Journal of Veterinary Behavior 37 (2020) 56e60

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Journal of Veterinary Behavior

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Canine Research

Successful dietary treatment of aggression and behavioral changes

in a dog
Anna Suñol a, *, Jorge Perez-Accino a, Molly Kelley a, Giacomo Rossi b,
Silke Salavati Schmitz a
a
University of Edinburgh, The Royal (Dick) School of Veterinary Studies and The Roslin Institute, Hospital for Small Animals, Midlothian, United Kingdom
b
School of Biosciences and Veterinary Medicine, University of Camerino, Matelica, Italy

a r t i c l e i n f o a b s t r a c t

Article history: A 7-year-old male neutered crossbreed dog was presented for investigation of a 2-year history of
Received 28 January 2020 worsening aggression and changes in behavior. Complete hematology, serum biochemistry, ammonia,
Received in revised form basal cortisol, total thyroxine, ionized calcium, testosterone levels, urine analysis, magnetic resonance
26 March 2020
imaging, and cerebrospinal fluid were unremarkable. A gluten-free hydrolyzed protein diet trial was
Accepted 13 April 2020
attempted. Three weeks after changing the diet, the dog’s behavior normalized and the aggression
Available online 11 May 2020
resolved. Additional blood tests to further investigate potential gastrointestinal pathology showed no
signs of gut inflammation or malabsorption; however, a mild or early protein-losing enteropathy was
Keywords:
aggressive
suspected based on elevation in fecal alpha1-proteinease inhibitor levels. Anti-transglutaminase-2 an-
canine tibodies and anti-gliadin antibodies were both found to be markedly elevated, suggesting gluten hy-
diet persensitivity. After the successful dietary trial, the dog experienced two instances of relapse associated
gluten with a change in diet. In both cases, he was returned to the initial gluten-free diet again, and the signs of
enteropathy aggression ceased within 4 days on each occasion. This case report describes the complete resolution of
permeability aggression and behavioral changes after feeding a hydrolyzed gluten-free diet in a dog with a suspected
nonceliac underlying gluten hypersensitivity. Diet modification should be considered a simple and safe
attempt of treatment or management of behavioral abnormalities in dogs when other common causes
have been ruled out.
Ó 2020 Elsevier Inc. All rights reserved.

Case presentation
A 7-year-old male neutered crossbreed dog presented to the
Neurology and Neurosurgery service for investigation of a 2-year
history of worsening aggressive behavior.
History and presenting signs
The dog was rescued by his current owner at the age of 1.5 years.
He was vaccinated against rabies and was up to date on preventa-
tive flea, tick, and deworming treatments. The dog regularly trav-
eled to Western continental Europe. He was fed a commercial dog
food from the time of adoption as a puppy and the owner did not
* Address for reprint requests and correspondence: Anna Suñol, Hospital for
Small Animals, Royal (Dick) School of Veterinary Studies, University of Edinburgh,
EH25 9RG Roslin, UK. Tel.: 0044-01316507650; fax: 0044-01316507652.
E-mail address: anna.sunol@ed.ac.uk (A. Suñol).
report any previous gastrointestinal (GI) signs. The dog was previ-
ously sociable, until 2 years before the consultation at which time
he began to display progressively more aggressive behavior.
Initially, this occurred in relation to meals where he guarded his
food. A specialist in animal behavior was consulted at this time;
however, the recommended changes in the dog’s feeding routine
achieved no improvement. Six months before presentation, he
developed intermittent signs of anxiety and nervousness triggered
by noise-producing household items (washing machine and fridge).
His owner reported occasional episodes in which he would stare at
walls. The aggressive behavior became more constant and unre-
lated to meals, including a tendency to bite spontaneously, espe-
cially children. A second specialist in animal behavior was
consulted and no cause of the clinical signs was determined.
The referring veterinarian performed a complete hematology,
serum biochemistry, ammonia, basal cortisol, total thyroxine,
ionized calcium, testosterone levels, and urinalysis, all of which
were unremarkable (see Table 1).

https://doi.org/10.1016/j.jveb.2020.04.009
1558-7878/Ó 2020 Elsevier Inc. All rights reserved.
 A. Suñol et al. / Journal of Veterinary Behavior 37 (2020) 56e60 57

Table 1
Results of the blood and urine tests performed in a 7-years-old crossbreed dog with a chronic history of aggression and changes in behavior

Test Value Reference ranges

Hematology
Red cells 7.57 1012/L 5.39-8.70
Hemoglobin 17.6 g/dL 13.4-20.7 g/dL
Hematocrit 0.508 l/L 0.383-0.565 l/L
Mean corpuscular volume 67.1 fL 59-76 fL
Mean corpuscular hemoglobin 23.2 pg 21.9-26.1 pg
Absolute reticulocyte count 37.1 109/L 110
White cells 5.8 109/L 4.9-17.6
Neutrophils (absolute) 3.48 109/L 2.94-12.67
Neutrophils 60%
Lymphocytes (absolute) 1.62 109/L 1.06-4.95
Lymphocytes 28%
Monocytes (absolute) 0.29 109/L 0.13-1.15
Monocytes 5%
Eosinophils (absolute) 0.41 109/L 0.07-1.49
Eosinophils 7%
Platelet count 162 109/L 143-448
Serum biochemistry
Total protein 59.4 g/L 54.9-75.3 g/L
Albumin 31.1 g/L 26.3-38.2 g/L
Globulin 28.3 g/L 23.4-42.2
Urea 3.8 mmol/L 3.1-10.1 mmol/L
Creatinine 70 mmol/L 44-133 mmol/L
Alanine aminotransferase 47.4 U/L 19.8-124 U/L
Alkaline phosphatase 36 U/L  130 U/L
Gamma-glutamyl transferase <2 U/L 2-5.7 U/L
Cholesterol 3.57 mmol/L 3.20-6.20 mmol/L
Sodium 148 mmol/L 135-155 mmol/L
Potassium 3.89 mmol/L 3.6-5.6 mmol/L
Chloride 113 mmol/L 100-116 mmol/L
Inorganic phosphorus 0.94 mmol/L 0.8-1.6 mmol/L
Calcium total 2.32 mmol/L 2.36-2.84 mmol/L
Ionized calcium 1.20 mmol/l 1.05-1.45 mmol/L
Ammonia 10 mmol/L 25-73 mmol/L
Glucose 5.9 mmol/L 3.6-7 mmol/L
Basal cortisol 55.8 nmol/L 20-230 nmol/L
Thyroid-stimulating hormone 0.12 ng/mL 0.00-0.50 ng/mL
Free thyroxine (T4) 12.7 pmol/L 7.7-47.6 pmol/L
Testosterone 0.26 nmol/L 1.5-26.0 nmol/L
References:
Castrated: <0.5
Cryptorchid: >0.5
Female: <0.5
Urine analysis
Specific gravity: 1.062; dipstick showed pH: 5.0; nitrite, urobilinogen, protein, hemoglobin, ketones, bilirubin, and glucose were negative
Gastrointestinal work-up
Cobalamin 807 ng/L 275 ng/L
Folate 15.6 mg/L 8.2-13.5 mg/L
Fecal alpha 1dperformed in triplicate Sample A: 21.1 mg/g A mean three-day a1-PI of  13.9 mg/g feces or
Sample B: 15.6 mg/g a maximum a1-PI of one individual sample
Sample C: 12.6 mg/g of  21.0 mg/g feces is considered abnormal.
Mean: 16.43
Maximum result: 21.1
Fecal calprotectin Nondetectable (<20 mg/g) No reference range established
TG2-IgA ELISAdperformed in triplicate 1.153 O.D.; (range 1.145-1.162) Buffer and conjugate negative control values were
0.191 and 0.156, respectively
AGA-IgG ELISAdperformed in triplicate 0.916 O.D.; (range 0.898-0.949) Buffer and conjugate negative control values were
0.075 and 0.099, respectively

Physical evaluation and differential diagnoses
On presentation, the dog was bright, alert, and responsive. Body
weight was 11.7 kg with a body condition score of 5/9. Vital pa-
rameters were within normal limits. An abbreviated neurological
examination was performed as his behavior precluded a full
neurological examination. This examination revealed normal
mentation, posture, gait, and sensation. Cranial nerve examination
was limited but also unremarkable. Proprioception and spinal re-
flexes were not assessed. A more detailed examination of other
body systems was not possible because of his aggressive behavior,
but was completed later under general anesthesia, and found to be
unremarkable. Based on the history and absence of other specific
neurological abnormalities, a forebrain lesion was suspected.
Differential diagnoses at this stage included central nervous
system neoplasia (primary [such as meningioma or glioma] or
secondary [metastatic]), degenerative condition (lysosomal storage
disease or organic aciduria), inflammatory encephalopathy
(meningoencephalitis of unknown origin), parasitic infections
(such as neosporosis or visceral larva migrans), and metabolic
disease (such as hepatic encephalopathy, hyperthyroidism, hypo-
glycemia, or hypocalcemia). Degenerative and metabolic
58 A. Suñol et al. / Journal of Veterinary Behavior 37 (2020) 56e60
conditions, as well as parasitic infections were deemed extremely
unlikely due to age of onset, the chronic, progressive presentation,
and the lack of any other specific signs or clinical abnormalities
(including the extensive laboratory work-up already performed by
the referring veterinarian). Intracranial disease (inflammatory or
neoplastic) could not be fully excluded at this stage; however, with
the chronicity of clinical signs, it also was deemed less likely. Other
causes for spontaneous aggression included (atypical) epileptic
seizures, an unusual case of idiopathic paroxysmal dyskinesia or
any type of undetected pain. However, no indicators of pain were
detected on clinical assessment and any of these conditions would
be expected to be intermittent/episodic rather than slowly pro-
gressing to a permanent state of behavioral abnormalities.
Diagnostic tests and treatment
Magnetic resonance imaging (MRI) of the head did not reveal
any abnormalities. Cerebrospinal fluid analysis (CSF; from the
cisterna magna) showed 0 total nucleated cells/mL (reference <5/
mL), and 24 mg/dL total protein (reference <30 mg/dL). Cytological
examination showed low cellularity comprising rare macrophages,
small lymphocytes, and small number of erythrocytes. Therefore,
CSF results were considered normal.
Based on the normal general physical and neurological exami-
nation, normal complete hematology, serum biochemistry, serum
ammonia, basal cortisol, total thyroxine, ionized calcium, testos-
terone levels, MRI and CSF analysis, a primary behavioral problem,
or an idiopathic condition was suspected. Further investigations
recommended at this stage included monitoring for hypoglycemia,
bile acid stimulation test, abdominal imaging, measurement of
urinary organic acids, and serum cobalamin, but were declined by
the owner.
Dietary modification was discussed with the owners as a
possible treatment trial. This treatment was offered based on
anecdotal evidence in dogs that dietary changes can modulate
behavior (DeNapoli et al., 2000), as well as increasing evidence and
awareness on the role of the gut-brain axis and food-responsive
psychiatric and neurological conditions in both dogs and people
(Poloni et al., 2009; Lowrie et al., 2015; Arshad et al., 2018;
Cerquetella et al.,2018).
A trial with a gluten-free (GF) hydrolyzed protein commercial
complete dog food (Purina Pro Plan HA Hypoallergenic) was sug-
gested, especially as this was considered a noninvasive, likely side
effectefree intervention. A slow transition over a 4-day period was
recommended and the owner was instructed to follow the feeding
guidelines provided by the manufacturer. Owing to the patient’s
concerning level of aggression, a consultation with a board-certified
veterinary behavioral specialist was also recommended again.
Outcome and follow-up
One week after initiation of the feeding transition period, the
owner reported a significant improvement in the dog’s behavior:
He was more relaxed and significantly less aggressive. A further two
weeks later, the dog was completely back to normal according to
the owner, with no signs of aggression. Given the unexpected
response to diet alone, a food-responsive enteropathy/food hyper-
sensitivity, or gluten hypersensitivity contributing to the dog’s signs
was suspected. However, as the dog was clinically well, further
invasive confirmatory investigations (such as abdominal ultrasound
or GI endoscopy with mucosal biopsies) were declined by the
owner. However, permission for additional blood and fecal tests to
further investigate potential GI pathology or gluten sensitivity was
obtained (see Table 1). Results were not consistent with intestinal
inflammation (based on low fecal calprotectin) or malabsorption
(serum folate and cobalamin within their respective reference
ranges). However, these results were suggestive of mild or early
protein-losing enteropathy (PLE) based on elevation in fecal
alpha1-proteinease inhibitor (a1-PI) [Gastrointestinal Laboratory,
Department of Small Animal Clinical Science, Texas A&M Univer-
sity] levels). To investigate a possible gluten sensitivity and as a
proxy for assessing gut permeability, serum anti-transglutaminase-
2 antibodies (TG2-IgA, an enzyme involved in the breakdown of
gliadin, a component of gluten in cereals) and anti-gliadin anti-
bodies (AGA-IgG) (Universita di Camerino, Province of Macerata,
Italia) were also assessed by ELISA (Vincenzetti et al., 2006). Both
TG2-IgA and AGA-IgG were found to be markedly elevated.
After the successful dietary trial, the dog experienced two in-
stances of relapse, both associated with a change in diet. Two weeks
after the clinical signs had completely resolved, the dog acciden-
tally ingested commercial cat food. He became aggressive on the
same day and for the following 4 days, but progressively returned to
normal thereafter while being fed his GF-hydrolyzed protein diet
exclusively. Two months later, the owner decided to change the diet
to another commercial complete dog food of an unknown brand
due to episodes of constipation. After 1 day, the dog started to
display aggressive behavior again. He was returned to the initial GF
diet again and again showed progressively decreasing signs of
aggression over the following 4 days. Repeat assessment of any
blood or fecal markers was unfortunately not performed, but the
dog remains well and without signs of aggression at the time of
writing (a total of 9 months after the initial presentation). He
continues to be fed the strict GF-hydrolyzed protein diet as a sole
food.
Discussion
This is the first report of successful dietary treatment of
aggression and behavioral changes in a dog. Overall, we postulate
that these results suggest the presence of either an enteropathy
primarily driven by gluten hypersensitivity, or a more unspecific
pathology leading to increased gut permeability (allowing the
secondary formation of the TG2 and AGA antibodies and associated
early gut protein loss).
In people, celiac disease (CD) is defined as an autoimmune dis-
order characterized by an inflammatory enteropathy secondary to
an immune reaction to gluten ingestion. Gluten comprises gliadin
and glutenin proteins (Lebwohl et al., 2013), with evidence sug-
gesting that the gliadin fraction induces the disease (Van de Kamer
et al., 1953).
Atypical non-GI signs have been described in people with CD
(Guandalini and Assiri, 2014). In 10 to 15% of CD patients, these
clinical signs manifest as psychiatric and neurological disorder-
sdincluding anxiety, depression, and personality disorders. The
most common neurological consequences include gluten ataxia,
gluten neuropathy, epilepsy, movement disorders, headache,
chronic migraines, progressive cognitive impairment, gluten en-
cephalopathy, and gluten myopathy (Wills and Unsworth, 2002; Zis
and Hadjivassiliou, 2019). Rarely, there have been cases described of
people presenting with similar clinical signs as described in this dog
such as a chronic history of aggression, behavioral alterations, and
severe anxiety. After an extensive work-up, they were diagnosed
with gluten hypersensitivity. In all those cases, a GF diet resulted in
clinical remission of encephalopathy and improvement of the
psychiatric symptoms (Poloni et al., 2009; Arshad et al., 2018). The
exact pathophysiology of the psychiatric and neurological pre-
sentations of CD in people is unknown, and different theories
including the implication of the gut-brain axis have been discussed
(Arshad et al., 2018). The gut-brain axis is a bidirectional commu-
nication system between the gut and the brain (Rhee et al., 2009).
 A. Suñol et al. / Journal of Veterinary Behavior 37 (2020) 56e60
Neurological signs related to gluten hypersensitivity are thought to
be caused by nutritional deficiencies, antibodies produced against
gluten proteins that inappropriately target the nervous system,
frontal cortical hypoperfusion, or direct damage to neurons, the
latter of which is referred to as gluten toxicity (Arshad et al., 2018).
The finding that anti-gliadin antibodies may cross-react and
negatively affect synapsin I, a neuronal phosphoprotein found in
most central and peripheral neurons and essential in forming and
sustaining the reserve pool of synaptic vesicles, may provide insight
into mechanisms mediating neurological dysfunction (Alaedini
et al., 2007).
In the veterinary literature, gluten hypersensitivity has been first
described as a heritable defect in Irish setters, resulting in chronic
enteropathy (Batt et al., 1984) and in Border terriers causing
paroxysmal gluten-sensitive dyskinesia (Lowrie et al., 2015).
Paroxysmal dyskinesia is a movement disorder causing episodes of
sustained muscular hypertonicity, difficulty or an inability to stand
and walk affecting one or several limbs (dystonia), tremors, and
whole body or head jerks (myoclonus) (Lowrie et al., 2018). The
same author indicated that some of these dogs also presented with
GI signs and gut inflammation (Lowrie et al., 2016).
To the authors’ knowledge, this is the first time that a GF diet has
led to a resolution of neurological abnormalities other than dyski-
nesia in a dog. The interaction between diet, intestinal pathology,
and behavior in dogs has been previously investigated. For instance,
it has been suggested that a diet high in tryptophan may reduce
some forms of aggression in dogs (DeNapoli et al., 2000). Inter-
estingly, decreased serum tryptophan has been reported in dogs
with protein-losing enteropathy (Kathrani et al., 2018) which might
play a role in some behavioral disorders associated with this con-
dition. In addition, some positive effects of a nutraceutical diet on
neuroendocrine parameters associated with stress, anxiety,
aggression, and numerous behavioral disorders have been
described (Sechi et al., 2017). Finally, results from a recent study in a
small number of dogs documented changes in the fecal microbiome
of aggressive dogs (Kirchoff et al., 2019), which could further the
understanding on how dietary management can influence the
function of higher central nervous system centers.
The biggest limitation of the diagnostic workup performed in
the case presented here is the lack of investigation concerning the
GI tract, most notably the absence of intestinal mucosal biopsies. In
humans, the final diagnosis of CD is traditionally based on
demonstrating compatible histopathological changes in the
duodenal mucosa. However, changes considered “typical” for CD
(lymphocytic enteritis and villous atrophy) are nonspecific and can
also be found in Crohn’s disease, Helicobacter pylori gastritis, food
allergies, bacterial and parasitic infections, and with the use of
chronic nonsteroidal anti-inflammatory drugs (Rosinach et al.,
2012). The European Society for Pediatric Gastroenterology, Hep-
atology and Nutrition suggests that duodenal biopsies might be
redundant for the diagnosis of gluten hypersensitivity (Husby et al.,
2012). It has been advised that the presence of consistent clinical
signs, high levels of TG2-IgA and AGA-IgG, and the improvement of
the clinical signs with a GF diet should offer a reliable diagnosis of
the disease (Guandalini and Assiri, 2014). Importantly, only 40% of
human CD patients with neurological manifestations will have an
enteropathy (Hadjivassiliou et al., 2010).
Serum TG2-IgA is the most common screening test for gluten
hypersensitivity in people, displaying a sensitivity up to 98% and
specificity of approximately 96% (Giersiepen et al., 2012). The AGA-
IgG had a sensitivity ranging from 80.1% to 98.6% and it is recom-
mended to be measured together with the TG2-IgA (Lebwohl et al.,
2018). Both TG2-IgA and AGA-IgG have been detected in dogs with
gut disease such as chronic inflammatory enteropathy and GI
lymphoma (Vincenzetti et al., 2006, Matsumoto et al., 2018). This
59
report lacks follow-up antibody levels after the resolution of the
aggression and behavioral changes. As the result of a follow-up test
would not have had any clinical consequences for the dog, it was
not considered ethical to perform this. This result, potentially, could
have shed light on the role gluten sensitivity was playing on this
case. Fecal a1-PI has been validated as a useful test for early
detection of PLE in dogs, before decreases in serum albumin con-
centration can be detected (Murphy et al., 2003). In the dog pre-
sented here, fecal a1-PI results were elevated and are therefore
consistent with this condition. However, PLE is not a defined dis-
ease, but rather a descriptive term and could be associated with a
number of different enteropathies. Fecal calprotectin has been
described as a potentially useful marker for dogs with chronic in-
flammatory enteropathy (Heilmann et al., 2018), similar to its use in
people with inflammatory bowel disease (Theede et al., 2015).
However, it has a moderate sensitivity of 80% and a specificity of
75%; therefore, further investigation is needed to evaluate its utility
in these patients (Heilmann et al., 2018). In addition, the test used
here to assess fecal calprotectin has not yet been validated in dogs;
hence, there is no established reference interval. The test can
measure a range of 20-8000 mg/g calprotectin, but lower values
than 20 mg/g have been reported in dogs with different forms of
chronic enteropathy (Heilmann et al., 2018). In the case presented
here, intestinal inflammation cannot be ruled out based on the fecal
calprotectin result. The ultimate cause of mild PLE and its relation
with the formation of TG2 and AGA antibodies could not be
determined.
Based on the points discussed previously, the results of the in-
vestigations performed together with the clinical course of disease
suggest that this dog might have suffered from nonceliac gluten
hypersensitivity. We hypothesize that alterations of the gut-brain
axis driven by gluten exposure caused the signs this dog pre-
sented with, and hence completely resolved with a GF diet.
Summary
This case report describes the complete resolution of aggression
and behavioral changes after feeding a hydrolyzed GF diet in a dog
with a suspected underlying gluten hypersensitivity. Diet modifi-
cation should be considered a simple and safe attempt for treat-
ment or management of behavioral abnormalities in dogs when
other common causes have been ruled out.
Acknowledgments
The authors would like to thank Prof. Romy Heilmann (Small
Animal Hospital, University of Leipzig, Germany) for the measure-
ment of fecal calprotectin.
The idea for the article was conceived by Anna Sunol and Silke
Salavati. The data were analyzed by Anna Sunol, Jorge Perez-Accino,
Molly Kelley, Giacomo Rossi, and Silke Salavati. The article was
written by Anna Sunol, Jorge Perez-Accino, Molly Kelley, Giacomo
Rossi, and Silke Salavati. All authors have approved the final article.
Ethical considerations
The authors declare no ethical concerns. This is a case report of
an owned dog, the relevance of which is understood and is aware of.
Hence, a consent form was signed.
Conflict of interest
Authors declare no conflict of interest.
60 A. Suñol et al. / Journal of Veterinary Behavior 37 (2020) 56e60

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