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The Local Defender and Functional Mediator: Gut Microbiome

Yang H. · Duan Z.

Author affiliations

Second Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, China

Corresponding Author

Zhijun Duan

Second Department of Gastroenterology

The First Affiliated Hospital of Dalian Medical University

222 Zhongshan Road, Xigang District, Dalian, Liaoning 0086-116011 (China)

E-Mail 15841123892@163.com, cathydoctor@sina.com

Related Articles for ""

Digestion 2018;97:137-145

Abstract

Background: The gut microbiome has been developing and making adaption all the time, which is consistent with their host from the initial colonization at birth or earlier. Emerging evidence is showing that dysbiosis is involved in various diseases associated with immune, metabolism, infection, nervous system, social behaviors, and psychopathology, etc., maybe via modulating gut barrier, microbiome-gut-brain axis, or some metabolites like short-chain fatty acids (SCFAs). Summary: In the review, we will conclude the recent researches related to the influence of microbiome on local structure, function, regulation, metabolism of gut, and systematic modulation to the host, as well as some affective factors such as diet or antibiotics. Key Messages: It is a reasonable hypothesis that the balance of bioactive factors or cells and the opposites such as the regulatory T/helper T17 balance and interleukin (IL)-10/IL-17 balance plays a vital role in homeostasis of immunity system. Meanwhile, the link between gut microbiome and immune system via microbiota-derived metabolite SCFAs involved in multi-function of the host locally and systematically has been revealed. We hope to contribute to the microbiome-targeted treatment and prevention of some diseases.

© 2018 S. Karger AG, Basel


Introduction

The human gastrointestinal tract harbors a unique microbial community, comprised mainly of bacteria, as well as archaea, viruses, and protozoa, which are approximately 1014 cells and highly variable among individuals [1], that undertake multiple functions in human health and disease [2]. Bacteroidetes as degraders of dietary fiber (DF), Firmicutes, Proteobacteria, Actinobacteria, and Verrucomicrobia are dominant in the gut, according to fecal microbiota of healthy individuals [3], which are immune-tolerant to the most extent and featured by specific metabolism containing fermentation, synthesis of secondary bile acids (BAs) production, metabolism including their products like short-chain fatty acids (SCFAs) [4, 5], influences on neural development and intestinal neuroendocrine [6], and interactions with the immune systems of host. Therefore the dysbiosis, induced by external factors, such as diet, antibiotic administration, or some emotional stress in the early stage of microbiota colonization, may induce various diseases associated with brain function and certain psychiatric conditions, gut motility and function, and local and systematic infection and auto-immunology [7-10]. In this review, the critical roles of microbiome as a component of gut barrier, local myenteric neurons and central nervous system (CNS), their functions included, and microbiome-gut-brain axis will be highlighted, which may be an implication in reducing and even curing some diseases.

Microbiome Colonization Resistance and Gut-Associated Lymphoid Tissue in Defensive Function

Microbiome Colonization Resistance and Role in Intestinal Epithelium Defensing

Colonization resistance, which means direct microbial effects, assumes a crucial role in defending pathogen invasion, always covering secretion of antimicrobial components, competition for nutrients and host receptors, and change of local redox status and pH by some metabolite such as SCFAs [11-13]. Some commensal bacteria can metabolize the O-linked glycans that attach itself to Muc2, which forms thicker mucin layer, and some bacteria like Lactobacillus rhamnosus GG encodes a mucus-binding pili protein or surface capsular polysaccharides adhering to the human intestinal mucus, thus competing and excluding exogenous organisms [14, 15]. As for nutrients competition [16, 17], various complex carbohydrates rich in human diet are metabolized by gut microbiota encoding broad appropriate hydrolytic enzymes, specifically Lactobacillus and Bifidobacterium, which can utilize fructo-oligosaccharides, β-galacto-oligosaccharides, gluco-oligosaccharides, and xylo-oligosaccharides as prebiotic for nutrients competition to drive their expansion and alter microbiota composition [18, 19]. Also, some bacteria can exclusively acquire more dispensable components. For instance, Escherichia coli Nissle 1917 can compete for iron and curb Salmonella typhimurium colonization of the mouse intestine [20].

Intestinal epithelial cells (IECs) expectantly contribute greatly to defensive function as a part of intestinal barrier based on the several unique structures such as tight and adhering junction greatly in the charge of non-muscle myosin II which is a key cytoskeletal motor [21], and pattern recognition receptors [22, 23], mostly toll-like receptors [24], and nucleotide binding oligomerization domain agents [25] interacting with gut microorganisms and their structural components such as lipopolysaccharides [26] to produce a range of functional molecules such as antimicrobial peptides induced by various pro-inflammatory cytokines, chemokines, and reactive oxygen species [27, 28]. Also gut bacteria can promote the development of IECs and the expression of mucus, and their metabolite SCFAs serve as predominant energy sources that are beneficial for intestinal epithelium and their junctions [29]. Disruption of these pattern recognition receptors attenuates the mucus layer remarkably and makes model mouse more susceptible to colitis. In clinic, various probiotics are widely used in treatment of gut diseases, such as inflammatory bowel disease (IBD), ulcerative colitis, etc., and prevention of dysbiosis during long-term antibiotics, which may play a potential role in preventing high-risk population from immunity gut diseases.

Interaction between Gut-Associated Lymphoid Tissue and Microbiome

Microbiome collectively inhabit the human gut barrier surfaces during birth, which promotes the host’s immune system maturation, and is also shaped by interaction with the host, and educate immune response as to the tonic level of their signals, rather than just random colonization. As the effector of adaptive immune response directly against gut-resident bacteria, secretory immunoglobulin A (IgA) enables mucosal immune system to establish homeostasis with gut microbiota after weaning [30-32]. Peyer’s patches are essential components of gut-associated lymphoid tissue and critical inductive sites where naive B cells differentiate into IgA-secreting plasma cells after recognizing exogenous luminal antigens. Micro-fold cells overlying the Peyer’s patch, specialized phagocytic epithelial cells with ability of antigens sampling and positioning of antigen-presenting cells, and lymphocytes based on different surfaces [33-35] can release antigens from the gut into the Peyer’s patches, where these antigens processed by antigen-presenting cells are presented to T and B cells to initiate the adaptive response. After T cell receptor recognizes the antigen presented in complex with major histocompatibility complex molecule [36], the T cells will differentiate into different sub-populations including the helper T (Th) cells capable of secreting specific cytokines, such as interleukin (IL)-17 from Th17, IL-10 from regulatory T (Treg) downregulating all other immune arms, and cytotoxic T cells expressing the CD8 glycoprotein [37-39]. Some bacterial taxa drive the development of intestinal Treg, whereas others facilitate Th17 T cell. For instance, Clostridium and Bacteroidetes are predominant in the gut microbiome, which are definitely associated deeply with immune response. The clostridial clade of segmented filamentous bacteria is intimately attached and induce strong immune responses including IgA, Th17, Treg-cell induction, and antimicrobial peptides restrict its colonization and shape the formation of a normal immune system [40-42]. Well Bacteroides fragilis, which express polysaccharide A capable of activating B cells and T cells, and toll-like receptors-2 pathway on FoxP3+ Treg cells, further increase the secretion of IL-10 by CD4+ T cells that offsets activation of Th17 CD4+ cells to maintain its intimate niche [43]. Recently, butyrate and propionate as SCFAs produced by Clostridium have been shown to enhance differentiation of Treg cells through acetylation and activation of the FoxP3 locus and inhibition of histone deacetylase (HDAC) enzymes. Intestinal resident macrophages (Mφs) stimulated from dietary amino acids via amino-acid-mediated mammalian target of rapamycin activation pathway can activate the production of Treg cells when antigens of dietary and bacterial are present in the intestinal lumen, which can limit excessive immune responses via producing robust amounts of IL-10 [44, 45]. The Treg/Th17 balance may be in great positive correlation with gut immune homeostasis, which can enable an adequate immune response to defend pathogens and prevent immune-mediated inflammatory diseases locally or systematically such as IBD, asthma, and rheumatoid arthritis, as Tregs are pivotally responsible for immune tolerance and Th17s are the main effector cells and recruit neutrophils and macrophages in immune response to treat infection. So if there is a relevance between the ratio of IL-10/IL-17 and the severity of some inflammatory diseases, and also a regulator like SCFAs, which may facilitate the balance between IL-10 and IL-17, probiotics composed mainly by Bacteroidetes to maintain the homeostasis of the dominant microbiome, such as Bacteroidetes, Firmicutes, and Proteobacteria, will be a better choice in the long-term treatment immune-mediated diseases in the gut (Fig. 1).

Fig. 1.

Role of microbiome in the balance of regulatory T (Treg) and helper T (Th17) in gut associated lymphoid tissue (GALT). After T cell receptor recognizing the antigen presented in complex with major histocompatibility complex molecule, the T cells will differentiate into different sub-populations including Th-17 and Treg with different biological functions. Th17 cells produce cytokine profiles such as interleukin (IL)-17, IL-6, and tumor necrosis factor (TNF)‑α, and recruit and activate neutrophils and macrophages, assisting in the clearance of pathogens, but the over-activation can lead to tissue damage. Treg cells produce immunosuppressive factors and induce apoptosis of CD4+ effector T cells, downregulating immune responses. Some bacterial taxa drive the development of intestinal Treg, whereas others facilitate Th17. Short-chain fatty acids ­(SCFAs) produced by Clostridium have been shown to enhance differentiation of regulatory T cells through acetylation and activation of the FoxP3 locus and inhibition of histone deacetylase enzymes. And intestinal resident macrophages (Mφs) can activate the production of Treg when antigens of dietary and bacterial are present in the intestinal lumen. The Treg/Th17 balance may be in great positive correlation with gut immune homeostasis which can enable an adequate immune response to defend pathogens and prevent immune-mediated inflammatory diseases locally or systematically such as inflammatory bowel disease (IBD), asthma, and rheumatoid arthritis.

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Initial Colonization and Immune-Mediated Diseases

Human gut microbiome commences colonization at birth, although some studies showed that the placenta contains a remarkable microbiome, possibly affecting child’s microbiome before delivery [46-48]. The colonization is strongly influenced by birth mode and infant feeding. In addition, host genetics, surrounding conditions, and antibiotic treatment are involved in the formation and modulation of intestinal microbiota [49-51]. After introducing solid foods, the infants’ intestinal microbiota undergo a rapid diversification and shift toward an adult-like microbiota, which will resemble that of an adult by 3 years old [52]. Once established, the gut microbiota tend to be relatively stable via subsequent regeneration itself after the temporary disruption of diet changes such as short-term travels and antibiotic use, although high variability between individuals is observed. The microbiota formation and establishing in early life occupy an essential position, which may pose further influence on children later in life, once disrupted. Data have shown that the association between cesarean birth and several immune-linked diseases later in life, like asthma, maybe partly attributed to microbial colonization [53, 54]. These diseases, are usually considered as “genetic disease,” which may be onset during childhood in a susceptible population induced by specific diet, or imperceptible onset in adult in some environments such as those filled with stress, which can be associated with emotion, habits, pressure, antibiotics use, acute or chronic gut infection, etc. [9, 55]. Researches have been carried on the human-associated microbial communities’ heritability, some of which showed the correlation with the gut microbiota diversity and provided evidence for variation [56]. However, it is hard to distinguish the contribution of each kind of microbiota initially colonizing after birth and adapting before 3 years of age and the host genetic factor involved in inflammatory diseases as mentioned above [55]. For example, genetic factors and the gut microbiota are both involved in IBD onset. What’s more, genetic diseases like asthma without genetic changes may just be attributed to the heritability of microbial communities from mothers or surroundings [57]. Thus, more knowledge on the mutual effects between composition of microbiota and host genetics as well as environments resulting in diseases may contribute to the new effective therapies. Some therapies have been advocated by clinical trials based on the modulation of the gut microbiota, demonstrating more effectiveness in prevention of inflammatory disorders than gene-target approaches. For instance, products containing probiotics or prebiotics are applied to improve vaginal health and influence a newborn’s health, which is becoming more popular [58]. And prebiotic intake during pregnancy and lactation has been suggested to attenuate the detrimental nutritional programming of offspring due to maternal obesity [59].

Relationship between Stress and Gut Disorders via Microbiome-Gut-Brain Axis

The microbiome-gut-brain axis encompasses the multidirectional communication between the microbiome, gut, and brain, with the objective of monitoring and integrating gut functions and linking them to the cognitive and emotional centers of the brain, via multiple pathways including hormonal, neural, and immune mediators [60, 61]. Gut microbiota can influence neural development, cognition, and behavior, and modulate nervous system function [62, 63], with researches showing the interrelationship between changes in behavior such as depression-like behaviors and modifications of the microbiota, such as the psychiatric side-effects of antibiotics containing anxiety, depression, psychosis, and delirium, which appears to represent direct mediators of psychopathology [64-66]. Meanwhile, the association of dysbiosis with disease, especially functional bowel disorders has acquired more attention [67]. Therefore, the evidence is emerging that the psychopathology like stress and depression have been recognized as common comorbidities in gastrointestinal disorders, with increasing exposure to psychological stressors [68, 69]. Maternal separation has been widely used as a model of stress in the microbiome-gut-brain axis researches [70, 71]. And rodents suffer separating from their mothers in early life when the establishment and maturation of the microbiome parallels the neurodevelopment [72], behave anxiously, and exhibit durative hyperactivity of the hypothalamic pituitary adrenal (HPA) axis with visceral hypersensitivity and altered gut cholinergic activity accompanied by increased intestinal permeability [73, 74], which seems similar to some features found in irritable bowel syndrome. Besides, germ-free mice also have an exaggerated but reversible effect for specific probiotics HPA axis in response to mild stressors, with the core of epinephrine and norepinephrine present in the gut, and reduced the expression of brain-derived neurotrophic factor in the cortex and hippocampus [75]. There are some treatments for mental diseases such as autism or depression with antibiotics or probiotics like B. fragilis, Lactobacillus helveticus R0052, and Bifidobacterium longum R0175, to ameliorate anxiety-like, repetitive, and depressive behavior [76, 77]. It is supportive that the development of gut microbiome contributes substantially to brain development like synaptogenesis and neuropsychiatric outcomes in later in life [78, 79], establishment of appropriate stress responses and relevant behaviors and gut functions, such as motility which was demonstrated to be related with a reduced ganglionic density and size of myenteric plexus in patients with slow transit constipation. Evidently, exposure to an insulting stressor affects the gut microbiota and serum metabolomic profile such as cytokines (IL-6 and monocyte chemotactic protein-1) and tryptophan and correlates with changes in levels of pro-inflammatory cytokines and intestinal secretory IgA, which impacts intestinal homeostasis and increase the risk of inflammation-related diseases and dysbiosis [80, 81]. In addition, microbiota can influence CNS function and modulated HPA axis function through neuronal activation of reflex circuits. Vagus nerve, highly innervating the gut, plays an essential role in gut motility via conveying peripheral information to the brain, as well as other parasympathetic activity such as regulation of heart rate, exerts anti-inflammatory effects, and has synergistic action with antidepressants, anxiolytics, and psychobiotics in which what specific roles gut microbiome play is still vague [82]. Therefore, to rectify, the dysbiosis is involved in modulation of brain function via gut-brain crosstalk, via direct effect of their metabolites like SCFAs, indirect action on vagus nerve, or other signal transduction pathways which is yet to be found out.

Various Roles of SCFAs, a Dominant Metabolite of Microbiome in Host

A growing body of work has focused on microbial metabolites and implicates diverse functions on the host. The SCFAs, in particular butyrate, propionate, and acetate [83-85], endowed with characteristics of preferred energy source for colonocytes, easy absorption into the portal vein participating in humoral adjustment, and increased possibility in access to blood brain barrier (BBB), whereas decreasing BBB permeability [86-88], respectively, which leaves acetate as the most abundant SCFA in peripheral circulation, derive from microbial fermentation of DFs in the cecum and colon [89], and benefit various aspects of host physiology. As acetate, propionate, and butyrate are acids with pKa values of approximately 4.8, the concentration of which gradually declines from the proximal to the distal, maybe due to the transporter with different affinity of monocarboxylate, and the pH ranging from 5.6 to 7.0, SCFAs suppress the intestinal pH implicating the effect of acidification, and depress the growth of pH-sensitive pathogens [90], protease activity to impair protein fermentation, the absorption of ammonia, and the formation of secondary BAs. Some research have indicated that SCFAs especially butyrate as the preferred substrate for the epithelial cells, play a part in the integrity of the mucosal and epithelial layers and gut barrier, which are associated with the proliferation, differentiation, and apoptosis of cell, increased MUC2 gene expression, and antioxidant activity [91]. Apart from the stimulation of motility demonstrated could be through the release of 5-hydroxytryptamine (5-HT) through stimulating 5-HT3 receptors located on the vagal sensory fibers in rats, and secretory activity via the enteric nervous system, SCFAs can curb appetite and sensitize insulin by promoting the production of satiety-inducing hormones, including peptide YY and glucagon-like peptide 1 through activating G-protein coupled receptor41 and 43 (GPR41 and GPR43) and leptin secreted from adipocyte, as well as the appetite inhibition of acetate across BBB on hypothalamus and gluconeogenesis facilitation of butyrate [92-95]. The effects of acetate, propionate and butyrate on host physiology are distinct and often vary. However, acetate could increase secretion of ghrelin to stimulate appetite in rodents fed a high-fat diet via Vagus nerve of the parasympathetic nervous system, leading to the opposite result compared with the above. HDACs inhibitors have been widely used as an anti-tumor agent for the ability in preventing the removal of acetyl from histone tails similar to histone acetyltransferases. SCFAs, butyrate in particular can directly activate G-coupled-receptors, inhibit HDAC, known as HDAC inhibitors in cancerous cells. While in normal cells, butyrate may play the role of a histone acetyltransferase activator, which induces different effects in a cell- and environment-specific context [96-99]. In addition, SCFA-mediated HDAC inhibition exerting anti-inflammatory effects can modulate gut immunity to be tolerant of beneficial commensals partly via regulating the ge­neration of Tregs [100, 101] and IL-10-producing T cells via GPR109A. SCFAs can also act on nervous system, such as peripheral neurons due to abundantly expressed GPR41, which transducts signal in boosting energy metabolic rate and heart rate, and a potential role in microglia maturation which has been demonstrated that microglia density was defective in the germ-free mice and restored by administered SCFAs, and activation of GPR43 was required [102, 103]. Together with previous lines of evidence, present data have proved that SCFAs and secondary BAs act upon enterochromaffin cells, inducing transcription of the rate-limiting 5-TH bio-synthetic enzyme thp1 [104] mentioned above, predicted to influence gut motility linked with microbiota (Fig. 2).

Fig. 2.

Various roles of short-chain fatty acids (SCFAs). As a dominant metabolite of microbiome in host, SCFAs are widely involved in homeostasis modulation of the host and display local and systematic roles via the gradually emerging pathways, with the constantly deepening exploration of gut microbiota. (1) SCFA-mediated histone deacetylase inhibition exerting anti-inflammatory effects can modulate gut immune to be tolerant of beneficial commensals partly via regulating the generation of Tregs and interleukin (IL)-10-producing T cells via GPR109A. (2) Apart from the stimulation of motility demonstrated maybe through the release of 5-hydroxytryptamine (5-HT) through stimulating 5-HT3 receptors located on the vagal sensory fibers in rats, and secretory activity via the enteric nervous system (ENS), SCFAs can act upon enterochromaffin cells (ECs), inducing transcription of the rate-limiting 5-TH bio-synthetic enzyme thp1, predicted to influence gut motility linked with microbiota. (3) SCFAs can curb appetite and sensitize insulin by promoting the production of satiety-inducing hormones, including peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) through activating G-protein coupled receptor41 and 43 (GPR41 and GPR43) and leptin secreted from adipocyte, as well as the appetite inhibition of acetate across blood brain barrier (BBB) on hypothalamus and gluconeogenesis (IGN) facilitation of butyrate. However, acetate demonstrated recently could increase secretion of ghrelin to stimulate appetite in rodents fed a high-fat diet via vagus nerve of the parasympathetic nervous system, leading to the opposite result. (4) Dysbiosis is greatly involved in various diseases associated with gut dysfunction, inflammatory disease, and psychopathology, etc., maybe via many mechanism such as modulating gut barrier, microbiome-gut-brain axis, or some metabolites like SCFAs.

/WebMaterial/ShowPic/913500

SCFAs and Liver Inflammatory Response

As mentioned above, SCFAs can enhance gut local defense via the function as predominant source of IECs and promptly mount innate immune responses during immunological challenges after combining with GPR41 and GPR43, and also suppress the systematic inflammatory response through HDAC inhibition and nuclear factor-κB, and regulate secretion of cytokines such as IL-10 and IL-17. Meanwhile, as a part of metabolites of gut microbiome, SCFAs will be absorbed in to circulation with a large amount through liver, which also indicates the microbiome-gut-liver axis. And it is indispensable to be involved in the liver immune reaction and fibrosis process due to the expression of their target receptors during liver injury. Therefore, it is reasonable to deduce that increasing SCFAs maybe via DF, and regulation of the gut microbiome by probiotics intake may bring benefits to chronic liver injury, especially immune-related liver diseases, which also indicates that the supplement of ­SCFAs is likely to be the necessary adjunctive therapy in the sustained treatment of chronic liver injury, as meaningful as the UDCA in PBC. However more research is needed.

Conclusion

As the researches of gut microbiome have been constantly deepened, the fact demonstrated from various aspects implicates that dysbiosis is greatly involved in various diseases associated with immune, metabolism, infection, nervous system, social behaviors, and psychopathology, etc., maybe via different mechanisms such as modulating gut barrier, microbiome-gut-brain axis, or some metabolites like SCFAs. And it is reasonable to believe that the balance of bioactive factors or cells and the opposites such as the Treg/Th17 balance and IL-10/IL17 balance plays a vital role in homeostasis including the gut function and immunity. Meanwhile, gut microbiome’s impact on brain and behavior has drawn great attention around worldwide; evidently, exposure to an insulting stressor affects psychopathology like stress and depression with changes of the gut microbiota, serum metabolomic profile, CNS, and HPA axis function. Also, various roles of microbiota-derived metabolite SCFAs have been revealed gradually, and there exists a relevance between the ratio of IL-10/IL-17 and the severity of some inflammatory diseases with dysbiosis, and also a regulator like SCFAs that may facilitate the balance between IL-10 and IL-17, which might bring prominent effects in the patient after application of probiotics composed mainly by Bacteroidetes or composed in specific ratio of different microbiome. Therefore, to reverse, hinder, or prevent the dysbiosis may be the key step in treatment of many diseases, although further exploration regarding the mechanisms is still required.

Disclosure Statement

There are no conflicts of interest in relation to any funding from or pecuniary interests in companies that could be perceived as a potential conflict of interest in the outcome of the research.


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Author Contacts

Zhijun Duan

Second Department of Gastroenterology

The First Affiliated Hospital of Dalian Medical University

222 Zhongshan Road, Xigang District, Dalian, Liaoning 0086-116011 (China)

E-Mail 15841123892@163.com, cathydoctor@sina.com


Article / Publication Details

First-Page Preview
Abstract of Review

Received: September 05, 2017
Accepted: October 31, 2017
Published online: January 08, 2018
Issue release date: Published online first (Issue-in-Progress)

Number of Print Pages: 9
Number of Figures: 2
Number of Tables: 0

ISSN: 0012-2823 (Print)
eISSN: 1421-9867 (Online)

For additional information: https://www.karger.com/DIG


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