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Clinical Neurosciences
Reconceptualizing anorexia nervosa
Cynthia M. Bulik, PhD, FAED ,1,2,3* Rachael Flatt, BS,4 Afrouz Abbaspour, PhD3 and Ian Carroll, PhD2
Anorexia nervosa (AN) has one of the highest mortality rates
of any psychiatric disorder. Treatments are often ineffective
and relapse is common. Most research attempting to under-
stand the underlying causes and maintenance factors of AN
has focused on environmental contributions, yet there is
much to be explored in terms of biological risk and mainte-
nance factors. In this paper, we focus primarily on AN
research related to genetics and the complex microbial com-
munity in the gut (intestinal microbiota), and how these
impact our conceptualization of this disorder. Emerging
research identifying significant negative genetic correlations
between AN and obesity suggests that the conditions may
represent ‘metabolic bookends’. The identification of under-
lying biological mechanisms may provide both insight into
extreme weight dysregulation on both ends of the spectrum
and new possible points of entry for AN treatment.
Anorexia nervosa (AN) is perplexing and widely misunderstood.
Decades of focus on sociocultural and familial factors have hindered
our ability to truly understand the causes and maintaining factors of
this devastating illness. In 2015, the Academy for Eating Disorders
released the ‘Nine Truths About Eating Disorders’ (Fig. 1). The ‘Nine
Truths’ is an aspirational document designed to widely disseminate
information about eating disorders that is evidence-based and unbi-
ased. To evaluate the science behind the Nine Truths, we thoroughly
reviewed the literature substantiating each of the truths.1 Many of the
truths are supported by a wealth of science, whereas others require
additional information to establish their veracity. For example, Truth
#5 states: ‘Eating disorders affect people of all genders, ages, races,
ethnicities, body shapes and weights, sexual orientations, and socio-
economic statuses.’ Although we know this to be true clinically, much
of the science that has been conducted on AN has been conducted on
females of European ancestry between adolescence and young adult-
hood. Indeed, much of the work that we review here reflects what is
known about that population. Concerted efforts are required to ensure
that our understanding about the causes of AN and its treatment, as
well as science about the other eating disorders (e.g., bulimia nervosa,
binge-eating disorder [BED], avoidant and restrictive food intake dis-
order), accurately captures the diversity of individuals who suffer
from these illnesses.
In this review, we summarize a plenary address delivered at the
World Congress of Psychiatric Genetics in Glasgow, Scotland in
2018. Our focus is on recent advances in science that address Truths
#7 (‘Genes and environment play important roles in the development
of eating disorders’) and #8 (‘Genes alone do not predict who will
develop eating disorders’). We report primarily on AN as most of the
1
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, USA
2
Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, USA
3
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
4
Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, USA
* Correspondence: Email: cbulik@med.unc.edu
Psychiatry and Clinical Neurosciences © 2019 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences
PCN
PCN FRONTIER REVIEW
Additionally, the reported microbial imbalance (dysbiosis) in
the gut microbiota in AN patients, potentially due to a
nutrient- and energy-deprived gut environment, implies alter-
ations in functional and metabolic capacity of the gut micro-
biome. The extent to which AN and obesity can also be
considered to be ‘microbiome bookends’ requires further
investigation. Finally, we discuss ongoing and future AN pro-
jects exploring the interplay between host genomics, the
environment, and cumulative microbial genomes (micro-
biome) as well as interventions at the microbial and gut
level.
Keywords: anorexia nervosa, environment, genetics, genome-wide
association study, microbiome.
http://onlinelibrary.wiley.com/doi/10.1111/pcn.12857/full
research has been done on that illness, but highlight work on the other
eating disorders that is currently underway.
What is anorexia nervosa?
AN is characterized by dangerously low bodyweight, indifference to
the seriousness of the illness, and female preponderance,2 and afflicts
0.9–4.0% of women in the USA and Europe.3–5 The prevalence of
AN in Japan has increased significantly over recent decades and has
been reported as 0.11% (0.03–0.28%; 1982); 0.13% (0.04–0.31%;
1992); and 0.43% (0.20–0.67%; 2002) in women.6 Reasons put for-
ward to account for this increase have focused on sociocultural phe-
nomena, including Westernization7 as well as non-Western ideals,
such as modesty and collectivism (harmony with the values of
society).8
AN is associated with high psychiatric comorbidity,9 high sui-
cide risk,10,11 and has the highest mortality rate of any psychiatric
disorder.11–14 With the advent of DSM-5,2 a presentation of ‘atypical
AN’ has also been recognized in which an individual meets all of the
diagnostic criteria for AN, except that despite significant weight loss,
the individual’s weight is within or above the normal range. It is
unknown whether the underlying biology of AN and atypical AN are
the same.
Phenomenology of anorexia nervosa
AN is intriguing as many of its behaviors are counterintuitive and
diverge from typical human experience. For example, for most of us,
starvation and even hunger are deeply unpleasant and to be avoided
at all costs. Humans strive to achieve energy balance (equal energy
intake as output) and, as evidenced by the global obesity epidemic,15
an ever-increasing portion of the world finds itself in prolonged
© 2019 The Authors 1
 Psychiatry and
Reconceptualizing anorexia PCN Clinical Neurosciences

NINE TRUTHS ABOUT EATING DISORDERS

Truth #1: Many people with eating disorders look healthy, yet may be extremely ill.
Truth #2: Families are not to blame, and can be the patients' and providers' best allies in treatment.
Truth #3: An eating disorder diagnosis is a health crisis that disrupts personal and family functioning.
Truth #4: Eating disorders are not choices, but serious biologically influenced illnesses.
Truth #5: Eating disorders affect people of all genders, ages, races, ethnicities, body shapes and weights, sexual orientations,
and socioeconomic statuses.
Truth #6: Eating disorders carry an increased risk for both suicide and medical complications.
Truth #7: Genes and environment play important roles in the development of eating disorders.
Truth #8: Genes alone do not predict who will develop eating disorders.
Truth #9: Full recovery from an eating disorder is possible. Early detection and intervention are important.
~~

Produced in collaboration with Dr. Cynthia Bulik, PhD, FAED, who serves as distinguished Professor of Eating Disorders in the School of Medicine at the University of North Carolina
at Chapel Hill, “Nine Truths” is based on Dr. Bulik’s 2014 “9 Eating Disorders Myths Busted” talk at the National Institute of Mental Health.

Leading associations in the field of eating disorders also contributed their valuable input.

The Academy for Eating Disorders along with other major eating disorder organizations (Families Empowered and Supporting Treatment of Eating Disorders, National Association of
Anorexia Nervosa and Associated Disorders, National Eating Disorders Association, The International Association of Eating Disorders Professionals Foundation, Residential Eating
Disorders Consortium, Eating Disorders Coalition for Research, Policy & Action, Multi-Service Eating Disorders Association, Binge Eating Disorder Association, Eating Disorder
Parent Support Group, International Eating Disorder Action, Project HEAL, and Trans Folx Fighting Eating Disorders) will be disseminating this document.

Fig.1 Academy for Eating Disorders’ nine truths about eating disorders.

positive energy balance (i.e., caloric intake greater than expenditure).
In stark contrast, individuals with AN report starvation to be rein-
forcing, anxiolytic, and occasionally euphorigenic16 and deny the
presence of typical hunger signals, potentially in part due to reduced
perception of body signals.17–19 Individuals predisposed to AN tend
to be anxious at baseline and report that food restriction has a
calming effect. Second, fats, favored by most humans especially when
combined with sugar,20,21 are aversive to individuals with AN.22,23
Third, for many people with AN, activity is more reinforcing than
food.24,25 Pathologically elevated activity is observed in between 37%
and 80% of individuals with AN,26–28 and is associated with poor
treatment outcome.27 Recent evidence from a genome-wide associa-
tion study (GWAS) revealed a positive genetic correlation between
measured physical activity and AN, suggesting that the mechanism
underlying this association may be in part under genetic control.29
Fourth, individuals with AN often experience an unexplained hyper-
metabolic period during renourishment, which can last for variable
durations and complicate recovery.30–32 Fifth, despite prolonged
under- or malnutrition and frank cachexia, individuals with acute AN
typically do not exhibit sickness behaviors commonly associated with
inflammatory processes seen in other somatic and psychiatric
illnesses,33,34 and only report feeling poorly once renourishment has
begun. Finally, weight loss after therapeutic weight restoration
(weight relapse) is common35 as the bodies of individuals with AN
appear to be pulled to revert to a low set or settling point36 even after
weight restoration.
To partially address some of these intriguing characteristics, we
are engaging in a programmatic line of research that explores actions
and interactions of genetics, the environment, and the intestinal
microbiota on AN risk and maintenance (Fig. 2). Herein, we discuss
progress in all three domains.
Eating Disorders Working Group of the Psychiatric Genomics Con-
sortium (PGC-ED). It is uncontested that AN is familial, with female
relatives of individuals with AN being 11 times more likely to
develop the illness than relatives of individuals without anorexia.38
Consistent with the diagnostic fluctuation seen across eating disorder
presentations,39 eating disorders do not breed true in families
(i.e., they co-aggregate). For example, the relative risks of full and
partial anorexia syndromes as well as DSM-IV eating disorder not
otherwise specified are elevated in first-degree relatives of individuals
with AN and bulimia nervosa.38,40
Replicated twin studies have confirmed heritability, with esti-
mates ranging from 0.28 to 0.7441–44 and narrower diagnostic criteria
being associated with higher heritability estimates.45 The consistency
of this work encouraged us to undertake a GWAS of AN and, in
2017, we reported the first adequately powered study representing a
collaborative effort including 3495 individuals with AN and nearly
11 000 controls without eating disorder histories from 12 case–
control cohorts.46 We estimated the single-nucleotide polymorphism-
based heritability h2SNP to be 0.20, which is consistent with estimates
for other psychiatric disorders. We also identified the first genome-
wide significant locus on chromosome 12 – a locus previously impli-
cated in type 1 diabetes47 and rheumatoid arthritis.48 Although
revealing the first significant association was a milestone, even more
intriguing results emerged from the pattern of observed genetic corre-
lations. Using linkage disequilibrium score regression,49,50 a tech-
nique that allows you to calculate genetic correlations between
phenotypes using summary statistics, we calculated genetic

Genetics Genotype/ Intestinal

Environment
The past decade has witnessed remarkable advances in identifying the gene expression microbiota
genetic basis of many psychiatric disorders.37 With the advent of
GWAS and large consortia and collaborations (representing over
40 countries across Europe, North America, Asia, South America,
Africa, and Australasia) that make collection of large samples feasi- Fig.2 Model for actions and interactions of genetics, the environment, and the
ble, AN has been included in these efforts via the actions of the intestinal microbiota in risk for and maintenance of anorexia nervosa.

2 Psychiatry and Clinical Neurosciences

 Psychiatry and
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correlations between AN and 159 psychiatric, medical, educational,
and personality phenotypes. These phenotypes included summary sta-
tistics from GWAS studies from global collaborative investigations of
body mass index (BMI), obesity, anthropometric, and metabolic traits.
After correcting for multiple comparisons, 29 correlations emerged as
significant, including schizophrenia; personality traits, such as neurot-
icism; and educational attainment. Less expected, we observed signif-
icant genetic correlations between AN and an array of metabolic and
anthropometric traits, including positive genetic correlations with
high-density lipoprotein cholesterol and negative genetic correlations
with BMI, obesity, fasting insulin, and fasting glucose. These findings
led to our initial statement on the importance of considering both psy-
chiatric and metabolic factors in understanding the etiology of
AN. We took this as preliminary evidence of shared genetics underly-
ing extremes of weight dysregulation (i.e., obesity vs AN). These
shared genetic factors may speak directly to the perplexing feature of
how individuals with AN reach, sustain, and relapse to dangerously
low BMI despite clinical renourishment. We hypothesized that this
‘weight relapse’ may represent the biological inverse of the reversion
to high set points commonly seen in the unsuccessful treatment of
obesity.51,52 Our findings supported the proposition that some of the
same genetic factors that influence normal variation in BMI, body
shape, and body composition may also influence dysregulation in the
opposite direction of these features in AN.
The second wave of investigations of the PGC-ED group yielded
a GWAS of 16 992 AN cases and 55 525 controls and identified eight
independent genome-wide significant loci.29 Results of this larger
study were more robust and revealed an even clearer pattern of
genetic correlations. Importantly, with increased statistical power, we
were able to show that the genetic correlations with metabolic traits
remained significant even when correcting for the effects of common
variants associated with BMI, raising the question of whether a funda-
mental metabolic dysregulation may explain the challenges faced with
treating the illness and helping sufferers gain and retain healthy
bodyweights. We encourage new lines of collaboration to further elu-
cidate what these metabolic parameters might be and to broaden our
conceptualization of the illness to include both psychiatric and meta-
bolic factors.
Results from this work raise the question of whether AN and
obesity may be metabolic mirror images on some dimensions. Clini-
cally, it is fairly easy for individuals with obesity to lose weight in the
short-term if they adhere to a ‘diet’, but weight regain is common,
and interindividual variability in response to weight loss interventions
is considerable.53–55 Explanations for weight regain are many and are
controversial, but it may reflect a biologically driven process to settle
at a previously attained high weight or fat mass.36 The field has not
uniformly conceptualized AN as the opposite of obesity, with consti-
tutional thinness (i.e., underweight, normal eating behavior, desire to
gain weight, no cognitive features of AN) typically occupying that
position,56,57 and showing significant biological differences from
AN.58 Although early writings proposed that AN might represent a
disorder of extreme BMI,59 we have typically attributed the rapid loss
of therapeutically restored weight to psychological or behavioral fac-
tors (e.g., purposeful pathological exercise, purging, body dissatisfac-
tion, and drive for thinness). We have been less attentive to biological
or metabolic processes that may pull the bodies of individuals with
AN down to an abnormally low set point (or settling point) and how
this differs from the biology underlying constitutional thinness. Clini-
cally, it is fairly easy to get individuals with AN to gain weight with
inpatient re-nutrition protocols; however, once they return to their typ-
ical environment, many will lose the weight that had been restored,
often quite rapidly. It is critical for us to identify factors that predict
who, once the body is exposed to a very high (obesity) or very low
(AN) weight, can stay within a normal weight range and who will
revert to the extreme pre-intervention weight and experience that pull
upwards or downwards. Moreover, comparing these processes to
those associated with the challenges of weight gain in individuals
with constitutional thinness60,61 may shed important light on
Psychiatry and Clinical Neurosciences
Reconceptualizing anorexia
differences in the underlying biology of weight dysregulation in the
presence versus absence of the cognitive factors associated with
AN. If we can identify the biological mechanisms that influence the
return to low weight and distinguish them from those seen in assisting
individuals with constitutional thinness with weight gain, we may be
able to isolate the processes underlying extreme weight dysregulation
in AN that extends beyond our current understanding from psycho-
logical, environmental, and behavioral perspectives. Genetic and bio-
logical studies of treatment outcome (i.e., comparing those who
maintain their renourished weight vs those who experience weight
relapse) will be an important source of this information.
Our observations suggest that harbingers of BMI dysregulation
may emerge very early in life. A recent study with participants of the
Avon Longitudinal Study of Parents and their Children (ALSPAC)
suggests that deviations from healthy BMI trajectories can be
observed very early in life in youth who go on to develop eating dis-
orders. Significant divergence below expected BMI trajectories begins
in boys by age 2 and in girls by age 4 who later go on to develop
AN.62 The opposite pattern, namely significant divergence above the
expected BMI trajectory, emerged for those who later developed
bulimia nervosa, binge-eating disorder, or purging disorder. Although
a strength of the ALSPAC study is the premorbid and longitudinal
measurements, other studies in the field report conflicting findings,
including higher childhood BMI being associated with later AN.63
Notably, several studies similarly report higher pre-morbid BMI or
obesity in the binge-type eating disorders.64,65 Although additional
work is required to reconcile some of the observed differences,
premorbid metabolic factors and weight may be relevant to the etiol-
ogy of eating disorders. In AN, premorbid low weight may represent
a key biological risk factor or early manifestation of an emerging dis-
ease process.
Genetic studies of AN have limitations that can be overcome. As
alluded to earlier, the samples included in the current GWAS are pri-
marily from European ancestry female populations. Although we have
some Asian and male samples, the sample sizes are inadequate to
determine the extent to which the same genetic factors are operative
in the illness across populations, and we have very few samples from
individuals of other ancestral backgrounds. Concerted efforts are
required to diversify our samples to address this critical research
question.
Epigenetics
The study of epigenetics in eating disorders is nascent. ‘Epigenetics’
refers to biochemical mechanisms that lead to changes in gene regula-
tion. These changes are either heritable or stable over the long term.66
We conducted a systematic review of epigenetics in eating disorders
and identified a small number of discoverable investigations: AN
(n = 13), bulimia nervosa (n = 6), and BED (n = 1; January 2003 to
October 2017).67 Although epigenetic processes fall into three catego-
ries – DNA modifications, histone modifications, and non-coding
RNA – most eating disorder studies explored methylation at candidate
genes (n = 13). Samples were small, and replication was non-existent.
As such, results were inconclusive and should be considered to be
exploratory. We encourage the scientific community to adopt sound
methodological approaches, to coordinate protocols across centers to
increase sample size, and to apply genome-wide designs, including
epigenome-wide association studies.
The external environment
Returning to the Academy for Eating Disorders’ Nine Truths, Truth
#7 underscores the role of the environment in eating disorder risk and
Truth #8 cautions that genes alone do not determine who develops
eating disorders. The majority of research on eating disorder risk fac-
tors has focused on the external environment, with an emphasis on
sociocultural risk factors contributing to thin ideal internalization and
body dissatisfaction. Perceived pressure to be thin, social
pressure,68,69 and peer context70 are associated with increases in
3

Reconceptualizing anorexia
eating pathology and onset of disordered eating behaviors. Along
similar lines, studies have demonstrated associations among social
pressures, social comparison, and body dissatisfaction (e.g., van den
Berg et al.71); additionally, eating-disorder-related social comparison
may mediate the relationship between thin ideal internalization and
body dissatisfaction.72 Looking beyond an individual’s immediate
social circle and the associated social pressures and comparisons,
those who experience greater exposure to media and thin ideal images
are more likely to diet, feel dissatisfied with their body, and exhibit
negative affect, potentially putting them at greater risk for engaging
in behaviors that increase risk for developing an eating disorder.68
Finally, there is mixed research on the impact of socioeconomic status
as well as race and ethnicity,73 yet experiencing adverse life events, a
common risk factor associated with many psychiatric disorders,
remains a significant, but non-specific, risk factor for eating
disorders.74
Research on environmental risk factors for AN has been unable
to definitively determine why some individuals are more prone to
environmental pressures toward thinness than others. While exposure
to societal thin ideals is nearly ubiquitous (especially with the globali-
zation of media and social media), why some individuals are more
vulnerable to the messages and more likely to engage in behaviors
that are entrees into frank eating disorders remains unknown and
could be answered by ongoing biological research.
The gut environment
Although much has been written about environmental risk factors in
eating disorders, the focus has primarily been on external environ-
mental influences.73 Indeed, the Academy for Eating Disorders’ Nine
Truths generally refer to the role of the external environment in
influencing AN risk and maintenance. Our work has focused on
another, internal, environment, namely that of the complex microbial
community residing in the gut: the intestinal microbiota. We address
the research question of the gut environment in individuals with AN
in fimo (samples derived from human excrement and examined scien-
tifically)75 and consider the biological setting created by an illness
characterized by severe and prolonged food and nutrient restriction.
As background, just like many organisms, enteric microbes also
have preferences for their environments. For example, altering the
dietary composition of fats, carbohydrates, and protein leads to
observable changes in the ratios of human intestinal microbes.76,77
We also know that food preferences (for sweet, bitter, sour, and
umami) can be influenced by host genotype.78
What are the characteristics of the gut environment of individ-
uals with AN? In the broadest terms, the gut environment is marked
by chronic caloric restriction, macronutrient imbalance (food groups
are often summarily avoided), micronutrient deficiencies, fluctuating
food availability (associated with binge–fast cycles in some), osmotic
perturbation (caused by laxative abuse in a subtype of patients as a
compensatory behavior), and high fiber content.79–84 Our program-
matic line of work rests on the fact that the human intestine is a com-
petitive environment and we hypothesize that the environment created
by AN may select for microbes that can subsist on low energy and
imbalanced nutrients. Compelling evidence suggests that the intestinal
microbiota not only influences host metabolism,85 but also affects
brain function and behavior.86 Accordingly, we hypothesize that the
microbial community selected by the AN-associated gut environment
might in turn affect host behavior and metabolic profile, further con-
tributing to the maintenance of the illness. We do not disregard the
possibility that a gut microbial imbalance, or dysbiosis of the gut
microbiota, might precede the onset of AN, although this is much
more difficult to study.
The relevance of the gut microbiota for the key features of AN,
including weight regulation, energy metabolism, anxiety, and depres-
sion, has been discussed in detail elsewhere.87,88 To expand on the
rationale for exploring the role of intestinal microbiota in AN and
other eating disorders, here we discuss the effect of gut microbes on
4 Psychiatry and Clinical Neurosciences
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regulation of satiety – another important aspect of AN (and other eat-
ing disorders). Research in laboratory animals suggests that bacterial
metabolites can influence brain mechanisms that control appetite and
energy homeostasis through the gut–brain axis.89 In an elegant study
conducted in mice, gut commensal Escherichia coli in its stationary
phase was found to produce a peptide mimetic of α-melanocyte stim-
ulating hormone, an anorexigenic and anxiogenic neuropeptide. This
bacterial peptide is called ‘caseinolytic proteinase B’ and was shown
to activate hypothalamic proopiomelanocortin-expressing neurons
directly or through stimulation of gut hormones, and thus regulate
feeding behavior.90 In patients with eating disorders (AN, bulimia
nervosa, and BED), plasma levels of caseinolytic proteinase B were
reported to be elevated compared to healthy controls.90 However,
results must be interpreted cautiously as sample sizes were small and
significance was marginal as results were not corrected for multiple
comparisons.
Another bacterial metabolite that was shown to influence energy
homeostasis through direct gut–brain neural communication is propi-
onate.91 Propionate, acetate, and butyrate are the most abundant
short-chain fatty acids (SCFA) in the colon and feces.85 SCFA are
the end products of fermentation of dietary fibers by anaerobic bacte-
ria in the colon, and have been extensively investigated in gut micro-
biome research. SCFA have been linked to multiple beneficial effects
on host energy metabolism.92 One of the identified SCFA mecha-
nisms of action, which connects cellular metabolism to gene expres-
sion, is inhibition of histone deacetylases.93 Post-translational histone
modifications are known to be important regulators of gene expres-
sion. Interestingly, in a study conducted on a small group of partici-
pants in Japan, Morita et al.94 showed that the concentrations of
acetic and propionic acid were significantly lower in AN patients
compared to healthy controls. In a European study with a relatively
larger number of samples, the total SCFA levels were shown to be
comparable between AN patients and participants with normal
weight.95 However, AN patients had lower concentrations of butyrate
correlated with decreased levels of butyrate-producing Roseburia spp.
compared with controls. A possible explanation for the discrepancies
between these two findings could be differences in the lifestyle and
diet in Japanese versus European participants. In two more recent
publications, AN patients were reported to have reduced excretion of
fecal butyrate and propionate compared to healthy individuals.96,97 In
addition, the concentrations of butyrate were inversely correlated with
levels of anxiety in patients with AN.96
Future studies investigating alterations in microbial metabolites
and their mechanisms of action in larger well-characterized samples
of individuals with AN – both during the acute phase of the illness
and after recovery – will lead to a more comprehensive understanding
of the role of gut microbiota in eating disorders and potentially delin-
eate between the effects of starvation versus the effects of illness. In
summary, the results of these studies, although intriguing, are limited
by the small samples sizes and the employed targeted approaches for
sequencing and measuring specific microbial metabolites. We do not
yet have a complete picture of the functional capacity of the micro-
biota in AN.
Formative work
Our early work in the area, conducted by Kleiman et al.98 on small
samples, characterized the taxonomy and diversity of the intestinal
microbiota in individuals with AN at low weight (acute illness at hos-
pital admission < 75% ideal body weight [IBW]) and after inpatient
therapeutic renourishment (>85% IBW) in comparison to healthy con-
trols. Bearing in mind that a diverse microbiota is a healthy micro-
biota, our work revealed lower microbial diversity between patients
with AN at both intake and discharge compared with controls, with
some normalization across treatment, but not matching the diversity
in healthy controls. The observed lower microbial diversity even after
renourishment could be a potential contributing factor to the high
relapse rate reported in AN patients. Further research aimed at
 Psychiatry and
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investigating the role of microbiota in treatment outcomes in terms of observed, this will provide evidence for the gut–brain–behavior axis
retaining therapeutically restored weight is warranted. and show that one of the core features of AN, namely anxiety, can
In this sample, we also observed a significant correlation be transmitted microbially.
between mood and microbial diversity such that lower diversity was
associated with higher self-report depression scores.98 Of note, this
was not observed in an independent sample of healthy controls who
Future directions
Ultimately, our goal and that of others is to probe in greater depth the
had a much more restricted range of responses on the mood mea-
ways in which the intestinal microbiota and host genetics act and
sures.99 Together, these observations raised the question of whether
interact to influence disease risk, trajectory, and recovery from
this aspect of the microbe–gut–brain axis is only detectable at more
AN. Evidence from twin studies suggests that the gut microbiota can
extreme levels of psychopathology. A recent large population investi-
be affected by host genetic variation, and that the interaction between
gation provided intriguing and replicated evidence for an association
the microbiome and host genome can influence the phenotype in the
between the gut microbiome and quality of life and depression.100 In
host.111,112 Of relevance, the concordance rate of carriage of the
addition, over the past decade, the number of clinical trials investigat-
archaeon Methanobrevibacter smithii was found to be significantly
ing the effect of probiotics on mood and anxiety disorders has
higher in monozygotic compared to dizygotic twin pairs.112 The
increased.101–103 Although there is still a need for more extensive
levels of M. smithii were reported to be elevated in AN patients and
mechanistic studies and trials in both healthy and clinical populations,
associated with efficiency of fermentation of dietary components.106
the promising results point to the therapeutic potential of targeting
To advance this science, we are currently recruiting large sam-
gut microbiota in the treatment of mood and anxiety symptoms.
ples of individuals with eating disorders from whom we obtain saliva
Herpertz-Dahlmann and coworkers have reviewed the therapeutic
for genotyping, stool samples for sequencing, and extensive pheno-
implications of gut microbiota specifically in relation to AN. In brief,
typic information. Our goal is to explore how host genomics and the
the authors discuss the benefits of targeting the microbiota with
intestinal microbiota act and co-act in AN, bulimia nervosa, and
approaches including nutritional interventions, pre- and probiotics,
BED. This is an evolving field with vastly different perspectives and
and drugs to improve energy retrieval, anxiety, and depressive symp-
opinions. Some teams posit that exploring the ways in which host
toms in individuals with AN.104,105
genomics and the microbiome interact to influence disease pheno-
Other studies have confirmed differences in the diversity and
types is an open frontier111 whereas others claim that environment
composition of the intestinal microbiota in individuals with AN com-
dominates over host genetics in shaping the human gut microbiota.113
pared to healthy controls and across the course of therapeutic
Fortunately, we will have the samples and data to address this ques-
renourishment.94–96,106–108 Whether the microbial profile is distinct in
tion directly relative to eating disorders.
each of the two types of AN (restrictive and binge–purging), has only
In addition, we have received approval from the Food and Drug
occasionally been explored,94,95 with one study finding no significant
Administration to test fecal microbiota transplantation (FMT) in the
difference in bacterial abundance between the two subpopulations,94
treatment of severe AN. Our field has struggled to find interventions
and another reporting distinct perturbations in microbial composition
for chronic AN and recent publications have begun to move toward
in each AN type and decreased microbial diversity in those who had
quality of life, palliative care, and even euthanasia for those with
history of laxative use.95 Previous research in mice and humans sug-
severe and enduring forms of the illness. As such, we believe it is
gests that acute use of laxatives can cause long-term alterations in the
important to test interventions that have been shown to give hope to
gut microbiome.109,110 However, the long-term impact of regular use
others with chronic and debilitating illnesses, for which we have some
of laxatives on microbiota in AN individuals is still unknown. In gen-
evidence of involvement of the intestinal microbiota in the disorder.
eral, the shifts in the intestinal microbial community can potentially
FMT is a safe and effective therapy for Clostridium difficile infection,
affect the production and release of various metabolites and signaling
which can cause life-threatening inflammation of the colon. Studies
molecules by gut microbial communities. When integrated with the
involving transplantation of intact, uncultured microbiota from
sequencing data, studying microbial metabolites will potentially yield
healthy humans to individuals with C. difficile -induced colitis or
a more in-depth understanding of the biological role of the gut micro-
patients with metabolic syndrome have yielded proof-of-principle that
biota and its interactions with the host.
the intestinal microbiota represents a valid therapeutic target for
treating or preventing disease.114–116 These findings provide a basis
for the use of FMT beyond the treatment of C. difficile. Careful
Ongoing work monitoring of outcomes will inform as to whether FMT is worthy
Our current work funded by the National Institute of Mental Health,
of additional study in controlled randomized placebo-controlled
called ‘Anorexia Nervosa: Investigation of the Gut Microbiome and
investigations.
Anxiety (ANIGMA)’, is building on our formative work to explore
Ultimately, we hope that this line of work will lead to novel
the key scientific questions in greater depth. We are testing
interventions for AN, and potentially bulimia nervosa and BED as
100 female patients with AN at admission (<75% IBW) and dis-
well. We know, for example, that renourishment can be uncomfort-
charge (>85% IBW) compared to healthy controls to characterize
able and even painful for individuals with AN and that delayed gastric
and correlate the composition and diversity of the intestinal micro-
transit time can complicate efforts at renourishment.117 We look
biota with adiposity, anxiety, and stress. In addition, we will be per-
toward prebiotic supplementation during refeeding to reduce discom-
forming fecal microbiota transplants from AN patients into germ-
fort, and potentially targeted probiotics to assist with reducing anxi-
free (GF) mice (mice grown in the absence of microbes). The use of
ety, depression, and eating disordered cognitions. Results of our FMT
GF mice has proven to be a valuable approach for functional and
pilot will inform as to whether this approach may be of value in the
mechanistic investigation of illness-associated microbiota. We are
treatment of severe AN.
exploring whether the presence and abundance of certain taxa within
the microbiota of AN patients will be associated with adiposity and
BMI in formerly GF mice. We are testing this hypothesis by per- Conclusion
forming dual-energy X-ray absorptiometry (DEXA) on the mice Our understanding of the etiology of AN is evolving and empirical
after colonization and adaptation to the human transplanted micro- support is expanding for the Academy for Eating Disorders’ Truths
biota. In the second aim of ANIGMA, we are exploring whether #7 (‘Genes and environment play important roles in the development
behavioral traits are transmitted into GF mice via fecal slurries from of eating disorders’) and #8 (‘Genes alone do not predict who will
AN patients at admission. Here we hypothesize that formerly GF develop eating disorders’). As GWAS sample sizes increase and
mice that are colonized by AN patient feces will display greater results become more robust,29,46 the importance of considering both
anxiety-like behaviors in open field and other behavioral tests. If psychiatric and metabolic factors in understanding AN is becoming
Psychiatry and Clinical Neurosciences 5

Reconceptualizing anorexia
increasingly clear. By paying closer attention to metabolic factors, we
may improve the interventions we deliver and outcomes we achieve
for AN. That said, the current work sheds light on the direction we
should follow. Scientific study should be directed toward uncovering
the mechanisms that underlie the metabolic dysregulation in AN, with
an eye toward developing targeted interventions. Moreover, the accu-
mulating evidence forwarding the intestinal microbiota as an inte-
grated facet of metabolism and a critical player affecting the host
behavior has inspired a holobiont approach toward human health and
illness, and AN is no exception. Even though gut microbiome
research in AN is in its infancy and needs to be expanded beyond
associations, the findings from obesity at the other end of the spec-
trum provide a blueprint for future research directions. Finally, we
propose that concomitant attention to genetics, external, and internal
(gut microbiome) environment and their interactions has the potential
to improve our understanding of the etiology and inform the develop-
ment of novel empirically informed therapeutic approaches for AN.
Acknowledgments
We acknowledge funding from the National Institute of Mental
Health (R01 MH105684; Carroll-PI; R01 MH109528; Sullivan-PI),
the Klarman Family Foundation (Bulik-PI); and the Swedish
Research Council (VR Dnr: 538-2013-8864; Bulik-PI). Portions of
this manuscript were presented at the World Congress of Psychiatric
Genetics, Glasgow, Scotland, October 2018.
Disclosure statement
C.M. Bulik: Shire (Scientific Advisory Board member); Pearson
(author, royalty recipient); OpenBiome (collaborator); uBiome (grant
recipient/collaborator). I. Carroll: Vivelix (consultant); OpenBiome
(collaborator); Salix Pharmaceuticals (former consultant). The other
authors have no conflicts of interest to disclose.
Author contributions
C.M.B. takes responsibility for all content of the paper. I.C. takes
responsibility for all content of the paper. A.A. contributed primarily
to the section on the gut microbiota. R.F. contributed primarily to
background research and the sections on the environment and sample
and participant diversity.
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