PMID:24123819

Citation	Hemarajata, P, Gao, C, Pflughoeft, KJ, Thomas, CM, Saulnier, DM, Spinler, JK and Versalovic, J (2013) Lactobacillus reuteri-specific immunoregulatory gene rsiR modulates histamine production and immunomodulation by Lactobacillus reuteri. J. Bacteriol. 195:5567-76
Abstract	Human microbiome-derived strains of Lactobacillus reuteri potently suppress proinflammatory cytokines like human tumor necrosis factor (TNF) by converting the amino acid l-histidine to the biogenic amine histamine. Histamine suppresses mitogen-activated protein (MAP) kinase activation and cytokine production by signaling via histamine receptor type 2 (H2) on myeloid cells. Investigations of the gene expression profiles of immunomodulatory L. reuteri ATCC PTA 6475 highlighted numerous genes that were highly expressed during the stationary phase of growth, when TNF suppression is most potent. One such gene was found to be a regulator of genes involved in histidine-histamine metabolism by this probiotic species. During the course of these studies, this gene was renamed the Lactobacillus reuteri-specific immunoregulatory (rsiR) gene. The rsiR gene is essential for human TNF suppression by L. reuteri and expression of the histidine decarboxylase (hdc) gene cluster on the L. reuteri chromosome. Inactivation of rsiR resulted in diminished TNF suppression in vitro and reduced anti-inflammatory effects in vivo in a trinitrobenzene sulfonic acid (TNBS)-induced mouse model of acute colitis. A L. reuteri strain lacking an intact rsiR gene was unable to suppress colitis and resulted in greater concentrations of serum amyloid A (SAA) in the bloodstream of affected animals. The PhdcAB promoter region targeted by rsiR was defined by reporter gene experiments. These studies support the presence of a regulatory gene, rsiR, which modulates the expression of a gene cluster known to mediate immunoregulation by probiotics at the transcriptional level. These findings may point the way toward new strategies for controlling gene expression in probiotics by dietary interventions or microbiome manipulation.
Links	PubMed PMC3889603 Online version:10.1128/JB.00261-13
Keywords	Animals; Artificial Gene Fusion; Colitis/chemically induced; Colitis/microbiology; Colitis/pathology; Cytokines/antagonists & inhibitors; Disease Models, Animal; Gene Expression Regulation, Bacterial; Genes, Reporter; Histamine/metabolism; Humans; Immunomodulation; Lactobacillus reuteri/genetics; Lactobacillus reuteri/immunology; Lactobacillus reuteri/isolation & purification; Lactobacillus reuteri/metabolism; Mice; Microbiota; Promoter Regions, Genetic; Transcription Factors/metabolism; Transcription, Genetic; Trinitrobenzenesulfonic Acid/toxicity
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
LACRE:E9RM36		GO:0050727: regulation of inflammatory response			P		Figure 5A: mice pretreated with culture supernatants from wild-type or complemented strain developed less severe colitis than mice pretreated with culture supernatants from rsiR mutant Figure 5B: concentration of SAA was lower in mice pretreated with culture supernatants from wild-type and complemented strain, concentration of SAA was higher in mice pretreated with culture supernatants from rsiR mutant	complete CACAO 9664
LACRD:A5VK67		GO:0045893: positive regulation of transcription, DNA-templated	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Fig. 1A: hdc gene expression decreased in rsiR mutants Fig 2: culture supernatants from wildtype had higher concentrations of histamine than culture supernatants from rsiR mutant	complete CACAO 9608
LACRD:A5VK67		GO:0046775: suppression by virus of host cytokine production	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Figure 4: wild-type suppressed production of human TNF, mutant rsiR less effective at suppressing production of TNF	complete CACAO 9663
LACRD:A5VK67		GO:0001694: histamine biosynthetic process	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Fig. 2: production of histamine was much higher in wildtype than mutant, even in presence of L-histidine (Lactobacillus reuteri converts L-histidine to histamine)	complete CACAO 10052
LACRD:A5VK67		GO:0052036: negative regulation by symbiont of host inflammatory response	ECO:0000315: mutant phenotype evidence used in manual assertion		P		TNBS was injected in mice to induce intestinal inflammation Fig. 5A: mice pretreated with wildtype supernatant experienced less inflammation than mice pretreated with mutant supernatant Fig. 5B: mice pretreated with wildtype supernatant produced less SAA than mice pretreated with mutant supernatant (SAA is secreted during the initial stages of inflammation)	complete CACAO 10069

References

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