Neuroactive compounds are synthesized by certain plants and microorganisms by undertaking different tasks, especially as a stress response. Most common neuroactive compounds in foods are gamma aminobutyric acid (GABA), serotonin, melatonin, kynurenine, kynurenic acid, dopamine, norepinephrine, histamine, tryptamine, tyramine and β-phenylethylamine.

2. Soniya Ashok Ranveer
Ph.D
Dairy Microbiology
Neuroactive
compounds in Food

3. Neuroactive compounds are synthesized by certain plants and
microorganisms by undertaking different tasks, especially as
a stress response
Most common neuroactive compounds in foods are gamma
aminobutyric acid (GABA), serotonin, melatonin,
kynurenine, kynurenic acid, dopamine, norepinephrine,
histamine, tryptamine, tyramine and β-phenylethylamine
Fermented foods contain some of these compounds, which
can affect human health and mood
Furthermore, probiotics and prebiotics are indispensable
elements for the understanding of the food-mood relationship
Neuroactive compounds

4. Ali dairy PAB, except P.freudenreichii subsp. freudenreichii are
able to metabolise lactose
This implies that PAB are equipped with a lactose transport system
and must be able to hydrolyse lactose as the first step of its
utilization
some psychobiotics strains were reported to inhibit inflammation
and decreased cortisol levels, resulting in an amelioration of the
symptoms of anxiety and depression.
Psychobiotics are efficacious in improving neurodegenerative and
neurodevelopmental disorders, including autism spectrum disorder
(ASD), Parkinson's disease (PD) and Alzheimer's disease (AD)

5. Neuroactive substance is
defined as a chemical
agent synthesized by a
neuron which affects the
properties of other
neurons and muscle cells
Many neuroactive
compounds have
significant roles as
neurotransmitters,
neuromodulators, and
neurohormones
These compounds have
been not only
synthesized by humans
but also plants and
microorganisms
Therefore, the presence
of neuroactive
compounds in foods is
inevitable
Neuroactive substance
In the historical process, serotonin, dopamine, and GABA were
confirmed as neurotransmitters in the central nervous system in
1953, 1958 and 1971, respectively

6. GABA
GABA, a primary inhibitory neurotransmitter, has many physiological functions
as blood pressure regulator, protector of cardiovascular disease, hormonal and
cell regulator.
In addition, it is associated with brain and psychiatric diseases
(Diana et al., 2014)
A special tea enriched with GABA, called GABA tea, has been produced in
recent years. Anaerobic treatment is the key stage for the accumulation of GABA
in GABA tea containing greater than 1500 μg/g of GABA
(Teng et al., 2017)
GABA were first isolated from broad potato tubers in 1949
Tea is one of the most important food sources of GABA
For instance, adrenaline is synthesized in humans during stress conditions.
Environmental stresses such as mechanical disruptions, cold and heat increase the
accumulation of gamma-aminobutyric acid (GABA) in plants

7. It was reported in a study that 3-hydroxy-L-kynurenine acts as
a prooxidant at low concentrations (5-20 μM) and antioxidant
at high concentrations (100 mM)
Colin-Gonzalez et al., 2014
3-hydroxyanthranilic acid has a prooxidative role because of its
autooxidation and generating free radicals.
kynurenine
Aro8 and Aro9 are the main enzymes responsible for
kynurenine production in Saccharomyces cerevisiae

8. Tryptophan is converted to tryptamine by tryptophan decarboxylase and then,
hydroxylation of tryptamine is carried out by tryptamine 5-hydroxylase to form serotonin
Serotonin has several physiological functions in plants including the development of plant
seed, root growth, detoxification, and adaptation to environmental changes
In addition to serotonin synthesis, tryptamine has a role in the synthesis of indole
alkaloids in plants
Tryptophan
Two major pathways for melatonin synthesis in plants have been proposed in the
literature
1. In the first pathway, serotonin is converted to N-acetylserotonin and then melatonin
by serotonin N-acetyltransferase and N-acetylserotonin O-methyltransferase/caffeic
acid O methyltransferase, respectively
2. In the second pathway, 5-methoxytryptamine is formed from serotonin by N-
acetylserotonin O-methyltransferase/caffeic acid O-methyltransferase and then, 5-
methoxytryptamine is converted to melatonin by serotonin N-acetyltransferase
Stressors such as cold, drought and chemicals stimulate the synthesis of melatonin as a
result of upregulation of melatonin biosynthetic genes

9. Neuroactive compound of functional foods: occurrence,
mechanism and potentional health effect
BAs such as dopamine (DA),
noradrenaline (NA), and serotonin (5-
HT) were quantitatively determined in
the culture liquid and the ultrasonically
disintegrated biomass sediment
An important communication channel is
based on neurochemicals, i.e., “any
chemicals produced by a microorganism
that are also recognized within
neurobiology as either
neurotransmitters, neuromodulators, or
neurohormones in a mammalian system”

10. • Fermentation is an effective
process for accumulation of
neuroactive compounds
• Food processing allows
modification of the amounts of
neuroactive compounds in
foods
• Food constituents may affect
the synthesis of neuroactive
compounds by gut microbiota
• Probiotics and prebiotics are
associated with human
psychological health
Effective process

11. • Certain non-fermented foods and fermented
foods contain neuroactive compounds
• Digestion of these foods can directly affect
human health
• On the other hand, microorganisms in the
gut synthesize microbial metabolites such as
SCFA and neuroactive compounds
depending on diet
• Dietary composition affects the presence of
precursors of neuroactive compounds that
reach the gastrointestinal tract
• In addition, different dietary patterns change
microbial profile in the gut Microbe-derived
neuroactive compounds in the gut can affect
central nervous system (Wall et al., 2014) and
SCFA produced by gut microbiota modulates
5-HT synthesis in ECC cells (DeCastro et al.,
2015)
• SCFA: Short chain fatty acids, GABA:
gammaaminobutyric acid, 5-HT: 5-
Diet-brain-gut-microbiome
interactions.

12. Serotonin
Serotonin, 5-hydroxytryptamine, is a neurotransmitter
synthesized in the central nervous system and
enterochromaffin cells of the gastrointestinal tract in which
the vast majority of serotonin is synthesized
It is involved in numerous behavioral and physiological
processes such as cardiovascular regulation, pain
sensitivity, reproductive behavior, cognition, impulsivity,
aggression, and mood
Vadodaria et al., 2018

13. Melatonin
Melatonin, N-acetyl-5-methoxytryptamine, is a neurohormone
synthesized mainly in the pineal gland of humans.
It is also produced in several cells and tissues such as retina and
gastrointestinal tract
(Tarocco et al., 2019)
Melatonin, known as sleep hormone, modulates circadian rhythm
and energy metabolism and has anti-inflammatory and
antioxidant effects
(Gomes et al., 2019)

14. Two major pathways for melatonin synthesis in plants have been
proposed in the literature
In the first pathway, serotonin is converted to N-acetylserotonin and
then melatonin by serotonin N-acetyltransferase and N-
acetylserotonin O-methyltransferase/caffeic acid O-
methyltransferase, respectively
In the second pathway, 5-methoxytryptamine is formed from
serotonin by N-acetylserotonin O-methyltransferase/caffeic acid O-
methyltransferase and then, 5-methoxytryptamine is converted to
melatonin by serotonin N-acetyltransferase
(Back et al, 2016)
Stressors such as cold, drought and chemicals stimulate the
synthesis of melatonin as a result of upregulation of melatonin
biosynthetic genes
Melatonin pathway

15. Catecholamines have several roles on human health including
regulation of motor activity, cognitive and executive functions,
and attention-related processes
(Szymańska et al., 2015)
Catecholamines

16. Histamine
Histamine is produced in the mast cells, basophils, histaminergic
neurons in the basal ganglia of the brain and enterochromaffin-
like cells in the stomach
Huang et al., 2018
It modulates gastric secretion, heart contractibility, cell growth,
circadian rhythm, memory and cognition
Nuñez et al, 2016

17. Trace amines
Tyramine, tryptamine and, beta-phenylethylamine are found in
low concentrations throughout the central nervous system.
Tryptamine is considered as a neuromodulator or
neurotransmitter
(Khan & Nawaz, 2016).

18. Effect of food processing on neuroactive compounds
To control the formation of neuroactive compounds in
foods, it is important to know the reasons/mechanisms
of the synthesis of the substances in the lifecycle of
plants and microorganisms

19. Tea is one of the most important food sources of GABA
bioactive amines (histamine, tyramine, tryptamine and β -
phenylethylamine) are mostly found in fermented foods as a result
of microbial decarboxylase activity, non-fermented foods also
contain histamine, tyramine, tryptamine and β -phenylethylamine
Raw food
Vegetables and fruits (red paprika, apple, cucumber, tomato,
carrot, onion, garlic, cauliflower, potato, broccoli) were found to
contain kynurenic acid with the highest concentration in broccoli
(0.418 μg/g) and the lowest concentration in red paprika (0.001
μg/g)

20. Biogenic monoamines (tyramine, tryptamine and serotonin) are
found in free form in plants
In addition, their conjugated derivatives with phenolic compounds
such as N-feruloylserotonin, feruloyltyramine an
caffeoyltryptamine called as hydroxycinnamic acid amides can
accumulate in plants
Compared to catecholamines and melatonin, GABA is generally
found in high concentrations in plant products
Continue…

21. Neuroactive compounds in foods and their levels
Fermented foods
Fermented foods mostly contain a range of neuroactive compounds in different
amounts.
Cocoa is the most important dietary source of serotonin and catecholamines.
Studies have demonstrated that lactic acid bacteria are the major GABA-
producing microorganisms
It is a remarkable result that cocoa had the highest concentration of kynurenic
acid (4.0-4.5 μg/g d.w) compared to other fermented foods
Raw and non-fermented foods
Much of the available literature on serotonin indicates that foods
including vegetables and fruits, nuts, chocolate, fish, green coffee
and infant formula contain serotonin ranging from 0.00003155 μg/g
(sweet cherry) to 3200 μg/g d.w (green coffee)
Casal et al., 2002

22. A large amount of histamine, tyramine, tryptamine and, β -
phenylethylamine can be found in fish and fish products, wine,
cheese and sausages
Main factors affecting bioactive amine concentrations in foods are
quality of raw materials, ripening conditions for cheese and
sausages, fermentation conditions (pH, temperature, time, O2),
starter cultures, availability of microorganisms, additives, storage
conditions
(Doeun et al, 2017)
Different fermentation conditions and microorganisms may allow
the formation of neuroactive compounds in different amounts and
profiles in fermented foods
Beer and bread, as yeast fermented foods, were found to contain
both kynurenine and kynurenic acid
Continue…

23. Target to treat metabolic disease

24. Formation mechanisms of neuroactive compounds in
humans, plants and microorganisms
Humans
Serotonin is formed via tryptophan which is an essential amino acid
in humans
Decreased number of Bifidobacterium was observed in the gut
microbiota of patients with Alzheimer's disease (AD)
According to a recent study, the relative abundances of anti-
inflammatory bacteria, including the genera Blautia, Roseburia and
Coprococcus, were significantly lower in fecal samples from patients
with Parkinson's disease (PD)
Dysregulation of the MGBA has been reported to correlate with
neuropsychological, GI, and metabolic disorders

25. The evidence of microbiota-gut-brain axis (MGBA)
communication can be found from the relationship
between gut dysbiosis with functional gastrointestinal
disorders and central nervous disorders
According to a recent study, the relative abundances of
anti-inflammatory bacteria, including the genera Blautia,
Roseburia and Coprococcus, were significantly lower in
fecal samples from patients with Parkinson's disease