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. 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, 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
Microbial symbiosis relies on interspecies communication. 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 and production of vitamins 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 microbiota 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-infectious diseases.
Regulation of immune responses Commensal bacteria in the GI tract survive despite the abundance of local immune cells. Homeostasis in the intestine requires stimulation of toll-like receptors by commensal microbes. When mice are raised in germ-free conditions, they lack circulating antibodies, and cannot produce mucus, antimicrobial proteins, or mucosal T-cells. Additionally, mice raised in germ-free conditions lack tolerance and often suffer from hypersensitivity reactions. 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. These data suggest that commensal microbes aid in intestinal homeostasis and immune system development. To prevent constant activation of immune cells and resulting inflammation, hosts and bacteria have evolved to maintain intestinal homeostasis and immune system development. For example, the human symbiont Bacteroides fragilis produces polysaccharide A (PSA), which binds to toll-like receptor 2 (TLR-2) on CD4+ T cells. While TLR2 signaling can activate clearance of peptides, PSA induces an anti-inflammatory response when it binds to TLR2 on CD4+ T cells. Through TLR2 binding, PSA suppresses pro-inflammatory TH17 responses, promoting tolerance and establishing commensal gut colonization. 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. These microbial metabolites are crucial for protecting the host from unnecessary inflammation in the gut.
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