Emerging role of gut microbiota in modulation of neuroinflammation and neurodegeneration with emphasis on Alzheimer's disease

https://doi.org/10.1016/j.pnpbp.2020.110112Get rights and content

Highlights

  • The microbiota-gut-brain axis reflects the complex bidirectional communication network connecting gut microbiota and brain.

  • The gut microbiota seems to play a vital role in regulation of neuroinflammation and neurodegeneration in Alzheimer’s disease.

  • The short chain fatty acids synthesized by gut microbes regulate the integrity of intestinal and blood brain barrier.

  • Altered gut dysbiosis may affect the innate immune function, production of cytokines and inflammatory mediators in brain.

  • Recent studies are focusing on the regulation of gut microbiota to control neuroinflammation and progression of AD.

Abstract

Alzheimer's disease (AD) is a complex multifactorial disease involving chronic neuroinflammation and neurodegeneration. It has been recently recognized that gut microbiota interacts with the brain, and it is termed as microbiota-gut-brain axis. Modulation of this axis has been recently reported to affect the pathogenesis of neurodegenerative diseases, such as AD. Gut microbiota has a pivotal role in regulating multiple neuro-chemical pathways through the highly interconnected gut-brain axis. Recent emerging evidences have highlighted that the intestinal microflora takes part in bidirectional communication between the gut and the brain. Due to this, the researchers have suggested that human gut microflora may even act as the “second brain” and may be responsible for neurodegenerative disorders like Alzheimer's disease. Dysbiosis of gut microbiota can induce increased intestinal permeability and systemic inflammation. This may lead to the development of AD pathologies and cognitive impairment via the neural, immune, endocrine, and metabolic pathways. Thus, the modulation of gut microbiota through personalized diet, oral bacteriotherapy may lead to alteration of gut microbiota their products including amyloid protein. It has been demonstrated that modulation of the gut microbiota induces beneficial effects on neuronal pathways consequently leading to delay the progression of Alzheimer's disease. Thus, this approach may provide a novel therapeutic option for treatment of AD.

Introduction

Alzheimer's disease (AD) is a chronic age-related progressive neurodegenerative disorder pathologically characterized by marked memory loss, cognitive impairment affecting ~45 million people worldwide. The pathological hallmarks of AD include amyloid beta (Aβ) deposition, hyperphosphorylated tau-proteins and neurofibrillary tangles (NFTs) in brain tissue (Kowalski and Mulak, 2019; Bostanciklioglu, 2019; Zhu et al., 2020). These structural and inflammatory lesions lead to a progressive loss of neurons in vulnerable regions of brain leading to AD. Additionally, the microglia and astrocytes are recognized as important contributors to the progression of inflammation. The significant accumulation of Aβ influences microglia (innate immune cells) triggering inflammation. The process of neuroinflammation, in general, is useful to clear Aβ deposition via phagocytosis (Almudena et al., 2013; Chételat, 2013). Nevertheless, the brain mediates several changes in the immune system (immunosenescence) during the process of aging influencing microglia and its associated immune responses (Ryu and McLarnon, 2009; Lee and Landreth, 2010). According to classical amyloid hypothesis, the Aβ42 is thought to initiate the structural and functional neurodegenerative process during AD pathology (Chételat, 2013; Lemere and Masliah, 2010; Sperling et al., 2011). However, the amyloid hypothesis does not fully explain the complexity involved in AD pathogenesis. This is evident from the repeated failures of anti-Aβ42 therapies in clinical trials (Lemere and Masliah, 2010; Hardy and Selkoe, 2002; Castellani and Smith, 2011). Considering the complexity of AD and a constant clinical failure of new anti-AD therapies, it is quite important to look at novel therapeutic targets to control its progression and pathogenesis.

Gut microbiota is identified to play a key role in regulating brain functions by maintaining a homeostatic control on the innate and adaptive immunity (Kowalski and Mulak, 2019; Cryan and Dinan, 2012; Claesson et al., 2012). Several recent literatures have reported an important relationship between the endogenous gut microbiota and the brain, termed as the microbiota-gut-brain (MGB) axis (Collins et al., 2012; Tremaroli and Bäckhed, 2012; Pistollato et al., 2016; Lloyd-Price et al., 2016; Brandscheid et al., 2017; Fang et al., 2020). The modification of gut microbiota as a therapeutic strategy in AD has gained the attention of the researchers in recent last years. This article aims to highlight the vital role of the gut microbiota in regulation of innate and adaptive immune response, neuroinflammation and neurodegeneration in AD.

Section snippets

Gut -brain axis – a crosstalk between gut microbiota and brain immune system

The bidirectional network of gut-brain axis makes it suitable for maintaining the homeostasis throughout the body including gastrointestinal tract as well as brain. The gut is connected to the brain by various pathways including, but not limited to the vagus nerve, tryptophan metabolism, neurotransmitters, immune system, hypothalamic-pituitary-adrenal (HPA) axis and microbial metabolites, majorly the short chain fatty acids (SCFA) (Wd, 2013; Rodríguez et al., 2015; Yano et al., 2015; Heneka et

Role of gut dysbiosis in Alzheimer's disease

The human gut harbor widely diverse and dynamically active population of microorganisms. These gut microbes share symbiotic relationship with the host, and are progressed to harmonize and integrate conserved metabolic signaling, orchestrate homeostasis and boost up the immunity, thereby ensuing its survival (Lloyd-Price et al., 2016; Proctor, 2011; Li et al., 2014; Gill et al., 2006). The functional spectrum of the gut microbiota is beyond the traditional understanding such as maintenance of

Therapeutic strategies for normal gut microbiota restoration

Till date, there has not been any disease-modifying therapy for AD. Emerging studies are focusing on regulating inflammatory response in the MGB-axis to delay the progression of AD. The individual-specific dietary habits have a role in development of gut microbial flora. Several complex dietary plant polysaccharides cannot be digested by human gut enzymes. Such polysaccharides are important for growth of gut bacteria, and are consumed and degraded by these microbes. These food substrates used

Limitations of studies involving gut microbiota and brain interactions

In spite of intense and focused research in the field of association of gut microbiome with neurodegenerative diseases, there are still certain limitations pointing towards a need for better mechanistic understanding of the process. The term, ‘gut dysbiosis’ refers to an imbalance in gut microbiota of the host, and seem to be very generalized and ill-defined. There are considerable niche variations between animal and human microbiome, in addition to inter- and intra-individual differences in

Conclusion

Recent emerging reports have highlighted a key regulatory role of gut microbiota in the normal physiological function of the MGB-axis. Gut microbiota controls the basic aspects of CNS, immunity, and behavior in health and disease. The alteration in gut microbiome is increasingly implicated in progression and pathogenesis of aging and neurodegenerative diseases in animal and human studies (Fang et al., 2020). Dysbiosis of gut microbiota seems to modulate immunological, neuronal, and metabolic

Author contributions

Divya Goyal and Syed Afroz Ali have prepared the first draft of manuscript and have contributed equally. Rakesh Kumar Singh has conceptualized, modified and prepared the final draft for submission.

Declaration of competing interest

The authors state no conflict of interest. All authors have read and approved the final version of manuscript for submission.

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