




































 Shankar et al. Reference Page


Berkeley
Pharma Tech
Journal of Medicine

Correspondence: 
aditis54@usc.edu

Keywords:
Anorexia nervosa
Gut-brain axis
Probiotics
Vitamins
Ketone supplements
Cognitive behavioral therapy 
Dietary supplements                     

Published July 31, 2025

Full Open Access 
 

Creative Commons Attribution 
License 4.0

Abstract
Anorexia nervosa (AN), one of the most prevalent eating disorders in the US, is 
characterized by abnormally low body weight due to an obsessive fear of gaining weight 
and a distorted perception of one’s own body image and weight. This review aims to 
provide critical insights into the impact of improving patients’ gut microbiome diversity, 
and the use of probiotics, vitamins, and other supplements as potential therapeutic 
targets for AN. Given the intricate relationship between gut health and psychological 
well-being, researchers have proposed enhancing gut microbiome diversity through 
dietary supplements as a potential adjunctive treatment. The proposed thesis asserts that 
dietary supplements such as vitamins, minerals, and probiotics can be a potential 
neurobiological treatment method for AN, based on their known ability to modulate gut-
microbiome diversity and address alterations in the gut-brain axis that are present in 
AN. Current treatments, such as cognitive behavioral therapy and family-based therapy, 
focus primarily on psychological and behavioral aspects. However, they may benefit from 
a more integrative approach that includes neurobiological treatments targeting the gut-
brain axis. This review explores the pathophysiology of AN, the gut-brain axis, and the 
potential for dietary supplements to modulate gut microbiome composition and improve 
therapeutic outcomes. Additionally, it discusses the implications of such treatments 
in combination with existing therapies and explains why further research is needed to 
establish personalized treatment plans for AN patients based on their unique 
microbiome profiles.

Promoting Gut Microbiome Diversity in 
Anorexic Patients: A Neurobiological 
Review
By: Aditi Shankar, Hayden Wong, Izabel Kwe and Luke Wang



 

 

1. Introduction 

Anorexia nervosa (AN) is a psychiatric disorder characterized by 
restrictive eating behaviors, an intense fear of weight gain, and a 
distorted body image, leading to significantly low body weight. 
Patients with AN maintain an abnormally low body weight through 
restrictive eating behaviors, excessive exercise, and/or other 
compensatory mechanisms.1 It is a common and deadly disorder 
across the world, having the highest mortality of any mental illness.2 
AN patients typically show symptoms of fatigue, low blood pressure, 
dietary restriction, purging, malnutrition, and excessive exercise. These 
symptoms can lead to complications like heart failure, kidney 
problems, and may even alter brain structure. Comorbid psychiatric 
conditions, including depression and anxiety, are frequently associated 
with AN and can exacerbate the disorder’s severity.3 Given adolescents' 
frequent use of social media, their perception of their bodies is 
constantly being shaped by others on the internet. This pressure 
causes more people to develop AN, hence pushing research into more 
treatments for AN. Currently, cognitive behavioral therapy (CBT) is 
the primary psychotherapeutic approach for AN, focusing on 
modifying maladaptive thoughts and behaviors related to eating and 
body image. This helps reduce anxiety surrounding food and promote 
healthier thought patterns. However, this only helps with the cultural 
and psychological causes of AN, and is still limited in its effectiveness. 
Another treatment is the family-based treatment (FBT), where the 
family of the patient takes over their diet.3 FBT has shown promise 
and patients have shown comparable remission rates to those receiving 
adolescent-focused therapy.4 While there is no FDA-approved 
medication, some off-label pharmacotherapies (e.g., olanzapine) are 
used.5 This review will look into the relationship between the digestive 
system and AN to propose a new treatment to combine the mental 
and physical aspects of AN therapy.  
 
The enteric nervous system (ENS) is a gastrointestinal tract neural 
network that controls digestive functions, while the vagus nerve serves 
as a link between the ENS and brain to convey information and 

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mediate reflexes based on gut conditions, and the microbes present in 
the gut.6 Containing the ENS and the vagus nerve, the gut-brain axis 
(GBA) is a complex network of nerves spanning from the gut to the 
brain, responsible for monitoring and designing the elaborate 
interactions between central and autonomic mechanisms regulating 
the emotional and cognitive parts of the brain along with peripheral 
intestinal functions such as entero-endocrine signaling, immune 
activation, intestinal permeability, and enteric reflex.7 Due to its 
intricate connection between ENS and the brain, the GBA can play a 
role in influencing a person’s craving for food, feeling of hunger along 
with food intolerances, digestion, metabolism, and other cognitive 
functions.8 Based on previous studies, there is growing evidence that 
gut microbiota can help in the regulation of the GBA and physiologic 
homeostasis through the means of vagal transmission, gut hormones, 
the immune system, and the hypothalamic-pituitary-adrenal axis.8 
This allows the microbiome-gut-brain axis to effectively communicate 
between the central nervous system and the gut.  
 
The gut microbiome is an ecosystem made up of the trillions of 
microbes that reside in the intestine and the environment surrounding 
it. These microbes can be categorized into bacteria, viruses, fungi and 
parasites. Diet and external exposures largely dictate the makeup of the 
gut microbiome. Maintaining its homeostasis is important as the gut 
microbiome interacts with different parts of our body such as the 
digestive, immune, nervous and endocrine system. Bile acids, primarily 
synthesized in the liver, undergo microbial metabolism in the gut, 
influencing lipid digestion and signaling pathways.9 Short chain fatty 
acids (SCFA) produced by microbes in their metabolism regulates 
immune response by initiating anti-inflammatory cytokine 
production. These SCFA are also responsible for releasing 
neurotransmitters such as serotonin which can affect memory and the 
learning process. Finally, microbes interact with enteroendocrine cells 
to release gut hormones and control appetite, nutrition absorption, 
and digestion.10 Given how gut microbiomes maintain proper 
metabolic and neurological functions, the symbiosis of host and 
microbes is crucial. Such a relationship is regulated through a feedback 

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system and the improper balance or dysbiosis of the gut microbiome is 
linked with anxiety, depression, autism-spectrum disorder and eating 
disorders. The proper balance of a gut microbiome is measured by its 
diversity, abundance and integrity. Metrics include alpha-diversity, 
which reflects the abundance of each taxon, and beta-diversity, which 
reflects differences in species composition. In gut dysbiosis, an increase 
in originally commensal species can act as pathogenic and the 
intestinal barrier integrity can be corrupted.10  
 
Although traditional treatments such as cognitive behavioral therapy 
(CBT) and family-based therapy (FBT) offer some relief, they often 
fall short in addressing the underlying neurobiological disruptions 
associated with the disorder. Recent studies suggest that alterations in 
gut microbiome diversity and the gut-brain axis play a crucial role in 
the mechanisms of AN. This review paper aims to explore the 
potential of dietary supplements, including vitamins, minerals, and 
probiotics, as therapeutic agents for AN by restoring gut microbiome 
diversity and perturbations in the gut-brain axis. By integrating gut 
microbiome-targeted interventions with traditional psychotherapeutic 
approaches, a more holistic treatment model for AN may emerge.  
 
This paper will investigate the gut-brain interactions associated with 
AN, compiling and analyzing scientific literature to identify effective 
treatment strategies. By examining research on signaling pathways and 
neurobiological aspects linked to AN, the review aims to highlight 
how substances affecting these pathways can serve as potential 
therapeutic targets. The primary objective is to provide insights into 
the impact of improving gut microbiome diversity and utilizing 
supplements like probiotics, vitamins, and other additives proposing a 
comprehensive treatment approach that integrates these with 
conventional therapies. Given their ability to restore gut-microbiome 
diversity and modify the gut-brain axis, dietary supplements can be a 
viable treatment method for AN if combined with traditional 
approaches, ultimately offering a more holistic approach to managing 
the disorder. 
 

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2. Pathophysiology of Anorexia 

2.1 Serotonin Pathway 

Serotonin, a monoamine neurotransmitter, is most prominently 
known for its role in the pathophysiology of many neuropsychiatric 
disorders. Serotonin receptors, also known as 5-Hydroxytryptamine 
(5-HT) receptors, are activated by the serotonin neurotransmitter and 
these receptors are found in central and peripheral nervous systems.10 
These neurotransmitters participate in regulating essential functions in 
the body such as motor control, cognition, motivation, and the reward 
system pathway. For example, in the CNS, serotonin plays a role in the 
regulation of mood and interpersonal perception. Divided into 7 
groups of G-protein-coupled receptors, each receptor activates a 
different intracellular secondary messenger cascade resulting in an 
inhibitory or excitatory effect. Serotonin is synthesized through a 
two-step metabolic pathway that involves first hydroxylating 
tryptophan (TRP) into 5-hydroxytryptophan by tryptophan 
hydroxylase. The second step involves the decarboxylation of 
5-hydroxytryptophan by an aromatic L-acid decarboxylase that finally 
results in the end-product of 5-HT.11 

5-HT receptors are responsible for regulating substrates including food 
consumption, anxiety control, learning, memory, locomotion, as well 
as prevention of depressive conditions. AN is often observed when 
changes in connectivity and neurotransmission or dysregulation is 
present in serotonergic systems.12 Past studies have shown that animals 
experience hypophagia or reduced ingestion of food when 5-HT1B 
and 5-HT2C receptors are stimulated. On the other hand, hyperphagia 
or the increased ingestion of food, is triggered through the activation of 
5-HT1A and 5-HT2B receptors.13 

As mentioned previously, serotonin is synthesized from TRP, in the 
two-step metabolic pathway, however, only a fraction of the total TRP 
available enters this metabolic pathway.14 Many aspects of AN research 
focus on this pathway of serotonergic systems since TRP depletion 
caused by external factors such as stress and inflammation lowers 

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peripheral and central serotonin levels.14 Some suggest that there are 
correlations between obsessive or anxious behaviors and serotonin and 
suggest that due to this correlation, starvation is a common outlet used 
by patients with AN to reduce emotional discomfort, known as 
dysphoria.  

Starvation however, negatively affects serotonergic transmission as it 
reduces the effectiveness of serotonin in the brain.14 Not only does this 
lead to various psychological issues such as anxiety and depression, but 
also aggravates the course of AN and any course of treatment. 

Although these aspects of AN research are of interest and are often of 
focus, many instances show that experimental data and clinical data are 
often conflicting in their results of the serotonergic system and how it 
is affected. Therefore, it is uncertain whether the changes that occur 
from symptoms of AN are causative or symptomatic. 

2.2 Dopamine Pathway 

Dopamine is a regulatory hormone within the mammalian nervous 
system. It is involved with regulating emotions and the motivation and 
reward system. The mesolimbic dopaminergic system is specifically 
associated with the food reward system. Food consumption activates 
the mesolimbic dopaminergic pathway, leading to dopamine release in 
regions such as the NAcc. This reinforces feeding behavior by 
associating food intake with pleasurable sensations, thereby motivating 
future consumption.15 

Dieting and excessive exercise activate the 
hypothalamic-pituitary-adrenal (HPA) axis, leading to cortisol release. 
This chronic stress response influences dopaminergic activity, 
contributing to heightened reward sensitivity associated with AN 
behaviors. Sustaining this release of dopamine eventually leads to the 
symptoms becoming addictive, causing subjects to display the 
symptoms shown in typical AN patients. Studies show that it becomes 
more and more rewarding to eat less and exercise more.16 This 
reward-driven behavior can become compulsive, reinforcing restrictive 
eating. 

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https://www.nature.com/articles/s12276-020-00532-4#%3A~%3Atext%3DStress%20affects%20dopamine%20levels%20and%2Cresponses%20to%20various%20environmental%20stimuli


 

 

Research has been done to investigate how dopaminergic 
neurotransmission is specifically affected by gut microbiota change.17 
/Gut microbiota can influence dopamine secretion through the vagus 
nerve by stimulating the nerve with metabolites, which impacts the 
dopamine level in the brain. Through many other ways such as the 
immune system and the hypothalamus-pituitary-adrenal axis, 
microbiota are tied with dopamine levels.17 Research shows that 
changes in these gut microbes target the dopaminergic transmission in 
the prefrontal cortex, striatum, hippocampus, nucleus accumbens 
(NAcc), and the amygdala in the brain. These regions are all directly 
involved with cognitive functions and emotional control, with the 
NAcc targeting motivation.18 Meanwhile, intestinal microbe 
composition also affects the mesocorticolimbic circuit in the brain, 
which has dopamine as its main neurotransmitter. 

Although the precise mechanisms remain under investigation, 
increasing evidence suggests a significant link between gut microbiota 
and dopaminergic regulation.19 Numerous treatments have been tested 
to see how dopamine may be used to alleviate AN symptoms. Most 
studies theorize that altering the diet to normal levels would lower or 
normalize the dopamine levels.18 Many trials have shown promising 
true remission in its patients. By using non selective dopamine 
antagonists, specifically Cis-flupenthixol and olanzapine, AN patients 
show reduced symptoms. Meanwhile, other studies proposed to 
increase the dopamine turnover to bring about a normalized dopamine 
level when eating food.19 Studies have demonstrated that tyrosine 
supplementation may help normalize dopamine levels disrupted in 
AN, though further research is needed in human populations. Fish oil 
has shown a similar effect, since it can normalize the expression of genes 
and neurotransmitters in the hippocampus and hypothalamus. More 
importantly, it increased the dopamine level in the hypothalamus.19 

 

 

 

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2.3 Appetite Regulating Pathway 

2.3.1 Orexigenic Pathway 

 

 

Figure 1. Appetite Regulating Pathways of AN. Describes the orexigenic 
and anorexigenic signaling pathways that modulates appetite in an inter-dependent 
fashion. OREXIGENIC: NPY projects to LH and inhibits three anorexigenic 
neurons in PVN: OXT, TH, and TRH, to increase appetite and fat storage20; AgRP 
acts as a competitive antagonist to α-MSH for the melanocortin 4 receptor (MC4R) 
in PVN; Orexin-A increases intracellular Ca2+ concentrations to promote NPY 
expression.21 On the other hand, Orexin decreases intracellular Ca2+ 
concentrations in POMC-expressing neurons21; Ghrelin travels through the vagus 
nerve to promote NPY/AgRP neurons and inhibits POMC neurons through 
paracrine signaling22-23; ANOREXIGENIC: PYY3-36 depolarized POMC neurons 
and increased its action potential by 93%.24 PYY3-36 also stimulates mesolimbic 
dopamine pathways by acting as a selective Y2 receptor agonist25; CRH works 
through the GLP-1 signaling pathway, which involves histamine and unknown 
feeding-relating neurons, to reduce food 
intake.26-27 ;Leptin is responsible for lowering NPY secretion by altering its 
voltage-gated K+ channels and decreasing its excitability.28 It also upregulates 
POMC through JAK-STAT3 phosphorylation pathway.29  In addition, leptin 
increases CRH levels in the hypothalamus30;POMC cleavage produces a-MSH 
which acts on MC4R in PVN to inhibit food intake. 

 

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Orexigenic pathways are those that promote food intake and increase 
appetite. Ingestive behaviors can be categorized into two types: 
appetite and consummatory. Ingestive behaviors can be divided into 
two phases: appetitive behaviors, which include food seeking, 
foraging, and hoarding; and consummatory behaviors, which involve 
food intake and digestion. For the detailed description of how these 
appetite-regulating pathways are connected refer to figure 1. 
 
The primary orexigenic pathway involves neuropeptide Y (NPY), a 
36-amino acid peptide predominantly expressed in the central nervous 
system, particularly within the hypothalamic arcuate nucleus (ArcN), 
where it plays a key role in appetite regulation. The NPY neurons are 
found in the arcuate nucleus (ArcN). NPY can detect hormones from 
stomach and fat adipocytes in promotion of food intake and fat tissue 
storage in adipose tissue cells. 
 
Specifically, NPY neurons in the ArcN project to lateral hypothalamus 
and feeding-regulating neurons in PVN to enact orexigenic 
pathways.31 In the NPY neurons, the orexigenic effects are mainly 
mediated through the Y1 and Y5 G protein coupled receptors.32 The 
Y5 receptor is suggested to contribute more to the consummatory 
effects of food regulation as the Y5 agonist, increased food intake by 
225-800% in foraging hamsters.33 Although studies remain 
inconclusive regarding the direct relationship between plasma NPY 
levels and AN, research indicates that reduced gut microbiome 
diversity, as observed in antibiotic-treated murine models, correlates 
with lower NPY levels.34  
Agouti-related peptide (AgRP), co-expressed with NPY in the arcuate 
nucleus, serves as a key regulator of energy homeostasis by responding 
to metabolic signals, such as leptin (satiety) and ghrelin (hunger).35 
AgRP neurons are stimulated by the hunger hormone ghrelin and 
inhibited by the satiety hormone leptin, thereby modulating feeding 
behavior. MC4R signaling has been implicated as an inhibitory factor 
in food intake as administration of MC4R agonists into PVN reduces 
food intake by 48% four hours post-injection.36 AgRP neurons also 
express GABA neurotransmitters which are capable of directly 

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inhibiting POMC anorexigenic neurons. Due to the nature of AgRP 
as an indicator of energy homeostasis, AN patients are concluded to 
have abnormally higher AgRP levels, as studies with acute and 
weight-restored AN showed that the plasma AgRP levels are elevated, 
and are correlated with a lower BMI score.35 
 
The appetite-regulating pathway is interconnected and involves 
multiple parts of the brain. In fact, orexin are orexigenic hormones 
synthesized in the lateral hypothalamus (LH) nucleus and promote 
NPY-positive neurons while inhibiting POMC-positive neurons in 
the ArcN. Orexin offers insight into how the physiological and 
psychological properties of AN are connected. 
 
Food aversion increases the expression of orexin in the LH, resulting in 
an increase in dopamine release in the accumbens nucleus.37 Such a 
connection to the brain reward circuit contributes to aversion to food 
consumption and encourages anorexic behaviors. Moreover, studies 
show that AN patients have abnormally high neural responses to both 
pleasant and aversive food stimuli, suggesting a dysfunction in 
pathways leading up to the neural reward response.38 Such evidence 
demonstrates the need to expand current treatment options for AN to 
address the physiological issues. 
 
Such interconnectedness is an example of the gut-brain relationship as 
ghrelin is a 28-amino acid peptide produced in the stomach that 
promotes NPY/AgRP expression. Acylated ghrelin is orexigenic, while 
non acylated ghrelin is involved in synthesizing anorexigenic mediators 
like urocortin in the hypothalamus.39 Ghrelin heavily relies on the 
vagus nerve to carry out its signaling functions.40 Its secretion is 
up-regulated with negative energy balance such as fasting and AN, and 
down-regulated with positive energy balance such as feeding and 
obesity. 
 
Furthermore, ghrelin acts on the reward circuit through the 
dopaminergic pathway.41 Paradoxically, ghrelin levels are elevated in 

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AN patients, likely as a compensatory response to chronic energy 
deficit, despite persistent appetite suppression.42  
 
2.3.2 Anorexigenic Pathways 
Anorexigenic pathways are those that reduce food intake, suppress 
appetite, and are interconnected with regulation of orexigenic 
pathways. One of the key anorexigenic pathways involves Peptide YY 
(PYY), a 36-amino acid peptide produced by enteroendocrine L cells 
in the ileum and colon.43 Circulating PYY levels increase 
postprandially, peaking approximately 1–2 hours after feeding. 
PYY1-36 and PYY3-36, belong to the same family as NPY and consist 
of five G protein-coupled receptors (Y1, Y2, Y4, Y5, Y6). PYY is able 
to cross the blood-brain barrier and inhibit NPY neurons through 
transmembrane diffusion from the circulation.44 Anorexigenic actions 
are carried out through the Y2 inhibitory receptor, which is 
abundantly expressed on NPY neurons in ArcN, since these effects 
were not observed in Y2 receptor knockout mice.45 On the other hand, 
PYY3-36 in ArcN promotes POMC neurons.45 PYY3-36 also 
stimulates mesolimbic dopamine pathways by acting as a selective Y2 
receptor agonist.46 This finding offers insights to evidence suggesting 
the dysfunction of the mesolimbic dopaminergic pathway in AN 
patients.47 Although results are inconsistent with regards to the PYY 
levels in AN patients, increased PYY levels reduces food intake and 
fasting PYY levels are higher in all AN presentations.48 
 
Although its specific anorexigenic action requires further research, 
Corticotropin-releasing hormone (CRH) acts as a hypothalamic 
neurotransmitter to reduce appetite.49 One of the ways CRH exerts its 
anorexigenic effects is through the glucagon-like peptide-1 (GLP-1) 
signaling.50 Another study suggested that NPY mediates the 
anorexigenic effects of CRH, as impaired activity of CRH neurons led 
to neuropeptide Y (NPY)-induced hyperphagia.51 Within the HPA 
axis, adrenocorticotropic hormone (ACTH), a downstream product 
of CRH, has been implicated in appetite suppression, as ACTH 
signaling precedes POMC activation, which exerts anorexigenic 
effects.52 CRH levels are elevated in AN patients, potentially as a 

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compensatory response to cortisol resistance, a phenomenon 
frequently observed in AN.53-54 
 
 
Mirroring the role of orexigenic ghrelin, Leptin acts as a “satiety 
hormone” and is responsible for regulating multiple feeding-regulating 
neurons including NPY, POMC, CRH.55-58 It is secreted from 
adipocytes, which are fat cells that store energy and its abundance is a 
key indicator of available energy due to its role as a peripheral 
hormone. In AN patients, reduced plasma circulating leptin levels 
were observed while a significant increase in the NPY inversely 
correlates with BMI scores.59 These studies hint at the dysregulation of 
neuropeptides and results in abnormal eating behaviors observed in 
AN. 
 
Finally, Proopiomelanocortin (POMC) functions similarly 
NPY/AgRP and produces anorexigenic effects by producing a-MSH 
to act on the PVN and decreases food intake. Due to the permeability 
of ArcN, POMC is heavily regulated by leptin and GABA. Stress has 
been linked to be a marker for AN, and under such conditions, 
POMC mRNA expression increases and activation of its neurons 
results in anorexigenic effects.59 As POMC neurons can express a long 
isoform of leptin receptors, leptin can activate the STAT3 pathway 
and increase the mRNA expression of POMC. Leptin modulates 
neighboring NPY-GABA neurons by reducing GABAergic inhibition 
onto POMC neurons, thereby enhancing anorexigenic signaling.60 

3. Current Treatments for AN 

Cognitive behavioral therapy (CBT) is among the most effective 
treatments for eating disorders, demonstrating relatively low relapse 
rates and significant symptom reduction. CBT begins by identifying 
sources of emotional distress that contribute to dysphoria. Using that 
knowledge, the therapist can understand the behavior and motivation 
of the patients and develop their problem-solving skills to cope with 
their situations. Each CBT strategy is tailored specifically between 
therapist and patient to help the patient eventually be able to practice 

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self-regulation.61 For patients with phobia, CBT has shown to have 
reduced hyperactivity in the insula and anterior cingulate cortex, 
regions known to have increased activity when processing phobic 
threats. In patients with OCD, CBT improved the hyperactivation of 
circuits that are associated with OCD, including the orbitofrontal 
cortex, anterior cingulate gyrus, and basal ganglia. In anxiety cases, 
patients had lower glucose uptake after CBT particularly in the right 
hippocampus, medial prefrontal cortex, and left ventral cingulate 
cortex, restoring the normal circulation.62 CBT facilitates cognitive 
restructuring, leading to neurobiological changes in brain regions 
involved in reward processing and emotional regulation. Studies 
report a remission rate of 33% for AN, with 77.3% of adult patients 
experiencing a significant reduction in disordered eating behaviors 
after a year of treatment.63-64 
 
Family based treatment (FBT) also focuses on restructuring the 
patient’s self-perception and any cognitive distortion on food intake. 
The major difference is that FBT seeks to include families as a resource 
to the child’s aid, as shown in figure 2 below. In Phase 1 of FBT, 
parents assume full responsibility for meal planning and supervision, 
ensuring adequate nutritional intake while reducing conflict 
surrounding food. Once the patient reaches a medically stable weight 
and eating-related distress decreases, Phase 2 gradually returns control 
over eating to the adolescent under parental guidance. Phase three 
revolves around resolving the still-lingering symptoms and any 
developmental issues disrupted by the condition, such as identity 
formation and self-image. The first randomly controlled trial (RCT) 
of FBT on AN patients showed that FBT was more efficient for 
18-year-olds and younger children in preventing relapse and weight 
restoration. In other RCTs, FBT has been proven to be effective in the 
long term for weight restoration and maintaining gains even five years 
after treatment. Studies show that merely 10 sessions of FBT course is 
just as effective as 20 sessions of individual oriented course, in terms of 
weight maintenance.65 At six and twelve months after trials, FBT was 
shown to be statistically superior to adolescent-focused therapy, 
differing by over 20 percentage points in remission rates.66 

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Figure 2. Family Based Therapy Process Flow for AN. 
As aforementioned, FBT has multiple stages and one of its advantages is the 
gradual improvement the patient will experience as it goes through each 
phase. Through creating a unity amongst the patient’s loved ones, the patient 
can feel more encouraged to correct their diet compared to CBT. 

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4. The Relationship Between the Gut Microbiome & 
Gut Brain Axis 

Figure 3. Bi-directional Gut-Brain Linkage. Summary of examples of the 
bi-directional communications between the gut microbiota and the brain. This 
linkage suggests the important role gut microbiota play in mental health disorders. 

 
As mentioned previously and depicted in Figure 3, the GBA is a 
bi-directional linkage between intestinal processes and the central 
nervous system. The central nervous system mainly communicates 
through vagus and pelvic nerves to intestinal targets such as the enteric 
nervous system. The hypothalamic–pituitary–adrenal axis, endocrine 
pathways and bacterial metabolites via blood circulation are all major 
connections between the GBA and gut microbiome.67 The gut 
microbiome consists of trillions of microbes that reside in the intestine 
and spans up to 500 species.68-69 The gut transmits signaling molecules 
through the enteric nervous system and vagus nerve, modulates 
immune responses and gut permeability, and maintains barrier 
integrity.8,67 The role of gut microbiota in neuropsychiatric disorders 
was first recognized in hepatic encephalopathy, where oral antibiotic 
treatment improved neurological symptoms.8 More recent studies link 
gut microbiome dysbiosis to AN and other psychiatric conditions.68 
More recently, the gut microbiota dysbiosis, referred to as the 
imbalance of microbial communities, has been linked closely with 

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anxiety, depression, autism-spectrum disorder and eating disorders.8,70 
Administration of lactobacillus and bifidobacterium strains can 
reduce cortisol release, which has been associated with reduced 
depression, lower pro-inflammatory cytokine levels and a healthy 
response to stress.71 
 
The gut microbiome can communicate with the brain through their 
bacterial metabolites. Gut microbes produce short chain fatty acids 
(SCFA) such as butyric acid, propionic acid, and acetic acid during 
metabolism.67 SCFAs activate the sympathetic “fight or flight” nervous 
system, influences memory process, and modulates food intake. For 
example, butyric acid, the product of sugar fermentation by obligate 
anaerobic bacteria, is responsible for inhibiting the release of 
anorexigenic peptide, CRH, levels and influencing appetite.72 These 
bacterial metabolites can also signal and regulate the synthesis of 
neurotransmitters in intestinal epithelial cells that act on the brain 
through the vagus nerve.67 
 
One of the other ways the gut microbiome communicates with the 
brain is through neurotransmitters. The gut microbiota produces 
metabolites that include neurotransmitters or their precursors. As 
shown in figure 3, certain neurotransmitters and precursors produced 
by gut microbiota can travel through the blood-brain-barrier (BBB) 
for signaling or further synthesis of neurotransmitters.67 Dopamine, 
serotonin and GABA are three neurotransmitters closely correlated to 
the pathology of AN. As mentioned in earlier sections, hypophagia is 
present when 5-HT1B and 5-HT2C receptors are stimulated. 
Staphylococcus in the gut can decarboxylate aromatic amino acid, 
dihydroxyphenylalanine and 5-hydroxytryptophan into dopamine and 
serotonin. Dopamine can then be transported via the 
blood-brain-barrier and reach the mesolimbic dopaminergic system 
usually associated with food reward. On the other hand, serotonin is 
mainly synthesized through the metabolites, SCFAs, secreted by 
bacteria strains that signal enterochromaffin cells to produce 
tryptophan hydroxylase.73 In fact, 90-95% of serotonin are mainly 
present in the epithelial enterochromaffin cells of GI tract.74 The 

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serotonergic and 5-HTergic system plays a role in mediating the onset 
of AN. GABA production is influenced by gut microbiota, with 
dietary factors such as a ketogenic diet increasing GABAergic activity. 
As an inhibitory neurotransmitter, GABA plays a role in appetite 
suppression, which may contribute to AN pathophysiology.75 
 
On the other hand, since this gut-brain-axis is a bi-directional linkage, 
the brain also affects the make-up of gut microbiota. The brain 
primarily communicates with the gut microbiota through secretion of 
signaling molecules from neuron, immune, and enterochromaffin 
cells. These signaling molecules depend on the neurotransmitter 
receptors present on bacteria. For example, E. coli O157:H7 contains a 
receptor for host epinephrine and norepinephrine.76 The brain can 
also alter microbiota composition through influencing the intestinal 
permeability. Stress increased colonic paracellular permeability by 
increasing the production of interferon-g and decreasing the 
expression of ZO-2 and occludin.77 The CRH receptors participate in 
colonic barrier dysfunction under mild stress in adult rats.78 Stress in 
the brain also induces the production of an antimicrobial protein, 
a-defensin, influencing the existing microbiota composition. 

5. Targeting Anorexia by Increasing Gut Microbiome 
Diversity 

Anorexia has been correlated with an altered gut microbiome due to 
the altered expression of orexigenic and anorexigenic peptides which 
are affected by a subpar gut microbiome shown in previous studies 
with anorexic mouse models.79 Studies have shown that alterations in 
the normal microbial composition, also known as gut dysbiosis, can be 
linked to AN patients, as well as the development of other eating 
disorders. In general, AN patients have a lower microbial diversity than 
healthy controls.80 During different phases of an anorexic patient’s 
disorder, there are significant shifts in gut microbiome composition.81 
More specifically, alpha diversity drastically decreases during the phase 
of weight loss.81 

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Morita et al. reported that AN patients exhibit reduced colonization of 
butyrate-producing bacteria, including Clostridium coccoides, 
Clostridium leptum, and Bacteroides fragilis, which may disrupt 
appetite-regulating signals.81 A decrease in butyrate-producing species 
and an increase in mucin-degrading species are also hallmarks of the 
gut microbiota in AN patients.83 In addition, during the phase of 
weight loss in AN patients, a review on the role of microbiota in the 
pathogenesis of eating disorders mentions that there is a reduction in 
Firmicutes and SCFAs in the gut microbiome, while there is an 
increase in Bacteroides, Actinobacteria, Enterobacteriaceae, and 
Methanobrevibacter smithii.81 The review, consisting of 16 different 
studies, concluded that microbial richness increased in anorexic 
patients after weight regain through stool transplantation. They also 
concluded that SCFA levels increased and the Firmicutes/Bacteroides 
(F/B) ratio normalized when there was weight gain and 
renourishment.81 As mentioned in the pathophysiology section, 
neuropeptide dysregulation is found in AN and the gut microbiota 
plays a key role in maintaining NPY, AgRP, and PYY levels.84 An 
alteration in the gut microbiota affects neurotransmitters which is 
similar to the case Borgo et al. reported. In the trial, an increase of 
Enterobacteriaceae, an antigen, which produces bacterial peptide 
caseinolytic protease b, mimics a-MSH and activates anorexigenic 
neurons.85 

These studies associating AN and gut-microbiome diversity, show that 
a restored gut microbiome may be a potential treatment option for 
eating disorders, and more specifically AN. AN patients’ altered gut 
microbiome conditions have been proven to influence gut permeability 
and inflammation, appetite changes, weight loss and gain, 
gastrointestinal symptoms, among other elements that impact the 
pathogenesis of AN. Understanding the relationship between a 
patient’s unique gut microbiome composition and their psychological 
condition can also be a key factor of focus for researchers and 
healthcare providers in order to determine the development of AN. 

 

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6.  Dietary Supplements as Treatment Method for 
Anorexia Nervosa 

6.1 Probiotics 

As mentioned in previous sections, AN patients are often observed 
with gut dysbiosis, characterized with abnormal levels of pathogenic 
bacterial species, a disrupted intestinal barrier integrity, and lowered 
diversity. To study whether such gut dysbiosis contributes to AN 
symptoms of weight loss and neuropsychiatric disturbances, Fan et al. 
reported that germ-free mice colonized with AN-derived microbiota 
resulted in reduced weight gain and increased anxiety-associated 
activities.86 Another study by Morisaki et al. conducted a study 
analyzing the gut microbiota of AN patients using polymerase chain 
reaction (PCR), and reported that patients exhibited preserving gut 
dysbiosis during inpatient nutritional therapy, CBT, and supportive 
psychotherapy, despite improved weight gain and psychological 
functions.87 This highlights that gut dysbiosis may not be restored only 
by weight gain and indicates the importance of targeting the gut 
microbiota in combination with traditional nutritional intervention 
therapies. Therefore, probiotics, including commercially available 
lactobacillus supplements, have been investigated as potential 
adjunctive treatments for AN, with the goal of restoring gut 
microbiome balance. 

6.1.1 Lactobacillus 

Lactobacillus species have been utilized in the clinical setting for 
improving gastrointestinal health.88 More recently, it has been linked 
with modulation of stress as studies of the GBA matures. 
Administration of lactobacillus bacterial strains can reduce the release 
of cortisol which leads to reduced depression, lower pro-inflammatory 
cytokine levels, and a healthy response to stress.89 Schwarzer et al. 
recently discovered, Lactobacillus plantarum probiotics 
supplementation attenuated weight loss and growth impairment in 
malnutritioned mice, suggesting the possible role of probiotic 
intervention for AN.90 

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Lactobacillus rhamnosus GG (LGG) is one of the probiotic strains 
being studied for treating AN due to its protective effect on the gut 
microbiota.91 It mostly resides in the colon mucosae and vagina and is 
key to maintaining genito-urinary health in preventing urinary tract 
infections. 

LGG has been identified as a key probiotic for AN treatment due to its 
role in maintaining intestinal barrier integrity by upregulating tight 
junction proteins, such as zonula occludens-1, thereby reducing gut 
permeability. Moreover, LGG modulates the gut-brain-axis by 
regulating the 5-HTergic intestinal system, increasing GABA receptors 
in the brian, increasing serotonin receptor expression and, overall, 
relieving anxiety-like behaviors.91 Bai et al. conducted a mouse model 
study on deoxynivalenol (DON)-induced anorexia, demonstrating that 
LGG supplementation alleviated anorexic symptoms by reducing 
intestinal inflammation and modulating appetite-related signaling 
pathways. Coinciding with information presented in previous sections, 
DON-induced anorexia mainly releases 5-HT, which acts as a 
neurotransmitter and leads to anorexia.92 

In the study’s experimental design, antibiotic-treated mice were 
separated into 4 study groups: control, DON, DON+LGG, LGG and 
after 4 weeks of treatment, researchers found that LGG prevented 
DON-induced anorexia by increasing crypt depth of the jejunum and 
ileum, strengthening the barrier integrity, and promoting nutritional 
uptake. LGG also remodeled the TLR4-MyD88-NF-κB signaling 
pathway and since TLR4-MyD88-NF-κB is responsible for 
lipopolysaccharide (LPS)-induced anorexia, LGG is able to alleviate 
anorexia mediated by pro-inflammatory cytokines. LGG also 
maintained butyric acid levels comparable to controls, whereas the 
DON group had a significant drop. This affirms previous research 
done that shows AN patients with lower butyric acid levels and 
demonstrates how LGG promotes food intake as butyric acid inversely 
correlates with anorexigenic CRH by influencing cortisol receptor in 
the intestine.93,72 In addition, LGG’s regulation of appetite regulating 
pathways (NPY, AgRP, PYY) allows for upregulation of food intake 
and remodels the gut microbiota. More importantly, LGG remodeled 

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the gut microbiota to ensure long-term benefits as 11/16 metabolites 
were increased by DON compared with control while they were 
decreased by LGG + DON. Moreover, Bai et al. conducted fecal 
microbiota transplantation (FMT) to antibiotic-treated mice and 
reported that FMT-LGG+DON prevented weight loss and low food 
intake present in FMT-DON. Further research will be needed to 
examine its efficacy on humans but its promising results can hopefully 
present a possible therapy in conjunction with nutritional and 
behavioral interventions for AN . 

Another treatment of interest is Lactobacillus acidophilus (L. 
acidophilus) and has been associated with modulation of weight in 
multiple clinical studies. L. acidophilus’s main function is to produce 
lactic acid from lactose and has gained popularity for its digestive 
health benefits with the production of “acidophilus milk” when 
prevalence for obesity is significant in the US.94 Although direct studies 
on L. acidophilus in AN patients are lacking, its ability to restore gut 
microbiome diversity, regulate inflammatory responses, and improve 
intestinal permeability suggests its potential as an adjunctive treatment. 
First of such studies dates back to 1952, in which 124 bottle-fed 
infants, added with 500,000,000 viable L. acidophilus organisms per 
quart into daily formula, were compared with 123 healthy controls. 
The results showed significantly larger weight gain during the first 
month than did the controls.95 Another 8-week randomized parallel 
study of the effects of probiotic drink on LDL-cholesterol and 
fibrinogen factors revealed that the group intaking yogurt with L. 
acidophilus showed weight gain.96 In a more recent study, researchers 
conducted a genomics study on seven Lactobacillus species associated 
with weight gain and have been able to classify L. acidophilus and L. 
reuteri, among others, as weight gain-associated strains.97 Although 
other studies indicate L. acidophilus’ capability in ameliorating obesity 
and reduce weight gain, such effects can be explained by L. acidophilus’ 
ability to restore gut microbiome diversity as this same study revealed 
its reversal of a obesity-induced gut dysbiosis. Overall, L. acidophilus 
increased alpha-diversity and restored alterations in beta-diversity 
which is key to the treatment of AN.98 

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Gut dysbiosis is characterized by a disrupted intestinal permeability 
leading to an outgrowth of Gram-negative LPS producing 
Proteobacteria and circulating LPS levels.98 The nutrient deficient 
environment of AN disrupts the intestinal barrier integrity, as Kleppe 
et al. reported zonulin family peptides, serum markers for integrity, are 
significantly lower than healthy controls.99 A disrupted barrier 
promotes LPS release resulting in low grade inflammation which 
exacerbates AN.100 In fact, LPS plays a crucial role in the 
pathophysiology of AN as it reduces food intake via a mechanism 
dependent on myeloid differentiation primary response 88 (MyD88) 
signaling, an inflammatory signaling pathway, within endothelial cells 
lining brain capillaries and neurons cells.101 One of the ways L. 
acidophilus restores gut microbiome homeostasis is through improving 
intestinal integrity and lowering gut permeability. Specifically, L. 
acidophilus strengthens the barrier by increasing the expression of 
epithelial mucosal proteins, intectin, and the tight junction proteins, 
Occludin.98 A strengthened intestinal barrier results in decrease in 
circulating LPS, as a clinical trial conducted on 71 obese women over 
the period of 12 weeks reported a decrease in LPS levels by 20.14% after 
administering L. acidophilus.102 Although these study subjects were 
not AN patients, they were all diagnosed with low-grade systemic 
inflammation caused by a gut barrier permeability dysfunction, which 
is characteristic of anorexia. In culmination, L. acidophilus’ unique 
ability to restore gut microbiome homeostasis through modulating the 
intestinal barrier integrity and LPS levels suggests its importance in 
treating AN. 

Currently, an ongoing phase 2 randomized controlled study conducted 
by the Medical University of Vienna is examining the effects of daily 
multistrain probiotics doses including L. acidophilus W22 in 30 
adolescent AN patients. This is the first study studying the 
administration of probiotics on adolescent AN patients and can be 
conclusive due to a double-blind randomized longitudinal design, the 
large sample size and the comparison with sex and age-matched healthy 
controls. 

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A final bacterial strain of interest is Lactobacillus reuteri (L. reuteri) 
and similar to L. acidophilus, studies have concluded that this strain is 
associated with weight gain.97 L. reuteri mainly produces organic acids, 
ethanol, which aids in inhibiting the colonization of pathogenic 
microorganisms. Its usual tendency to colonize in the GI tract is the 
reason it is considered an optimal candidate for probiotic use.103 With 
regards to AN, L. reuteri is capable of strengthening the intestinal 
barrier by preventing microbial translocation from the gut lumen to 
the tissues, restore microbiome homeostasis through inhibiting 
pathogenic microorganism colonization, and reduce the production of 
pro-inflammatory cytokines.104 A recent 3-year clinical trial in Croatia 
investigated the effects of L. reuteri DSM17938 on 31 adolescent AN 
patients with comorbid constipation. After six months, 93% of the L. 
reuteri group achieved weight normalization, compared to 63% in the 
placebo group.105 Constipation is often frequently accompanied with 
AN weight loss and can further discourage food intake.106 This study 
reported that after 3 months, constipation relief was higher in the L. 
reuteri than in the placebo group (87% vs. 63%), and such relief can 
pave the way for nutritional recovery interventions. Overall, L. reuteri 
is a potential safe and effective way of mitigating AN and constipation 
in adolescents, due to its positive effects on weight normalization, 
patient compliance, constipation relief, which can lead to more 
effective nutritional recovery. 

6.2 Vitamins 

Vitamins are organic compounds that are essential to the human body 
for organs to perform various essential physiological processes, 
including metabolism, immune function, and cellular homeostasis. 
Previous research has shown that there is significant association 
between vitamins and improving gut microbiome diversity, specifically 
with Vitamin D, A, and E.108,115,121 Most of these vitamins need to be 
consumed through one’s diet from sources such as meats, fruits, and 
vegetables. AN patients are especially at risk of malnutrition can lead to 
gut complications like having deteriorating intestinal barriers, 
consequently leading to inflammation and general discomfort from 

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eating. Vitamin D, A, and E have all been found to assist with 
preserving gut barrier function and promoting microbiome health. 

6.2.1 Vitamin D 

Vitamin D is an important nutrient in development and especially in 
the regulation of the microbiome. With AN patients consuming less 
food, patients are at high risk of vitamin D deficiency which could 
create a positive feedback loop of worsening symptoms. Vitamin D 
influences the microbial composition through vitamin D receptor 
genes (VDR), which regulates immune responses and microbial 
homeostasis. Vitamin D regulates the expression of antimicrobial 
peptides, such as cathelicidins and defensins, which help maintain gut 
mucosal integrity by preventing dysbiosis and promoting epithelial 
repair.108 Through this, Vitamin D controls the health of the gut by 
protecting against inflammation with the expression of VDR genes.109 
This is shown in one particular study, in which the fecal microbiome of 
50 adolescent women were tested after receiving Vitamin D 
supplements. Results showed an increase in Firmicutes and 
Bifidobacteria, with a reduction in Bacteroidetes, a marker of 
inflammatory response. Also, a reduction of VDR gene expression can 
increase the proteobacteria population, causing an increase in 
inflammation. This is also supported by a study in which VDR genes 
in mice were removed and subsequently the subjects showed severe gut 
inflammation, shown with increased amounts of Bacteroidetes.110 With 
adequate supplementation of Vitamin D, the VDR genes are able to 
prevent the pathogenic microbes from outcompeting the beneficial 
bacteria, the leading cause of gut dysbiosis.109 

Vitamin D can help alleviate many other organ complications arising 
from AN. Vitamin D deficiency is often associated with liver and 
kidney diseases, and with the inherent malnutrition experienced by 
AN patients, they are more prone to such diseases. Singh et. al tested 
the effect of Vitamin D supplementation on subjects and discovered 
improved liver function along with decreasing the ratio of aspartate 
aminotransferase (AST)/alanine aminotransferase (ALT). Kidney 
function also improved as the ratio of serum blood-urea-nitrogen 

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(BUN)/Creatinine decreased. In the same study, the relative 
abundance of Bifidobacterium and Akkermansia increased, as did the 
Firmicutes and healthy Bacteroidetes probiotic phylums, while on the 
other hand, the Prevotella phylum decreased. In addition, the study 
also showed that the Vitamin D supplementation led to a statistically 
significant greater diversity of microbiota.111 Although more research is 
still needed, scientists still speculate that AN is related to the dysbiosis 
of the gut microbiota.112 If an association between gut dysbiosis and 
AN is confirmed, Vitamin D supplementation could serve as a 
potential adjunct therapy for improving gut health and alleviating 
gastrointestinal symptoms. 

An ongoing trial for the past two years aims to further study the effect 
of Vitamin D on gut microbiota and intestinal barriers, especially in 
patients with irritable bowel syndrome (IBS). The researchers have 
currently found that when the concentration of Vitamin D is reduced, 
symptoms seem to be connected to the concentration. 
Supplementation of Vitamin D has shown alleviation of IBS 
symptoms and researchers are investigating the mechanisms of 
dissecting fecal microbiome samples through 16S rRNA gene 
sequencing and detecting the expressions of Z0-1, occluding in 
intestinal mucosa. If Vitamin D can indeed help with alleviating any 
organ complications arising from AN, then Vitamin D can be a good 
supplement to start helping alleviate symptoms of AN. Through 
feeding the patients their proper amount of Vitamin D, they can 
prevent gut complications arising from AN. 

As aforementioned, Vitamin D supplements can be important in 
restoring the nutritional balance to maintain a healthy digestive system. 
Vitamin D supplements will aid AN patients who suffer from 
gastrointestinal issues in immune function and enhance nutrient 
absorption, a step in the overall recovery process. Through alleviating 
the general discomfort and the organ complications arising from the 
disorder, patients can eventually feel comfortable again to eat healthily. 

 

 

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6.2.2 Vitamin A 

Vitamin A is an essential nutrient involved in various physiological 
functions, including the maintenance of gastrointestinal 
homeostasis.113 Vitamin A is derived from two primary dietary sources: 
retinol, found in animal products such as meat and fish, and 
provitamin A carotenoids, obtained from fruits and vegetables. Not 
only is Vitamin A essential in homeostasis, but it also maintains a 
protective effect on the intestinal mucosal barrier and gut mucosal 
integrity.114 Patients who suffer from AN tend to not get the required 
nutrients and supplements they need to maintain their health and gut 
microbiome. Without the consumption of foods like meat, fish, fruits, 
and vegetables, anorexic patients drastically lack Vitamin A intake. A 
research trial conducted by Pattanakitsakul et. al. studied the nature of 
Vitamin A deficient rats and discovered that additional Vitamin A 
supplementation protects the intestinal mucosal barrier even after 
chemotherapy treatment, which is known to drastically affect gut 
microbiome composition.115 This protective role of Vitamin A can be 
useful in implementing and preserving a healthy gut microbiome 
composition that is required in anorexic patients. 

Another study conducted in Chongqing Medical University located in 
China studied the gut microbiome composition of vitamin A-deficient 
and vitamin A-sufficient groups amongst patients experiencing 
diarrhea.116 They observed that gut microbiota richness was not 
different between the two groups, but that there was significantly lower 
microbiome diversity in patients with deficient Vitamin A according to 
the Shannon and Simpson Index, a traditional method used to measure 
species diversity.117 This means that patients with sufficient Vitamin A 
had ample quantity of gut microbiota species, and in specific the study 
found that Escherichia-Shigella and Clostridia phylotypes were found 
more prominently found in the Vitamin A sufficient group, while the 
deficient group was largely composed of Enterococcaceae, including the 
enteric pathogen Enterococcus faecalis. Enteric pathogens, such as 
Enterococcus faecalis, are typically harmless in the intestinal 
environment of healthy individuals, but the species’ overabundance in 
the gut can quickly result in infections that spread throughout the 

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body and even promote tumor formation.118 In addition, people with 
underlying health problems, in this instance, patients with AN, with a 
weakened immune system, are more likely to face additional health 
issues due to their diet lacking Vitamin A amongst other nutrients. 
Other studies have also shown that intake of retinol, a dietary 
supplement derived from Vitamin A and as mentioned previously to 
be found in meat and fish, can increase or even re-establish ratios 
between Proteobacteria and Actinobacteria as well as Proteobacteria and 
Firmicutes.119 This would be useful in anorexic patients since there are 
significant changes in the quality, quantity, composition of gut 
microbiota during the phase of weight loss. These studies suggest that 
Vitamin A may play a role in maintaining gut microbiome balance and 
mucosal integrity, which could be particularly beneficial for AN 
patients experiencing intestinal dysbiosis. 

6.2.3 Vitamin E 

A fat soluble antioxidant, Vitamin E functions as a fat-soluble 
antioxidant that supports plasma membrane repair and maintains 
intestinal barrier integrity by reducing oxidative stress and 
inflammation. Vitamin E also helps protect the gut microbiota from 
pathogenic invasion. There are eight different types of Vitamin E, but 
the most common form and most present and active in humans is 
a-tocopherol.120 Significant Vitamin E uptake shows a positive 
association with the Firmicutes phylum and negative association with 
Bacteroidetes. Firmicutes are important gut bacteria for metabolism and 
Bacteroidetes, while sometimes beneficial, overabundance of this 
species can be damaging for gut barriers as it degrades the mucus 
barriers of intestines.121 In addition, a study on lactating women found 
that those with higher Vitamin E intake were associated with a decrease 
in proteobacteria, known to contain many pathogens and cause 
inflammation.119 This supports the idea that Vitamin E deficiency can 
increase inflammatory response. Due to anorexic patients’ lack of 
nutrient intake, Vitamin E supplementation, along with other 
vitamins, could drastically improve the state of a patient’s gut 
microbiome and protect them from further health complications that 
can arise from pathogens and inflammation of the gut. 

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While research in determining the exact quantities of vitamins to 
administer in order to obtain the best results for the gut microbiome 
are lacking, specifically in regards to Vitamin E supplementation, a 
recent study from 2020 shows that a lower-level consumption of 
Vitamin E changes the composition of the gut microbiota while also 
increasing spleen and body weight. The study assigned mice with 
similar body weight to three varying groups, a control, low-level 
Vitamin E (0.06 mg per 20 g of body weight), and high-level Vitamin E 
(0.18 mg per 20 g of body weight). Comparing the body weights of the 
mice before and after Vitamin E supplementation showed that while all 
groups increased in weight (including control), the low Vitamin E 
group had the most weight gain as well as the highest ratio of 
Firmicutes to Bacteroidetes in the gut microbiome.120 Since the ratio of 
F/B is drastically altered in anorexic patients, implementation of lower 
quantities of Vitamin E based on a patient’s body weight can promote 
weight gain and renourishment, while also enhancing gut microbiome 
composition. Meanwhile, another study was conducted where iron 
and Vitamin E were taken together as supplements. The test group was 
shown to have a differing microbiome composition with a decrease in 
Bacteroidetes and an increase in Firmicutes. There was also an increase 
in Roseburia, a producer of butyrate, a short-chain fatty acid that can 
help with gut mucosal barrier. 

The study concluded that ultimately the combination of iron and 
Vitamin E benefited microbiome composition by assisting the growth 
of butyrate-producing bacteria.122 

6.3 Fatty Acids and Ketone Supplements 

Ketones are metabolic intermediates formed as byproducts of fat 
metabolism. When people starve, their bodies enter ketosis, a state 
where the brain shifts from using glucose to using ketones for energy. 
This state can reduce anxiety and provide a sense of reward, which 
might explain why some people with AN find starvation soothing. A 
ketogenic diet (KGD) can replicate the state of ketosis without actual 
starvation.123 The diet is high in fat from foods like avocados and nuts, 
moderate in lean protein like fish, eggs, and lean pork/beef, and is very 

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low in amounts of carbohydrates from leafy greens and non-starchy 
vegetables.124-125 It has been used effectively to reduce seizures in 
epilepsy and is being studied for other neurological conditions. This 
shift affects various brain pathways and can have significant effects on 
neurological health, similar to the effects seen in epilepsy treatment. 
While no published studies have evaluated KGD specifically for AN, 
preliminary evidence suggests potential benefits in addressing energy 
deficits and gut microbiome alterations. However, further research is 
needed to determine its clinical applicability. 

6.3.1 Ketone Body Metabolism Overview 

Ketone body metabolism involves coordinated processes across 
multiple organs, including the liver, muscles, and brain, to regulate 
energy homeostasis. Ketone bodies are vital energy sources for the 
nervous system, especially when glucose is scarce. In healthy adults, 
ketone levels fluctuate daily, contributing to about 5% of energy 
expenditure in the fed state and up to 20% during fasting or 
starvation.126 These levels rise significantly during fasting, exercise, 
neonatal periods, or late pregnancy.126 Other tissues such as skeletal 
muscle, heart, and kidneys also metabolize ketone bodies. This 
turnover includes production from fatty acids in liver hepatocytes and 
disposal by extrahepatic tissues.127  

Fatty acids, released from adipose tissue, enter hepatocytes and 
undergo β-oxidation in the mitochondrial matrix, leading to ketone 
body production, primarily from acetyl-CoA.127 Ketogenesis is 
regulated by hepatic glucose availability, mitochondrial redox state, 
β-oxidation efficiency, TCA cycle flux, and the hormonal balance 
between glucagon and insulin, which collectively determine ketone 
body production.126 Overall, ketone bodies are crucial energy sources 
for various processes ranging across all bodily systems and mechanisms 
and changing levels in a person’s body highly affects how energy is 
utilized and the balance of hormones, and other substances, in the 
body. Therefore, reinforcing the ketone body prevalence in a patient’s 
body may have a significantly positive impact on reestablishing 
homeostasis and energy efficiency throughout recovery from AN. 

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6.3.2 Ketones and Short-Chain Fatty Acids (SCFAs) 

Ketone bodies serve as an alternative energy source during periods of 
low carbohydrate intake, supporting various organs, including the 
brain and muscles. They help modulate the redox state within cells, 
potentially reducing oxidative stress and supporting cellular health.126 

They are precursors for lipid synthesis, playing a role in lipid storage 
and metabolism.126 Ketone bodies can also act as signaling molecules 
that influence pathways involved in inflammation, cell growth, and 
differentiation.126 The production of ketone bodies in the gut is 
regulated by the microbiome and dietary factors, suggesting an 
intricate relationship between ketones and gut health. 

Given the severe caloric deficits in AN patients, ketone bodies could 
provide a critical energy source, helping to restore overall energy 
balance.128 AN is often associated with gut dysbiosis which is 
essentially the imbalance of the microorganisms that reside in the body, 
especially in the gut or skin.129 Due to their multifaceted role in the 
body, ketone bodies could help restore microbial diversity, which is 
crucial for gut health and nutrient absorption. They may reduce 
inflammation in the gut, a common issue in AN, thereby promoting a 
healthier gut environment.126 The ability of ketone bodies to influence 
cell proliferation and differentiation in the gut lining could also help 
maintain or restore gut mucosal integrity, which is essential for proper 
nutrient absorption.127 The ambiguous roles of ketone bodies suggest 
they could be used as part of a comprehensive treatment strategy for 
AN. Their benefits in energy provision, gut health, and inflammation 
modulation make them a promising adjunct to traditional treatments 
like CBT and FBT which address the disease from a more neurological 
basis without also assessing the physical imbalances caused by AN. 

According to other studies, ketone bodies, such as 
beta-hydroxybutyrate (BHB), significantly impact cerebral fuel 
metabolism.128 They exhibit a glucose-sparing effect by substituting for 
glucose in the brain, particularly noticeable during fasting or ketogenic 
diets.128 This metabolic adaptation not only supports brain function 
but also suggests potential therapeutic benefits for conditions like AN, 

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where compromised glucose metabolism can occur.128 Ketone bodies 
enhance cerebral energy metabolism without altering ATP levels, 
indicating their efficiency as a neuroprotective substrate.128 
Additionally, ketone bodies possess antioxidant and anti-inflammatory 
properties, potentially mitigating oxidative stress and 
neuroinflammation, common in neurodegenerative diseases.128 These 
insights highlight the therapeutic potential of elevating ketone bodies 
in managing disorders characterized by impaired glucose metabolism, 
including those affecting brain health like AN. 

There are a few ongoing clinical trials that are investigating the impact 
of short-chain fatty acids and ketone supplements on eating behavior 
and overall nutritional states. One current trial led by Dr. Elske Vrieze 
in Belgium is specifically testing the psychobiological effects of SCFAs 
in patients suffering from AN.130 The study consists of administering 
SCFAs or a placebo through colon-delivery capsules over six weeks, in 
addition to standard psychotherapeutic treatment regimens, to 
evaluate changes in stress responses, eating habits, body mass index 
(BMI), gut microbiota, gastrointestinal symptoms, and related 
psychological conditions.130 These scientists aim to understand how 
metabolites in the gut microbiota can impact human stress systems and 
eating behaviors to facilitate potential therapeutic targets for anorexia 
and other psychiatric disorders.130 Another ongoing clinical trial being 
done at UC San Diego is specifically testing the effect of BHB as a 
nutritional supplement for anorexic and bulimic patients, and how 
BHB ingestion impacts brain function.131 Researchers will compare the 
effects of ketone supplementation versus placebo on brain activity 
using EEG measurements, with participants taking a ketone drink 
twice daily for two weeks.131 

Overall, the growing number of studies surrounding the role of ketone 
bodies in human health and disease emphasizes the importance of 
understanding their role as potential therapeutic targets. While there 
are still limited studies on how ketone bodies directly correlate to AN, 
there has already been substantial research regarding how it influences 
other psychiatric and chronic diseases like Alzheimer’s, Parkinson's 
Disease, fatty liver disease, heart failure, among others.128 Ketone 

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bodies play vital roles in energy metabolism, redox balance, lipid 
synthesis, and cellular signaling. For individuals with AN, these 
properties suggest that ketone bodies might help address some of the 
condition's critical aspects, such as energy deficiency and gut health. 
They may serve as crucial mediators of a patient’s microbiome. While 
promising, these potential applications require further research to 
confirm their efficacy and safety in clinical settings, ensuring that 
interventions are tailored to the unique needs of AN patients. 

7. Practical Applications 

These findings highlight the potential role of dietary supplements, 
including vitamins, minerals, and probiotics, in treating AN. 
Integrating vitamin supplementation, dietary supplements, ketogenic 
diets with current therapies will overall provide a more comprehensive 
approach to treating AN. This review paper may also encourage 
ongoing and future clinical trials to evaluate the effectiveness of these 
supplements and find ways to develop more personalized treatment 
plans based on individual gut microbiome profiles. Further research on 
these substances may enable physicians to assess gut microbiome 
composition and optimize nutritional interventions tailored to 
individual patient needs. 

7.1 Clinical and Nutritional Rehabilitation Treatment 
Plans 

Patients with AN often suffer from severe nutritional deficiencies and 
altered gut microbiome, which contribute to both physical and 
psychological symptoms. Effective nutritional rehabilitation is crucial 
for the recovery of AN patients. Traditional refeeding programs may 
benefit from the inclusion of dietary supplements to address specific 
deficiencies and support gut health. Integrating specific dietary 
supplements and tailoring them to patient-specific needs introduces a 
way to provide a more personalized treatment plan for AN patients. 
Since the makeup of everyone’s gut microbiome is unique, 
understanding the impact of specific substances and how varying 
amounts of them affects each patient is key to targeting the distinct 

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ways the disorder is influencing them. Dietitians can also create 
individualized supplement plans based on the specific needs and 
deficiencies of each patient. Potential outcomes of individualized 
supplement-based interventions may include improved gut 
microbiome diversity, enhanced nutrient absorption, and potential 
benefits for mental well-being through gut-brain axis modulation. 
However, these effects require further clinical validation. 

7.2 Psychiatric Support Strategies 

AN is also often accompanied by psychiatric symptoms such as anxiety, 
depression, and obsessive-compulsive behaviors, which can be 
influenced by gut health. Incorporating dietary supplements into 
psychiatric support strategies can provide a holistic approach to 
treatment. Psychiatrists and therapists can work with dietitians to 
ensure that patients receive supplements that support both mental and 
physical health. This integrated strategy aims to reduce psychiatric 
symptoms, improve adherence to treatment plans, and increase the 
likelihood of sustained recovery. 

The integration of dietary supplements into treatment strategies for 
AN offers a promising approach to addressing the complex nutritional 
and psychiatric needs of patients. By restoring gut-microbiome 
diversity and supporting the gut-brain axis, these supplements can 
enhance both physical and mental health outcomes. Continued 
research and careful implementation will be key to maximizing the 
benefits of this approach. 

8. Limitations/Implications 

While dietary supplements hold promise as a potential treatment for 
AN by restoring gut-microbiome diversity and addressing alterations 
in the gut-brain axis, significant limitations exist. Addressing these 
limitations through rigorous research, personalized treatment 
approaches, and enhanced regulatory oversight is crucial to fully realize 
the potential benefits of dietary supplements in the treatment of AN. 

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As of now, there is an extremely limited scope of research regarding 
incorporating these supplements into AN treatment regimens. 
Research on dietary supplements in AN treatment is still in its early 
stages, with most studies being limited by small sample sizes, short 
follow-up periods, and a lack of randomized controlled trials. The 
limited scope of resources prevents us from fully examining variability 
in individual responses and the heterogeneity in patient responses 
necessitates personalized treatment approaches, complicating the 
standardization of supplement-based interventions. There is also lack 
of research on the potential risks and side effects of dietary 
supplements in relation to AN, how they interact with other AN 
treatments, and regulatory and quality control issues. 
Over-supplementation of certain vitamins and minerals can lead to 
toxicity and therefore correct quantities of supplements to administer 
needs to be determined. Probiotics may cause gastrointestinal 
disturbances in some individuals. Additionally, the purity and quality 
of supplements can vary widely. The interactions between dietary 
supplements and other treatments are not well-understood, and there 
is a risk of adverse interactions or diminished efficacy when combined 
with certain medications or therapeutic modalities. Variability in 
supplement quality, dosing, and labeling accuracy can also pose 
challenges for ensuring consistent and safe administration of 
supplements. 

Another limitation to this treatment approach to consider is patients’ 
compliance and acceptance of the treatment regimen. Individuals with 
AN often exhibit resistance to treatment, including dietary 
interventions.132 Fear of weight gain, mistrust of new treatments, and 
the psychological complexity of the disorder can lead to poor 
compliance with prescribed supplement regimens. 

Ensuring patient compliance and acceptance of dietary supplements 
requires extensive education, support, and possibly behavioral 
interventions, which can be resource-intensive.132 Overall, the limited 
scope of current research restricts our ability to draw definitive 
conclusions about the efficacy and safety of dietary supplements for 
treating AN. 

Berkeley Pharma Tech Journal of Medicine | 106 



 

 

9. Future Directions 

While the components in this review show advantages for using dietary 
supplements as a treatment for improving gut microbiome diversity, 
there is limited research on its effectiveness in relation to AN 
specifically. It is important to consider areas of future research that can 
maximize the potential of dietary supplements and improve the 
effectiveness of current treatment methods. As mentioned before, 
utilizing dietary supplements for AN along with conventional 
therapies (i.e. CBT), can propose a comprehensive treatment approach 
that offers a holistic approach to managing and treating the disorder. 
Studying this combination of traditional treatment methods with 
additional supplementation, scientists can compare the effectiveness of 
the combined approach versus solely traditional methods.  

Future research should focus on comparative studies evaluating the 
efficacy of various dietary supplements, including probiotics, vitamins, 
fatty acids, and ketone supplements. Examining their effects both 
individually and in combination may help identify the most effective 
strategies for improving gut microbiota diversity in AN patients. In 
addition, although time consuming, conducting long-term studies 
would help assess the effects of dietary supplements in improving gut 
diversity in specifically anorexic patients as well as examine the longer 
term effect and side effects of using these supplements. These 
long-term studies can also be closely connected to evaluating the 
impacts of weight restoration in AN patients while monitoring a 
patient’s psychological well-being. 

Personalized medicine, including microbiome-based interventions and 
genetic screening, may improve treatment outcomes by tailoring 
dietary supplement regimens to individual AN patients. However, 
further research is needed to develop standardized implementation 
strategies. Since each individual’s gut microbiome is unique in 
composition and is developed fully approximately one to two years 
after birth, these personalized treatment plans targeting specific areas in 
a patient’s gut profile can improve, in this circumstance for example, 
microbiome imbalances in patients with AN.133 These personalized 

Berkeley Pharma Tech Journal of Medicine | 107 



 

 

approaches can also take into account genetic predispositions which 
can be beneficial in tailoring dietary supplement intake and regimens 
to target specific deficiencies that are present in a particular patient. 

10. Conclusion 

Patients with AN suffer from both nutritional deficiencies and a 
disrupted gut microbiome, and traditionally nutritional intervention 
strategies and behavioral therapies are employed to restore weight gain 
and improve psychological functions. However, this leaves the gut 
microbiome unaddressed, as studies increasingly reported the presence 
of gut dysbiosis after traditional nutritional therapy, CBT, and 
supportive psychotherapy. Dietary supplements can act as a promising 
add-on in meeting the unaddressed areas in AN treatment. Probiotic 
strains from the lactobacillus genus, such as L. acidophilus, L. reuteri, 
and L. rhamnosus GG, have proven to improve weight gain, relieve 
constipation (a symptom often preventing AN patients from receiving 
nutritional interventions), positively modulate the appetite-regulating 
pathways, and strengthen the intestinal barrier integrity.  

While probiotics are the most extensively studied dietary intervention 
for gut microbiome modulation in AN, further research is needed to 
determine the specific effects of different probiotic strains in human 
clinical trials. Vitamin D plays an integral role in microbial 
composition through its receptor genes, regulation of gut mucosa, and 
is shown to positively remodel the gut microbial makeup of AN 
patients. Vitamin A maintains the intestinal barrier integrity and is 
positively correlated with microbiome diversity and Vitamin E, similar 
to Vitamin A and D, strengthens barrier integrity, protects against 
pathogenic microbes, and reduces intestinal inflammation. While some 
vitamins, such as vitamin D, have shown potential in microbiome 
modulation, direct clinical evidence supporting their role in AN 
treatment remains limited, warranting further investigation. Ketone 
bodies offer an alternative intervention acting as a critical energy 
source, restoring cerebral fuel metabolism, and in repairing gut 
mucosal integrity due to its role in influencing cell proliferation in the 
gut lining. Fatty acids play a role in ketone body production, and 

Berkeley Pharma Tech Journal of Medicine | 108 



 

 

SCFAs modulate appetite-regulating pathways. While there are no 
published studies on the effects of ketogenic diet for AN, ongoing 
clinical trials investigating SCFAs and Ketone supplements as potential 
anorexic treatment are promising.  

By combining traditional therapies with dietary supplements, dietitians 
can tailor-make treatments to address the unique nutritional and gut 
microbiome deficiencies in each patient. However, more 
comprehensive and diverse clinical trials are needed to determine the 
efficacy of both individual dietary supplements and its combination 
with traditional therapies in the treatment for AN. 

Berkeley Pharma Tech Journal of Medicine | 109 



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