key: cord-0878646-h38i12jf
authors: Li, Kunyu; Ly, Kevin; Mehta, Sunali; Braithwaite, Antony
title: Importance of crosstalk between the microbiota and the neuroimmune system for tissue homeostasis
date: 2022-05-23
journal: Clin Transl Immunology
DOI: 10.1002/cti2.1394
sha: 52c7499cc1b33f0466d67d2ca144590dd96e7028
doc_id: 878646
cord_uid: h38i12jf

The principal function of inflammation is cellular defence against ‘danger signals’ such as tissue injury and pathogen infection to maintain the homeostasis of the organism. The initiation and progression of inflammation are not autonomous as there is substantial evidence that inflammation is known to be strongly influenced by ‘neuroimmune crosstalk’, involving the production and expression of soluble signalling molecules that interact with cell surface receptors. In addition, microbiota have been found to be involved in the development and function of the nervous and immune systems and play an important role in health and disease. Herein, we provide an outline of the mechanisms of neuroimmune communication in the regulation of inflammation and immune response and then provide evidence for the involvement of microbiota in the development and functions of the host nervous and immune systems. It appears that the nervous and immune systems in multicellular organisms have co‐evolved with the microbiota, such that all components are in communication to maximise the ability of the organism to adapt to a wide range of environmental stresses to maintain or restore tissue homeostasis.

The immune system is a built-in defence system in complex organisms that exists to protect the host from health threats such as tissue injury, pathogen infection and tumorigenesis. During immune defence, the biological process of inflammation is responsible for initiating an immune response. This involves the production and secretion of inflammatory cytokines and chemokines, which, together with the expression of cell surface receptors, form signalling cascades that integrate both innate and adaptive immune cells into the immune response. It was originally thought that the cells in the immune system are solely responsible for facilitating inflammation and immune responses. However, there are clear regulatory links with the nervous system that show the immune system is not autonomous, but functions in close association with the nervous system. It is now clear that these two systems are intimately connected and reciprocally influence the function of each other, and this constitutes the neuroimmune network. 1 Anatomically, nerves and immune cells are connected throughout the human body. Mechanistically, nerve cells and immune cells produce soluble factors that communicate through their cognate receptors to regulate immune processes such as inflammation. Indeed, the central nervous system (CNS) has been suggested to be a virtual secondary lymphoid organ that is involved in the regulation of immune responses throughout the human body. 2 Communication between neurons and immune cells in the regulation of inflammation contributes not only to cellular defence, but also to inflammatory-associated pathology. As a result of restrictive entry of immune cells into the brain, brain cells other than the neurons, such as microglia and astrocytes, also act as a first line of defence to control inflammation and immune responses in both CNS and peripheral tissues. [3] [4] [5] [6] [7] [8] [9] In addition to communication between different cells within the organism, interspecies communication between the microbiota and host brain cells, neurons and immune cells occurs, and can have an impact on health and disease. Herein, we briefly summarise the involvement of neurons and immune cells in the regulation of inflammation, as well as the involvement of microbiota in the development of the nerve and immune systems. We then focus on recent findings on the contribution of microbiota in the regulation of cellular defence.

The initiation of immune responses All living organisms are constantly exposed to environmental threats and potential invasion by harmful substances. To protect against these dangers, mammalian hosts operate a surveillance mechanism that is commonly known as immunosurveillance. It is a monitoring process of the immune system to detect pathogen invasion and neoplastically transformed cells and destroy them to enhance the survival of the host. 10 This task is performed by the joint action of the two arms of the immune system: the innate and the adaptive. Innate immunity is the first line of defence against pathogen invasion, and innate immune cells react immediately upon detection of 'danger' in an antigen non-specific manner. Adaptive immunity is the second line of defence that requires the help of innate immune cells for activation and adaptive immune cells react to their targets in an antigen-specific manner. The family of pathogen-associated molecular patterns (PAMPs) that are derived from microbes and damage-associated molecular patterns (DAMPs) derived from host cells are the main categories of 'danger' molecules that initiate innate immune responses and inflammation. 11 Upon pathogen invasion or tissue damage, these molecules are released and detected by pattern recognition receptors (PRRs) that are expressed by innate surveillance immune cells. Toll-like receptors (TLRs) are a class of PRRs that sense the presence of conserved microbial molecular patterns for early immune recognition of a pathogen. The binding of PAMPs or DAMPs to TLRs on innate immune cells such as macrophages initiates infectious or non-infectious acute inflammatory responses, respectively. These events result in intracellular cascades such as the Nuclear factorkappa B (NF-jB) pathway to initiate the transcription of both pro-and anti-inflammatory cytokines. 12 This leads to subsequent activation and recruitment of adaptive lymphocytes to the site of inflammation, where cytokines such as IFNc, IL-10 or TGF-b are released to clear the infection and/or to settle down inflammation and initiate tissue repair ( Figure 1 ). When acute inflammation fails to settle, it can progress to prolonged, low-level inflammation resulting in chronic conditions such as autoimmune diseases and cancer. Therefore, the level and the process of inflammation are tightly regulated to avoid inflammation-associated pathology.

The nervous system regulates numerous physiological responses, including movement, digestion, body temperature, stress and secretion of various enzymes and hormones. All these responses are regulated by communication between neurons of different parts of the nervous system, with the central nervous system (CNS) in the brain and the peripheral nervous system (PNS) that connects the CNS to every part of the body through the spinal cord. Neurons communicate with each other to send messages to and from the brain and spinal cord to various parts of the body by both electrical and chemical signals involving a range of soluble molecules that interact with cell surface receptors. 13 The signalling process initiates as dendrites, which receive external stimuli followed by the cell body generating an electrical signal (action potential) that propagates along the axon to the nerve terminal. This results in the release of chemical signalling molecules as neuronal messengers, such as neurotransmitters, 14 to regulate the responses of target cells such as neurons, muscles and immune cells (Figure 2a) . Cells of the nerve system participate in immune surveillance and cellular defence at different levels and regions via both neural and non-neural communicating pathways. 15 These include the blood-brain barrier (BBB) pathway, 16 the neuroendocrine pathways 17 and the microbiotagut-brain (MGB) axis, 18 in which soluble molecules such as neurotransmitters, hormones and cytokines are the main communication tools. 1, 19 Neuroimmune regulation of inflammation and cellular defence

Research in the area of neuroimmunology has revealed that neurological signalling utilising soluble molecules is involved in the communication between neurons and immune cells, which regulates inflammation and immune responses.

Neurons have been found to express various cytokine and chemokine receptors such as the IL-6 receptor and CXCR4 that allow them to receive proinflammatory stimuli from immune cells. [20] [21] [22] Treatment with TNF-a and IL-1b has been shown to evoke a neural response in mouse vagus nerve cells in a dose-dependent manner. 23 Indeed, these proinflammatory cytokines were found to be more effective than LPS, norepinephrine, and nerve growth factor for activating primary neurons in cultures. 24 In addition to immune cells, human and mouse neurons express TLRs 25,26 that enable them to directly detect danger signals. 27, 28 Expression of TLR-7 by mouse airway neurons was also found to be increased after stimulation with neuropeptide substance P and contributes to airway inflammation and immune defence. 29 Activation of sensory neurons through either cytokine or PAMPs/ DAMPs leads to the production of neuronal signalling molecules, including neurotransmitters (reviewed in Pinho-Ribeiro et al. 30 ; Figure 2b ). In addition, neurons are also capable of producing cytokines to regulate inflammation. This has been observed where stimulation of P2X purinoceptor 7 receptors (P2X7Rs) on the neural membrane trigger the release of multiple cytokines by mouse neurons and provide neuroprotection. 31 Similar to neurons, many subsets of immune cells have been found to express receptors for various neurotransmitters as well as being capable of producing neurotransmitters upon activation. 32,33 Serotonin, which is a multifunctional neurotransmitter, has been found to drive both proinflammatory 34 and antiinflammatory 35,36 responses through serotonin receptors expressed on mouse immune cells such as T cells. Gamma-aminobutyric acid (GABA), which is a neurotransmitter in the brain and pancreatic islets, has been found to inhibit the release of inflammatory cytokines by human peripheral blood mononuclear cells (PBMC) and CD4 + T cells by blocking calcium signalling and NF-jB activity. 37,38 Treatment with GABA or GABAergic drugs in mouse bone marrow-derived macrophages (BMDM) inhibited the production of proinflammatory cytokines TNF-a and IL-6 but enhanced antimicrobial responses of BMDM through intracellular calcium release and autophagy. 39 Recent studies by two independent groups have both reported that mouse T cellderived acetylcholine promotes immune infiltration and the production of proinflammatory cytokines at the site of pathogen invasion to clear the infection. 40, 41 Therefore, signalling through neurotransmitters and their receptors can lead to either pro-or anti-inflammatory responses, depending on the local stimuli and the target cells they are acting on (reviewed in Hodo et al.). 42 Overall, cells of the immune and nervous systems communicate with each other through a common language using soluble molecules and cell surface receptors. Such signalling processes allows the integration of neurological and immunological signals to detect pathogen invasion, regulate inflammation and orchestrate tissue homeostasis. 33,43,44

It was originally considered that the foetal and perinatal immune systems develop in a relatively sterile environment where microbial and maternal immune cells have restricted entry. However, the human placenta and amniotic fluid have been found to harbour a unique microbiome, which shares features of microbiota detected in the infant meconium and might contribute to the initiation of microbiota colonisation in the gut. 45, 46 In addition, a recent human study discovered the presence of several types of bacteria in the foetal gut, skin, placenta and lungs in the 2 nd trimester of gestation. 47 These bacteria were found to be able to induce activation of memory T cells isolated from the foetal mesenteric lymph node, suggesting their contribution in priming the foetal immune cells during early human development. 47 It is now clear that microbial encounters occur in at least three stages of early mammalian life: in utero during pregnancy, microbes acquired at the time of delivery, and microbes established postnatally by the acquisition of maternal and environmental bacteria. [48] [49] [50] The early life exposures to microbiota imprint long-lasting changes in the offspring's nervous and immune systems that affect the health and risk of diseases throughout life. 51-55 The enteric nervous system (ENS), which is part of the autonomic nervous system (ANS), is a unique nervous system that largely functions independently from but does communicate with the CNS. Innervation of the gut by a network of ENS provides a unique opportunity for gut microbiota to form a multidirectional communication axis with the local neurons, immune cells and also cells of the brain. 56 This forms the microbiota-gut-brain (MGB) axis, which drives a variety of processes including intestinal barrier function, blood-brain barrier (BBB) function and neuroimmune crosstalk to regulate not only brain health 57 but also the development and function of the host defence systems (reviewed in Bistoletti et al. 18 and others). [58] [59] [60] Microbiota are important for the development of the nervous and immune system

The importance of microbiota in the development and health of the brain and CNS has been clearly shown in mice lacking gut microbiota, where development of anxiolytic-like behaviour and neurodegenerative disease was observed. 61-63 Compared to specific pathogen-free mice, germfree mice were found to have altered expression of genes involved in signalling mechanisms that affect motor control and anxiety behaviour. 64 Mice transplanted with gut microbiota from patients with neurobehavioral disorders also showed altered brain structure and anxious behaviour. 65 Studies in obese and non-obese individuals also found that alterations in microbial composition affect brain microstructure and cognitive function. 66 Maternal probiotic administration of mice with Lactobacillus acidophilus and Bifidobacterium infantis has been shown to promote neuronal and oligodendrocyte progenitor cell development in the offspring. 67 At the molecular level, the microbiota has been found to not only regulate the production, transportation and functioning of neurotransmitters but are also capable of producing neurotransmitters to regulate the development of the brain and CNS. 68, 69 Bifidobacteria, which are a group of commensal bacteria in the gut, have been found to harbour the gene and enzymatic machinery to generate neurotransmitters such as GABA and tyrosine. 70 Altering the composition of the gut microbiota with a high-sugar and high-fat diet altered neurotransmitter metabolism and affected brain function. 71 Although the precise molecular mechanisms of microbiota interaction with host cells are largely unknown, there is growing evidence that the microbiota interact with host cells and affect their development and function through microbial-derived soluble molecules (reviewed in Silva et al. 72 and Wall et al.). 73 Short-chain fatty acids (SCFAs) are the one of the most studied metabolites produced by the gut microbiota through fermentation of dietary fibre and indigestible polysaccharides. Microbialderived SCFAs has been found to promote the production of serotonin by host cells. 74 This contributes to the maintenance of the neuroanatomy and maturation of the enteric nervous system (ENS). 75 Mice fed with a diet containing a low level of SCFAs during gestation have been found to have impaired neurocognitive functions of the offspring. 76 Germ-free mice and mice deficient for SCFA receptors have both been found to display global defects in the maturation and function of microglial cells, leading to impaired cellular defence in the CNS. 77 In another mouse study, microbial metabolites other than SCFAs derived from spore-forming gut bacteria were also found to serve as signalling molecules to regulate the biosynthesis of serotonin, contributing to gastrointestinal motility and platelet function. 78 To endow the newborn with the ability to mount an immune response against pathogen invasion after birth, mammalian immunity starts to develop during the prenatal period of life and continues to evolve throughout the lifetime of the individual. 79 Maternal microbiota and early life microbiota exposure during birth and through breast milk have been found to influence the lineage development and the education of the hematopoietic cells, as well as functional responses of immune cells in the newborn. 49, 80 The effects of microbiota on immune cells have also been found to occur via their metabolites. Mucosal-associated invariant T cells (MAIT) are gut resident innate immune cells that play an important role in gut inflammation and defence against pathogen infection. Bacterial riboflavinderived antigen, 5-OP-RU, was found to be able to travel from mucosal surfaces to the thymus and be taken up by the major histocompatibility complex class I-related protein (MR1) to promote the generation of MAIT. 81, 82 Consequently, early life exposure to microbial riboflavin can regulate the development of and also interact with MAIT cells, to promote gut immunity and homeostasis. 83 The SCFA butyrate, a major gut metabolite, has also been found to facilitate either the differentiation of T regulatory cells or effector T helper-1 cells under different conditions, suggesting that the influence of gut microbiota on the differentiation of immune cells is subjected to the local environment. 84 

In addition to the development of the nervous and immune systems, microbiota influence the ability of neurons, brain and immune cells to regulate inflammation. 85 Astrocytes are a subtype of glial cells that have a wide range of functions within the CNS, including structural support in the brain, uptake and release of neurotransmitters, defence against oxidative stress, tissue repair and maintenance of the BBB. [86] [87] [88] They have also been reported to regulate inflammation and contribute to a range of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. 89 A recent study in germ-free mice showed that microbiota are required for a subset of LAMP1 + TRAIL + astrocytes to fight inflammation in a mouse model of autoimmune encephalomyelitis (EAE). Using specific gene knockout mice, these astrocytes were found to limit inflammation in the CNS by inducing apoptosis of inflammatory T cells through binding of TRAIL to death receptor 5 (DR5) expressed on T cells. 90 More importantly, the expression of TRAIL on astrocytes was dependent on the production of IFN-c by meningeal natural killer cells (NK), which were induced by the microbiota. 90 This study identifies a previously unknown mechanism of how microbiota modulate the production of proinflammatory cytokines by brain 'immune cells' to support brain health.

Another mechanism of microbiota interaction with the CNS is through the BBB, where they can alter BBB integrity, change BBB transport rates and induce the release of neuroimmune substances from the barrier cells (reviewed in Logsdon et al.) . 91 The microbiota have also been found to protect against inflammation in the neonatal brain by regulating BBB function and preventing IL-1b-induced microglia and astrocyte activation through NF-jB/IjB signalling in the developing brain. 67 Aryl hydrocarbon receptor (AhR) is a transcription factor found in virtually all neurons and some subsets of immune cells. It is involved in the development of nervous and immune systems, acts as a biosensor in intestinal neural signalling to regulate intestinal immunity and regulates the onset and progression of inflammation. [92] [93] [94] [95] [96] [97] The microbiota have been found to induce neural expression of AhR, which enable the neurons to sense and respond to the luminal environment by upregulating neuron-specific effector mechanisms. 96 The effects of microbiota on AhR have been found to occur via SCFAs where they upregulate AhR signalling to limit intestinal inflammation by mediating IL-10 and IL-22 production. 98 An interdependent relationship has been found between the microbiota and AhR signalling in regulating inflammation. Mice fed with a diet lacking AhR ligands that drive AhR signalling 99 were found to have alterations of the gut microbiota correlating with reduced IgA levels. 100 Mice fed with AhR ligands-free diet also had enhanced susceptibility to dextran sodium sulphate (DSS) induced colitis that correlated with alterations in the microbiome. 99 In addition to their indirect effects on immune responses, microbiota and their derivatives can also affect immune cells directly to modulate inflammation. CD4 -/CD8double-negative T cells (DNTs), which are important players in autoimmune disease, were found to be dramatically increased in both the brain and peripheral blood of stroke patients and a mouse model of neuroinflammation. 101 SCFAs derived from intestinal bacteria of patients with Alzheimer's disease were recently found to activate intestinal NLRP3 inflammasome, leading to upregulation of proinflammatory cytokine production by intestinal DNTs. 102 In addition, bacterial N-formylated peptides and the poreforming toxin a-haemolysin have also been shown to induce calcium influx and an action potential, which directly activate sensory neurons to modulate inflammation and immune infiltration. 103 Microbiota dysbiosis is associated with neuroimmune dysregulation of inflammation A highly diverse gut microbial community has beneficial effects on brain health, the function of the nervous immune system and cellular defence against pathogen infection. 104, 105 Under normal physiological conditions, gut commensal microbes establish a mutualism, or symbiosis with the host that allows better nutrient supply, improved metabolic attributes such as vitamins and fatty acids, and defence against invasion by pathogenic microorganisms. [106] [107] [108] However, in some instances, the symbiotic relationship is impaired leading to dysbiosis. Dysbiosis is characterised by disruption to microbial homeostasis, reduced microbial diversity and loss of beneficial bacteria. It is associated with a range of diseases and complications, including inflammation-induced pathology, 109 autoimmune diseases, 110-113 impaired immune response to vaccination and viral infection, 114, 115 and defective brain function and brain inflammation. 116, 117 Multiple factors are known to lead to microbial dysbiosis, and antibiotic usage is the most studied. Experimental evidence suggests that antibiotic use during pregnancy, infancy and childhood dramatically alters the composition of the gut microbiota, leading to dysbiosis that correlates with long-lasting health complications. 118 Administration of antibiotics transiently alters the microbial composition and affect central levels of brain-derived neurotrophic factors and behaviour in mice. 119 In a recent study, altering the microbial composition by antibiotics was found to decrease the levels of serotonin and dopamine in the hypothalamus and the circulation of piglets. 120 Decreased bacteria-derived SCFAs by antibiotic usage also affect the ability of the gut microbiota to control intestinal inflammation and alter the immune response and neuronal signalling in the gut. [121] [122] [123] [124] The pathogenic mechanisms caused by microbial dysbiosis are associated with alterations of intestinal permeability, BBB function and metabolic pathways of several neurotransmitters affecting neuroimmune regulation of inflammation. [125] [126] [127] [128] Moreover, infection by SARS-CoV-2 was reported to alter the composition of gut microbiota and promote intestinal and systemic inflammation leading to BBB damage. 129 These in turn are associated with activation of microglia and astrocytes to promote the degeneration of neurons and inflammation in the brain. [130] [131] [132] Therefore, dysbiosis caused by either antibiotic or pathogen infection sets up a feedback circle to further promote dysbiosis and inflammation.

The HPA axis is a neuroendocrine mechanism that mediates a stress response to control physiological and immunological responses. Although stress is very common, not all stresses are associated with neuroinflammation/pathology and the nuances that link one to the other are still inconclusive. While short-term stress can enhance immunoprotection, chronic stress is known to suppress protective immune responses and exacerbate inflammation to promote pathological immune responses. [133] [134] [135] In a mouse study, chronic stress was found to stimulate the release of neuron-derived damage signals, which attract and activate microglia to eliminate the 'distressed' neurons. 136 This caused destruction of the connection between the distressed neuron with other neurons, leading to loss of connectivity between brain cells and hence functional complications and brain pathology. Norepinephrine, which acts both as a stress hormone and neurotransmitter, has been found to compromise immune responses by attenuating the production of IFN-c and augmenting IL-10 production in vitro, in mice and humans after LPS challenge. 137 Stress hormones such as glucocorticoid have been shown to promote cancer progression by suppressing the production of anti-tumor IFN-c and inducing immune dyfunction. [138] [139] [140] [141] In addition to direct immunomodulatory effects through stress hormones, stress can also lead to neuroimmune dysregulation of inflammation through microbial dysbiosis. Both animal and human research on the effects of different stress paradigms have found that chronic stress and early life stress affect the structure and function of the gut microbiota, which in turn affects immunoregulatory responses and the microbiotagut-brain axis. [142] [143] [144] [145] A study in an experimental model of psychological stress also showed that stress-induced microbial dysbiosis was associated with compromised intestinal and BBB function in rodents. 138 The association between neurological stress and dysbiosis has also been demonstrated in a mouse study in which maternal stress altered the vaginal microbiome, which in turn affected the microbial composition in the neonatal gut. 146 This corresponded with changes in metabolite profiles and disruption of amino acid profiles, which affected neonatal brain development and increased risk of neurological disorders. 146, 147 Early life stress has been shown to increase plasma corticosterone that was associated with an increase in intestinal permeability of the immature gut in 10-day-old rat pups. 148 Furthermore, chronic stress also enhanced the expansion of inflammation-promoting bacteria, leading to dysbiosis, compromised function of the mucosal barrier and facilitating inflammation as shown in a mouse model of DSS-induced colitis. 149 Besides neurological stress, gut inflammation in various contexts, including pathogen infection, 150 chemical treatment 151 and defective immunity, 152 has also been found to drive bacterial dysbiosis as the inflamed gut is particularly conducive to the blooms of pathogenic but not to symbiotic microbes. 153 Gut microbiota isolated from mice that had brain inflammation can also alter brain functional connectivity when transplanted into germ-free mice. 154 For example, Akkermansia muciniphila (A. muciniphila), which is a species of human intestinal mucin-degrading bacterium, has been shown to have anti-inflammation effects 155, 156 and alters gut barrier function. 157 In a recent study, expansion of A. muciniphila in the gut was shown to upregulate the T regulatory cell response to ameliorate neuroinflammation in an experimental mouse model of autoimmune encephalomyelitis (EAE). 158 Collectively, these findings suggest that inflammation, chronic stress and microbial dysbiosis are closely associated and interplay with each other to influence the outcome of neuroimmune regulation. 127 Therefore, the health of the gut and brain is interlinked, as intestinal inflammatory disorders and many disorders of the central nervous system (CNS) are often accompanied by each other, which are all related to the dysregulation of inflammation and compromised immune mechanisms. 159, 160 The utilisation of host neuronal factors by pathogens to affect immune defence

The microbiota can sense changes in the host environment to adjust their responses to the host to benefit their growth. Access to iron is important for bacterial survival and growth during infection. Therefore, sequestering iron is one of the strategies utilised by mammalian hosts to prevent the growth of pathogens. 161 However, pathogenic Escherichia coli O157:H7 and Salmonella enterica serovar Typhimurium have been found to express genes that allow them to respond to catecholamines and norepinephrine to increase iron acquisition to enhance pathogen survival. 162 These neurotransmitters also act as chemoattractants to increase mobility and upregulate the expression of genes that are associated with bacterial colonisation and virulence. 162 Some pathogens have been reported to hijack the host regulatory mechanisms to facilitate their survival and infection. Staphylococcus aureus (S. aureus) has also been shown to be able to modulate inflammation by inducing calcium flux and action potentials in the host, which activates the sensory neurons to modulate an inflammatory response. 103 Streptococcus pyogenes are also able to directly activate nociceptors (a type of sensory neurons) by releasing streptomycin S. 163 Activation of nociceptor leads to the release of neuropeptide calcitonin gene-related peptide (CGRP) to inhibit the recruitment of neutrophils and phagocytic killing of S. pyogenes. 163 These findings suggest that pathogenic microorganisms promote their survival by evading the host defence systems.

The ability of the microbiota to regulate their growth in response to environmental cues is largely because of a fundamental microbial system, the Quorum sensing (QS), which is a cellcell communication process that bacteria use to monitor local population density. 164 It relies on the production and detection of group-level response to chemical signalling molecules called autoinducers. 165 As bacteria reproduce, an increase in the concentration of autoinducers allows bacteria to detect and respond to cell population density and nutrient deprivation in the environment by altering the programme of gene expression. 165, 166 QS has been found to regulate a variety of physiological functions in bacteria, including symbiosis, virulence, antibiotic production, sporulation and formation of biofilm/ bacterial colonies. [167] [168] [169] [170] [171] Thus, communication via the production of QS molecules allows individual bacteria within the community to share information, coordinate and carry out colonywide activities to enhance the survival and fitness of the community. 172 Although receptor specificity is required for cooperation within the species, multiple QS receptors have been found to display a wide range of reactivities to both self and non-selfderived QS signals. 173 This indicates that QS is also involved in the crosstalk between different microbial communities to regulate survival, competition and cooperation (Figure 3a) . QS can regulate interspecies communication to shape the balance of the microbial community and influence the ability of opportunistic pathogens to cause infection. 174, 175 A study on S. aureus showed that the expression of genes by other Staphylococcal species under the control of the QS system exerts an inhibitory effect on the density and virulence of S. aureus. 176 In another animal study, increased production of QS signalling molecule autoinducer 2 (AI-2) by Escherichia coli (E. coli) was found to counterbalance antibiotic-induced microbial dysbiosis. 177 This favored the expansion of Firmicutes phylum, which is important for many gut functions and promoted recovery of gut homeostasis after antibiotic treatment. 177 The findings of these studies suggest that interspecies communication using QS is required to maintain microbiota-host symbiosis and homeostasis.

Bacterial QS has also been found to modulate the functions of human neural and immune cells via a range of QS molecular targets that are expressed on the host cells 178, 179 (Figure 3a) . In a mouse study, three chemically diverse QS oligopeptides were found to be able to cross the BBB and influx into the mouse brain. 180 QS molecules can also activate microglial cells to produce IL-6 and TNF-a in vitro in an NF-jB-dependent manner. 161 In an in vitro transwell model, AI-2 was found to activate NF-jB-mediated inflammatory pathways followed by upregulation of negative feedback elements that might serve to temper the inflammatory response for immune tolerance to commensal microbes. 181 In addition, colonisation of mice by commensal human gut bacteria was found to promote AI-2 production upon Vibrio cholerae invasion to protect the host from the pathogen infection. 182 While QS signals from commensal microbiota support gut homeostasis and immunity, those from pathogens can promote infection by manipulating the host immune system 178 (Figure 3b ). QS peptides PapRIV produced by Bacillus cereus species have been found to be able to cross the gastrointestinal tract and the BBB and reach the brain to activate the production of proinflammatory cytokines by microglia leading to neurotoxic effects. 179 In vitro infection of macrophages by Group A Streptococcus was also found to inhibit their activation and production of proinflammatory cytokines through QS signalling. 183 The QS molecule N-3O-dodecanoylhomoserine lactone (3O-C12) produced by Pseudomonas aeruginosa (P. aeruginosa) is able to modulate immune responses through multiple mechanisms. These include enhancing infiltration of immune cells and inflammatory responses, induce the release of reactive oxygen species (ROS) and promote apoptosis of neutrophils. [184] [185] [186] [187] [188] Interestingly, serotonin has been found to activate bacterial QS to enhance the virulence of P. aeruginosa both in vitro and in an animal host. 189 It is possible that QS is the control centre that allows pathogenic organisms to hijack the host components to enhance their survival and infection. Indeed, S. aureus was recently found to be able to produce neuromodulatory mediators leading to a biphasic response in extrinsic sensory afferent nerves, increased membrane permeability in cultured sensory neurons and altered intestinal motility and secretion. 190 Genetic manipulation revealed that the production of these neuromodulatory mediators by S. aureus was initiated by two key QS-regulated classes of poreforming toxins that mediate excitation and inhibition of extrinsic sensory nerves. 190 The findings of this study suggest the potential roles of bacterial QS molecules in the modulation of MGB communication to influence intestinal inflammation and pathogen infection.

To counterattack the immunomodulatory effect of microbes, host cells can also fight back by secreting signalling molecules that mimic QS molecules. Studies in zebrafish, mice and human cells showed that host AhR acts as a sensor to qualitatively and quantitatively detect P. aeruginosa QS molecules to regulate the scale and Figure 3 . Quorum sensing signalling contributes to tissue homeostasis and pathology. (a) In response to pathogen invasion, commensal bacteria produce QS molecules. Signalling from these QS molecules inhibit the growth of pathogenic organisms, modulate immune responses and induce expansion of commensal bacteria to counterbalance dysbiosis and restore homeostasis of the gut microbial community. (b) QS molecules produced by pathogenic bacterial can modulate inflammation by targeting multiple host cells. They alter the gut permeability and cross the BBB to induce activate neurons and other brain cells such as microglia cells to upregulate the production of inflammatory cytokines. QS molecules can also bind to receptors on immune cells to induce secretion of proinflammatory mediators, induce apoptosis of neutrophils and inhibit macrophage activation. These events further promote pathogen infection, dysbiosis and inflammation, leading to tissue pathology.

intensity of host defence mechanisms. 191 In addition, mouse mast cells were recently found to be able to detect 24 QS molecules derived from Gram-negative bacteria via G protein-coupled receptor Mrgprb2 to promote host defence against pathogen invasion. 192 In response to bacteria or tight-junction disruption, or when cultured in PBS only, mammalian epithelia are also capable of producing an AI-2 mimic to activate QS. 193 Decreased production of an AI-2 mimic by epithelial cells in the absence of bacterial derived pore-forming toxins suggests that sensing 'danger' is necessary for the host to defend against pathogen invasion. 193 However, the consequence of QS activation was not investigated in this study. Nevertheless, the findings of this study suggest that the production of bacterial QS mimics by mammalian cells might foster cross-kingdom signalling to promote hostbacterial symbioses.

Thus, QS signals from commensal microbiota facilitate symbiosis, which is beneficial for host homeostasis and immunity, whereas QS from pathogenic organisms might represent a master control centre that regulates pathogen invasion. Through QS, microbiota influence the host immune response, MGB axis and development of inflammatory disorders. 178, 194, 195, 196 CONCLUSION Extensive research in the area of neuron-immune interaction has changed our view as to how the immune system functions. It is now clear that immune system is intimately linked with the nervous system in which each system is in constant communication with the other. This occurs through the sharing of secreted molecules and their respective receptors including both cytokines and neurotransmitters. It is also clear that this neuroimmune signalling is modulated by the gut microbiota which also involves secreted molecules, mostly bacterial metabolites such as SCFAs, highlighting a conserved mechanism of intercellular communication across evolution. This constant communication involving feedback and feedforward loops enables ongoing surveillance of the external and internal environments of the host organism to ensure physiological homeostasis and mutualism. Based on the same principle of enhancing the survival and fitness of the community/organisms, we also propose that neuroimmune communication is a strategy that multicellular organisms have adopted from bacterial quorum sensing to enhance the adaptability of the host. However, neurological stress, inflammation and dysbiosis can alter the symbiotic relationship, leading to dysregulation of the host defence mechanisms and tissue pathology. The involvement of microbiota in the development of the nervous and immune systems since the prenatal stage suggests that microbial dysbiosis could be the initiator that leads to dysregulation of inflammation via the neuroimmune network. Indeed, a 'stressed gut', which is associated with microbial dysbiosis, has been found to cause a 'stressed mind', leading to many health complications. 197 Thus, maintaining a healthy gut microbiome appears to be the key for maintaining the health of the brain and immune system: enhancing immune defence and minimising inflammatory disorders. 198, 199 For instance, probiotics have been widely used to improve gut health and immune functions in both animals and humans. 200, 201 Psychobiotics, which are microbes with the ability to produce 'mind-altering' neurotransmitters, have also been suggested to be used as a potential therapeutic strategy in the prevention and/or treatment of certain neurological conditions and neuroimmune dysregulation. 202 In the final analysis, the interplay between pathogen and their host might potentially influence the co-evolution of the host and the microbiota to affect the outcome of human health. Research on the molecular interactions between host-and microbial-derived soluble/signalling factors might also identify potential targets to treat pathogen infections, inflammation, as well as enhance host immune defence to other health threats. of 

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Neuronal release

Neurotransmitter Profiles are altered in the gut and brain of mice mono-associated with bifidobacterium dentium

A diet high in sugar and fat influences neurotransmitter metabolism and then affects brain function by altering the gut microbiota

The role of short-chain fatty acids from gut microbiota in gut-brain communication

Bacterial neuroactive compounds produced by psychobiotics

Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells

Gut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks

Butyrate, but not propionate, reverses maternal diet-induced neurocognitive deficits in offspring

Host microbiota constantly control maturation and function of microglia in the CNS

Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis

The managed immune system: protecting the womb to delay the tomb

Microbiota regulate the development and function of the immune cells

Microbial metabolites control the thymic development of mucosal-associated invariant T cells

The effects of 5-OP-RU stereochemistry on its stability and MAIT-MR1 axis

MAIT cells are imprinted by the microbiota in early life and promote tissue repair

The microbial metabolite butyrate induces expression of Th1-associated factors in CD4 + T cells

Regulation of inflammation by microbiota interactions with the host

The role of astrocytes in the central nervous system focused on BK channel and heme oxygenase metabolites: a review

Astrocytes are necessary for blood-brain barrier maintenance in the adult mouse brain

Astrocyte sodium signaling and the regulation of neurotransmission

Reactive astrocytes in neurodegenerative diseases

Gut-licensed IFNc + NK cells drive LAMP1 + TRAIL + antiinflammatory astrocytes

Gut reactions: How the blood-brain barrier connects the microbiome and the brain

More than a cell biosensor: aryl hydrocarbon receptor at the intersection of physiology and inflammation

The aryl hydrocarbon receptor (AHR) as a potential target for the control of intestinal inflammation: insights from an immune and bacteria sensor receptor

Aryl hydrocarbon receptor (AhR)-dependent

Ozone-induced aryl hydrocarbon receptor activation controls lung inflammation via interleukin-22 modulation

Neuronal programming by microbiota regulates intestinal physiology

Feedback control of AHR signalling regulates intestinal immunity

Intestinal microbiotaderived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity

Dietary AhR ligands regulate AhRR expression in intestinal immune cells and intestinal microbiota composition

Depletion of dietary aryl hydrocarbon receptor ligands alters microbiota composition and function

Double-negative T cells remarkably promote neuroinflammation after ischemic stroke

SCFAs promote intestinal double-negative T cells to regulate the inflammatory response mediated by NLRP3 inflammasome

Bacteria activate sensory neurons that modulate pain and inflammation

Diversity, stability and resilience of the human gut microbiota

A healthy gastrointestinal microbiome is dependent on dietary diversity

Host-bacterial mutualism in the human intestine

The role of the microbiome for human health: from basic science to clinical applications

Role of the gut microbiota in nutrition and health

The gut microbiome alterations and inflammationdriven pathogenesis of Alzheimer's disease-a critical review

Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma

Antibiotic prescription and food allergy in young children

Association between antibiotic treatment during pregnancy and infancy and the development of allergic diseases

Antibiotic use and the development of inflammatory bowel disease: a national case-control study in Sweden

Early-life antibiotic-driven dysbiosis leads to dysregulated vaccine immune responses in mice

Gut dysbiosis and neuroimmune responses to brain infection with Theiler's murine encephalomyelitis virus

Dysbiosis of gut microbiota and microbial metabolites in Parkinson's Disease

The gut microbiota and Alzheimer's disease

Antibiotics in early life: dysbiosis and the damage done

The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice

Antibiotics-induced modulation of large intestinal microbiota altered aromatic amino acid profile and expression of neurotransmitters in the hypothalamus of piglets

The contribution of gut bacterial metabolites in the human immune signaling pathway of noncommunicable diseases

Immune system activation and depression: roles of serotonin in the central nervous system and periphery

Serotonin disturbs colon epithelial tolerance of commensal E. coli by increasing NOX2-derived superoxide

Serotonin regulates innate immune responses of colon epithelial cells through Nox2-derived reactive oxygen species

Unhealthy gut, unhealthy brain: The role of the intestinal microbiota in neurodegenerative diseases

The Gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology

From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Induced Parkinson's disease in mouse: potential association between neurotransmitter disturbance and gut microbiota dysbiosis

Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19

The impact of chronic intestinal inflammation on brain disorders: the microbiota-gut-brain axis

Microbiotagut-brain communication in the SARS-CoV-2 infection

COVID-19-related neuropathology and microglial activation in elderly with and without dementia

Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology

Effects of stress on immune function: the good, the bad, and the beautiful

Chronic stress enhances microglia activation and exacerbates death of nigral dopaminergic neurons under conditions of inflammation

Norepinephrine dysregulates the immune response and compromises host defense during sepsis

Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity

Psychological stress suppresses innate IFN-gamma production via glucocorticoid receptor activation: reversal by the anxiolytic chlordiazepoxide

Glucocorticoids promote breast cancer metastasis

Chronic stress-induced immune dysregulation in cancer: implications for initiation, progression, metastasis, and treatment

Stress gets into the belly: Early life stress and the gut microbiome

Structural & functional consequences of chronic psychosocial stress on the microbiome & host

Effects of stress on commensal microbes and immune system activity

Gut microbiota are associated with psychological stress-induced defections in intestinal and blood-brain barriers

Alterations in the vaginal microbiome by maternal stress are associated with metabolic reprogramming of the offspring gut and brain

Stress-induced perinatal and transgenerational epigenetic programming of brain development and mental health

Changes in intestinal glucocorticoid sensitivity in early life shape the risk of epithelial barrier defect in maternal-deprived rats

Chronic stress promotes colitis by disturbing the gut microbiota and triggering immune system response

Hostmediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae

Gut microbiota-induced immunoglobulin G controls systemic infection by symbiotic bacteria and pathogens

Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice

Mechanisms of inflammation-driven bacterial dysbiosis in the gut

Gut microbiota from mice with cerebral ischemia-reperfusion injury affects the brain in healthy mice

Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemiainduced inflammation in Apoe -/-mice

The anti-inflammatory effects of Akkermansia muciniphila and its derivates in HFD/CCL4-induced murine model of liver injury

Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions

Oral administration of miR-30d from Feces of MS patients suppresses MS-like symptoms in mice by expanding Akkermansia muciniphila

Neurologic manifestations in inflammatory bowel diseases: current knowledge and novel insights

Inflammatory bowel disease: an increased risk factor for neurologic complications

Sequestration and scavenging of iron in infection

Molecular profiling: catecholamine modulation of gene expression in Escherichia coli O157:H7 and Salmonella enterica Serovar Typhimurium

Blocking neuronal signaling to immune cells treats Streptococcal invasive infection

Quorum sensing: cell-to-cell communication in bacteria

Quorum sensing signalresponse systems in Gram-negative bacteria

Nutrient reduction induced stringent responses promote bacterial quorum-sensing divergence for population fitness

Quorum sensing in bacteria

Quorum sensing-mediated regulation of staphylococcal virulence and antibiotic resistance

Attenuation of quorum sensing controlled virulence factors and biofilm formation in Pseudomonas aeruginosa by pentacyclic triterpenes, betulin and betulinic acid

Bacterial quorum-sensing systems and their role in intestinal bacteria-host crosstalk

Bacterial interspecies quorum sensing in the mammalian gut microbiota

How bacteria talk to each other: regulation of gene expression by quorum sensing

Quorum sensing signal selectivity and the potential for interspecies cross talk

Detection of gut microbiota and pathogen produced N-acyl homoserine in host circulation and tissues

Bacteria-host communication: the language of hormones

Cross-talk between Staphylococcus aureus and other staphylococcal species via the agr quorum sensing system

Manipulation of the quorum sensing signal AI-2 affects the antibiotic-treated gut microbiota

Intestinal interplay of quorum sensing molecules and human receptors

BV-2 microglial cell activating quorum sensing peptide

Quorum sensing peptides selectively penetrate the blood-brain barrier

Bacterial secretions of nonpathogenic Escherichia coli elicit inflammatory pathways: a closer investigation of interkingdom signaling

Members of the human gut microbiota involved in recovery from Vibrio cholerae infection

A Streptococcus quorum sensing system enables suppression of innate immunity

Pseudomonas aeruginosa autoinducer modulates host cell responses through calcium signalling

The Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl)homoserine lactone contributes to virulence and induces inflammation in vivo

Pseudomonas aeruginosa quorum sensing molecule N-3-oxododecanoyl-l-homoserine lactone activates human platelets through intracellular calcium-mediated ROS generation

Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxocalcium signaling

The bacterial quorum-sensing signal molecule N-3-oxododecanoyl-L-homoserine lactone reciprocally modulates pro-and anti-inflammatory cytokines in activated macrophages

Serotonin activates bacterial quorum sensing and enhances the virulence of Pseudomonas aeruginosa in the host

Identification of a quorum sensing-dependent communication pathway mediating bacteria-gut-brain cross talk

Host monitoring of quorum sensing during Pseudomonas aeruginosa infection

A connective tissue mast-cell-specific receptor detects bacterial quorumsensing molecules and mediates antibacterial immunity

A host-produced autoinducer-2 mimic activates bacterial quorum sensing

The quorum sensing peptides PhrG, CSP and EDF promote angiogenesis and invasion of breast cancer cells in vitro

Role of quorum sensing in bacterial infections

Impact of N-Acyl-Homoserine lactones, quorum sensing molecules, on gut immunity

Gutmicrobiota-brain axis and its effect on neuropsychiatric disorders with suspected immune dysregulation

Target dysbiosis of gut microbes as a future therapeutic manipulation in Alzheimer's disease

Revisit gut microbiota and its impact on human health and disease

The impact of probiotics on gut health via alternation of immune status of monogastric animals

Effects of probiotics on gut microbiota: mechanisms of intestinal immunomodulation and neuromodulation

From probiotics to psychobiotics: live beneficial bacteria which act on the brain-gut axis

The authors declare that they have no conflict of interest.

The role of microbiota in the regulation of tissue homeostasis K Li et al.The role of microbiota in the regulation of tissue homeostasis K Li et al.

The contents of this page will be used as part of the graphical abstract of html only. It will not be published as part of main.Inflammation is an indispensable process that is required to initiate cellular defense and maintain homeostasis. The process of inflammation is tightly regulated by the immune system and beyond to ensure the survival benefit of the host and also limit pathology. This manuscript is about how microbiota contributes to the development and function of nerves and immune systems to regulate inflammation and immune response.