Microbial symbiosis and immunity
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Long-term close-knit interactions between symbiotic microbes and their host can alter host immune system responses to other microorganisms, including pathogens, and are required to maintain proper homeostasis.[1] The immune system is a host defense system consisting of anatomical physical barriers as well as physiological and cellular responses, which protect the host against harmful microorganisms while limiting host responses to harmless symbionts. Humans are home to 1013 to 1014 bacteria, roughly equivalent to the number of human cells,[2] and while these bacteria can be pathogenic to their host most of them are mutually beneficial to both the host and bacteria.
The human immune system consists of two main types of immunity: innate and adaptive. The innate 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 the complement cascade to identify foreign bacteria and activate necessary cell responses, and white blood cells that remove foreign substances. The adaptive immune system, or acquired immune system, is a pathogen-specific immune response that is carried out by lymphocytes through antigen presentation on MHC molecules to distinguish between self and non-self antigens.
Microbes can promote the development of the host's immune system in the gut and skin, and may help to prevent pathogens from invading. Some release anti-inflammatory products, protecting against parasitic gut microbes. Commensals promote the development of B cells that produce a protective antibody, Immunoglobulin A (IgA). This can neutralize pathogens and exotoxins, and promote the development of immune cells and mucosal immune response. However, microbes have been implicated in human diseases including inflammatory bowel disease, obesity, and cancer.
General principles
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Microbial symbiosis relies on interspecies communication.[3] between the host and microbial symbionts. Immunity has been historically characterized in multicellular 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 an autoimmune 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.
Gastrointestinal tract
The human gastrointestinal tract (GI tract) consists of the mouth, pharynx, esophagus, stomach, small intestine, and large 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 pathogenic bacteria, archaea, viruses, and eukaryotes. In return many of these microbes complete important functions for the host including breakdown of fiber[4] and production of vitamins[5] where gut microbes have at least a role in the production of vitamins such as A, B2, B3, B5, B12, C, D and K.
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 gastrointestinal
Regulation of immune responses
Commensal bacteria in the GI tract survive despite the abundance of local immune cells.[6] Homeostasis in the intestine requires stimulation of toll-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 lack tolerance and often suffer from hypersensitivity reactions.[6] Maturation of the GI tract is mediated by pattern recognition receptors (PRRs), which recognize non-self pathogen 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.
Commensal gut microbes create a variety of metabolites that bind aryl 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.
Development of isolated lymphoid tissues
Microbes trigger development of isolated
Additionally, there are other mechanisms by which commensals promote maturation of isolated lymphoid follicles. For example, commensal bacteria products bind to
Protection against pathogens
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]
Immunoglobulin A
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 of TH17 and FOXP3+ regulatory T cells.[15][16] Given its critical function in the GI tract, the number of IgA-secreting plasma cells in the jejunum is greater than the total plasma cell population of the bone marrow, lymph, and spleen 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 by dendritic cells located beneath peyer's patches and in the lamina 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 and MyD88 KO 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.
Antimicrobial peptides
Members of the microbiota are capable of producing antimicrobial peptides, protecting humans from excessive intestinal inflammation and microbial-associated diseases. Various commensals (primarily Gram-positive bacteria), secrete bacteriocins, peptides which bind to receptors on closely related target cells, forming ion-permeable channels and pores in the cell wall.[19] The resulting efflux of metabolites and cell contents and dissipation of ion 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 the ribosome (colicin E3), inhibiting synthesis of peptidoglycan, a major component of the bacterial cell 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 as
Fortification fucose
The intestinal epithelium in humans is reinforced with
Skin
The
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.
Role in disease
An equilibrium of