Role Of Pattern Recognition Receptors And The Microbiota in Neurological Disorders Part 1

Abstract

In recent years, the gut microbiota has been increasingly implicated in the development of many extraintestinal disorders, including neurodevelopmental and neurodegenerative disorders. 

Recent studies have shown that the gut microbiome plays an important role in cognition. It can affect memory and learning ability. For most people, this may be a surprising concept.

The gut microbiome is an ecosystem composed of various microorganisms, including bacteria, fungi, viruses, etc. These microorganisms can affect our physical and mental health by secreting metabolites into the blood and brain.

Recent studies have shown that the gut microbiome can affect human behavior and cognitive function. For example, a healthy gut flora can improve anxiety, depression, and mood instability. In addition, it can help strengthen memory and learning ability, which is helpful for both learning and work.

Our gut flora can affect our brain in different ways, such as increasing the permeability of the blood-brain barrier, so that certain metabolites can pass through the brain. This substance can promote neuronal development and synaptic formation, as well as the plasticity of the nervous system.

Some studies have also found that improvements in the gut microbiome can reduce the risk of cognitive decline in the elderly. Moreover, methods to increase the abundance of gut flora are very practical and feasible. We can promote intestinal nutrient reabsorption by changing our diet and lifestyle and increasing the intake of probiotics, which will have a positive impact on the regulation of the gut microbiome.

In conclusion, a happy and healthy gut microbiome is a key factor in promoting brain health and improving learning and memory. We should learn how to keep our gut healthy to achieve better performance in learning and work. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because it has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidative and inflammatory responses in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

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Despite this growing connection, our understanding of the precise mechanisms behind these effects is currently lacking. Pattern recognition receptors (PRRs) are important innate immune proteins expressed on the surface and within the cytoplasm of a multitude of cells, both immune and otherwise, including epithelial, endothelial, and neuronal. 

PRRs comprise four major subfamilies: the Toll-like receptors (TLRs), the nucleotide-binding oligomerization domain leucine-rich repeats-containing receptors (NLRs), the retinoic acid-inducible gene 1-like receptors, and the C-type lectin receptors. 

Recognition of commensal bacteria by PRRs is critical for maintaining host-microbe interactions and homeostasis, including behavior. 

The expression of PRRs on multiple cell types makes them a highly interesting and novel target for the regulation of host-microbe signaling, which may lead to gut-brain signaling. Emerging evidence indicates that two of the four known families of PRRs (the NLRs and the TLRs) are involved in the pathogenesis of neurodevelopmental and neurodegenerative disorders via the gut-brain axis. 

Taken together, increasing evidence supports the role of these PRRs in the development of neurological disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis, via the microbiota–gut-brain axis.

Graphical Abstract

The microbiota-gut-brain (MGB) axis is involved in the pathogenesis of diseases both in the brain, including neurodevelopmental and neurodegenerative disorders, and diseases of the gut, including inflammatory bowel diseases. 

Pattern recognition receptors (PRRs) such as TLRs and NLRs are implicated in the development of these complex gut-brain disorders, in part via dysbiosis of the gut microbiota and alterations in the immune response.

Keywords

gastrointestinal tract; microbiota; neurodegenerative; pattern recognition receptor.

Introduction

The understanding of the importance of the gut microbiota and its role in the regulation of the physiology of the brain has grown exponentially in recent years. Humans are home to millions of microorganisms that reside both on the body (on the surface of the skin) and inside the body (gastrointestinal (GI) tract, nose, and lungs). 

In fact, given this complex role, the gut microbiota is now considered to be a virtual organ in and of itself (Baquero & Nombela, 2012). Colonization of the microbiota begins at birth (Davis, 2016), with the early neonatal microbiome being dynamic and continuously modified as the child develops (Zhuang et al. 2019b). 

For example, breastfed infants are host to species involved in the metabolism of colostrum present in breast milk, most notably Bifidobacteria infantis (Jiang et al. 2018). 

Upon the introduction of solid food, the infant microbiome shifts towards a more adult-like composition, increasing its diversity and complexity (Ku et al. 2020). 

Additionally, studies have found that the gut microbiota is essential for the correct development of both the brain (Braniste et al. 2014; Lu et al. 2018) and the immune system (Schwarzer et al. 2019) beginning in early life. Therefore, recognition of commensal bacteria by the innate immune system is critical for maintaining host-microbe interactions and homeostasis, including behavior.

Pattern recognition receptors

Pattern recognition receptors (PRRs) are part of the first line of innate immune defense following a pathological insult. They are expressed on multiple immunes (leukocytes, macrophages, etc.) and non-immune cells (epithelial cells, endothelial cells, and neurons) and respond to a variety of bacterial and viral ligands, including peptidoglycan (PGN), lipopolysaccharide (LPS), double-stranded RNA, and CpG DNA, for example. 

PRRs comprise four major subfamilies: the Toll-like receptors (TLRs), the nucleotide-binding oligomerization domain leucine-rich repeats-containing receptors (NLRs), the retinoic acid-inducible gene 1-like receptors (RLRs), and the C-type lectin receptors (Walsh et al. 2013). 

In response to a pathological insult, the innate immune response is initiated by PRRs through the binding of pathogen-associated molecular patterns (PAMPs), in turn triggering multiple intracellular signaling pathways, such as nuclear factor-κB (NF-κB), interferon regulatory factors, and mitogen-activated protein kinase, resulting in the production of cytokines and chemokines (Fawkner-Corbett et al. 2017). 

For this review, we will focus on the TLR and the NLR families. Despite continuous exposure to PAMPs in the lumen of the GI tract, intestinal epithelial cells (IECs) do not typically respond to commensal bacteria (Round & Mazmanian, 2009). 

This is due in part to PRR expression restricted to intracellular compartments, or basolateral expression in IECs, limiting their exposure to luminal PAMPs. Commensal bacteria are beneficial to the host (LeBlanc et al. 2017; Hiippala et al. 2018; Balakrishnan et al. 2019) by helping maintain immune surveillance. 

PRRs are crucial in maintaining these homeostatic interactions between the gut and the commensal microbiota, able to distinguish between pathogenic and commensal organisms. 

For example, distinct molecular signatures of the bacterial cell wall component PGN can elicit a variety of host immune gene patterns (Bersch et al. 2020). Commensal bacteria can drive myeloid differentiation primary response protein 88 (MyD88) signaling through TLR stimulation, inducing anti-microbial peptide production by Paneth cells that restrict bacterial colonization on the surface of the intestine, thereby limiting pro-inflammatory immune responses (Vaishnava et al. 2011). 

While other innate immune receptors also help maintain the balance between the host and the microbiota, these studies highlight a critical role for PRRs in this function. 

Dysbiosis, or the disruption of the composition of the gut microbiota, has been implicated in numerous diseases not only those that impact the GI tract (e.g. inflammatory bowel diseases (IBD); Lupp et al. 2007; Kang et al. 2010) but also in diseases of the brain (e.g. neurodevelopmental and neurodegenerative diseases; Sampson et al. 2016; Hughes et al. 2018; Sun & Shen, 2018), lung (e.g. asthma; Liu et al. 2019; Zhuang et al. 2019a) and immune system (e.g. rheumatoid arthritis (Liu et al. 2013) and multiple sclerosis (MS; Cantarel et al. 2015)). 

While it remains unclear whether dysbiosis is causative or correlative in many cases, its impact on GI mucosal barrier function and host-microbe interactions can disrupt immune homeostasis in the rest of the body. 

Consequently, altered host-microbe interactions and subsequent GI pathophysiology could allow the commensal microbiota to gain access to the surrounding tissue, potentially leading to inflammation and damage (Garrett et al. 2010). 

Here we discuss the role of two PRR families, NLRs and TLRs, that are implicated in the development of neurological disorders and the intersection of the microbiota and the innate immune system (Fig. 1).

Nod-like receptors

The NLR receptor family can be divided into three different sub-groups: (1) inflammasome forming NLRs (i.e. NLRP1, NLRP3), (2) positive regulatory NLRs (i.e. Nod1, Nod2), and (3) negative regulatory NLRs (i.e. NLRx1, NLRC3), each with a separate and distinct signaling pathway and downstream effect (Coutermarsh-Ott et al. 2016) (Fig. 2). 

The inflammasome-forming group of NLRs consists of NLRP1, NLRP3, NLRP6, NLRP4, and NLRC5, which form multiprotein complexes. These NLR proteins multiplex with, for example, apoptosis-associated speck-like protein and procaspase-1, to initiate proinflammatory cytokine expression. 

Inflammasome complexes, including NLRP1 and NLRP3, have been implicated in the development of many neurological disorders, for example, several single nucleotide polymorphisms of NLRP1 have been associated with Alzheimer's disease (AD). 

Additionally, NLRP1 mRNA is upregulated in neurons of AD patients (Pontillo et al. 2012). Furthermore, amyloid-β plaques have been shown to stimulate purinergic receptors initiating activation of the inflammasome, in turn contributing to late-stage AD (Tan et al. 2014). 

In a mouse model of chronic constriction injury-induced neuropathic pain, the NLRP1 inflammasome was significantly activated in the hippocampus. Inhibition of the downstream product of NLRP1 attenuated the observed depression-like behavior in these mice (Li et al. 2019). 

Dysbiosis has been observed in AD patients, suggesting a possible avenue of further research to fully elucidate the mechanisms and interconnectivity of NLRP1 in the brain with the host microbiota. In line with these findings, NLRP3 signaling has also been implicated in the development of major depressive disorder via the hypothalamic–pituitary–adrenal axis (Inserra et al. 2018). 

In Parkinson's disease (PD) patients, NLRP3 levels were found to be upregulated in the serum, correlating with α-synuclein levels, a hallmark of disease severity (Chatterjee et al. 2020). 

Additionally, in mice, it was found that α-synuclein activates NLRP3 via microglial endocytosis (Zhou et al. 2016). Deficiency in caspase-1, a member of the NLRP3 inflammasome complex, significantly reduced microglial activation indicating a possible role for the NLRP3 inflammasome in PD pathogenesis (Zhou et al. 2016; Gordon et al. 2018). 

Taken together, this suggests that intestinal dysbiosis may trigger altered NLRP signaling both in the gut and in the brain, leading to neurodegeneration in the brain. 

The nucleotide-binding oligomerization domain (NOD) proteins are a family of positive regulatory NLRs that detect fragments within the cell walls of many bacteria, activating signaling pathways driving pro-inflammatory and anti-microbial responses. The two best-characterized members of the NLR family are Nod1 and Nod2. 

They are unique in their function in that they sense bacterial PGN in the host cytosol as opposed to microbial ligands at the cell surface or within endosomes. Nod1 and Nod2 regulate activation of NF-κB transcription via a receptor-interacting serine/threonine-protein kinase 2-dependent mechanism in response to unique PGN fragments leading to the expression of proinflammatory cytokines (Caruso et al. 2014). 

Nod1 is ubiquitously expressed in many cell types, primarily in immune cells (Uhlen et al. 2015), neurons, endothelial cells, and epithelial cells of many organs (Caruso et al. 2014). 

While Nod2 expression is slightly more restricted, it has been identified in lymphocytes, Paneth cells, and IECs (Franchi et al. 2009). Importantly, studies have shown that both Nod1 and Nod2 receptors are also expressed in the brain, including within the hippocampus on multiple cell types such as neurons, astrocytes, and microglia (Ogura et al. 2003; Arentsen et al. 2017) suggesting that they play an important role within the central nervous system. 

Nod1 and Nod2 serve a critical role in responding to specific bacterial pathogens. For example, the enteric mouse pathogen Citrobacter rodentium induces an IL-17 response via a Nod1- and Nod2-dependent pathway (Rubino et al. 2013). 

Mice deficient in Nod1 and Nod2 are highly susceptible to infection with Listeria when they are first exposed to LPS or E. coli. The results of this study implicate that cells consistently exposed to microbial stimuli, such as in the GI tract, are characterized by low TLR expression and can become resensitized to commensal bacteria in the absence of Nod1 and Nod2 (Kim et al. 2008). 

Several studies have indicated that the recognition of pathogenic bacteria in intestinal cells lacking TLRs relies on Nod1 (Girardin et al. 2001; Zilbauer et al. 2007).

As Nod1 and Nod2 are activated by PGN, they are also important in maintaining gut homeostasis by priming the immune system in the absence of infection, employing the gut microbiota as its stimulus (Clarke et al. 2010; Claes et al. 2015). 

Mice deficient in both Nod1 and Nod2 (NodDKO) display stress-induced anxiety-like behavior, cognitive impairment, and depression (Pusceddu et al. 2019). In the hippocampus, NodDKO mice displayed decreased 5-HT at baseline and following acute stress. 

In particular, Nod1 expression on IECs was identified as a specific factor in regulating the stress response and serotonergic signaling, but the precise signaling mechanisms behind this effect have yet to be fully elucidated (Pusceddu et al. 2019). 

Numerous studies have implicated the NLR family as important PRRs in the development of neurological diseases mediated by the gut microbiota. However, much is still unclear about the mechanism of action of these effects. Given these findings, the NLR family, in particular Nod1 and Nod2, remain attractive targets for the development of therapeutics for the treatment of many of the aforementioned neurological disorders. 

PGN derived from commensal gut bacteria can cross the blood-brain barrier into the central nervous system (CNS), with levels of PGN within the brain increasing with age (Arentsen et al. 2017). 

Several PGN-sensing molecules, such as the peptidoglycan recognition protein (PGRP) PRRs and NLRs, are highly expressed in the neonatal brain during early development and are highly susceptible to changes in the gut microbiota (Arentsen et al. 2017). 

Knockout of PGN recognition molecule 2 (Pglyrp2) induces behavioral changes and alterations in the autism spectrum disorder risk gene c-Met in a sex-specific manner (Arentsen et al. 2017). Taken together, these findings highlight a novel role for PRRs in maintaining behavior and CNS function.

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