Abstract
BackgroundHistamine is a key mediator of the anti-inflammatory activity conferred by the probiotic organism Lactobacillus reuteri ATCC PTA 6475 in animal models of colitis and colorectal cancer. In L. reuteri, histamine synthesis and secretion requires l-histidine decarboxylase and a l-histidine/histamine exchanger. Chloride channel (ClC)-family proton/chloride antiporters have been proposed to act as electrochemical shunts in conjunction with amino acid decarboxylase systems, correcting ion imbalances generated by decarboxylation through fixed ratio exchange of two chloride ions for one proton. This family is unique among transporters by facilitating ion flux in either direction. Here we examine the histidine decarboxylase system in relation to ClC antiporters in the probiotic organism Lactobacillus reuteri.ResultsIn silico analyses reveal that L. reuteri possesses two ClC transporters, EriC and EriC2, as well as a complete histidine decarboxylase gene cluster (HDC) for the synthesis and export of histamine. When the transport activity of either proton/chloride antiporter is disrupted by genetic manipulation, bacterial histamine output is reduced. Using fluorescent reporter assays, we further show that ClC transporters affect histamine output by altering intracellular pH and membrane potential. ClC transport also alters the expression and activity of two key HDC genes: the histidine decarboxylase (hdcA) and the histidine/histamine exchanger (hdcP).ConclusionsHistamine production is a potentially beneficial feature for intestinal microbes by promoting long-term colonization and suppression of inflammation and host immune responses. ClC transporters may serve as tunable modulators for histamine production by L. reuteri and other gut microbes.
Highlights
Histamine is a key mediator of the anti-inflammatory activity conferred by the probiotic organism Lactobacillus reuteri American Type Culture Collection (ATCC) PTA 6475 in animal models of colitis and colorectal cancer
Extracellular chloride concentration and pH regulate histamine output via proton/chloride antiporters Previous work indicates that the histidine decarboxylases of lactic acid bacteria, including Lactobacillus species, function best at acidic pH [18, 24, 32]
Since Chloride channel (ClC)-family transporters can modulate both intracellular pH and chloride concentration, we examined the effects of the extracellular environment on histamine production by L. reuteri
Summary
Histamine is a key mediator of the anti-inflammatory activity conferred by the probiotic organism Lactobacillus reuteri ATCC PTA 6475 in animal models of colitis and colorectal cancer. The human breast milkderived strain L. reuteri ATCC PTA 6475 ( known as strain MM4-1A) has been shown to reduce inflammation in murine models of colitis and inflammationassociated colorectal cancer [12,13,14,15] This strain has been shown to reduce production of proinflammatory cytokines by primary macrophages isolated from pediatric Crohn’s Disease patients [16] and to diminish antibiotic-associated side effects in Helicobacter pylori infected patients [11]. In vitro studies using a human monocytoid cell line demonstrate that the anti-inflammatory effects of L. reuteri 6475 are closely linked with the bacterium’s ability to produce histamine [17]
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