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    • One class of microbial derived metabolites

    2022-07-15

    One class of microbial-derived metabolites that have received significant attention are the short-chain fatty acids (SCFA), which include butyrate, acetate and propionate. The production of SCFA occurs in the colon following microbial fermentation of dietary fibers and SCFA can also be consumed in certain foods such as butter [5]. SCFAs are an important energy source for colonocytes and regulate the assembly and organization of tight junctions. Importantly, SCFA promote dendritic cell regulatory activity resulting in the induction of regulatory lymphocytes and IL-10-secreting T cells. Abnormalities in the production of SCFAs (due to dietary factors and/or dysbiosis) have been suggested to play a role in the pathogenesis of type-2 diabetes, obesity, inflammatory bowel disease, colorectal cancer and allergies [6]. The SCFA-induced immunoregulatory activities have largely been attributed to their binding and activation of G protein-coupled receptors (GPCRs) such as GPR41, GPR43 and GPR109a [7]. In addition to SCFAs, the microbiota can secrete a wide range of other metabolites that can also influence mucosal immune responses via activation of GPCRs. One such metabolite is histamine. Histamine (2-[4-imidazolyl]-ethylamine) is a low-molecular-weight biogenic amine and was first chemically synthesized by Windaus and Vogt in 1907. Dale and Laidlaw reported the first biological functions of histamine in 1910, whereby they demonstrated that histamine induced smooth muscle-stimulating and vasodepressor action previously observed during anaphylaxis [8]. Subsequently histamine was isolated from many different tissues, thus its name was based on the Greek word ‘histos’, which means tissue. Histamine binds to four known histamine receptors (HRs) and a range of ‘blockbuster’ drugs have been developed for H1R and H2R, the inventors of which were awarded Nobel prizes in 1957 (Daniet Bovet) and 1988 (James Black). Drugs targeting H3R and H4R are currently being evaluated.
    Immune regulation by histamine Innate and adaptive immune cells throughout the body can produce histamine by decarboxylation of the amino NSC228155 l-histidine by the enzyme histidine decarboxylase (HDC) [9]. Mast cells, basophils, gastric enterochromaffin-like cells and histaminergic neurons are the best-described cellular sources of histamine. Other cells such as platelets, monocytes/macrophages, dendritic cells, neutrophils and lymphocytes may upon stimulation also express HDC. Activity of HDC is influenced by cytokines including IL-1, IL-3, IL-12, IL-18, GM-CSF, macrophage-colony stimulating factor, TNF-α and calcium ionophore [10]. In the case of mast cells and basophils, histamine is stored in large quantities and released upon cellular activation. All other cells secrete histamine following synthesis and do not store it intracellularly [11]. Before secretion, histamine can be metabolized by ring methylation (HNMT—histamine-N-methyltransferase) to N-methylhistamine, or by oxidative deamination (DAO—diamine oxidase) to imidazole acetic acid. As DAO is secreted extracellularly, this enzyme may be responsible for scavenging extracellular histamine, while HNMT remains within the cytosol and thereby metabolizes intracellular histamine [12, 13].
    Histamine-secreting bacteria In addition to mammalian cells, a number of different bacterial strains have been identified as being able to secrete histamine following decarboxylation of histidine via HDC activity. The best described are those bacteria that are able to secrete histamine in food products. Their presence is monitored and controlled in cheese, meat, vegetables, dairy products and also during beer and wine fermentation [35, 36]. However the most notorious examples of histamine secreting bacteria are those associated with spoiled fish and sea food products. Histamine fish poisoning (HFP), or scombroid food poisoning, is an illness associated with consumption of high levels of histamine in fish, following the metabolism of histidine in the fish by bacteria during inappropriate handling during storage or processing [37, 38]. The earliest record of the disease was in 1799. Symptoms of HFP resemble those of food allergy and can include facial itching, torso or body rash, nausea, vomiting, diarrhoea, tachycardia, hypotension, respiratory distress and in rare severe cases may result in death [39]. HFP is often misdiagnosed as a food allergic response. The bacterial species with histidine decarboxylase activity and which have been implicated in HFP include Morganella morganii, Eschericha coli, Hafnia alvei, Proteus vulgaris, Proteus milabilis, Enterobacter aerogenes, Raoultella planticola, Raoultella ornithinolytica, Citrobacter freundii, Pseudomonas fluorescens and Photobacterium damselae [40].