Book Chapter - 3

A Comprehensive Review of Medicinal
Herbs Improving Gut-Brain Health
Akila Ramanathan, K. Reeta Vijaya Rani,

Mullaicharam Bhupathyraaj, Sathvik Sridhar, Javed Shareef, and
Sabin Thomas
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Gut Microbiota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Gut-Brain Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Gut Microbes and Neurological Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
CNS Diseases and the Microbiota-Gut-Brain Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
The Advantages of Gut Microbiome Alteration for Mental Health Issues . . . . . . . . . . . . . . . . . . . . . . 14
Herbs and Phytochemicals That Protect Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Herbs That Protect Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Phytochemicals in the Defense of Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Abstract
Have you ever had a gut feeling or had butterflies in your stomach? These
sensations originating from your abdomen suggest a possible connection between
A. Ramanathan (*)
College of Pharmacy, Sri Ramakrishna Institute of Paramedical Sciences, Coimbatore, TN, India
K. R. V. Rani
Surya School of Pharmacy, Vikravandi, TN, India
M. Bhupathyraaj
College of Pharmacy, National University of Science and Technology, Muscat, Oman
e-mail: [email protected]
S. Sridhar · J. Shareef
Department of Clinical Pharmacy & Pharmacology, Ras Al Khaimah College of Pharmacy, Ras Al
Khaimah Medical & Health Sciences University, Ras Al Khaimah, UAE
e-mail: [email protected]; [email protected]
S. Thomas
School of Pharmacy, College of Health Sciences, University of Nizwa, Nizwa, Oman
e-mail: [email protected]
© Springer Nature Singapore Pte Ltd. 2024 1

E. Mohamed (ed.), Handbook of Neurodegenerative Disorders,
https://doi.org/10.1007/978-981-19-3949-5_36-1
2 A. Ramanathan et al.
your gut and brain. Moreover, recent studies suggest that the condition of your
abdomen might affect the condition of your brain and vice versa. In recent times,
experts and the general public have paid more attention to the brain-gut axis.
Numerous studies are being conducted to identify the processes linking alter-
ations in brain function to the composition of the gut microbiome. It should go
without saying that the gut microbiota is important for neurogenesis, mental and
cognitive development, emotions, behavior, and the development of neuropsy-
chiatric disorders.
Several studies, both preclinical and clinical, demonstrate how the gut micro-
biota can influence overall health. The gut microbiota produces important bio-
logical products through the gut-brain axis that are directly associated with the
onset and progression of neurological and psychiatric conditions such as multiple
sclerosis, epilepsy, depression, anxiety, bipolar disorder, autism, schizophrenia,
Parkinson’s disease, Alzheimer’s disease, and dementia. As the problem with gut
health is fixed, symptoms usually become better.
Researchers have discovered many medicinal herbs that may be useful in their
quest for better mental and digestive health as well as the restoration of the brain-
gut axis balance. The best herbs and phytochemicals that enhance brain function
by modifying the gut flora are covered in this chapter.
Keywords
Gut microbiota · Gut-brain axis · CNS diseases · Herbs · Phytochemicals · Gut
microbiome alteration
Introduction
The human microbiota is a diverse and dense microbial ecology that has been known
to exist in humans for almost a century. This microbial community consists of
billions of bacteria with a biomass estimated at 1.5 kg, which is comparable to the
liver, the biggest organ in the body. The gut microbiota, which consists of
1000–1200 different cell types (species) and encodes 150 times more genes (the
microbiome) than our own genome, may be thought of as an organ in and of itself.
The gut microbiota is very dynamic and varies both spatially (along the length of the
intestine) and temporally (with age). In addition, a host’s genetic makeup, food,
medications taken orally, and a variety of other environmental variables can all affect
the composition of the intestinal microbiota. The bacteria in the gut. Because it has
evolved to perform specialized roles that enhance human metabolism and physiol-
ogy, the gut microbiota is vital to human health (Kovatcheva-Datchary et al. 2013).
However, under some conditions, such as dysbiosis, it is believed that the
microbiota might lead to illnesses in which the “gut-brain axis” and the central
nervous system (CNS) are crucial. This guarantees the appropriate upkeep of
intestinal homeostasis (Carabotti et al. 2015).
A Comprehensive Review of Medicinal Herbs Improving Gut-Brain Health 3
As research on gut microbiota has advanced, it is now possible to explain the

mechanism by which herbal medicines work on many disorders. This provides a
strong basis for the widespread and scientific therapeutic use of herbal medications.
Herbal medications can be metabolized by the gut bacteria to create new, absorbable,
potent small molecules with potent pharmacological effects. Additionally, the makeup
of the gut microbiota and its secretions can be regulated by herbal medications, and
altered gut microbiota and secretions have therapeutic benefits. Changes in the gut
microbiota and its secretions, along with absorbable active small compounds, can
direct pertinent research to investigate deeper-level underlying mechanisms or path-
ways for potential application in disease prevention and treatment (An et al. 2019).
Gut Microbiota
Numerous microorganisms, including bacteria, fungus, parasites, and viruses, can be

found in the human gut. The gastrointestinal tract alone is home to around 100 million
bacteria, which is 10–100 times more than the total number of eukaryotic cells in the
body. Following years of coevolution, the human body and gut bacteria have devel-
oped into a mutually beneficial symbiotic relationship. Six major phyla, namely
Firmicutes, Bacteroidetes, Proteobacteria, Actinomycetes, Verrucomicrobia, and
Fusobacteria, make up the majority of gut bacteria; Bacteroidetes and Firmicutes
are the predominant flora (Eckburg et al. 2005).
The breakdown of complex polysaccharides in food by gut microbes, for
instance, can impact human metabolic processes and play a significant role in
supporting adult development and homeostasis. Furthermore, gut microbes have
the ability to control fat distribution, gut motility, and the gut barrier (Bercik et al.
2012). In addition to inhibiting pathogen colonization and promoting the growth of
gut-associated lymphoid tissue, gut microbes can impact host mitochondrial and
energy metabolism. The complex relationship that governs interactions between
hosts and microbes suggests that when this relationship is aberrant, the microorgan-
isms may contribute to the development of disease or accelerate its progression.
In order to understand the physiological roles that these microorganisms play and,
eventually, to prevent and treat diseases by managing the microorganism species,
recent research has centered on determining the variety of these bacteria. Recent
research, for instance, has shown that gut microbes can improve the effectiveness of
chemotherapy medications that are often used (Daillere et al. 2016).
Particularly age and nutrition can have a major influence on gut microbiota
(Yatsunenko et al. 2012; David et al. 2014), and a variety of research on humans
and animals have shown that dietary variations can significantly alter the microbiota.
For instance, because of the differences in their daily meals, the species of colonized
bacteria in the guts of Europeans and those from rural Africa are very different
(De Filippo et al. 2010).
Wu et al. (2011) examined stool samples from 98 individuals and discovered that
Bacteroides was primarily linked to a diet high in animal fat and proteins and
Prevotella to a diet high in carbohydrates. Disease and infection can also negatively
impact the host’s natural gut flora, which can have detrimental effects on the host.
For instance, in rats, altering the gut microbiota can result in chronic visceral pain
and stress-related conditions like irritable bowel syndrome (O’Mahony et al. 2014).
The human body and its symbiotic microbiota organisms form a complex micro-
ecological system. Variations in the number and composition of gut microorganisms
can impact the function of the gut barrier, increase the secretion of harmful sub-
stances, and decrease the secretion of substances that are good for the body, which
can result in enteral and external diseases.
Gut-Brain Axis
The gastrointestinal system and the central nervous system (CNS) are intimately
linked, and the CNS is crucial in controlling gut homeostasis and function. Thus, the
gut microbiota may influence the central nervous system and nerve cells, take part in
the control of nervous system activity, and influence the etiology and development of
disorders linked to the nervous system. The intricate relationship that exists between
the population of gut microorganisms and the host is called the microbiota-gut-brain
axis. Recent studies on gut microbiology have focused on the microbiota-gut-brain
axis. Apart from investigating the connection between gut microbiology and brain
activity, much research has focused on the impact of this relationship on human well-
being.
Numerous pathways, such as the vagus nerve, the immune system, the enteric
nervous system (ENS), or the metabolic activities of gut bacteria, can establish a
connection between the brain and the gut (Suganya and Koo 2020) (Fig. 1). The
central nervous system (ANS), the autonomic nervous system (ENS), and the
gastrointestinal tract all share co-dominance over this organ. There are four levels
of neural control that govern enteric nerves (Mulak and Bonaz 2004). The local
regulation issued by the ENS is the first level. Similar to the brain and spinal cord,
the ENS is made up of two nerve plexuses, the myenteric and submucosal plexuses,
through which motor and sensory neurons connect to perform an independent
function of information integration and processing.
Information from both CNS and ENS nerves is received by the prevertebral
ganglia, which make up the second level. The CNS is at level three. The CNS
transmits its regulatory information to the ENS or acts directly on gastrointestinal
effector cells through the autonomic nervous system and the neuroendocrine system
to regulate the smooth muscle, glands, and blood vessels after integrating various
bits of information from various centers of the brain and spinal cord when they
receive signals regarding internal or external environmental changes. The fourth
level is made up of the advanced centers of the brain; information coming from the
cortex, subcortex, and basal ganglia converges down to specific stem nuclei of the
brain stem.
The gut and the brain are connected by a network of neurons called neuroendo-
crine networks. These networks connect the gastrointestinal tract to the CNS at
various levels. The gut and the brain function together through the gut-to-cortex axis.
Fig. 1 Schematic diagram illustrating the brain-gut communication system. Numerous pathways,
including the autonomic nervous system (ANS), enteric nervous system (ENS), hypothalamic-
pituitary-adrenal (HPA), immunological system, endocrine system, and neurological system, have
significant implications on this bidirectional link. (Reproduced from Suganya K and Koo BS, 2020)
Neurodegenerative disorders of any kind will affect the gut and the brain. The brain
and intestines are connected via the vagus nerve (Forsythe et al. 2014).
Dysfunction of the microbiota-to-brain axis has been linked to depression, anx-
iety disorders, irritable bowel syndrome (IBS), inflammatory bowel disease, and
other CNS diseases. The body’s vagus nerve regulates the activity of several organs,
including the heart rate and the motility of the intestines. It can also send messages
from the peripheral immune system to the central nervous system. An anti-
inflammatory reaction can be triggered by the gut’s vagus signal to combat the
sepsis that microbes have caused. Through the vagus nerve, gut microbes may
influence brain activity; following a vagotomy, the microbes will lose their ability
to control behavior (Bravo et al. 2011). Not even animals given probiotic treatment
showed altered behavior following vagotomy. Similarly, vagotomized mice’s behav-
ior was not improved by the Bifidobacteria therapy, despite prior reports of its
effectiveness (Baldi et al. 2021) (Fig. 2).
The immune system can be directly impacted by gut microbes; therefore, immune
activation could be the means by which microbial effects are transferred to the
central nervous system (Forsythe and Bienenstock 2010). Because microorganisms
are crucial to an organism’s immune system, they can also boost the anti-tumor
Fig. 2 Gut-brain axis in eubiosis and dysbiosis condition. (A) Eubiosis; (B) dysbiosis condition.
AHR aryl hydrocarbon receptor, FMT fecal microbiota transplant, SCFA short-chain fatty acid,
SIRT1 Sirtuin 1. (Reproduced from Baldi et al. 2021)
immunological action of medications by encouraging T-cell transformation and

accumulation (Sivan et al. 2015; Vetizou et al. 2015). By keeping the gut’s homeo-
stasis intact, the immune system contributes significantly to overall health. The
immune systems of the elderly are compromised, which leads to alterations in the
microorganism-brain relationship and consequent behavioral changes. The develop-
ment and activity of microglia, which are immune cells in the central nervous
system, can be regulated by the metabolism of gut microbes, which can impact
CNS function (Erny et al. 2015).
By generating chemicals that attach to receptors both within and outside of the
gastrointestinal tract, microorganisms can also alter the neurophysiological state of
their host. Bravo et al. discovered that mice given L. rhamnosus (JB-1) probiotics
showed reduced anxiety-like and depressed behaviors as well as altered GABA Aα2
mRNA level in the region of the brain responsible for controlling certain behaviors.
The large intestine’s gut microbes digest the food fibers to create short-chain fatty
acids (SCFAs). SCFAs can enhance the neurodevelopment and cognitive perfor-
mance of animals suffering from neurodegenerative diseases in animal models
(Stilling et al. 2014; Macfabe 2012). However, when Macfabe injected rats with a
particular kind of SCFA, namely propionic acid (PPA), the rats had neurochemical
alterations and traits associated with autism (Barrett et al. 2012). These neurochem-
ical alterations resulted in mitochondrial dysfunction through neuroinflammation,
elevated oxidative stress, and antioxidant depletion. The gut-brain axis of the
microbiota is influenced by other chemicals generated from microorganisms, includ-
ing acetylcholine, histamine, melatonin, and serotonin, which are neural activation
molecules (Zhao et al. 2008).
Furthermore, research has demonstrated that moderating adult hippocampal
neurogenesis (AHN) by the microbiome may have an impact on the central nervous
system. The lateral ventricle and mature hippocampal formation are sites of neuronal
proliferation. Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, depres-
sion, and other neurological disorder-related illnesses and symptoms can all be
influenced by AHN, which also has a function in learning and memory (Ogbonnaya
et al. 2015). According to a recent study by Ogbonnaya et al., there is a difference
between the hippocampus neurons of normal and sterile mice. Additionally, the
quantity of AHN was not affected by microbiota colonization after weaning, indi-
cating that microbes play a significant role in AHN early in life.
Gut Microbes and Neurological Functions
The effects of microorganisms on behavior and cognition are becoming more well
acknowledged. Growing research indicates that disruptions of gut microbes are the
cause of many illnesses and that microbial signals can govern key bodily systems in
healthy individuals (Schroeder and Backhed 2016). The introduction of a single,
distinct flora has been linked to the development of anxiety-like behavior in animals,
according to early research, and this shift was followed by the activation of brain
neurons that were dependent on gut information that was sent from the vagus nerve
to the brain (Goehler et al. 2005).
A further investigation discovered that the receptor mice may exhibit behavior
like that of the donor mice if the fecal bacteria from mice exhibiting a certain
behavior type were introduced into mice exhibiting a different behavior type. The
investigation behavior of sterile Bagg albino (BALB/c) mice increased when the
microorganisms of specific-pathogen-free (SPF) Swiss mice were transferred to their
bodies; however, the exploration behavior of sterile Swiss mice decreased compared
to normal Swiss mice when the microorganisms of SPF BALB/c mice were trans-
ferred to their bodies, suggesting that behavior type may be directly associated with
microorganisms (Bercik et al. 2011).
The association between symbiotic gut bacteria and the hypothalamic-pituitary-
adrenal (HPA) axis was initially reported by Sudo et al. in 2004 (Sudo et al. 2004). In
sterile mice, corticosteroid hormone and adrenal hormone levels were greater in
reaction to stress than in animals with normal microflora. Bifidobacterium coloniza-
tion of the gut can reduce the elevated HPA response, but this suppression can only
be started in the early stages of development, suggesting that the HPA axis’s
neuronal control must be inhibited by the most basic exposure to microorganisms.
Hippocampal memory can be affected by disruptions to the HPA axis, which is
crucial for learning and memory. Sterile mice had lower levels of c-fos, N-methyl-D-
aspartate (NMDA), and brain-derived neurotrophic factor (BDNF) (Gareau et al.
2011). These chemicals are involved in memory retention, cognitive function, and
other neurological functions.
The host’s cognitive performance can be affected by changes in the gut microbes
present in sterile animals, as well as by the use of probiotics, antibiotics, and fecal
microorganism colonization. For instance, probiotic supplementation 1 week before
illness can stop both the alterations in cognitive behavior brought on by stress and
the disruption of microorganisms produced by the infection. Probiotics have been
shown by Liang et al. to dramatically ameliorate the cognitive impairment brought
on by long-term restraint stress (Liang et al. 2015). In a human study, probiotic-
containing fermented milk was given to female participants, and functional magnetic
resonance imaging (fMRI) testing revealed changes in the activity in the brain areas
responsible for memory and sensory processing (Tillisch et al. 2013). The afore-
mentioned investigations discovered a strong correlation between brain development
and function and the maintenance of the equilibrium condition of normal gut
microbes.
CNS Diseases and the Microbiota-Gut-Brain Axis
Schizophrenia
About 1% of people worldwide are afflicted with schizophrenia. Patients with the
disorder may have positive symptoms like hallucinations and disordered speech,
negative symptoms such as a lack of interest or desire, and cognitive deficiencies like
poor memory and executive functioning (Marder and Cannon 2019). Schizophrenia
is linked to dysbiosis of the gut microbiota, according to growing data. One case-
control study, for example, revealed that individuals with schizophrenia had gut
microbiota dysbiosis (Liang et al. 2022). One study revealed that individuals with
schizophrenia had higher levels of Veillonella and decreased amounts of Roseburia
and Ruminococcus (Li et al. 2021). A different study revealed that individuals with
schizophrenia exhibited a distinct gut microbiota composition, along with a height-
ened prevalence of Lachnospiraceae. Additionally, the gut microbiota may influence
neurochemistry and neurological function by modifying the metabolism of
chemicals linked to the operation of the enteric and central nervous systems, such
as GABA. It may be helpful to treat schizophrenia by supplementing patients with
good gut flora, which was lacking in these individuals. Alternately, using medication
or functional foods to reduce the detrimental gut microbiota which was exclusively
observed in people suffering from schizophrenia might be another treatment
approach.
Autism
Various degrees of interpersonal barriers, language development difficulties, and
stereotyped behavior are some of the symptoms of autism spectrum disorder (ASD),
a form of comprehensive brain function development disease that starts during the
early stages of growth (<36 months). Since gastrointestinal symptoms are present in
up to 70% of autistic individuals and environmental variables, particularly gut
dysbiosis, are implicated in the development of ASD, it is believed that ASD is
linked to disruption of the gut-brain axis (Mayer et al. 2014). Gastroesophageal
reflux, constipation, diarrhea, and other gastrointestinal issues affect most people
with autism. According to research by Mazurek et al., 24% of 2973 ASD patients
had at least one form of gastrointestinal ailment (Mazurek et al. 2013). The severity
of ASD was shown to be closely correlated with the gastrointestinal symptoms, as
reported by Adams et al. (2011). ASD kid patients also had considerably higher rates
of diarrhea, abdominal distension, and constipation than normal children. Addition-
ally, compared to normal children, ASD patients have a noticeably greater gut
microbial burden of the species Clostridium and Faecalibacterium (Inoue et al.
2016; Song et al. 2004).
Anxiety
Anxiety is one of the most common mental diseases (Penninx et al. 2021). There is
proof that anxiety and certain gut microorganisms are related. For instance, anxiety
might arise from societal exclusion. According to research, those who experienced
social exclusion had higher Prevotella abundances but considerably lower Firmicutes/
Bacteroidetes ratios and Faecalibacterium spp. abundances (Kim et al. 2022). Addi-
tionally, a study including 198 Spanish people discovered that anxiety sufferers had a
reduced Simpson’s diversity index (Malan-Müller et al. 2023). Furthermore, microbial
richness and diversity were decreased in individuals with generalized anxiety disorder
(GAD), along with lower levels of Firmicutes spp. and microbiota that generate SCFAs
but higher levels of Fusobacteria and Bacteroidetes (Jiang et al. 2018).
Depression
One of the main issues in public health is depression (Malhi and Mann 2018).
Depression is linked to a high suicide rate and can have a number of significant
consequences. Research revealed a link between depression development and the
occurrence of gut microbiome dysbiosis (Tan et al. 2021; Winter et al. 2018).
Research comparing the abundances of 16 bacterial families and the makeup of
the fecal microbiota in four phyla between healthy individuals and patients with
major depressive disorder (MDD) revealed clear differences (Chen et al. 2018).
Patients experiencing depressive episodes had a comparatively lower alpha diversity
of gut microbiota, according to another study (Jian et al. 2020). Furthermore,
research based on a sizable microbiome population cohort revealed that depression
patients had lower levels of Dialister and Coprococcus spp. (Valles-Colomer et al.
2019). Additionally, the data demonstrated that MDD patients had increased Pre-
votella, Klebsiella, and Streptococcus levels.
Additionally, research revealed that patients with major depressive disorder
(MDD) had higher concentrations of Prevotella, Klebsiella, Streptococcus, and
Clostridium XI but lower concentrations of Bacteroidetes (Lin et al. 2017). Further-
more, an infection with Helicobacter pylori (H. pylori) may cause a pathological
state of the gastrointestinal flora. For example, a cross-sectional study involving
5558 Chinese individuals found that women with H. pylori had a significantly higher
risk of depressive symptoms than men (Gu et al. 2019). This could be explained by
the fact that women were more likely than men to experience anxiety and depression
because of the link between H. pylori and cancer (Liu et al. 2018). Additionally,
premenopausal women with depression had higher levels of estradiol-degrading
bacteria (Klebsiella aerogenes) compared to healthy controls (Li et al. 2023).
Bipolar Disorder
Cognitive and functional impairment is a common result of bipolar disorder, a
chronic and incapacitating condition that frequently recurs (Vieta et al. 2018).
Numerous strong lines of evidence connect bipolar illness to the gut microbiota.
One study, for example, found that people with bipolar illness had a lower diversity
of gut microbiota and a higher abundance of Clostridiaceae and Collinsella
(McIntyre et al. 2021). Furthermore, an investigation conducted across a cross-
sectional sample revealed a correlation between flavone factor and bipolar illness
(odds ratio (OR), 2.9; 95% CI, 1.6–5.2) (Coello et al. 2019). Patients with bipolar
illness showed a substantial drop in Faecalibacterium, according to another cross-
sectional investigation (Evans et al. 2017). Further, it was noted that individuals with
bipolar illness had lower levels of Ruminococcaceae and Faecalibacterium but
higher levels of Actinobacteria and Coriobacteria (Painold et al. 2019).
Multiple Sclerosis
Multiple sclerosis is an immune-mediated neurologic illness that is characterized by
demyelination and axonal destruction (Axisa and Hafler 2016). There are four types
of multiple sclerosis: relapsing-remitting MS (RRMS), progressive-relapsing MS
(PRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS).

Numerous investigations have been conducted to examine the gut microbiota of MS
patients in comparison to healthy controls, with varying conclusions. Several studies
have found that in RRMS patients, the quantity of Firmicutes (such as Dorea and
Blautia) is higher, while the quantity of Parabacteroides, Clostridium,
Faecalibacterium, or Prevotella is lower (Miyake et al. 2015; Cekanaviciute et al.
2018; Chen et al. 2016a). According to Chen et al. (2016b), another study also
revealed that MS patients had reduced Sutterella abundance and greater levels of
Akkermasia, Bilophila, Mycoplana, and Pseudomonas (Cantarel et al. 2015; Jangi
et al. 2016). All these research findings demonstrated that the gut microbiota of
patients with RRMS is characterized by a reduction in bacteria that are involved in
T-regulatory and CD4+ responses, which may have an impact on the MGB axis, and
an excess of bacteria that promote inflammation.
Alzheimer’s Disease
Around 20% of women and 10% of men will get AD over their lifetime. Alzheimer’s
disease is the most prevalent neurodegenerative disease affecting the elderly popula-
tion, accounting for 60% to 70% of cases of dementia. Age-related processes,
neuroinflammation, atrophy of neurons, synaptic loss, and synaptic dysfunction by
synthesized factors are some of the characteristics of Alzheimer’s disease (AD), which
is characterized by progressive cognitive impairment and behavioral changes such as
memory loss, disorientation, and loss of mobility. AD’s classical pathology consists of
over-phosphorylated tau protein-containing neurofibrillary tangles and amyloid-beta
(Ab) extracellular neurotic plaques, which are found throughout the cerebral cortex.
The latter primarily originates in the medial temporal lobe before diffusing to the
isocortical areas of the temporal, parietal, and frontal lobes (Zhang et al. 2022).
The increasing prevalence of Ruminococcus, Atopobium, and Enterobacteriaceae
and the reduced diversity of key microbiota groups such as Lactobacilli,
Bacteroides, and Prevotella are associated with the frailty of the host (Tiihonen
et al. 2009). What’s interesting is that these microbial communities are linked to the
host’s behavior and emotions, which can lead to cognitive impairment. Research has
shown that AD alters the gut microbiome. AD patients showed varied microbiota,
higher Bacteroidetes abundance, and lower Firmicutes, Proteobacteria, and
Actinobacteria abundance as compared to healthy controls (Zhuang et al. 2018;
Ling et al. 2020). The gut microbiota of SAPM8 mice, which had cognitive and
learning impairments comparable to those of AD patients, was also found to have a
significantly different composition from the healthy control group. The gut micro-
biota’s correlation density and clustering operational taxonomic unit also declined
(Vogt et al. 2017). A different study (Marizzoni et al. 2020) found that the microbiota
in AD patients was more abundant in SAPM8 models. This microbiota included
no-rank f Lachnospiracea, unclassified f Lachnospiraceae, and Alistypes. When
compared to 3-year-old wild-type mouse models, the microbiota composition of
the transgenic AD pathology-like models was similar, but the diversity began to
change after 6 months of age. Additionally, the abundance of Proteobacteria and
Erisilopelotrichaeae was higher in the AD pathology-like models.
Parkinson’s Disease
According to Tysnes and Storstein (2017), Parkinson’s disease (PD) is the second
most common neurodegenerative ailment after Alzheimer’s disease (AD), affecting
over 1% of the elderly population and 0.3% of the global population overall (Tysnes
and Storstein 2017). A major abnormality in the function of the substantia nigra and
striatum causes Parkinson’s disease (PD), a progressive neurodegenerative disease
marked by the loss of voluntary movement control. Among them are changes in
mitochondria, an excess of reactive oxygen species, phosphorylated forms of the
neuronal protein α-synuclein (αSyn), the degeneration of dopaminergic neurons, and
an increase in microglia activation (Blandini et al. 2000). Intestinal dysbiosis may
have a role in the initiation, growth, and course of Parkinson’s disease (PD),
according to mounting data (Zhu et al. 2022). When prodromal and/or clinically
diagnosed PD patients were compared to control participants, the gut microbiota of
the former group was shown to be dysbiotic.
The most frequent modification in the microbiome linked to Parkinson’s disease
is the existence of Helicobacter pylori stomach infections. Levodopa, a dopaminer-
gic agonist, has been shown to be absorbed more readily when there is an H. pylori
infection. Small intestinal bacterial overgrowth (SIBO) is the term for the excessive
proliferation of bacteria in the small intestine and is another microbiota modification
linked to Parkinson’s disease (PD). It has been demonstrated that in individuals with
Parkinson’s disease (PD), both SIBO and H. pylori produce motor impairment and a
decrease in the diversity level of GM (Çamcı and Oğuz 2016; Fasano et al. 2013).
Research by Hopfner et al. (2017) discovered that PD patients had significantly
higher abundances of Lactobacillaceae, Enterococcaceae, and Barnesiellaceae than
the control group, pointing to a possible function for GM in PD (Hopfner et al.
2017). Patients with Parkinson’s disease (PD) have been shown to have a reduction
in Faecalibacterium bacteria and an increase in Ralstonia bacteria in their intestinal
mucosa. In addition, the amount of fecal bacteria from the genera Blautia,
Coprococcus, and Roseburia was much lower in PD participants than in non-PD
subjects (Forsyth et al. 2011). Research has examined the potential of Lactobacillus
casei Shirota, a particular strain of gut microbiota, to enhance bowel movement, ease
constipation in Parkinson’s disease, and lower the morbidity of Parkinson’s disease
(Cassani et al. 2011).
Huntington’s Disease
Huntington’s disease (HD) is an autosomal dominant rare disease that manifests at an
estimated worldwide frequency of 2.7 cases per 100,000 persons with an onset age
of 35 to 44 years (Erkkinen et al. 2018; Gatto et al. 2020). The three primary signs of
HD are motor symptoms, a mental disorder, and cognitive impairment. Motor
disruption causes dysphagia, which results in weight loss and trouble breathing
and ultimately results in death (Rosas et al. 2008). Furthermore, aberrant HTT
growth leads to HTT malfunction in transcriptional processes, histone modification,
brain development, and mitochondrial function, which ultimately causes the afore-
mentioned symptoms (Sun et al. 2017). There is currently no effective treatment for
HD, even though its origin and symptoms are well understood.
The gut microbiota may be used in the diagnosis and treatment of HD since
evidence has emerged linking it to neurological health (Wasser et al. 2020). Sexual
differences are one way that HD may be identified by changes in the variety or
richness of gut flora (Du et al. 2020). The gut microbiota of an HD mouse model was
recently compared to that of wild-type mice. The results showed that the number of
Clostridiales decreased while the number of Bacteroidetes and Lactobacillales
increased in the male HD mouse model. The quantity of Clostridiales was shown
to be lower in female HD mice, whereas Coriobacteriales, Erysipelotrichales,
Bacteroidales, and Burkholderiale were found to be more prevalent. More microbial
diversity was also demonstrated by male HD mice than by either female or wild-type
mice (Zhang et al. 2022). Another study indicated that the absence of microbiota
contributed to the aggravating of internal HD phenotypes in mice with low levels of
myelin-related proteins and mature oligodendrocytes in the prefrontal cortex. This
resulted in decreased callosal myelination and white matter plasticity (Radulescu
et al. 2020); the loss of microbiota was found to exacerbate internal HD character-
istics, according to the study.
Amyotrophic Lateral Sclerosis

The condition known as amyotrophic lateral sclerosis (ALS), or “motor neuron
disease,” gradually destroys the upper and lower motor neurons in the brain and
spinal cord (Brown and Al-Chalabi 2017). With disease heterogeneity at the genetic
and neuropathological levels, ALS is a multisystem NDD. Adult-onset localized
muscular weakness and atrophy, mainly in the limb muscles, are among its clinical
characteristics. A bulbar onset, ankylosarthria, dysphagia, dysphonia, masseter
weakness, and frontotemporal dementia with minor behavioral and cognitive abnor-
malities may occur in certain patients with the illness. Although there is significant
variance in individual outcomes, ALS is a progressive disease with a median
survival of around 2–3 years following the start of symptoms. Current
neuroprotective treatments are thought to be sufficient nonetheless. The primary
feature of the illness is the cytoplasmic aggregation of transactive response
DNA-binding protein of 43 kDa (TDP-43 protein), which is expressed by TARDBP
and present in almost 95% of ALS patients. Numerous investigations have shown
proof that genetic mutations (such as those in C9ORF72 and SOD1) cause ALS.
However, a number of pathways lead to both sporadic and monogenic ALS. Even
though a number of studies indicate that environmental risk factors are linked to
ALS, there isn’t any proof that individual risk variables control total risk; still, they
may have an impact on GM (Wright et al. 2018).
A new study from 2022 examined a mutual link between 98 human genome
variants and ALS. A higher likelihood of ALS was linked to a higher relative
abundance of OTU4607 Sutterella and Lactobacillales ORDER. Research
employing the SOD1G93 A mouse model revealed that reduced levels of
Butyrivibrio fibrisolvens, the bacteria that generate butyrate, are linked to ALS.
Compared to untreated controls, butyrate treatment enhanced intestinal barrier
function and postponed mortality. Furthermore, in the ALSSOD1G93 A mouse
model, gut dysbiosis and GM alterations were seen, especially in the
pre-symptomatic period (prior to immune cell activation or expansion, muscle

atrophy, and motor impairment). It has also been demonstrated that gut dysbiosis
and immunological responses are related to the prognosis of ALS. While
Akkermansia muciniphila species improved illness outcomes, Blacheret et al. dem-
onstrated that GMofSOD1G93A may be altered with gut microbiota supplements,
including Parabacteria distasonis and Ruminococcus torques (Suganya and Koo
2020).
The Advantages of Gut Microbiome Alteration for Mental Health

Issues
Certain probiotic bacterial strains have been demonstrated to alter the behavior of
research animals (McKernan et al. 2010; Bravo et al. 2011; Savignac et al. 2014).
Moreover, human studies have shown that these findings may be applicable
(Nardelli et al. 2017). Several bacterial genera belonging to the phyla Bacteroidetes,
Firmicutes, Proteobacteria, and Actinobacteria have significant changes in the
presence of these genera in MDD patients (Phyu and Tangpong 2013). Research
found that giving a probiotic Lactobacillus strain to animals with stress-induced
HPA axis dysfunction increased BDNF levels, which in turn enhanced glucocorti-
coid control of the HPA axis (Clapp et al. 2017). Research conducted on people and
rats revealed that taking a probiotic composition including Bifidobacterium longum
and L. helveticus had positive psychological benefits in healthy human volunteers
and anxiolytic-like activity in rodents (Messaoudi et al. 2011). Furthermore, a
multispecies probiotic randomized, placebo-controlled study with 40 individuals
reported notable mood improvements, including a decrease in depressive symptoms
and violent thoughts (Steenbergen et al. 2015).
Probiotics, prebiotics, and dietary interventions are only a few of the methods
for modifying gut microbes that are readily available. The gut microbiome may be a
new target for maintaining mental balance, according to mounting evidence, and
bacteria that promote mental health are being referred to as “psychobiotics.” In both
healthy and sick populations, psychobiotics have shown promise in elevating mood,
lowering anxiety, and enhancing cognitive performance. Though the term
“psychobiotics,” which originally referred to beneficial living organisms like bacte-
ria that are especially beneficial for mental health, has recently come to include
prebiotics, whose effects on the brain are bacterially mediated (Dinan et al. 2013).
Prebiotics are described as substrates, including nondigestible carbohydrates or
plant polyphenols, that are specifically used by host microbes to provide a health
benefit (Gibson et al. 2017). It is also important to think about defining psychobiotics
more broadly to encompass any drug, such as probiotics, prebiotics, synbiotics, and
postbiotics, that has psychobiotic qualities or that has a microbiome-mediated
psychological effect (Sarkar et al. 2016).
In light of this, medicinal plants stand to benefit greatly as prospective
psychobiotics since they interact with gut microbiota, which in turn targets the
microbiota-gut-brain axis (MGBA), potentially improving mental health. Complex
combinations of components are found in medicinal plants. The oral bioavailability

of several of these substances is poor. Due to their relatively large molecular weight
and polarity, some are only weakly absorbed in the upper gastrointestinal system.
Others are taken in but undergo a prolonged first-pass metabolism, which is followed
by biliary secretion (Dey 2019). When these substances come into contact with the
colon bacteria, a reciprocal interaction may take place. On the one hand, due to their
powerful enzymatic capabilities, gut bacteria may break down plant components,
producing metabolites with different pharmacological activity profiles and bioavail-
ability. Conversely, plant components might influence the makeup and activity of the
gut microbial population, leading to, say, higher concentrations of microbiota-related
metabolites or health-promoting bacteria (Chen et al. 2016b; Adeyemi et al. 2010).
Thus, the word “phyto-psychobiotics” could be used to characterize medicinal plants
whose effects on mental health are mediated by modulating the gut microbiota
through prebiotic-like effects, postbiotic-like effects mediated by the active second-
ary metabolites generated by the gut microbiome from the indigestible herbal
ingredients, or even antibiotic-like effects, as some medicinal herbs do by lowering
the amount of pathogenic bacteria (Dhama et al. 2013; Rosenblat and McIntyre
2018).
Herbs and Phytochemicals That Protect Neurons
Herbs That Protect Neurons
Sales of herbal preparations have increased as a result of the “Green” movement in

Western civilization, which has altered public perceptions to the idea that organically
produced materials and extracts are intrinsically safer and more appealing than items
made with synthetic chemicals (Capasso et al. 2000; Plotkin 1992). Primitive health
care for humans and animals is provided via phytomedicine to around 80% of the
population in poor nations (Harvey 1999). Many herbs have been used in traditional
medicine to treat cognitive problems, including memory-related illnesses and neu-
rodegenerative diseases like Alzheimer’s disease (AD). Complex mixtures of
organic substances, such as fatty acids, sterols, alkaloids, flavonoids, glycosides,
saponins, tannins, and terpenes, are present in herbal products. It is believed that
traditional medicines are effective and have few or no side effects because supporters
of herbal medicines describe a plant’s therapeutic value as coming from the syner-
gistic effects of the various plant components, as opposed to the individual chemicals
of conventional medicines isolated by pharmacologists. Roughly one-quarter to
one-half of modern medications were originally derived from plants.
In Asian nations, more than 120 traditional medicines are utilized to treat
problems of the central nervous system (CNS) (Gong and Sucher 1999). The
following herbal remedies used in Indian medicine have had encouraging results
in neuropsychopharmacology: Allium sativum, Bacopa monnierae, Centella
asiatica, Celastrus paniculatus, Nicotiana tabaccum, Withania somnifera, Ricinus
communis, Salvia officinalis, Ginkgo biloba, Huperiza serrata, Angelica sinensis,
Uncaria tomentosa, Hypericum perforatum, Acorus calmus, Curcuma longa,

Terminalia chebula, Physostigma venosum, Enhydra fluctuans, Valeriana wallichii,
Glycyrrhiza glabra, and so forth (Kumar and Khanum 2012). The following list
includes some of the traditional herbs that have been utilized for centuries and their
neuroprotective properties.
Ginkgo biloba L.
Ginkgo biloba (Ginkgoaceae) is referred to as a maiden hair tree, kew tree, ginkyo,
and yinhsing and is endemic to East Asia. It has been utilized in traditional Chinese
medicine to treat memory loss brought on by blood circulation irregularities
(Chandrasekaran et al. 2001). By increasing oxygen delivery and aiding in the
body’s removal of free radicals, the herb has memory-enhancing properties. Terpe-
noids bilobolide, ginkgolides, flavanoids, steroids (sitosterol and stigmasterol), and
organic acids (ascorbic, benzoic, shikimic, and vanillic acid) are examples of
phytoconstituents. Quercetin, keampferol, and isorhamnetin make up the majority
of the flavonoid fraction, while the diterpenic lactones, or ginkgolides A, B, C, J,
and M, represent terpenic derivatives.
Panax ginseng
Ginseng, also known as Asian Ginseng, is one of the most widely used species in
both Korean traditional medicine and Kampo (Japanese traditional medicine). Gin-
seng refers to a group of several species within the Panax (from the Greek pan ¼ all
and akèia ¼ cure) genus and the family of Araliaceae growing in northeastern Asia.
This is one of the most popular herbs in Chinese medicine for enhancing vitality. It
has been used for thousands of years as a tonic and energizing herb, as well as an
antiaging one (Nocerino et al. 2000). Ginseng root is an adaptogenic plant that
increases the body’s resilience to stress, trauma, anxiety, and exhaustion by modi-
fying immunological function. Ginsenosides, which are present in ginseng root, are
triterpenic saponin complexes.
Bacopa monnieri
The herb Bacopa monnieri, sometimes known as “Brahmi,” has long been utilized in
Ayurvedic therapy. It was traditionally used as a brain tonic to improve learning and
memory, as well as to relieve anxiety and epileptic conditions in patients (Anand
et al. 2011a). Among the several active ingredients in Bacopa are the saponins
D-mannitol, hersaponin, and monnierin, as well as the alkaloids brahmine and
herpestine. Since then, other bacosides and bacopasaponins have been found,
along with betulic acid, beta-sitosterol, stigmastarol, and other active ingredients.
Bacosides A and B are the components of Bacopa that give it its cognitive benefits
(Singh and Dhawan 1997). By promoting kinase activity, neuronal synthesis, syn-
aptic activity restoration, and eventually nerve impulse transmission, the bacosides
help heal injured neurons (Russo and Borrelli 2005).
Centella asiatica
A psychoactive medicinal plant that has been used as a medhya rasayna in the
Ayurvedic school of medicine for millennia is Centella asiatica (CA) L. Urban (syn.
Hydrocotyle asiatica L.), a member of the Apiaceae (Umbelliferae) family (Nalini
et al. 1992; Anand et al. 2011b). Reduced oxidative stress parameters have been
demonstrated. This plant’s major bioactive constituents are highly variable tri-
terpenoid saponins, such as related sapogenins and asiaticoside, oxyasiaticoside,
centelloside, brahmoside, brahminoside, thankunoside, and isothankunoside. There
are other triterpenoid acids present as well, such as betulic acid, asiatic acid,
madecassic acid, and isobrahmic acid.
Withania somnifera
Ashwagandha, or Withania somnifera (WS), is a plant that has been utilized for
millennia in the Indian Ayurvedic medical system due to its vast variety of health
advantages. It has been shown to increase cognition and strengthen the nervous
system’s capabilities. The active ingredients in Withania somnifera, known as
withanolides, are mostly responsible for its medicinal qualities. The ability of WS
and its components to function as antioxidants, anti-inflammatory, anti-cancer,
hemopoietic, and rejuvenating agents accounts for its multimodal positive effects.
Numerous neurological illnesses, including cerebral ischemia, anxiety disorders,
Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, have been
demonstrated to benefit from WS.
WS is sometimes referred to as Indian Ginseng because withanolides share struc-
tural similarities with the ginsenosides found in Panax ginseng (Singh et al. 2010).
Withaferin-A was the first withanolide family member to be isolated from WS out of all
the withanolides found in WS root extract (Palliyaguru et al. 2016). Apart from
withanolides, the alkaloid components of WS root extract consist of 3-a-
gloyloxytropane, choline, cuscohygrine, isopelletierine, anaferine, and anahydrine, as
well as somniferine, somnine, somniferinine, withananine, pseudo-withanine, tropine,
and pseudotropine. Among the main components of WS that are employed for their
effects on nervous system illnesses are withaferin-A, withanolide-A, withanoside-IV,
and several sitoindosides (Raghavan and Shah 2015; Tiwari et al. 2014).
Convolvulus pluricaulis
Convolvulus pluricaulis, (Shankhpushpi), Ayurvedic medicine has been in use for
centuries to treat nervous system ailments (insanity, epilepsy, hysteria, insomnia, and
psychoneurosis), rejuvenators, anti-aging, mental stimulants, anxiolytic, neuro-
protective, anti-oxidants, analgesics, immunomodulatory, anti-microbial, anti-diabetic,
cardiac disease, tranquilizers, and primarily to enhance memory and intellect (Amin
et al. 2014). According to recent research on the neuroprotective qualities of
Shankhpushpi, it has antioxidant and anti-apoptotic qualities as well as defensive against
plasmid DNA damage, telomer damage, and H2O2-induced cytotoxicity (Sharma et al.
2022).
Nardostachys jatamansi
The plant known as Nardostachys jatamansi (NJ) (D. Don) DC is a well-known
memory-enhancing herb with a long history of medical usage, dating back to the
Ayurvedic and Unani systems of traditional medicine, which date back to
1000–800 B.C. It has been used to treat depression, epilepsy, hysteria, syncope,
and mental weakness either alone or in combination with other herbs. N. jatamansi
is rich in sesquiterpenoids, coumarins and their derivatives, phenols, flavonoids,
alkaloids, lignans, and neolignans. This plant contains special pyranocoumarins
that have a range of pharmacological effects (Stefanachi et al. 2018). The
pyranocoumarins found in N. jatamansi include dihydrojatamansin, seselin,
jatamansine (Anupama et al. 2023).
Phytochemicals in the Defense of Neurons
The use of phytoconstituents for neuroprotection or the prevention of neurodegen-

erative illnesses has attracted a lot of interest from the scientific community and the
general public. Numerous phytochemicals have been demonstrated to exhibit
neuroprotective properties in neurological disease models in animals and cell cul-
tures. Numerous studies showing the neuroprotective properties of natural product
constituents such as ginsenosides, a-tocopherol, lycopene, and resveratrol have been
reported in hundreds of publications (Ikeda et al. 2003). Several significant phyto-
chemicals used for neuroprotection are discussed in the following sections.
Phenols
Studies conducted in vitro, in vivo, and in clinical trials have shown evidence that
polyphenols found in citrus, apple, and grape juices have a greater neuroprotective
effect than antioxidant vitamins. Green tea’s phenolic compounds, known as
epicatechins and catechins, have the ability to shield neurons from a variety of
oxidative and metabolic insults. These insults include, but are not limited to,
reducing mutant huntingtin misfolding and neurotoxicity in Huntington’s disease
models, protecting retinal neurons against ischemia reperfusion injury, and shielding
dopaminergic neurons from damage caused by 6-hydroxydopamine in a rat model of
Parkinson’s disease. It has been proposed that catechins inhibit the development of
Alzheimer’s disease and shield neurons from the illness’s processes.
By boosting the quantity of helpful bacteria and lowering the quantity of harmful
bacteria, tea phenols (TPs) function as a great modulator to control the composition of
the intestinal flora, preserving the integrity of the intestinal barrier (Xu et al. 2023).
According to research, consuming green tea polyphenols (GTP) can reduce the
amount of the phylum Synechococcus and Clostridium spp. and increase the amount
of Firmicutes. It can also inhibit the level of induction of the inflammatory signaling
pathway TLR4, which can lead to intestinal cell wall repair and decrease the expres-
sion of the inflammatory factors IL-6, TNF-α, and IL-1β. The anti-inflammatory
metabolite SCFAs, which controls microglia maturation and development, may be
Fig. 3 The interaction between the gut microbiome and tea polyphenols improves immunity in
cognitive impairment. (Reproduced from Xu et al. 2023)
produced by Faecalibacterium prausnitzii. Consequently, it stands to reason that TPs

regulate diseases of the brain (Fig. 3) (Xu et al. 2023).
Flavonoids
Flavonoids have garnered significant attention lately due to their ability to regulate
brain activity and avert age-related neurodegeneration. Following
6-hydroxydopamine lesioning, individual flavonoids, such as the citrus flavanone
tangeretin, have been shown to preserve nigro-striatal integrity and functionality,
indicating that they may have potential as neuroprotective agents against the under-
lying pathology linked to Parkinson’s disease (Youdim et al. 2004). Flavonoids need
to pass across the blood-brain barrier (BBB), which regulates the entry of xenobi-
otics into the brain, in order to enter the brain in situ as well as in vitro models.
Studies have revealed that flavonoids are present in the gastrointestinal system in
higher quantities and for a longer period of time than they are in the circulation. In
addition, flavonoids undergo considerable alteration in the human body, which may
impact biological activity and antioxidant efficiency (Chen et al. 2022). As a result,
flavonoids’ indirect effects on the gut-brain axis and gut microbiota may be more
significant than their direct effects on the central nervous system.
When flavonoids reach the intestines, they are broken down by microbes and then
control the microbiota in the gut. According to studies, flavonoids have the ability to
change the structure and function of the gut microbiota, control the growth of
particular bacterial taxa, and provide a host of other health advantages for people
(Xiong et al. 2023). In particular, flavonoids can disrupt or change the permeability
of potentially pathogenic taxa’s cell membranes, hence inhibiting their proliferation
and gut colonization. This eventually decreases the pathogenicity of these organ-
isms. Examples of these taxa include Escherichia coli and Staphylococcus aureus.
Additionally, flavonoids support the growth and proliferation of beneficial bacteria

like Lactobacillus and Bifidobacterium species by acting as metabolic substrates.
This maintains a stable, beneficial gut community, which is crucial for the health of
the gut, liver, and other organs in addition to the brain. By influencing the
microbiota-gut-brain axis, flavonoids might indirectly affect the central nervous
system (CNS) through several pathways (Zhang et al. 2014).
Alkaloids
Alkaloids have the potential to impact the central nervous system (CNS), including
brain and spinal cord nerve cells that regulate several bodily processes and behav-
iors. The autonomic nervous system, which controls respiration, heart rate, circula-
tion, and internal organs, may also be impacted. The indole carbon-nitrogen ring,
present in indole alkaloids, is also present in psilocybin, ergine, and other fungal
alkaloids, as well as the mind-altering medication lysergic acid diethylamide (LSD).
These alkaloids may conflict with or impair serotonin’s physiological effects in the
brain (Pearson 2001). Blood flow is significantly affected by ergot alkaloids, which
were first believed to be the primary mode of action. The CNS and spinal cord are
impacted by tropane
Terpenoids and Saponins

Alkaloids such as scopolamine, hyoscyamine, and atropine are obtained from
Datura. An extremely effective analgesic and narcotic medication is morphine, an
isoquinoline alkaloid that is extracted from Papaver somniferum, or opium poppy.
Gamma-aminobutyric acid (GABA) is increased in brain synapses as a result of
morphine’s potent binding to the μ-opioid receptor (MOR) in the central nervous
system. One of the most powerful vasodilators available is vinpocetine, an alkaloid
derived from Vinca minor. Studies on the effects of vinpocetine in clinical settings
show that it selectively increases cerebral blood flow and metabolism, including
improved absorption of glucose, which may mitigate the consequences of hypoxia
and ischemia.
Alkaloids from Sophora alopecuroides L. enhanced mice’s depressive-like
behaviors and indications. The alkaloids reduced the diversity of the gut microbiota
in CUMS mice and reduced the number of “harmful” bacteria species that were
differentially prevalent in the gut. A Spearman analysis revealed a relationship
between depression-like behaviors and indications of depression and the differential
microbiota (Lactobacillus, Helicobacter, Oscillospira, Odoribacter, Mucispirillum,
and Ruminococcus). These findings suggest that alkaloids alleviate depression in
mice by modifying gut microbiota when paired with predictive analysis of gut
microbiota function (Zhang et al. 2021).
Triterpenoid saponins (Radix astragali, Herba centellae, Radix ginseng, Radix
polygalae, and Folium gynostemmae) or steroid saponins (Radix polygonatae,
Semen foenugraeci) are found in many herbal medications derived from medicinal
plants that have clinical effects in mild depression, anxiety, cognitive impairment,
sleeplessness, and fatigue. The potential therapeutic advantages of saponins in many
disorders have long attracted interest. However, their low bioavailability, sometimes
less than 1%, and their poor pharmacokinetic features have hindered the develop-
ment of these molecules into medications. Since it is mainly unclear how saponin-
rich plants affect the central nervous system, the gut microbiota’s metabolization and
modification of these plants have become viable targets.
Trigonella foenum-graecum L., Trigonella sibiricum L. These medicinal plants
have psychoactive effects on the brain and are rich in saponins (saponins), which
play an important role in mental health. T. foenum-gruecum has been shown to
significantly reduce the dysbiotic effects of high-fat diets (HFDs) in mice, particu-
larly in Firmicutes. Feeding this plant positively altered gut microbiome composi-
tion and immunological parameters in weaning pigs. A saponin-rich extract from
Polygonatum sibiricum was found to increase probiotic bacteria and reduce the
presence of potentially harmful species in cultivation-based plate count assays
(Pferschy-Wenzig et al. 2022).
Polysaccharides
Essential macromolecules, polysaccharides, have been demonstrated to prevent or
suppress neurological diseases. Recent research has shown that polysaccharides
protect neurons in a variety of ways. It is commonly recognized that inflammation
and oxidative stress are linked to damage to neuronal cells and that the immune
system is a major contributor to the increased risk of neurodegenerative illnesses.
The principal bioactive polysaccharide found in Aloe vera, acemannan, is an anti-
oxidant and neuroprotective immunomodulator that enhances cognitive function in
middle-aged individuals experiencing mental exhaustion (Sun et al. 2020). Like-
wise, lentinan, fucoidan, astragalus polysaccharides, and ginseng polysaccharides all
derived from plants, fungi, and animals have been extensively utilized in the medical
industry to create polysaccharide-based medications.
The gut microbiota modifies inflammatory signaling, which might be a factor in
the onset of neurodegenerative diseases. It’s interesting to note that polysaccharides
may have neuroprotective effects and control microbial ecosystems. The gut-brain
microbiota axis may be affected by nerves, immunology, or the endocrine system.
The gut, brain, and immune system dysfunctions enhance the development and
progression of NDs. Endocrine, vagus nerve, immunological, and other humoral
pathways are among the ways that the gut microbiota and its main metabolites, or
SCFAs, influence brain function and behavior (Shaik et al. 2020). SCFAs are
essential for brain development and preserve CNS homeostasis by fostering the
proliferation and maturation of brain microglia. According to Gao et al. (2021), a
plant polysaccharide derived from Cistanche deserticola restores gut-microbiota-
brain axis equilibrium, therefore improving cognitive performance in mice in an
aging paradigm produced by D-galactose. So, gut flora and associated metabolites
may protect against NDs through the mediation of polysaccharides (Gao et al. 2021).
Essential Oils
Aromatherapy and conventional medicine have long recognized the use of essential
oils (EOs) and their constituents in the treatment of a wide range of illnesses.
Biochemical and pharmacological characteristics, including neuroprotection, anti-
inflammatory, and antioxidant properties, are exhibited by the metabolites found in

essential oils. Herbaceous plants contain naturally occurring antioxidants that shield
cells from harm caused by reactive oxygen species (ROS). Because these antioxi-
dants can counteract the effects of free radicals, they have been proposed as a
therapeutic option to prevent the loss of neurons (Abuhamdah et al. 2015).
According to Luciana Cristina B. Fernandes (2021), essential oils with terpenoids
as major constituents were able to significantly improve the natural antioxidant
system and, consequently, reduce neuronal losses, which in turn led to significant
improvements in behavioral tests. Salvia lavandulifolia (Bercik et al. 2012), Prop-
olis (Kovatcheva-Datchary et al. 2013), Bergamot (Kovatcheva-Datchary et al.
2013), Pistacia lentiscus (Kovatcheva-Datchary et al. 2013), Aloysia citrodora
(Kovatcheva-Datchary et al. 2013), and Rosa damascena (Kovatcheva-Datchary
et al. 2013) were investigated and evaluated for various neurological disorders
(Fernandes et al. 2021).
In another in vitro culture study including 12 gut bacterial species, lavender and
orange blossom essential oils showed selective inhibitory effects against potentially
pathogenic gut germs while having a reduced effect on gut microbes (Pferschy-
Wenzig et al. 2022).
Conclusion
For many neurological diseases, the MGBA is considered a crucial therapeutic

target. The strong polarity and molecular weight of secondary plant metabolites
make them poorly absorbed in the upper GI tract, yet they are present in a wide
variety of therapeutic plants. Thus, it is very probable that they engage in interactions
with the gut microbiota, which might consequently alter the MGBA. The findings
show signs of a potential interaction between the MGBA and health-promoting or
SCFA-producing bacterial species, as well as good impacts on dysbiotic microbiome
conditions and anti-inflammatory properties. Herbal medicines and the gut micro-
biota may interact in a way that moderates their impact on mental health. Therefore,
it is suggested that the plant components found in these herbs, which are therefore
referred to as phyto-psychobiotics, execute their neuroprotective effects by acting on
both the host and the microbiota in several ways.
It has been demonstrated that several chemical classes, including polyphenols and
polysaccharides, have prebiotic properties. Phytochemical elements that favorably
influence the gut microbiota of the host and impart health benefits have been referred
to as flavobiotics or phytobiotics. Moreover, polyphenols function as duplibiotics,
which means that these phytoconstituents influence the microbiome in two ways:
first, by acting as prebiotics and favorably promoting the growth of beneficial
bacteria, and second, by exerting antimicrobial properties similar to those of antibi-
otics. Additionally, some plant components can be broken down by the gut micro-
biota into compounds that are pharmacologically active, as well as other postbiotics
like SCFAs, lactate, and phenolic metabolites. These can either act locally in the gut
or be absorbed by the epithelial cells and offer additional health benefits to the host
through various pathways, including the MGBA. Nonetheless, studies directly

evaluating the synergistic effects of multiple phytochemical constituents in medic-
inal plants on MGBA-related targets or pathways are rare, if not non-existent, for
many candidate plants with clinically proven effects on mental health. Numerous
single plant components have been investigated in vitro and in vivo for their
neuroprotective properties.
To improve our knowledge of the potential impacts of these plants on the MGBA,
further research of this kind is desperately needed. Therefore, it is advised that in
order to investigate the potential impact of these medicinal plants on the MBGA,
future clinical research evaluating the impact of medicinal plants on mental health
should also analyze the makeup and function of the gut microbiome. This would
make it easier to understand why some people react well to interventions while
others might not, possibly because they don’t have the microbes necessary to convert
certain plant components into active metabolites. Furthermore, as a first step toward
exploring the complex bidirectional interaction between plant constituents and the
gut microbiome, combining in vitro GI models that include both upper and lower GI
tract simulation with multi-omics approaches such as metagenomics, metabolomics,
metatranscriptomics, and metaproteomics can be employed. These methods will
shed light on the mechanism of action and health advantages of herbal remedies.
They will also aid in the discovery of novel active plant components and their
potential to function through the MGBA or offer more advantages to the host.
Cross-References
▶ The Contribution of the Gut-Brain-Microbiota Axis to Brain Health Throughout

the Lifespan
▶ The Gut-Microbiota and NDG: What is the Interplay
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A Comprehensive Review of Medicinal

Herbs Improving Gut-Brain Health

Akila Ramanathan, K. Reeta Vijaya Rani,

© Springer Nature Singapore Pte Ltd. 2024 1

As research on gut microbiota has advanced, it is now possible to explain the

Numerous microorganisms, including bacteria, fungus, parasites, and viruses, can be

immunological action of medications by encouraging T-cell transformation and

Gut Microbes and Neurological Functions

CNS Diseases and the Microbiota-Gut-Brain Axis

(PRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS).

Amyotrophic Lateral Sclerosis

pre-symptomatic period (prior to immune cell activation or expansion, muscle

The Advantages of Gut Microbiome Alteration for Mental Health

combinations of components are found in medicinal plants. The oral bioavailability

Herbs and Phytochemicals That Protect Neurons

Herbs That Protect Neurons

Sales of herbal preparations have increased as a result of the “Green” movement in

Uncaria tomentosa, Hypericum perforatum, Acorus calmus, Curcuma longa,

Phytochemicals in the Defense of Neurons

The use of phytoconstituents for neuroprotection or the prevention of neurodegen-

produced by Faecalibacterium prausnitzii. Consequently, it stands to reason that TPs

Additionally, ﬂavonoids support the growth and proliferation of beneﬁcial bacteria

Terpenoids and Saponins

inﬂammatory, and antioxidant properties, are exhibited by the metabolites found in

For many neurological diseases, the MGBA is considered a crucial therapeutic

through various pathways, including the MGBA. Nonetheless, studies directly

▶ The Contribution of the Gut-Brain-Microbiota Axis to Brain Health Throughout

Forsythe P, Bienenstock J, Kunze WA (2014) Vagal pathways for microbiome-brain-gut axis

Liang S, Wang T, Hu X, Luo J, Li W, Wu X, Duan Y, Jin F (2015) Administration of Lactobacillus

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