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Acknowledgements: The authors would like to thank Maharishi Markandeshwar University, Haryana, India,
for providing the requisite facilities to carry out this study.
Received: 14.03.20
Accepted: 17.04.20
Abstract
It has been suggested that an intricate communication link exists between the gut microbiota and the
brain and its ability to modulate behaviour of an individual governing homeostasis. Metabolic activity
of the microbiota is considered to be relatively constant in healthy individuals, despite differences in
the composition of microbiota. The metabolites produced by gut microbiota and their homeostatic
balance is often perturbed as a result of neurological complications. Therefore, it is of paramount
importance to explore the link between gut microbiota and brain function and behaviour through
neural, endocrine, and immune pathways. This current review focusses on the impact of altered gut
microbiota on brain functions and how microbiome modulation by use of probiotics, prebiotics, and
synbiotics might prove beneficial in the prevention and/or treatment of neurological disorders. It is
important to carefully understand the complex mechanisms underlying the gut–brain axis so as to use
the gut microbiota as a therapeutic intervention strategy for neurological disorders.
The human body harbours a diverse community There are a number of mechanisms that support
of symbiotic, commensal, and pathogenic the interaction between the brain and gut
micro-organisms including bacteria, viruses, microbiota, either in relation to neural, endocrine,
and fungi, collectively known as the microbiota. immune, or metabolic signalling pathways. There
In recent times, the relationship between brain is also a significant bridging between the brain
and gut microbiota has become an important and gut microbiota at the chemical level, as has
component of wider research studies. The been seen through the use of various hormones
microbiome consists of the combined genetic such as corticotropin-releasing hormone in the
material of the micro-organisms in a particular pituitary and the neurotransmitters dopamine,
environment that may constitute the whole serotonin, and GABA.3
body or a specific part of the body. There
exists a bidirectional microbiome gut–brain GUT MICROBIOTA–BRAIN CROSS TALK
axis communication, which enables the gut
microbiota to interact with the brain and vice
Gut microbiota are thought to be greatly
versa.1 This communication between the
influenced by stimulating the HPA axis and
microbiota and central nervous system
sympathetic nervous system. The stimulation
(CNS) is established through autonomous,
of the HPA axis is a major constituent of stress
neuroendocrinological, gastrointestinal,
response, which has been well established
and immunological systems. Pathological
through genetic and post-delivery environmental
complications are known to alter the levels of
factors.4 Past studies in mouse models have
neurotransmitters, and therefore the balance
observed variations in host behaviour in the stress
between them, exacerbating the hypothalamus–
stimuli response. The observations indicated that
pituitary–adrenal (HPA) axis activity and
the gut microbiota can influence the progression
leading to chronic inflammation.2 The intestinal
of the HPA reaction to stressors.5
secretions, porousness of the gut, and gut
motility, along with the structure–function activity Significant behavioural alterations have been
relationship, are also greatly influenced by the known to be caused by a diverse range of
CNS. Conversely, the gut microbiota, by secreting micro-organisms. In mice, toxoplasmosis and
certain chemicals, are known to affect the brain bacterial infections altered the behaviour
functions as well.2 Even anxiety/stress and social of the mice in such a way that they became
issues are reported to affect bile secretions by unresponsive to the smell of cats, meaning the
altering the genes responsible for bile production.2 mice could be easily preyed upon.6 There are
some probable pathways involved in the
Many preclinical studies have suggested that association between the gut microbiota and
the microbiome and the microbiota could be the brain that could help the transmission of
key regulators in predisposing organisms towards information from gut to brain. The information
various disorders, including neurodegenerative can be processed for better understanding
disorders, because alterations to the composition through the roles of short-chain fatty acids
of the human gut microbiota are linked to a (SCFA) and neuroglia, and tryptophan and its
variety of neuropsychiatric conditions including metabolites, as well as accessing pathways
depression, autism, Alzheimer’s disease (AD), at the neural level.7 At neural levels, the
multiple sclerosis (MS), and Parkinson’s disease conduction of information from the intestine
(PD). However, studies are limited and it is to the CNS through nerves/neurons, has been
not confirmed whether there is a direct link successfully demonstrated in mice.8 In one
between the microbiota and brain disorders, or if study, Bifidobacterium infantis administration
microbiota indirectly influence by virtue of to germ-free mice resulted in increased
secondary effects.3 It has been shown that one expression of c-Fos,9 a principal alteration in
may improve the gut microbiota by the intake the brain that changes the conversion of short-
of probiotics, fermented foods, and prebiotic term incitements into long-term responses.
fibres in the diet; a healthy lifestyle; reducing The enhanced expression was moderately
biosynthesis, blood platelets biosynthesis, and for microbes associated with the gut microbiome
numerous molecules in the CNS.13 The kynurenine have a vast range of functions with respect
pathway is known to be controlled by the enzyme to the human body as they aid digestion,
indolamine 2, 3-dioxygenase, in which the develop the immune system, and support
majority of tryptophan is involved in. Further, the mental health.19
cytokine levels reportedly boost the tryptophan-
kynurenine route in the pathway. The metabolic The key communication route between CNS and
products of kynurenine have been reported to gut microbiota is via the vagus nerve, which acts
affect the functioning of neural cells.14 Kynurenic as a thread between them. Fluctuation in the
acid (KYNA), produced by kynurenine, acts signal of the nerve can result in immunoregulation
antagonistically at the broad-spectrum ionotropic effects and dysfunction of the nervous system.
glutamate receptors. In case of neurological This may lead to gastrointestinal diseases,
complications such as schizophrenia, the levels intestinal distress, anxiety, depression, diseases
of this tryptophan metabolite are elevated in the such as irritable bowel syndrome, MS, AD, PD,
brain and cerebrospinal fluid. KYNA is known and inflammatory bowel disease (IBD), etc.20
to antagonise the function of α7 nicotinic and Several studies have evidenced the improvement
N-methyl-d-aspartate (NMDA) receptors, both in levels of cytokines by vagal stimulation.21,22
of which are required for cognitive processes Enteroendocrine cells transmit biological
and normal brain development. Therefore, KYNA signals from the gut to the brain via stimulation
levels are very critical for the predisposition by bacterial metabolites, hormones such as
towards neurological disease.15 cholecystokinin, peptide YY, and serotonin.
These mediators bind to chemoreceptors and
Similarly, carbohydrates levels are thought to upon binding, activate the neural afferent fibres.
influence the mood and behaviour of humans. In another study, subtypes of enteroendocrine
Carbohydrates in our diet are known to stimulate cells were reported to complete the signal by
insulin discharge in the body; they lead to direct communication with the gut through vagal
the release of blood sugar into cells and the afferent fibres.23
production of energy, simultaneously triggering
the entry of tryptophan into the brain which has
Default mode network displays high levels Iron is a metal that is fundamental to basic
of activity throughout the resting state and processes such as DNA synthesis, respiration in
neutralises during the enactment.62 mitochondria, and oxygen transportation. The
paramagnetic nature of iron, as determined
Magnetic Resonance Spectroscopy through advanced MRI techniques, has led to
new insights into the iron testimony in vivo in the
Magnetic resonance spectroscopy provides the human brain.65
neural substrate information of the brain, accessing
the levels of choline, creatine, glutamate, glucose, MICROBIOTA VERSUS DISEASE-
and N-acetyl aspartate. GENETIC PREVIEW
With magnetic resonance spectroscopy, some
key investigations can be performed in cases of There are variety of factors that have been
neurological or neurosurgical disorders.63,64 reported to be associated with the improvement
of the gut microbiome that impact the human
health (Table 2).61-70
There are many factors that can affect the CHALLENGES AND LIMITATIONS OF
microbial flora inhabiting the gut, but recent
THE MICROBIOTA RESEARCH
findings discovered that specific host genetic
variants influence an individual towards
microbiome dysbiosis.69 The host regulates the The impact of the microbiota on human health
composition of the gut microbiome through has been significant in guiding us to newer
the secretion of IgA, antimicrobial peptides, diagnostic and therapeutic approaches to treat
and microRNA.70 neurological disorders (Figure 1); however,
concrete clinical studies or large cohorts of
Genes encode many proteins that shape the randomised trials are lacking. Also, complex
microbiome by appropriately regulating the intricacies of host microbial interactions,
availability of nutrients, and the level of the microbial environment, the underpinning human
immune response generated. The secretion microbiome, and how additive, subtractive, or
of antimicrobial peptides was found to be modulatory strategies influence such interactions,
decreased with mutations in NOD2, ATG16L1, and are not completely understood. Additionally,
LRRK2 genes.71,72 there is a lack of knowledge so far about
comprehensive understanding of the rules
The abundance of Lactobacillus spp. is governing invasion, resilience, and succession in
found to decrease because of variants in a host-associated microbial environment, which
the CLEC7A and CARD9 genes, resulting in altered is quintessential for the development of long-
activities of dendritic cells and macrophages. term cell-based therapeutics.77 The majority of
Increased abundance of Escherichia spp. studies pertaining to microbiota have been tested
and Bacteroides vulgatus alongside a decrease in rodents which are correlated to humans in a
in Faecalibacterium spp. was associated with generalised fashion, despite having differences
variants in NOD2.73,74 The increased production of in their respective microbiomes. Effective
IgG and IgA against commensal microbiota has therapeutic studies considering microbiota as a
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