phenotype and the need for larger studies and more funding is the 2022 study by Johansson et al. [ 50 ] evaluating polygenic association with AN severity and long-term outcomes. Here, the authors delineated severe and enduring AN criteria, including duration of illness, clinical impairment, BMI, and having undergone at least one previous treatment attempt. They also specified requirements for the AN subtype, thereby narrowing the population. The study, which included 2843 participants followed for up to 16 years (mean: 5.3 years), provided evidence supporting the possible clinical utility of PGSs for assessing eating disorder risk but also noted the need for larger studies and sample sizes to increase statistical power.

In summary, based on the literature reviewed, genetic studies of AN continue to focus largely, but not exclusively, on younger female participants with shorter durations of illness. These findings are not surprising given that the majority of those diagnosed with AN are female, the lack of clearly defined criteria for severe and enduring AN and the need for large numbers of participants to assess significance in genetics research.

Attempts to provide criteria for labeling those with severe mental illness as chronic or treatment-resistant need to be executed with care, as has been critically reviewed for illnesses such as schizophrenia and depression [ 92 , 93 ]. Care should also be taken when defining criteria for severity of AN, which has a higher mortality rate than depression or schizophrenia [ 94 ]. However, not defining AN severity more clearly and not focusing on a more severe and enduring phenotype in research may decrease the likelihood of identifying the possible underlying biological etiology of AN. As noted by Wonderlich et al. [ 20 ] and responding commentaries by Dalle Grave [ 95 ], Wildes [ 96 ], and McIntosh [ 97 ], a lack of consensus and studies specifically targeting those with severe and enduring AN has resulted in patients being subjected to repetitive employment of largely ineffective treatment strategies resulting in a sense of hopelessness and shame and increasing the risk of suicide [ 98 ]. This review of the literature found that a duration of illness ≥7 years and an unsuccessful response to previous evidence-based treatment were the most common inclusion criteria employed, as were various measures of psychological and physical severity.

AN was once thought to be primarily caused by dysfunctional family dynamics and social and cultural pressures [ 99 ]. We now have evidence that genetics plays a significant role in its etiology. In recent years, there has been an evidence-based push to reconceptualize AN as a metabopsychiatric disorder [ 7 ]. Functional magnetic resonance imaging (fMRI) continues to provide data on the functioning of the brains of those with AN [ 100 ]. The use of large-scale GWAS and genome-wide methylation studies has been gradually revealing the interplay between genetics and environment in AN etiology and persistence, and genetic correlations with other psychiatric disorders [ 16 , 101 , 102 ]. These are all positive advances; however, as evidenced by the individuals included in these studies, female teens and young adults with shorter durations of illness appear to be the primary participants.

Historically, males have been underrepresented in AN research [ 103 ]. Until 2013, the DSM listed amenorrhea as a criterion for AN, thereby reinforcing the notion that AN affects only females [ 61 ]. According to the literature reviewed, males continue to be underrepresented in AN research.

The challenge of recruiting participants for inclusion in large-scale genetic studies of AN is significant. Of the indicated criteria, the most challenging for researchers to assess is the lack of response to prior evidence-based treatment. Most of the treatments described as evidence-based are not administered according to a defined protocol, making retrospective assessment nearly impossible. Furthermore, those with more severe symptoms of longer duration are often treated in a plethora of settings over many years.

For many of the publications, the data indicate that there were participants meeting the criteria defined in the first aim. However, as these individuals were not assessed as a group, it was not possible to determine whether outcomes for this subset may have differed from those with a less severe presentation. The purpose of the publications that either did not perform these assessments or did not report them in their studies was not to delineate this level of detail, so their absence is understandable. One of the reasons for this may be the small number of individuals meeting the criteria for severe and enduring AN, coupled with the need for a large enough “n” to provide any meaningful statistical assessment, which in turn points back to the need for larger studies and additional funding.

Nevertheless, several studies made concerted efforts to focus on a defined severe and enduring phenotype. For example, Kushima et al. [ 74 ] limited their study cohort to those reporting a lifetime lowest BMI < 15 kg/m 2 , with the median for included participants reported as 11.3 kg/m 2 , and a mean age of 37.9 years. The authors specifically stated that they focused on the “severe subgroup of patients because patients with severe symptoms or treatment-resistance are more likely to carry rare deleterious variants of large effect”, citing a schizophrenia study [ 104 ] as support.

The ultimate goal of AN research is to identify contributing factors to the manifestation and intractability of the disease and, in turn, develop superior evidence-based treatments tailored to the patient. Will next generation sequencing gene panels help in the diagnosis of AN [ 105 ]? Kushima et al. [ 74 ] suggested that rare copy number variants associated with neurodevelopmental disorders may correlate with more severe eating disorder subtypes. Is it possible to identify those at higher risk of developing severe and enduring illness earlier and in turn treat those patients based on their specific genetic and environmental circumstances instead of employing generic therapy that may work for most patients with eating disorders but is less effective for those in this cohort? Can artificial intelligence be employed to better identify risk in individuals with AN [ 106 ]? Will we one day regularly employ genetic testing and pharmacogenetics in treating mental illness, including AN [ 107 , 108 ]? Several international projects, including ANGI and the Comprehensive Risk Evaluation for Anorexia Nervosa in Twins (CREAT) are attempting to answer these questions and many more [ 109 , 110 ]. Although these projects do not focus specifically on the severe and enduring phenotype, the availability of in-depth participant health and demographic information paired with genetic analysis should allow for studies of these subsets.

The criteria for evaluating the severity and intractability of AN are evolving, as is the understanding of the disorder. The purpose of a scoping review is to map the literature on an evolving topic and to identify gaps. As such, unlike a systematic review, this review does not attempt to assess the quality of the research conducted, but rather the inclusiveness of study participants. The authors do not attempt to define the severe and enduring phenotype or suggest how the research community should create consensus on the definition. However, by assessing the current literature, we highlight the gaps between the intent to focus on those with severe and enduring AN and the inclusion of this group in published research.

Conclusion and future directions

In conclusion, this review provides an overview of the currently used criteria employed by the research community to define the severity of AN and assesses the last decade of genetics research for the inclusion of study participants meeting these criteria. We found that the following combination of assessments and criteria was used most often in the literature to define AN severity and intractability:

Illness duration of ≥ 7 years.

lack of positive response to at least two previous evidence-based treatments.

A BMI meeting the DSM-5 criteria for extreme AN.

An assessment of psychological and/or behavioral severity indicating a significant impact on quality of life.

We also found, especially in recent years, that there has been an attempt to better define severe and enduring AN in hopes of identifying patients, tailoring treatment, and improving outcomes. However, although a small subset of genetic studies reviewed specifically attempted to focus on a severe and enduring phenotype, there was a lack of aligned defining criteria. Furthermore, there is a continued focus on younger females with shorter disease durations.

Those with AN are often stigmatized, and their shame is amplified by the perception that AN is voluntary or even a lifestyle choice [ 111 , 112 , 113 ]. Those with severe and long-lasting illness are less likely to respond to currently available treatment modalities and have higher levels of mortality [ 20 ]. However, they also represent a subgroup of individuals for which genetic findings may be especially helpful [ 74 ]. Therefore, it is suggested that future genetics studies make a concerted effort to include older participants, those with longer illness durations, and those whose quality of life is most significantly impacted. It is also critically important that more objective, empirically based techniques, such as biomarker and brain structure and function analysis, be developed to more definitively classify the severe and enduring phenotype, which to this point has primarily been categorized through subjective means [ 32 , 60 , 96 , 114 ]. There has been considerable effort in recent years to expand the definition of AN in hopes of being more inclusive and identifying those who may benefit from treatment. However, although expansion has increased the sample size for genetic studies, it could be that focusing on those with longer-lasting and more severe symptomology, even though this is a much smaller group of those with AN, would provide a better chance of identifying the genetic etiology of the disorder. Recent advances have left us far better equipped to make significant progress in developing evidence-based treatments for those with severe and enduring AN. However, these advances require the inclusion of this subgroup in both research and practice.

Limitations

One limitation of the current review is that due to the wide range of similar terminology used to refer to a severe and enduring AN phenotype in the published literature, the searches performed may have left out pertinent articles and viewpoints. Furthermore, although comprehensive for the three electronic databases, the literature search did not include gray literature; thus, information from sources such as dissertations may have been missed.

Data availability

No datasets were generated or analysed during the current study.

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The authors would like to thank Dr. Michael Lutter for his valuable insight and review of the paper.

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Ramsay, S., Allison, K., Temples, H.S. et al. Inclusion of the severe and enduring anorexia nervosa phenotype in genetics research: a scoping review. J Eat Disord 12 , 53 (2024). https://doi.org/10.1186/s40337-024-01009-9

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ORIGINAL RESEARCH article

Anorexia nervosa and bulimia nervosa: a mendelian randomization study of gut microbiota.

• 1 Graduate School, Beijing University of Chinese Medicine, Beijing, China
• 2 Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
• 3 Postdoctoral Research Station, China Academy of Chinese Medical Sciences, Beijing, China
• 4 Postdoctoral Works Station, Yabao Pharmaceutical Group Co., Ltd., Yuncheng, China

Background: Anorexia nervosa (AN) and bulimia nervosa (BN) poses a significant challenge to global public health. Despite extensive research, conclusive evidence regarding the association between gut microbes and the risk of AN and BN remains elusive. Mendelian randomization (MR) methods offer a promising avenue for elucidating potential causal relationships.

Materials and methods: Genome-wide association studies (GWAS) datasets of AN and BN were retrieved from the OpenGWAS database for analysis. Independent single nucleotide polymorphisms closely associated with 196 gut bacterial taxa from the MiBioGen consortium were identified as instrumental variables. MR analysis was conducted utilizing R software, with outlier exclusion performed using the MR-PRESSO method. Causal effect estimation was undertaken employing four methods, including Inverse variance weighted. Sensitivity analysis, heterogeneity analysis, horizontal multivariate analysis, and assessment of causal directionality were carried out to assess the robustness of the findings.

Results: A total of 196 bacterial taxa spanning six taxonomic levels were subjected to analysis. Nine taxa demonstrating potential causal relationships with AN were identified. Among these, five taxa, including Peptostreptococcaceae , were implicated as exerting a causal effect on AN risk, while four taxa, including Gammaproteobacteria , were associated with a reduced risk of AN. Similarly, nine taxa exhibiting potential causal relationships with BN were identified. Of these, six taxa, including Clostridiales , were identified as risk factors for increased BN risk, while three taxa, including Oxalobacteraceae , were deemed protective factors. Lachnospiraceae emerged as a common influence on both AN and BN, albeit with opposing effects. No evidence of heterogeneity or horizontal pleiotropy was detected for significant estimates.

Conclusion: Through MR analysis, we revealed the potential causal role of 18 intestinal bacterial taxa in AN and BN, including Lachnospiraceae . It provides new insights into the mechanistic basis and intervention targets of gut microbiota-mediated AN and BN.

1 Introduction

Recent epidemiological studies indicate that 16% of global mortality can be attributed to mental disorders, rendering them among the leading causes of disability and premature death worldwide ( Murray et al., 2020 ; Arias et al., 2022 ). Eating disorders are one of the common types of mental disorders, exhibiting an age-standardized prevalence of 174.0 per 100,000 population. The prevalence of eating disorders in high-income countries is about three times the global average ( GBD 2019 Mental Disorders Collaborators, 2022 ). Anorexia nervosa (AN) and bulimia nervosa (BN) represent the most prevalent types of eating disorders and are uniquely identified as psychiatric conditions with elevated mortality risk in the Global Burden of Disease Study 2019 ( GBD 2019 Demographics Collaborators, 2020 ). A common feature of patients with both disorders is an excessive focus on weight and body shape and attempts to control weight. Patients with AN often adopt excessive behaviors to avoid weight gain, while patients with BN experience multiple overeating followed by inappropriate weight-compensating behaviors ( Timko et al., 2019 ). Studies have suggested that AN and BN may share the same psychopathological features and have reciprocal transformations, manifesting as similar behaviors, such as impulsivity and compulsion ( Howard et al., 2020 ).

Cognitive behavioral therapy is the first-line treatment for adults with AN and BN ( Treasure et al., 2020 ). Nevertheless, a meta-analysis found that over 60% of patients failed to fully abstain from core symptoms even after receiving the best available treatments ( Slade et al., 2018 ). Maudsley model and focal psychodynamic psychotherapy are also first-line treatments for adults with AN. For adults with BN, third-wave behavioral therapies are feasible attempts, such as dialectical behavior therapy, acceptance and commitment therapy. However, previous evaluations have shown little difference in efficacy between these therapies and cognitive behavioral therapy ( Byrne et al., 2017 ; Linardon et al., 2017 ). For adolescents with AN and BN, family-based interventions are recommended as first-line treatments by international evidence-based guidelines ( Hilbert et al., 2017 ). However, a Cochrane review suggests that the evidence favoring family-based interventions over standard treatment or other psychological approaches is not very solid ( Fisher et al., 2019 ). Therefore, new treatments for AN and BN, such as the novel ghrelin receptor agonist, and transcranial direct-current stimulation are still worthy of in-depth research and exploration ( van Passel et al., 2020 ; Solmi et al., 2021 ).

The gut microbiota intricately participates in various physiological processes crucial for human well-being, including metabolic regulation and immune homeostasis ( Fujisaka et al., 2018 ; Chen et al., 2022 ). Emerging evidence suggests that the microbiota and the central nervous system communicate bidirectionally via the microbiota-gut-brain axis, thereby influencing the pathophysiology of psychiatric disorders ( Agirman et al., 2021 ; Cryan and Mazmanian, 2022 ; Fan et al., 2023 ). A recent study found that, multiple bacterial taxa, such as Clostridium , were altered in AN and correlated with estimates of eating behavior and mental health ( Fan et al., 2023 ). A systematic review provided a clearer picture of the gut microbiota characteristics of AN patients. Preserved alpha-diversity and decreased beta-diversity were found in the qualitative synthesis. Three gut microbes ( Alistipes, Parabacterioides and Roseburia ), are able to effectively differentiate patients from controls ( Di Lodovico et al., 2021 ). Analogously, investigations into BN have corroborated a potential association between gut microbiota and BN development. Different pathological behaviors may be associated with a reduction in microbial diversity and typical microbiota-derived metabolites ( Castellini et al., 2023 ). These findings underscore the intertwined relationship between gut microbiota and the progression of AN and BN. However, the causal link between specific bacterial taxa and AN and BN necessitates further elucidation.

Conventionally, randomized controlled trials represent the gold standard for establishing causality. However, ethical dilemmas, compliance issues and difficulties in family coordination add additional challenges to the study of AN and BN, especially for adolescents ( Frostad and Bentz, 2022 ; Tsiandoulas et al., 2023 ). Mendelian randomization (MR) offers a pragmatic alternative approach for assessing causality by utilizing single nucleotide polymorphisms (SNPs) as genetic instrumental variables (IVs) to statistically infer the causal impact of exposures on outcomes ( Kurilshikov et al., 2021 ). This method emulates the random allocation process, thereby mitigating the influence of confounding variables ( Emdin et al., 2017 ). Moreover, since the microbiome does not induce alterations in an individual’s DNA sequence, analyzing the causal relationship between gut microbiota and AN and BN through MR studies holds practical clinical relevance ( Thomas, 2019 ). In this investigation, we employed two-sample MR analysis to scrutinize the potential causal role of gut microbiota in AN and BN, delineated specific pathogenic bacterial taxa, and elucidated their similarities, disparities, and associated mechanisms.

2 Materials and methods

2.1 study overview.

According to the law of independent assortment, genetic variants will be randomly assorted to gametes during meiosis. MR analysis uses this law as a principle to simulate randomized controlled trials using SNPs as genetic IVs. Because of this, MR study is seen as an appropriate method for analyzing the causal effects of exposure on clinical outcomes.

In this study, each bacterial taxon contained in the gut microbiota was categorized as a separate exposure. Of all, 196 gut microbiota taxa were selected as exposures ( Kurilshikov et al., 2021 ), AN and BN were defined as the outcome variable ( Wade et al., 2013 ; Duncan et al., 2017 ). Two-sample MR analysis was conducted using summary statistics from genome-wide association studies (GWAS) to discern which bacterial taxa were causally associated with AN and BN, respectively. The overall design of the study is shown in Figure 1 .

Figure 1 . Flow chart of the study. GWAS, genome wide association study; SNPs, single nucleotide polymorphisms; MR, Mendelian randomization; LD, linkage disequilibrium; IVW, inverse variance weighted.

The analysis adhered to three pivotal assumptions inherent to MR studies ( Emdin et al., 2017 ; Skrivankova et al., 2021 ): (1) genetic variation in exposed populations correlates with the exposure of interest, (2) genetic variation remains independent of confounding variables, and (3) genetic variation influences outcomes solely through the exposure of interest. The causal relationship between exposure factors and outcome factors was confirmed by testing 3 hypotheses that confirmed an indirect relationship between IV and outcome variables and was achieved only by exposure factors. A detailed information chart is provided in Supplementary material ( Skrivankova et al., 2021 ).

2.2 Genetic association data screening for AN and BN

All SNP data related to AN and BN were sourced from the MRC IEU OpenGWAS data infrastructure ( Lyon et al., 2021 ), developed by the MRC Integrated Epidemiology Unit at the University of Bristol. This repository aggregates genetic associations from 50,037 GWAS datasets, totaling 346,312,366,530 genetic associations. Considering sample size, sequencing depth, ethnicity, and data recency, GWAS datasets for AN and BN authored by Duncan et al. (2017) and Wade et al. (2013) , respectively, were selected. These studies encompassed 13 study cohorts with a combined sample size of 16,919 individuals, drawn from diverse pedigrees to mitigate bias ( Supplementary Tables S1, S2 ).

2.3 The selection of IVs

The genetic IVs of each bacterial taxon were obtained from the MiBioGen consortium, which comprised 18,340 individuals from 24 cohorts. The consortium utilized standardized analytical pipelines for both microbiota phenotype and genotype, ensuring uniform data processing methods. This approach was employed to mitigate potential variations introduced by technical differences in generating microbiota data ( Kurilshikov et al., 2021 ). This study used three different regions (V4: 10,413 samples, 13 cohorts, V3–V4: 4,211 samples, 6 cohorts and V1–V2: 3,716 samples, 5 cohorts) (V: hypervariable region sequencing for identifying bacterial taxa) of the 16S rRNA gene to analysis the composition of gut microbiota and identified genetic variants that influent the relative abundance of microbial taxa by use of microbiota Quantitative Trait loci mapping ( Kurilshikov et al., 2021 ). Following the removal of 15 unknown bacterial taxa, the final dataset encompassed 196 taxa ( Supplementary Table S3 ).

SNP screening entailed the following criteria ( Sanna et al., 2019 ): (1) genome-wide SNPs with significance ( p < 1 × 10 −5 ), (2) exclusion of weak IVs with an F -statistic <10, (3) linkage disequilibrium (LD) testing to ensure independence of selected IVs ( r 2 < 0.1 within a 500 kb range), and (4) removal of SNPs with incompatible or palindromic allele frequencies.

2.4 MR analysis and sensitivity assessment

MR analysis was conducted using R software (version 4.3.2) to evaluate the potential causal effect of gut microbes on AN and BN risk. MR estimates for each SNP were derived using the Wald ratio method, with meta-analysis performed using four methods: Inverse variance weighted (IVW), MR Egger, weighted median, and weighted mode ( Hartwig et al., 2017 ). The IVW method, recognized for its superior accuracy under practical conditions ( Bowden et al., 2016 ), served as the primary analytical approach, supplemented by the other three methods. Bonferroni correction was applied at each taxonomic level (phylum, class, order, family, and genus) to account for multiple comparisons. MR estimates with p  < 0.05 were considered statistically significant, while false discovery rate (FDR) p -values <0.05 denoted unequivocal significance. All estimates were expressed as odds ratio (OR) with a 95% confidence interval (CI) per standard deviation increase in the corresponding exposure.

The MR-PRESSO test was employed to identify outliers and address heterogeneity. In instances of detected heterogeneity among genetic IVs, outliers were eliminated, and MR analysis was re-executed. Sensitivity analyses were conducted via the leave-one-out method, Cochran’s Q statistic was utilized to assess potential heterogeneity, and the MR Egger intercept test was employed to estimate horizontal pleiotropy. Finally, the Steiger method facilitated causal directionality analysis to mitigate potential effects of reverse causation.

3.1 Overview of genetic IVs

Multiple SNPs were considered for each of the 196 bacterial taxa, following stringent screening based on genome-wide significance thresholds, LD testing, and validation of the F statistic. Any SNPs identified as outliers by MR-PRESSO (global test: p  < 0.05) were excluded. All retained SNPs exhibited F -statistics exceeding 10, indicating a robust correlation between the genetic IVs and the corresponding bacterial taxa. The final roster of retained SNPs and pertinent statistics are detailed in Supplementary Tables S4, S5 .

3.2 Relationship of intestinal bacterial taxa to AN and BN

Among the 196 taxon phenotypes examined, stringent Bonferroni correction did not reveal any unequivocal and significant causal relationships between gut microbiome and the risk of AN or BN (FDR p < 0.05). Nevertheless, based on analyses employing the IVW method and three additional methods, we ascertained potential causal relationships between certain intestinal taxa and the risk of AN or BN ( p < 0.05).

As shown in Table 1 , we identified nine taxa with potential causal relationships with AN. Among these nine taxa, Peptostreptococcaceae (IVW OR = 1.341, 95% CI 1.039–1.733, p  = 0.024), Coprococcus3 (IVW OR = 1.563, 95% CI 1.084–2.252, p  = 0.017), Escherichia Shigella (IVW OR = 1.490, 95% CI 1.109–2.003, p  = 0.008), Lachnospiraceae NC2004 group (IVW OR = 1.287, 95% CI 1.019–1.626, p  = 0.034), Lachnospiraceae UCG010 (IVW OR = 1.363, 95% CI 1.018–1.825, p  = 0.038) were determined to have a causal effect on AN risk. And Cyanobacteria (IVW OR = 0.724, 95% CI 0.563–0.930, p  = 0.012), Gammaproteobacteria (IVW OR = 0.619, 95% CI 0.406–0.943, p  = 0.026), Mollicutes RF9 (IVW OR = 0.740, 95% CI 0.584–0.939, p  = 0.013), and Eubacterium brachy group (IVW OR = 0.778, 95% CI 0.643–0.942, p  = 0.010) trended toward a lower risk of AN. Among the other three MR analysis methods (MR Egger, weighted median, weighted mode), only the weighted median method for the Coprococcus3 and Lachnospiraceae NC2004 group and the MR Egger calculations for Escherichia Shigella were statistically significant. It is noteworthy that all these results are in agreement with the IVW calculation method for this group, which to some extent reflects the stability of the results.

Table 1 . Significant MR results of potential causal effect of gut microbiota on AN.

The scatter plot ( Figure 2 ) visualized the causal relationship between gut bacterial taxa and AN. Each point in the graph represents a SNP, and the short lines of the cross at each point reflect its 95% CI. The abscissa is the effect of the SNP on the exposure (gut microbe), and the ordinate is the effect of the SNP on the outcome (AN). The slash lines of different colors represent the MR fitting results of different calculation methods. A slope greater than 0 indicates that the exposure factor (gut microbe) is a disadvantage of AN. For the fitting results of different methods, the results of IVW are generally the main ones. As shown in Figure 2 , except for Cyanobacteria and Lachnospiraceae NC2004 group , the results of the other MR analysis methods for the remaining seven taxa were in agreement with their respective IVW results. However, despite the inconsistencies between the MR Egger method results of these two gut microbes and the IVW method, the results of the IVW method remained robust due to their wide CIs and loss of statistical significance.

Figure 2 . Scatter plots of MR analysis of potential causal effect of 9 gut microbiota on AN. (A) Cyanobacteria , (B) Gammaproteobacteria , (C) Mollicutes RF9 , (D) Peptostreptococcaceae , (E) Coprococcus3 , (F) Escherichia Shigella , (G) Eubacterium brachy group , (H) Lachnospiraceae NC2004 group , (I) Lachnospiraceae UCG010 . IVW, inverse variance weighted; AN, anorexia nervosa; MR, Mendelian randomization; SNP, single nucleotide polymorphism.

As shown in Table 2 , we identified nine taxa with potential causal relationships with BN. Among these nine taxa, Clostridiales (IVW OR = 1.128, 95% CI 1.016–1.252, p = 0.024), Bilophila (IVW OR = 1.114, 95% CI 1.021–1.214, p = 0.015), Coprobacter (IVW OR = 1.085, 95% CI 1.005–1.171, p = 0.037), Holdemania (IVW OR = 1.096, 95% CI 1.016–1.182, p = 0.018), Ruminococcaceae UCG009 (IVW OR = 1.082, 95% CI 1.004–1.166, p = 0.038), and Slackia (IVW OR = 1.101, 95% CI 1.004–1.208, p = 0.041) were determined to be the increased risk of BN. While Rhodospirillales (IVW OR = 0.921, 95% CI 0.851–0.996, p = 0.038), Oxalobacteraceae (IVW OR = 0.937, 95% CI 0.890–0.985, p = 0.011), Lachnospiraceae UCG008 (IVW OR = 0.927, 95% CI 0.871–0.987, p = 0.018) were identified as protective factors. Of the other three MR analysis methods, only the weighted median method for the Rhodospirillales , Oxalobacteraceae , Bilophila , and Holdemania were statistically significant. All of these results are consistent with the IVW calculations for this group, reflecting the stability of the study results. As shown in Figure 3 , except for Rhodospirillales , Ruminococcaceae UCG009 , and Slackia , the results of other MR analysis methods for the remaining six taxa were in agreement with their respective IVW results. However, the results of the IVW method remained robust due to the wide CIs and loss of statistical significance of the MR Egger method. It is worth noting that due to the relative shortage of SNPs in Slackia , the MR Egger method calculates too wide CIs, which to some extent reflects the disadvantage of the method being overly conservative.

Table 2 . Significant MR results of potential causal effect of gut microbiota on BN.

Figure 3 . Scatter plots of MR analysis of potential causal effect of 9 gut microbiota on BN. (A) Clostridiales , (B) Rhodospirillales , (C) Oxalobacteraceae , (D) Bilophila , (E) Coprobacter , (F) Holdemania , (G) Lachnospiraceae UCG008 , (H) Ruminococcaceae UCG009 , (I) Slackia . IVW, inverse variance weighted; BN, bulimia nervosa; MR, Mendelian randomization; SNP, single nucleotide polymorphism.

3.3 Sensitivity analysis of MR results

Prior to conducting MR analysis, MR-PRESSO analysis was performed to exclude potential abnormal SNPs. Subsequent tests were undertaken to ensure the sensitivity of the findings and mitigate potential biases. The list of SNPs retained after the exclusion of aberrant SNPs by the MR-PRESSO method, along with relevant statistics, are presented in Supplementary Tables S4, S5 . Further MR-PRESSO global test analysis revealed no outliers among IVs with significant causal relationships with AN or BN, as detailed in Table 3 .

Table 3 . Significance levels of different tests for MR results.

However, there might be heterogeneity in IVs from different analysis platforms, experiments, and populations, which can affect the results of MR analysis ( Cui et al., 2023 ). To assess potential heterogeneity, Cochran’s Q statistic was computed, with all p -values exceeding 0.05, indicating the absence of heterogeneity in the study. This finding was corroborated by the results of funnel plot analyses ( Supplementary Figures S1, S3 ). When IVs affect outcomes through factors other than exposure factors, they indicate that IVs are pleioty. Pleiotropy leads to the failure of the independence and exclusivity assumptions ( Bowden et al., 2015 ; Verbanck et al., 2018 ). MR Egger intercept test results yielded p -values greater than 0.05, signifying the absence of pleiotropy in the study. Similarly, Steiger method analyses affirmed that all significant findings implicated gut microbiota in AN or BN, with no evidence of reverse causality interference. Finally, sensitivity analysis employing the leave-one-out method demonstrated that the exclusion of any individual SNP did not substantially alter the results ( Supplementary Figures S2, S4 ). These comprehensive analyses bolster the sensitivity and validity of the MR findings regarding the causal relationship between intestinal bacterial taxa and AN or BN.

4 Discussion

The escalating health and social burden attributed to eating disorders underscores the urgent need for effective treatments ( Murray et al., 2020 ; Arias et al., 2022 ). It has been well-documented that eating disorders such as AN and BN interact with a range of mental and organic disorders ( AlHadi et al., 2022 ). Blocking the progression of AN and BN by modulating the gut microbiota and its metabolites has received widespread attention from clinical researchers ( Jiao et al., 2023 ; Himmerich and Treasure, 2024 ). However, the ethical dilemma and compliance problems in adolescent treatment add additional challenges to clinical research ( Frostad and Bentz, 2022 ; Tsiandoulas et al., 2023 ). By leveraging genetic IVs, MR analysis facilitates a deeper understanding of the intricate interplay between gut microbiota and eating disorders, thereby offering promising avenues for targeted therapeutic interventions ( Thomas, 2019 ).

Employing a two-sample MR analysis framework with GWAS datasets, we identified nine bacterial taxa with potential causal associations with AN and nine bacterial taxa with potential causal associations with BN. A previous study found that core microbiota depletion signs were observed in patients with AN. Overrepresented taxa in patients taxonomically belonged to Alistipes , Clostridiales , Christensenellaceae , and Ruminococcaceae . And underrepresented taxa were Faecalibacterium , Agathobacter , Bacteroides , Blautia , and Lachnospira ( Prochazkova et al., 2021 ). Similar studies have found that gut microbiota-associated metabolites, such as trimethylamine N-oxide ( Wagner-Skacel et al., 2022 ), choline ( Doose et al., 2023 ), serotonin ( Hata et al., 2019 ), and p-cresyl sulfate ( Miyata et al., 2021 ), in the onset and progression of AN and BN.

In this investigation, we identified five bacterial taxa, including Peptostreptococcaceae , Coprococcus3 , Escherichia Shigella , Lachnospiraceae NC2004 group , and Lachnospiraceae UCG010 , as potential causes for the increased risk of AN. The findings concerning Coprococcus and Escherichia Shigella align with those reported in a previous meta-analysis study ( Zang et al., 2023 ). Hanachi et al. (2019) reported a decrease in the richness and diversity of gut microbiota in severely malnourished AN patients who received enteral nutrition. This study further identified a negative correlation between the severity of functional intestinal disorders in AN patients and Peptostreptococcaceae by 16S rRNA analysis. This seems to contradict our conclusion that Peptostreptococcaceae is a potential cause of AN. However, the abundance of Peptostreptococcaceae is influenced by a variety of factors. The abundance of Peptostreptococcaceae is increased in stool samples from patients with ulcerative colitis and colorectal cancer ( Cheng et al., 2020 ). And it tends to decrease after probiotic consumption, suggesting that the abundance of Peptostreptococcaceae is easily influenced by food intake and probiotics ( Hibberd et al., 2017 ; Zaccaria et al., 2023 ). This appears to explain the decrease in the abundance of Peptostreptococcaceae in patients with functional intestinal disorders of AN after receiving enteral nutrition, which is not related to the onset of AN. This finding underscores the intricate role of the intestinal microbiota in the interplay between AN pathogenesis and its accompanying symptoms.

Our investigation also revealed that four bacterial taxa, namely Cyanobacteria , Gammaproteobacteria , Mollicutes RF9 , and Eubacterium brachy group , exhibited the potential to reduce the risk of AN. Previous 16S rRNA investigations have highlighted correlations between Eubacterium and AN ( Hanachi et al., 2019 ; Yuan et al., 2022 ), but directional causality remains elusive, a view that is confirmed by our findings. These microbes are one of the major producers of butyrate and play an important role in immunomodulatory processes at the intestinal mucosal level, which may be one reason for the reduced risk in AN patients ( Yuan et al., 2022 ). Cyanobacteria are single-celled prokaryotes capable of oxygen-producing photosynthesis, which are mainly used in fields such as fertilizers and fuels ( Arias et al., 2021 ). Recent studies have found that Cyanobacteria contains a variety of bioactive components that can induce autophagy and apoptosis, regulate epigenetic modifications, and exert antitumor effects ( Bouyahya et al., 2024 ). Xu et al. (2019) found that Cyanobacteria were associated with neuropsychological behavior induced by long-term alcohol exposure, and the mechanism may be related to the secretion of brain-derived neurotrophic factor. Depression-like behavior induced by a high-fat diet in mice is also associated with increased abundance of Cyanobacteria ( Hassan et al., 2019 ). Similarly, Gammaproteobacteria have been shown to be abundant in young adults with major depressive disorder, regardless of psychotropic medication ( Liu et al., 2020 ). Mice exposed to chronic social defeat stress showed mild depressive-like behavior and an increase in the abundance of Mollicutes ( Kosuge et al., 2021 ). And a study on anti-anxiety drugs found that (R)-ketamine might work by downregulating Mollicutes ( Yang et al., 2017 ). Based on the available evidence, these gut microbes ( Cyanobacteria, Gammaproteobacteria, Mollicutes ) are all positively associated with depression, and their potential role in reducing AN risk remains to be confirmed by clinical studies. These three types of gut microbes seem to help distinguish between AN and depression, which have similar clinical manifestations.

In a previously published MR analysis, Actinobacteria , Bilophila , Holdemania , Lactobacillus , Ruminococcaceae UCG009 , and two unknown gut microbes were identified as risk factors for the development of AN, which is very different from our conclusions ( Xia et al., 2023 ). Interestingly, the results are highly similar to those of our BN study. Reviewing the original published GWAS datasets, we found that the main reason for this was because the earlier GWAS datasets could not be distinguished from the two disease subtypes at a technical level due to the crossover of AN and BN diagnoses ( Boraska et al., 2014 ). At the same time, the limitations of detection techniques have resulted in relatively small numbers of SNPs captured from earlier datasets, limiting the exploration of more critical causal associations ( Duncan et al., 2017 ). Therefore, our study can be regarded as an update of this study, which provides cross-validation of the findings of BN in this study.

In our results, six taxa, including Clostridiales , Bilophila , Coprobacter , Holdemania , Ruminococcaceae UCG009 , and Slackia , are potential contributors to the increased risk of BN. Ruminococcaceae are positively associated with autism, depression, and are abundant in patients with AN ( Prochazkova et al., 2021 ). Similar studies showed that the abundance of Clostridiales in feces of activity-based anorexia mice with food restriction increased significantly ( Breton et al., 2019 ). Given the crossover nature and common pathological basis of AN and BN diagnoses, their potential risks to BN are promising. Bilophila is an opportunistic pathogen, and the close association of increased abundance with intestinal inflammation has been confirmed ( Alexander et al., 2023 ; Zahavi et al., 2023 ). Recent studies have found that a ketogenic diet can exacerbate cognitive impairment caused by intermittent hypoxia, the mechanism of which is associated with impairment of hippocampal function due to the enrichment of gut microbes such as Bilophila ( Olson et al., 2021 ). Changes in Bilophila abundance have been observed in patients with mental disorders such as autism spectrum disorders. As for Coprobacter , its abundance is currently thought to be associated with chronic insomnia and cognitive function ( Feng et al., 2021 ). Similarly, Holdemania exhibits a high abundance in patients with depression ( Barandouzi et al., 2020 ) and is closely associated with anxiety and Parkinson’s disease ( Jang et al., 2020 ). Slackia stands out as a typical causative agent, however, recent studies suggest that it may be involved in the development of Alzheimer’s disease ( Nagpal et al., 2019 ). Therefore, although there are no reports about Coprobacter , Holdemania and Slackia in patients with AN or BN, their research is still worthy of attention.

Our study identified three taxa— Rhodospirillales , Oxalobacteraceae , and Lachnospiraceae UCG008 —as protective factors for BN. Rhodospirillales is mainly used in water purification and new energy sources ( Chun et al., 2018 ). Zhang et al. (2023) found that sleep deprivation led to a significant increase in the abundance of Rhodospirillales and enhanced pro-inflammatory cytokine responses as well as learning and memory impairments in mice. Another study found a significant increase in the abundance of Rhodospirillales in socially isolated mice ( Siddi et al., 2024 ). Studies of Oxalobacteraceae have found that it reduces the risk of delirium, attention deficit hyperactivity disorder ( Wang et al., 2023 ; Yu et al., 2023 ). Therefore, these gut microbes may have a close relationship with mental disorders, and further clinical research on AN and BN is worth exploring.

It is notable that AN and BN share similar clinical mechanisms, yet previous studies have not consistently identified a specific group of gut microorganisms commonly associated with both disorders. In our current investigation, we observed that while the Lachnospiraceae NC2004 group and Lachnospiraceae UCG010 were identified as risk factors for AN, Lachnospiraceae UCG008 emerged as a protective factor for BN. Previous studies have found that Lachnospiraceae NC2004 group was able to reduce the risk of gastroduodenal ulcers, and was able to reduce circulating inflammatory cytokine levels ( Xue et al., 2023 ). Lachnospiraceae UCG010 may reduce the risk of cholelithiasis and narcolepsy ( Liu et al., 2023 ; Sheng et al., 2024 ). In contrast, Lachnospiraceae UCG008 has been shown to be associated with a higher risk of periodontitis ( Ye et al., 2023 ), and is a potential risk factor for hemorrhagic stroke ( Shen et al., 2023 ). Based on current evidence, we cannot definitively explain the contradiction between the different genera of Lachnospiraceae , but it appears to be related to inflammation and immunity ( Sun et al., 2021 ; Zeng et al., 2023 ). However, despite belonging to distinct strains, Lachnospiraceae appears to be a common influencing factor for both AN and BN. Previous research has linked reductions in Lachnospiraceae to an increased risk of developing depression ( Liu et al., 2022 ), autism ( Li et al., 2023 ), and Alzheimer’s disease ( Hung et al., 2022 ). The elevated risk of AN observed in our study further underscores the widespread association of Lachnospiraceae with mental disorders ( Wang et al., 2023 ). Notably, although Lachnospiraceae have exhibited favorable organismal protective effects across a spectrum of diseases ( McCulloch et al., 2022 ; Yan et al., 2023 ), their contrasting effects on AN and BN suggest a complex relationship between gut microbiota and disease that warrants further elucidation. The exact mechanism underlying these observations remains to be clarified through additional clinical intervention studies.

The therapeutic feasibility of microbial supplements for the treatment of psychiatric disorders has gained considerable recognition ( Sanada et al., 2020 ; Góralczyk-Bińkowska et al., 2022 ). Liu et al. confirmed that probiotic supplementation mitigated intestinal damage induced by dietary restriction in AN patients ( Liu et al., 2021 ). Subsequent clinical investigations substantiated that administering a probiotic complex reduces inflammation levels and gastrointestinal distress symptoms in AN patients ( Gröbner et al., 2022 ). There is a potential causal relationship between the gut microbiota and AN and BN identified in this study, and the regulation of these microbiota by probiotics may be a promising therapeutic target for AN and BN.

In this study, we have, for the first time, elucidated the causal relationship of certain intestinal taxa with AN and BN, offering novel perspectives for subsequent mechanistic exploration and drug research. Leveraging causal inference through MR design effectively circumvented the influences of confounding bias and reverse causation. Furthermore, we conducted rigorous tests to ensure the sensitivity of our findings. However, this study does entail some limitations. Firstly, the sample size and the number of relevant loci in the current gut microbiota GWAS data are constrained. To mitigate the risk of inadequate IVs at the genus and species levels, potentially leading to imprecise bacterial characterization, we conducted summary analyses of bacterial features at higher taxonomic levels. It is anticipated that with advancements in microbiome GWAS and the accumulation of larger sample sizes, more specific bacterial features will be discerned and complemented. Secondly, to enhance statistical power, the gut microbiota and disease GWAS datasets analyzed in this study were amalgamated from multi-source samples. While this approach facilitates broader extrapolation of conclusions, it may introduce some heterogeneity in the results. Therefore, despite employing a meticulous methodology to exclude heterogeneous data, the results should be interpreted cautiously.

5 Conclusion

In summary, our study identified the potential causal involvement of 18 intestinal bacterial taxa, notably including Lachnospiraceae , in the pathogenesis of AN and BN through MR analysis. These potentially valuable gut microbiota may indicate the risk of disease development and provide feasible targets for the pathogenesis of AN and BN and probiotic therapy. Further clinical intervention and intestinal microbial testing have broad prospects for the research and treatment of AN and BN.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary material , further inquiries can be directed to the corresponding author.

Author contributions

ZYu: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft. MG: Data curation, Formal analysis, Investigation, Writing – original draft. BY: Data curation, Formal analysis, Investigation, Writing – original draft. YW: Data curation, Investigation, Writing – original draft. ZYa: Investigation, Software, Writing – original draft. RG: Funding acquisition, Project administration, Resources, Supervision, Writing – review & editing.

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The study was financially supported by the National Key R&D Program of China (2019YFC1709300) and Science and Technology Innovation Project of China Academy of Chinese Medical Sciences (CI2021A04701).

Conflict of interest

MG was employed by Yabao Pharmaceutical Group Co., Ltd.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmicb.2024.1396932/full#supplementary-material

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Keywords: anorexia nervosa, bulimia nervosa, gut microbiota, Mendelian randomization analysis, eating disorders

Citation: Yu Z, Guo M, Yu B, Wang Y, Yan Z and Gao R (2024) Anorexia nervosa and bulimia nervosa: a Mendelian randomization study of gut microbiota. Front. Microbiol . 15:1396932. doi: 10.3389/fmicb.2024.1396932

Received: 06 March 2024; Accepted: 24 April 2024; Published: 09 May 2024.

Reviewed by:

Copyright © 2024 Yu, Guo, Yu, Wang, Yan and Gao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Rui Gao, [email protected]

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