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Long-term close-knit interactions betweensymbioticmicrobes and their host can alter host immune system responses to other microorganisms, includingpathogens, and are required to maintain properhomeostasis.^[1] Theimmune system is a host defense system consisting of anatomical physical barriers as well as physiological and cellular responses, which protect thehost against harmful microorganisms while limiting host responses to harmlesssymbionts. Humans are home to 10¹³ to 10¹⁴bacteria, roughly equivalent to the number of human cells,^[2] and while these bacteria can be pathogenic to their host most of them aremutually beneficial to both the host and bacteria.

The human immune system consists of two main types of immunity: innate and adaptive. Theinnate immune system is made of non-specific defensive mechanisms against foreign cells inside the host including skin as a physical barrier to entry, activation of thecomplement cascade to identify foreign bacteria and activate necessary cell responses, andwhite blood cells that remove foreign substances. Theadaptive immune system, or acquired immune system, is a pathogen-specific immune response that is carried out bylymphocytes throughantigen presentation onMHC molecules to distinguish between self and non-selfantigens.

Microbes can promote the development of the host's immune system in the gut and skin, and may help to preventpathogens from invading. Some release anti-inflammatory products, protecting against parasitic gut microbes.Commensals promote the development ofB cells that produce a protective antibody,Immunoglobulin A (IgA). This can neutralize pathogens andexotoxins, and promote the development of immune cells and mucosal immune response. However, microbes have been implicated in human diseases includinginflammatory bowel disease, obesity, and cancer.

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Microbialsymbiosis relies oninterspecies communication.^[3]between the host and microbial symbionts. Immunity has been historically characterized inmulticellular organisms as being controlled by the host immune system, where a perceived foreign substance or cell stimulates an immune response. The end result of this response can vary from clearing of a harmful pathogen to tolerance of a beneficial microbe to anautoimmune response that harms the host itself.

Symbiotic microorganisms have more recently been shown to also be involved in this immune response indicating that the immune response is not isolated to host cells alone. These beneficial microorganisms have been implicated in inhibiting growth of pathogens in the gut and anti-cancer immunity among other responses.

The humangastrointestinal tract (GI tract) consists of themouth,pharynx,esophagus,stomach,small intestine, andlarge intestine, and is a 9-meter-long continuous tube; the largest body surface area exposed to the external environment. The intestine offers nutrients and protection to microbes, enabling them to thrive with an intestinal microbial community of 10¹⁴ beneficial and pathogenicbacteria,archaea,viruses, andeukaryotes. In return many of these microbes complete important functions for the host including breakdown of fiber^[4] and production ofvitamins^[5] where gut microbes have at least a role in the production of vitamins such asA,B2,B3,B5,B12,C,D andK.

In the human gut the immune system comes into contact with a large number of foreign microbes, both beneficial and pathogenic. The immune system is capable of protecting the host from these pathogenic microbes without starting unnecessary and harmful immune responses to stimuli. The gastrointestinalmicrobiota has a direct effect on the human body's immune responses. meaning a regular microbiota is necessary for a healthy host immune system as the body is more susceptible to infectious and non-infectiousdiseases.

Commensal bacteria in the GI tract survive despite the abundance of local immune cells.^[6] Homeostasis in the intestine requires stimulation oftoll-like receptors by commensal microbes.^[6] When mice are raised in germ-free conditions, they lack circulating antibodies, and cannot produce mucus, antimicrobial proteins, or mucosal T-cells.^[6] Additionally, mice raised in germ-free conditions lacktolerance and often suffer fromhypersensitivity reactions.^[6] Maturation of the GI tract is mediated bypattern recognition receptors (PRRs), which recognize non-selfpathogen associated molecular patterns (PAMPs) including bacterial cell wall components and nucleic acids.^[7] These data suggest that commensal microbes aid in intestinal homeostasis and immune system development.^[6]

To prevent constant activation of immune cells and resulting inflammation, hosts and bacteria have evolved to maintain intestinal homeostasis and immune system development.^[8] For example, the human symbiontBacteroides fragilis producespolysaccharide A (PSA), which binds totoll-like receptor 2 (TLR-2) onCD4⁺ T cells.^[9] While TLR2 signaling can activate clearance of peptides, PSA induces an anti-inflammatory response when it binds to TLR2 on CD4⁺ T cells.^[9] Through TLR2 binding, PSA suppresses pro-inflammatory TH17 responses, promotingtolerance and establishing commensal gut colonization.^[9]

Commensal gut microbes create a variety of metabolites that bindaryl hydrocarbon receptors (AHR). AHR is a ligand-inducible transcription factor found in immune and epithelial cells and binding of AHR is required for normal immune activation as the lack of AHR binding has been shown to cause over activation of immune cells.^[1] These microbial metabolites are crucial for protecting the host from unnecessary inflammation in the gut.

Microbes trigger development of isolatedlymphoid follicles in the small intestine of humans and mice, which are sites of mucosal immune response. Isolated lymphoid follicles (ILFs) collect antigens throughM cells, developgerminal centers, and contain many B cells.^[10]Gram-negative commensal bacteria trigger the development of inducible lymphoid follicles by releasingpeptidogylcans containingdiaminopimelic acid during cell division.^[10] The peptidoglycans bind to theNOD1 receptor onintestinal epithelial cells.^[10] As a result, the intestinal epithelial cells expresschemokine ligand 20 (CCL20) andBeta defensin 3.^[10]CCL20 andBeta-defensin 3 activate cells which mediate the development of isolated lymphoid tissues, including lymphoid tissue inducer cells and lymphoid tissue organizer cells.^[10]

Additionally, there are other mechanisms by which commensals promote maturation of isolated lymphoid follicles. For example, commensal bacteria products bind toTLR2 andTLR4, which results inNF-κB mediated transcription ofTNF, which is required for the maturation of mature isolated lymphoid follicles.^[11]

Microbes can prevent growth of harmful pathogens by altering pH, consuming nutrients required for pathogen survival, and secreting toxins and antibodies that inhibit growth of pathogens.^[12]

IgA prevents entry and colonization of pathogenic bacteria in the gut. It can be found as a monomer, dimer, or tetramer, allowing it to bind multiple antigens simultaneously.^[13] IgA coats pathogenic bacterial and viral surfaces (immune exclusion), preventing colonization by blocking their attachment to mucosal cells, and can also neutralize PAMPs.^[8][14] IgA promotes the development ofTH17 and FOXP3+ regulatory T cells.^[15][16] Given its critical function in the GI tract, the number of IgA-secreting plasma cells in thejejunum is greater than the total plasma cell population of thebone marrow,lymph, andspleen combined.^[13]

Microbiota-derived signals recruit IgA-secreting plasma cells to mucosal sites.^[8] For example, bacteria on the apical surfaces of epithelial cells are phagocytosed bydendritic cells located beneathpeyer's patches and in thelamina propria, ultimately leading to differentiation of B cells into plasma cells that secrete IgA specific for intestinal bacteria.^[17] The role of microbiota-derived signals in recruiting IgA-secreting plasma cells was confirmed in experiments with antibiotic-treated specific pathogen free andMyD88KO mice, which have limited commensals and a decreased ability to respond to commensals. The number of intestinal CD11b⁺ IgA⁺plasma cells was reduced in these mice, suggesting the role of commensals in recruiting IgA-secreting plasma cells.^[18] Based on this evidence commensal microbes can protect the host from harmful pathogens by stimulating IgA production.

Members of the microbiota are capable of producing antimicrobial peptides, protecting humans from excessive intestinal inflammation and microbial-associated diseases. Various commensals (primarilyGram-positive bacteria), secretebacteriocins, peptides which bind to receptors on closely related target cells, formingion-permeable channels and pores in the cell wall.^[19] The resulting efflux of metabolites and cell contents and dissipation ofion gradients causes bacterial cell death.^[19] However, bacteriocins can also induce death by translocating into the periplasmic space and cleaving DNA non-specifically (colicin E2), inactivating theribosome (colicin E3), inhibiting synthesis ofpeptidoglycan, a major component of the bacterialcell wall (colicin M).^[19]

Bacteriocins have immense potential to treat human disease. For example, diarrhea in humans can be caused by a variety of factors, but is often caused by bacteria such asClostridioides difficile.^[19]Microbispora strain ATCC PTA-5024 secretes the bacteriocin microbisporicin, which kills Clostridia by targetingprostaglandin synthesis.^[20] Additionally, bacteriocins are particularly promising due to their difference in mechanisms thanantibiotics meaning manyantibiotic-resistant bacteria are not resistant to these bacteriocins. For example,in vitro growth ofmethicillin-resistantS. aureus (MRSA) was inhibited by the bacteriocinnisin A, produced byLactococcus lactis.^[19][21] Nisin A inhibits methicillin-resistantS. aureus by binding to the precursor to bacterial cell wall synthesis,lipid II. This hinders the ability to synthesize the cell wall, resulting in increased membrane permeability, disruption of electrochemical gradients, and possible death.^[22]

The intestinal epithelium in humans is reinforced withcarbohydrates likefucose expressed on theapical surface of epithelial cells.^[23]Bacteroides thetaiotaomicron, a bacterial species in theileum andcolon, stimulates thegene encodingfucose, Fut2, in intestinal epithelial cells.^[23] In this mutualistic interaction, the intestinal epithelial barrier is fortified and humans are protected against invasion of destructive microbes, whileB. thetaiotaomicron benefits because of it can use fucose for energy production and its role in bacterial gene regulation.^[23]

Theskin microbiota is vital as a line of defense against infection, a physical barrier between the environment and the inside of the host. Commensal microbes that live on the skin, such asStaphylococcus epidermidis, produceantimicrobial peptides (AMPs) that aid the host immune system.^[24] These AMPs signal immune responses and maintain an inflammatoryhomeostasis by modulating the release ofcytokines.^[24]S. epidermidis secretes a small molecule AMP which leads to increased expression of Human β-defensins.^[24]S.epidermidis also stimulates IL-17A+ CD8+ T cells production that increases host immunity.^[25]

Exposure to these skin commensal bacteria early in development is crucial for host tolerance of these microbes as T cell encounters allow commensal antigen presentation to be common during development.^[26]S. epidermidis and other important microflora work similarly to supporthomeostasis and general health in areas all over the human body such as theoral cavity,vagina,gastrointestinal tract, andoropharynx.^[24]

An equilibrium of symbionts and pathobionts is critical to fight off outside pathogens and avoid many harmful disorders.Dysbiosis, or imbalances in the bacterial composition of the intestine, has been implicated in inflammatory bowel disease, obesity, and allergic diseases in humans and other animals.^[27]

Gut microbes may play a role incancer development through a variety of mechanisms. Sulfate-reducing bacteria producehydrogen sulfide, which results ingenomicDNA damage.^[28] Higher rates of colon cancer are associated with higher amounts of sulfate-reducing bacteria in the gut.^[28] Additionally,anaerobic bacteria in the colon transform primarybile acids into secondary bile acid which has been implicated in colorectal carcinogenesis.^[28] Gut bacteriametabolites such asshort-chain fatty acids (SCFAs),B vitamins and N¹, N¹²-diacetylspermine have also been implicated in suppressing colorectal cancer.^[1]Gram-negative bacteria producelipopolysaccharide (LPS), which binds toTLR-4 and throughTGF-β signaling, leads to the expression of growth factors and inflammatory mediators that promoteneoplasia.^[28]

Members of a healthygut microbiome have been shown to increaseinterferon-γ-producingCD8 T-cells and tumor-infiltratingdendritic cells (TILs) in the intestine.^[29] Not only do these CD8 T-cells enhance resistance againstintracellular pathogens such asListeria monocytogenes but they also have been shown to be important in anti-cancer immunity specifically against MC38adenocarcinoma where they along with the TILs increaseMHC I expression.^[29]

The human microbiome modulates the host immune in positive ways to help defend itself from potential pathogens but can also lead to immune overreactions to foreign substances, even sometimes attacking the host itself.Inflammatory bowel disease (IBD) andasthma are two disorders that have been found to be impacted by microbiota metabolites causing immune reactions. Short-chain fatty acids (SCFAs) have been linked to a decrease in allergic inflammation in asthma^[30] while both SCFAs and B vitamins have been shown to decrease IBD inflammation.^[31]

SCFAs (acetate,butyrate andpropionate) are metabolites created by bacteria in the gut, these molecules then inhibithistone deacetylases (HDACs) as well asG protein-coupled receptors, acting assignaling molecules.^[1] Inhibition of HDACs downregulatesnuclear factor-κB (NF-κB) and the pro-inflammatorytumor necrosis factor (TNF) as well as having anti-inflammatory effects onmacrophages anddendritic cells.^[1]

Activation of mucosal immunity and the intestinal microbiota may contribute to inflammatory bowel disease. Many bacteria cause inflammation in the gut includingEscherichia coli, which replicate inmacrophages and secretescytokine tumor necrosis factor.^[32] However, some bacteria, including the human symbiontB. fragilis, may preventcolitis by producingpolysaccharide A (PSA).^[33] PSA induces production ofIL-10, an immunosuppressive cytokine that suppresses inflammation.^[34] Treatment of bone-marrow-derived dendritic cells and naïve CD4⁺ T cells with purified PSA resulted in increased IL-10 production.^[34]

To mimic colitis and activate inflammatory T cells in an experimental condition, wild-type mice were treated with trinitrobenzen sulphonic acid (TNBS).^[34] Thereafter, these mice were given PSA orally. Pro-inflammatory cytokine expression (IL-17a andTNFα) in CD4⁺ cells was measured withELISA. The researchers found that compared to the CD4⁺ cells in the control mice, CD4⁺ cells in PSA-treated mice produced reduced levels of the pro-inflammatory cytokines IL-17a and TNFα.^[34] Furthermore, after intestinal colonization withB. fragilis,IL-23 expression bysplenocytes was markedly reduced.^[34] These data suggest that PSA secreted byB. fragilis suppresses the inflammatory process during colitis by leading to increased production of IL-10 and decreased production of IL-17, TNFα, and IL-23.^[34]

Commensal bacteria may also regulate immune responses that cause allergies. For example, commensal bacteria stimulateTLR4, which may inhibit allergic responses to food.^[35]

Major metabolic diseases have been found to be impacted by gut microbiota metabolites, includingheart disease,kidney disease,type 2 diabetes andobesity.^[1] Breakdown ofL-carnitine from red meat by gut microbes intotrimethylamine N-oxide (TMAO) has been associated withatherosclerosis, which can lead to obesity, heart disease and type 2 diabetes^[36] while both heart and kidney disease events can be predicted by high freep-Cresol levels.^[37] SCFAs modulates renin secretion by binding Olfr78, lowering blood pressure and decreasing the risk of kidney disease.^[38]

Studies with germ-free mice have suggested that the absence of gut microbes protects against obesity.^[39] While the exact mechanism by which microbes play a role in obesity has yet to be elucidated, it has been hypothesized that the intestinal microbiota is involved in converting food to usable energy and fat storage.^[39]

Gut microbiota impacts many facets of human health, even neurological disorders that can be caused by molecule or hormone imbalance.Autism spectrum disorder (ASD),^[1]central nervous system dysfunction^[1] anddepression^[40] have all been found to be impacted by the microbiota.

While ASD is regularly described by behavioral differences it also can present with gastrointestinal symptoms.^[41] Dysbiosis of the GI tract has been noted in some ASD individuals, leading to an increased intestinal permeability.^[41] In the mouse model mice with ASD and GI tract dysbiosis (maternal immune activation) increased intestinal permeability was found as was corrected by the introduction of human gut bacterial symbiontB. fragilis.^[41]

Microglia development have a pivotal role in central nervous system dysfunction, bacterial metabolite SCFAs regulatemicroglia homeostasis that is crucial for regular CNS development.^[42] Also pivotal for brain development is the creation of tight junctions at theblood-brain barrier in order to control passage between the blood and brain. Germ-free mice have increased blood-brain barrier permeability due to decreased expression of tight junction proteinsoccludin andclaudin-5 as compared to normal gut microbiota mice.^[43]

Butyrate-producing bacteria and thedopamine metabolite3,4-dihydroxyphenylacetic acid have been linked to higher quality of life indicators whileγ-aminobutyric acid has been linked to higher levels of depression.^[40]

• Immune system

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