Impact of the gut–brain axis on neurodegenerative diseases and potential benefits of probiotics

INTRODUCTION

The human gastrointestinal (GI) tract, particularly the lower intestine, is the common habitat of microorganisms. This area forms an interface between microbes and intestinal epithelial cells. This colonised form of microbial population in the GI tract is called the gut microbiota, which comprise bacteria, archaea, viruses, fungi, protozoa and helminths.^[1,2] Among the microorganisms, bacteria are predominant and approximately 3 × 10¹³ bacteria are present in the gut.^[3] The common phyla of bacterial populations are Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria and Fusobacteria. Gut microbiota have several physiological benefits. They ferment indigestable sugar to produce B vitamins (B1, B2, B6, biotin, folic acid and B12), vitamin K, short-chain fatty acids (SCFAs), indole derivatives, phenolic compounds and polyamines. Gut microorganisms inhibit the colonisation and proliferation of pathogenic bacteria. SCFAs show immunomodulatory and anti-inflammatory effects.

Alteration in the gut microbial population (abundance of pathogenic organisms) causes dysbiosis. Several factors, such as chronic GI tract infection, antibiotic treatment, dietary impairment and ageing, increase the risk of dysbiosis. Dysbiosis promotes the occurrence of different diseases, including gastritis, diarrhoea, ulceration, inflammatory bowel disease (IBD), obesity, metabolic disorders, diabetes, cardiovascular diseases, GI and extra-GI cancers, allergic reactions, depression and neurodegenerative diseases.^[4]

The connection between the brain and GI functions was first established in the classical experiment of Pavlov. Later, several articles exhibit the bidirectional routes of gut–brain association.^[5-8] The useful relationship between gut microbial activities and brain functions forms the gut–brain axis (GBA). The effective role of intestinal microflora on brain functions starts during intrauterine life. Gut microbiota help in the maturation and development of the brain. GBA regulates neuroendocrine functions, metabolic activities, brain functions and cognitive behaviour. Germ-free animals or potent antibiotic treatment show neurochemical changes and impaired brain functions.^[9] GBA potentially regulates neuroimmune functions. Dysbiosis influences oxidative stress (OS), inflammatory response and neurodegeneration.

Probiotic organisms (Lactobacillus spp., Bifidobacterium spp) prevent dysbiosis and protect the GI tract from pathogenesis. Several prebiotic substances like inulin, fructooligosaccharides, galactooligosaccharides, resistant starch and pectin influence the growth of probiotic bacteria and increase the beneficial effects. Fermented food and drinks, and beverages are rich sources of probiotic bacteria. They produce SCFAs and other beneficial metabolites to prevent inflammatory reactions and neurodegenerative diseases. The present review focuses on the role of GBA in the development of neurodegenerative diseases, such as multiple sclerosis (MS), Parkinson’s disease (PD) and Alzheimer’s disease (AD), and the impacts of probiotic bacteria as the protective factor.

THE GBA

The bidirectional relationship between gut microbiota and the central nervous system (CNS) is recognised as the GBA [Figure 1]. Gut microbiota has a role in the maturation and development of the human CNS.^[10] The functions of the autonomic nervous system (ANS), and the hypothalamic-pituitary-adrenal (HPA) axis as well as the enteric nervous system (ENS), are associated with intestinal flora.^[11] The metabolic products of gut microbiota have important roles in neurogenesis, immunomodulatory effects and neural activities. Improper lifestyle, stress and faulty food habits alter GI functions, metabolic activities and neuroendocrine functions. Collectively, these effects can modify the distribution pattern and functional aspects of the gut microbiota.^[12,13] On the other hand, Smith^[9] reported that any impairment in gut microbiota altered the activity of CNS. Gut microbiota has a role in neurogenesis. They regulate the hippocampal neurogenesis for the progression of the learning and memory process.^[14]

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Figure 1:

Functions of gut–brain axis and impacts of dysbiosis.

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Gut microbiota have different effects on the host’s metabolism and synthesis of neuroactive compounds that modulate neural functions, plasticity and behaviour. Gut bacteria also help in the maintenance of the integrity of the blood–brain barrier. Any impairment in the blood–brain barrier promotes gliomagenesis. Disruption of the blood–brain barrier increases the infiltration of immune cells in the brain tissue. On the other hand, the improper activity of gut microbiota changes the functions of the host immune system and cytokine release.

A higher degree of inflammation occurs during dysbiosis. Inflammatory response increases OS, leukocyte infiltration, cytokine release and activation of the signalling pathways. Proinflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, IL-8, IL-12, and tumour necrosis factor-α (TNF-α) promote chronic inflammation and induce the production of reactive oxygen species (ROS). Chronic inflammation and ROS are crucial factors for neurodegeneration. The experimental study of Smith revealed that germ-free animals or any impairment in gut microbiota in animals altered the functions of CNS.^[9] The germ-free animals exhibit problems in higher brain functions like poor learning and memory formation, improper emotion and behaviour.^[15] These types of impairments are associated with microbiome-induced alteration in neuro-chemistry. The gut microbiomes change the activity of 5-HT (5-hydroxytryptamine/serotonin), BDNF (brain-derived neurotrophic factor) and NMDA (N-methyl D-aspartate) receptors. Thus, dysbiosis not only starts GI diseases but also intensifies CNS disorders.

The vagus is the most important nerve in the GI system. It regulates motility and secretory functions of the GI tract. This nerve maintains the gut–brain functions bi-directionally. Any dysfunction in the vagal system promotes mood disorder, neurodegenerative diseases, GI pathogenesis and IBD.^[16] Microbial metabolites increase the secretion of 5-HT, cholecystokinin (CCK) and peptide YY is the name of a protein from hormone-secreting GI cells through TLR (toll-like receptor) response. These factors activate the vagal afferent and complete the gut–brain circuit.^[17,18]

Macrophages, CD8⁺, Treg and CD4⁺ (CD: cluster of differentiation) T-helper cells are involved in immunity. Lymphocytes cross the blood–brain barrier and are distributed in the CNS. Gut microbiota activate the immune-competent cells. Bacteroides fragilis activates Th1 through polysaccharide A. Segmented filamentous bacteria Acinetobacter baumannii and Porphyromonas uenonis can activate Th17 cells.^[8] The IFN-γ-producing Th1 cells induce MS while IL-4-producing Th2 cells exert a protective role.^[19] Kleinewietfeld and Hafler reported that Foxp3-expressing Treg cells produced anti-inflammatory cytokines IL-10 and TGF-β. Clostridium stimulates the development of Treg cells.^[20] Therefore, gut microbiota always maintain a balance among the immune-competent cells.

The microglia cells are present throughout the CNS. They are involved in synaptic transmission and neural circuit formation.^[21] These cells also protect the brain from pathogenesis and regulate phagocytosis, inflammation and cytokine production.^[22] Microglia cells are in two states, pro-destructive (M1 microglia) and tissue-regenerating (M2 microglia). This process is interconvertible. In response to the pathogenic challenges, microglia stimulate T cells for the secretion of TNF-α, IL-6 and IL-1β as the proinflammatory cytokines. On the other hand, T cells also secrete IL-4 and IL-13 that help to transform the M1 microglia to M2 microglia, resulting in a diminution of inflammatory response. Impaired stimulation and activity of M1 and M2 microglia cells can promote tumour formation in the brain.^[23] Gut microbiota regulate the maturation and activity of microglia cells. The germ-free animals or antibiotic-treated animals showed a large number of naïve microglia cells and fewer mature microglia cells, resulting in functional impairment [Figure 1].^[8]

Astrocytes are abundantly present in the CNS. They maintain the integrity of the blood–brain barrier, ionic balance, perfusion ratio and nutrient supply.^[24] Gut microbial metabolite indole-3-aldehyde [aryl hydrocarbon receptors (AHR) agonist] is synthesised from tryptophan and can bind with the AHR of astrocytes. This binding prevents inflammatory response through IFN-I signalling [Figure 1].^[25] The metabolites of gut microbiota elevate the expression of occludin and claudin-5 to increase the strength of tight junction and the integrity of the blood–brain barrier.^[26] Boillot et al. reported that oral microbes Porphyromonas gingivalis activated the astrocytes by TLR4 for the induction of chronic inflammation.^[27]

EFFECTS OF THE GBA ON NEUROLOGICAL DISORDERS

IMPACTS OF PROBIOTIC ORGANISMS ON NEURODEGENERATION

CONCLUSION

Recently, neurodegenerative diseases have been a serious problem globally, and there are several causes for these diseases, including sleep disorders, OS, neuroinflammation, circadian rhythm dysfunction and others. The GBA is an essential connection for the regulation of brain functions and also protects the brain from neurodegeneration. Neuroinflammation is one of the critical factors in neurodegenerative diseases. Microbial metabolites maintain brain health and regulate the inflammatory response that protects the neurons from apoptosis and degeneration. Physiological stress and dysbiosis disturb the functions of GBA and increase the risk of neurodegenerative diseases. Circadian rhythm dysfunction is another factor that influences neurodegenerative diseases in different ways. It disrupts the activity of gut microbiota and exerts negative impacts on GBA. Therefore, multidimensional research is essential to explore the importance of probiotics in the protection of neurodegenerative diseases. Moreover, sufficient clinical trials are required to establish the benefits of probiotic bacteria against neurological disorders. Thus, integrative research can open a new arena to fight against neurodegenerative diseases.