CoChat
Sign Up
Cited by 491Probiotics and Fermented FoodsMast cells and histaminePolyamine Metabolism and Applications

Histamine Derived from Probiotic Lactobacillus reuteri Suppresses TNF via Modulation of PKA and ERK Signaling

Open access
Thomas, Carissa M., Hong, Teresa, van Pijkeren, Jan Peter, Hemarajata, Peera, Trinh, Dan V., Hu, Weidong, Britton, Robert A., Kalkum, Markus +1 more·2012·PLoS ONE
DOI 10.1371/journal.pone.0031951PMC PMC3285189
Open this paper in CoChat — free accountOpen PDF

Abstract

Beneficial microbes and probiotic species, such as Lactobacillus reuteri, produce biologically active compounds that can modulate host mucosal immunity. Previously, immunomodulatory factors secreted by L. reuteri ATCC PTA 6475 were unknown. A combined metabolomics and bacterial genetics strategy was utilized to identify small compound(s) produced by L. reuteri that were TNF-inhibitory. Hydrophilic interaction liquid chromatography-high performance liquid chromatography (HILIC-HPLC) separation isolated TNF-inhibitory compounds, and HILIC-HPLC fraction composition was determined by NMR and mass spectrometry analyses. Histamine was identified and quantified in TNF-inhibitory HILIC-HPLC fractions. Histamine is produced from L-histidine via histidine decarboxylase by some fermentative bacteria including lactobacilli. Targeted mutagenesis of each gene present in the histidine decarboxylase gene cluster in L. reuteri 6475 demonstrated the involvement of histidine decarboxylase pyruvoyl type A (hdcA), histidine/histamine antiporter (hdcP), and hdcB in production of the TNF-inhibitory factor. The mechanism of TNF inhibition by L. reuteri-derived histamine was investigated using Toll-like receptor 2 (TLR2)-activated human monocytoid cells. Bacterial histamine suppressed TNF production via activation of the H(2) receptor. Histamine from L. reuteri 6475 stimulated increased levels of cAMP, which inhibited downstream MEK/ERK MAPK signaling via protein kinase A (PKA) and resulted in suppression of TNF production by transcriptional regulation. In summary, a component of the gut microbiome, L. reuteri, is able to convert a dietary component, L-histidine, into an immunoregulatory signal, histamine, which suppresses pro-inflammatory TNF production. The identification of bacterial bioactive metabolites and their corresponding mechanisms of action with respect to immunomodulation may lead to improved anti-inflammatory strategies for chronic immune-mediated diseases.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0031951

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In vitro evidence has shown histamine produced by L. reuteri suppressed human monocytoid production of TNF-α via the TLR.

    “Although little is known about how the microbial production of histamine in the host gut affects host physiology, in vitro evidence has shown histamine produced by L. reuteri suppressed human monocytoid production of tumor necrosis factor (TNF)-α via the TLR (Thomas et al., 2012).”

    From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Thomas et al., 2012

    The Results section, “Histamine inhibits TNF production via the H2 receptor,” reports that histamine inhibited TNF production in TLR2-activated human monocytoid cells. It identifies the histamine H2 receptor, not TLR, as the route of suppression; TLR2 was used to activate the cells. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 67

  1. [1]Yan F Cao H Cover TL Whitehead R Washington MK 2007 Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology 132 562 575 17258729 PMC3036990
  2. [2]Clarke MB Sperandio V 2005 Events at the host-microbial interface of the gastrointestinal tract III. Cell-to-cell signaling among microbial flora, host, and pathogens: there is a whole lot of talking going on. Am J Physiol Gastrointest Liver Physiol 288 G1105 1109 15890712
  3. [3]Reuter G 2001 The Lactobacillus and Bifidobacterium microflora of the human intestine: composition and succession. Curr Issues Intest Microbiol 2 43 53 11721280
  4. [5]Spinler JK Taweechotipatr M Rognerud CL Ou CN Tumwasorn S 2008 Human-derived probiotic Lactobacillus reuteri demonstrate antimicrobial activities targeting diverse enteric bacterial pathogens. Anaerobe 14 166 171 18396068 PMC2494590
  5. [6]Morita H Toh H Fukuda S Horikawa H Oshima K 2008 Comparative genome analysis of Lactobacillus reuteri and Lactobacillus fermentum reveal a genomic island for reuterin and cobalamin production. DNA Res 15 151 161 18487258 PMC2650639
  6. [7]Santos F Spinler JK Saulnier DM Molenaar D Teusink B 2011 Functional identification in Lactobacillus reuteri of a PocR-like transcription factor regulating glycerol utilization and vitamin B12 synthesis. Microb Cell Fact 10 55 21777454 PMC3162504
  7. [8]Lin YP Thibodeaux CH Pena JA Ferry GD Versalovic J 2008 Probiotic Lactobacillus reuteri suppress proinflammatory cytokines via c-Jun. Inflamm Bowel Dis 14 1068 1083 18425802
  8. [9]Iyer C Kosters A Sethi G Kunnumakkara AB Aggarwal BB 2008 Probiotic Lactobacillus reuteri promotes TNF-induced apoptosis in human myeloid leukemia-derived cells by modulation of NF-kappaB and MAPK signalling. Cell Microbiol 10 1442 1452 18331465
  9. [10]Watanabe T Nishio H Tanigawa T Yamagami H Okazaki H 2009 Probiotic Lactobacillus casei strain Shirota prevents indomethacin-induced small intestinal injury: involvement of lactic acid. Am J Physiol Gastrointest Liver Physiol 297 G506 513 19589943
  10. [11]Konstantinov SR Smidt H de Vos WM Bruijns SC Singh SK 2008 S layer protein A of Lactobacillus acidophilus NCFM regulates immature dendritic cell and T cell functions. Proc Natl Acad Sci U S A 105 19474 19479 19047644 PMC2592362
  11. [13]Murzyn A Krasowska A Stefanowicz P Dziadkowiec D Lukaszewicz M 2010 Capric acid secreted by S. boulardii inhibits C. albicans filamentous growth, adhesion and biofilm formation. PLoS One 5 e12050 20706577 PMC2919387
  12. [14]Thomas CM Versalovic J 2010 Probiotics-host communication: Modulation of signaling pathways in the intestine. Gut Microbes 1 148 163 20672012 PMC2909492
  13. [15]Preidis GA Versalovic J 2009 Targeting the human microbiome with antibiotics, probiotics, and prebiotics: gastroenterology enters the metagenomics era. Gastroenterology 136 2015 2031 19462507 PMC4108289
  14. [16]Gionchetti P Rizzello F Morselli C Poggioli G Tambasco R 2007 High-dose probiotics for the treatment of active pouchitis. Dis Colon Rectum 50 2075 2082; discussion 2082–2074 17934776
  15. [17]Alfaleh K Bassler D 2008 Probiotics for prevention of necrotizing enterocolitis in preterm infants Cochrane Database Syst Rev CD005496 18254081
  16. [18]Pena JA Rogers AB Ge Z Ng V Li SY 2005 Probiotic Lactobacillus spp. diminish Helicobacter hepaticus-induced inflammatory bowel disease in interleukin-10-deficient mice. Infect Immun 73 912 920 15664933 PMC547020
  17. [19]Christensen HR Frokiaer H Pestka JJ 2002 Lactobacilli differentially modulate expression of cytokines and maturation surface markers in murine dendritic cells. J Immunol 168 171 178 11751960
  18. [20]Banerjee A Gerondakis S 2007 Coordinating TLR-activated signaling pathways in cells of the immune system. Immunol Cell Biol 85 420 424 17637696
  19. [21]Carter AB Monick MM Hunninghake GW 1999 Both Erk and p38 kinases are necessary for cytokine gene transcription. Am J Respir Cell Mol Biol 20 751 758 10101008
  20. [22]Guha M Mackman N 2001 LPS induction of gene expression in human monocytes. Cell Signal 13 85 94 11257452
  21. [23]Waltereit R Weller M 2003 Signaling from cAMP/PKA to MAPK and synaptic plasticity. Mol Neurobiol 27 99 106 12668903
  22. [24]Funaki C Hodges RR Dartt DA 2010 Identification of the Raf-1 signaling pathway used by cAMP to inhibit p42/p44 MAPK in rat lacrimal gland acini: role in potentiation of protein secretion. Invest Ophthalmol Vis Sci 51 6321 6328 20671279 PMC3055758
  23. [25]Pena JA Thompson-Snipes L Calkins PR Tatevian N Puppi M 2009 Alterations in myeloid dendritic cell innate immune responses in the Galphai2-deficient mouse model of colitis. Inflamm Bowel Dis 15 248 260 19037851 PMC2627792
  24. [26]Guma M Stepniak D Shaked H Spehlmann ME Shenouda S 2011 Constitutive intestinal NF-{kappa}B does not trigger destructive inflammation unless accompanied by MAPK activation. J Exp Med 208 1889 1900 21825016 PMC3171091
  25. [27]Xia J Bjorndahl TC Tang P Wishart DS 2008 MetaboMiner-semi-automated identification of metabolites from 2D NMR spectra of complex biofluids. BMC Bioinformatics 9 507 523 19040747 PMC2612014
  26. [28]Koyama J Taga S Shimizu K Shimizu M Morita I 2011 Simultaneous determination of histamine and prostaglandin D(2) using an LC-ESI-MS/MS method with positive/negative ion-switching ionization modes: application to the study of anti-allergic flavonoids on the degranulation of KU812 cells. Anal Bioanal Chem 401 1385 1392 21725829
  27. [29]Trip H Mulder NL Rattray FP Lolkema JS 2011 HdcB, a novel enzyme catalysing maturation of pyruvoyl-dependent histidine decarboxylase. Mol Microbiol 79 861 871 21208300
  28. [30]Martin MC Fernandez M Linares DM Alvarez MA 2005 Sequencing, characterization and transcriptional analysis of the histidine decarboxylase operon of Lactobacillus buchneri. Microbiology 151 1219 1228 15817789
  29. [31]Lucas PM Wolken WA Claisse O Lolkema JS Lonvaud-Funel A 2005 Histamine-producing pathway encoded on an unstable plasmid in Lactobacillus hilgardii 0006. Appl Environ Microbiol 71 1417 1424 15746344 PMC1065165
  30. [32]Thomason L Court DL Bubunenko M Costantino N Wilson H 2007 Recombineering: genetic engineering in bacteria using homologous recombination. Curr Protoc Mol Biol Chapter 1 Unit 1 16 18265390
  31. [33]van Pijkeren JP Britton RA 2012 High efficiency recombineering in lactic acid bacteria. Nucleic Acids Res in press PMC3378904 22328729
  32. [34]Sander LE Lorentz A Sellge G Coeffier M Neipp M 2006 Selective expression of histamine receptors H1R, H2R, and H4R, but not H3R, in the human intestinal tract. Gut 55 498 504 16299042 PMC1856162
  33. [35]Vannier E Miller LC Dinarello CA 1991 Histamine suppresses gene expression and synthesis of tumor necrosis factor alpha via histamine H2 receptors. J Exp Med 174 281 284 2056280 PMC2118872
  34. [36]Wang L Gantz I DelValle J 1996 Histamine H2 receptor activates adenylate cyclase and PLC via separate GTP-dependent pathways. Am J Physiol 271 G613 620 8897880
  35. [37]Taffet SM Singhel KJ Overholtzer JF Shurtleff SA 1989 Regulation of tumor necrosis factor expression in a macrophage-like cell line by lipopolysaccharide and cyclic AMP. Cell Immunol 120 291 300 2541929
  36. [38]Dohlsten M Kalland T Sjogren HO Carlsson R 1988 Histamine inhibits interleukin 1 production by lipopolysaccharide-stimulated human peripheral blood monocytes. Scand J Immunol 27 527 532 2897711
  37. [39]Elenkov IJ Webster E Papanicolaou DA Fleisher TA Chrousos GP 1998 Histamine potently suppresses human IL-12 and stimulates IL-10 production via H2 receptors. J Immunol 161 2586 2593 9725260
  38. [40]Takahashi HK Morichika T Iwagaki H Tamura R Kubo S 2003 Histamine downregulates CD14 expression via H2 receptors on human monocytes. Clin Immunol 108 274 281 14499251
  39. [41]Nakamura T Ueno Y Goda Y Nakamura A Shinjo K 1997 Efficacy of a selective histamine H2 receptor agonist, dimaprit, in experimental models of endotoxin shock and hepatitis in mice. Eur J Pharmacol 322 83 89 9088875
  40. [42]Masaki T Chiba S Tatsukawa H Noguchi H Kakuma T 2005 The role of histamine H1 receptor and H2 receptor in LPS-induced liver injury. FASEB J 19 1245 1252 16051691
  41. [43]Handley SA Dube PH Miller VL 2006 Histamine signaling through the H(2) receptor in the Peyer's patch is important for controlling Yersinia enterocolitica infection. Proc Natl Acad Sci U S A 103 9268 9273 16717182 PMC1482599
  42. [44]Aschenbach JR Honscha KU von Vietinghoff V Gabel G 2009 Bioelimination of histamine in epithelia of the porcine proximal colon of pigs. Inflamm Res 58 269 276 19184353
  43. [45]Jutel M Watanabe T Akdis M Blaser K Akdis CA 2002 Immune regulation by histamine. Curr Opin Immunol 14 735 740 12413523
  44. [46]Jutel M Watanabe T Klunker S Akdis M Thomet OA 2001 Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 413 420 425 11574888
  45. [47]Guillet R Stoll BJ Cotten CM Gantz M McDonald S 2006 Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 117 e137 142 16390920
  46. [48]Wu G 2009 Amino acids: metabolism, functions, and nutrition. Amino Acids 37 1 17 19301095
  47. [49]Coeffier M Marion-Letellier R Dechelotte P 2010 Potential for amino acids supplementation during inflammatory bowel diseases. Inflamm Bowel Dis 16 518 524 19572337
  48. [50]Son DO Satsu H Shimizu M 2005 Histidine inhibits oxidative stress- and TNF-alpha-induced interleukin-8 secretion in intestinal epithelial cells. FEBS Lett 579 4671 4677 16107255
  49. [51]Andou A Hisamatsu T Okamoto S Chinen H Kamada N 2009 Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages. Gastroenterology 136 564 574 e562 19027739
  50. [52]Fuller MF Reeds PJ 1998 Nitrogen cycling in the gut. Annu Rev Nutr 18 385 411 9706230
  51. [53]Yang XD Ai W Asfaha S Bhagat G Friedman RA 2011 Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+immature myeloid cells. Nat Med 17 87 95 21170045 PMC3075560
  52. [54]Nelson KE Weinstock GM Highlander SK Worley KC Creasy HH 2010 A catalog of reference genomes from the human microbiome. Science 328 994 999 20489017 PMC2940224
  53. [55]Frese SA Benson AK Tannock GW Loach DM Kim J 2011 The evolution of host specialization in the vertebrate gut symbiont Lactobacillus reuteri. PLoS Genet 7 e1001314 21379339 PMC3040671
  54. [56]Drouault S Anba J Corthier G 2002 Streptococcus thermophilus is able to produce a beta-galactosidase active during its transit in the digestive tract of germ-free mice. Appl Environ Microbiol 68 938 941 11823240 PMC126667
  55. [57]Walter J Heng NC Hammes WP Loach DM Tannock GW 2003 Identification of Lactobacillus reuteri genes specifically induced in the mouse gastrointestinal tract. Appl Environ Microbiol 69 2044 2051 12676681 PMC154805
  56. [58]Bron PA Grangette C Mercenier A de Vos WM Kleerebezem M 2004 Identification of Lactobacillus plantarum genes that are induced in the gastrointestinal tract of mice. J Bacteriol 186 5721 5729 15317777 PMC516819
  57. [59]Klaassens ES Boesten RJ Haarman M Knol J Schuren FH 2009 Mixed-species genomic microarray analysis of fecal samples reveals differential transcriptional responses of bifidobacteria in breast- and formula-fed infants. Appl Environ Microbiol 75 2668 2676 19286790 PMC2681671
  58. [60]Corthier G Delorme C Ehrlich SD Renault P 1998 Use of luciferase genes as biosensors to study bacterial physiology in the digestive tract. Appl Environ Microbiol 64 2721 2722 9647856 PMC106452
  59. [61]Alifano P Fani R Lio P Lazcano A Bazzicalupo M 1996 Histidine biosynthetic pathway and genes: structure, regulation, and evolution. Microbiol Rev 60 44 69 8852895 PMC239417
  60. [62]Hungerford JM 2010 Scombroid poisoning: a review. Toxicon 56 231 243 20152850
  61. [63]Nuutinen S Panula P 2011 Histamine in Neurotransmission and Brain Diseases. Adv Exp Med Biol 709 95 107 21618891
  62. [64]Jones SE Versalovic J 2009 Probiotic Lactobacillus reuteri biofilms produce antimicrobial and anti-inflammatory factors. BMC Microbiol 9 35 19210794 PMC2653509
  63. [65]Weljie AM Newton J Mercier P Carlson E Slupsky CM 2006 Targeted profiling: quantitative analysis of 1H NMR metabolomics data. Anal Chem 78 4430 4442 16808451
  64. [71]Delaglio F Grzesiek S Vuister GW Zhu G Pfeifer J 1995 NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J Biomol NMR 6 277 293 8520220
  65. [72]Johnson BA Blevins RA 1994 NMRView: A computer program for the visualization and analysis of NMR data. J Biomol NMR 4 603 614 22911360
  66. [74]Gosetti F Mazzucco E Gianotti V Polati S Gennaro MC 2007 High performance liquid chromatography/tandem mass spectrometry determination of biogenic amines in typical Piedmont cheeses. J Chromatogr A 1149 151 157 17408679
  67. [75]Saulnier DM Santos F Roos S Mistretta TA Spinler JK 2011 Exploring metabolic pathway reconstruction and genome-wide expression profiling in Lactobacillus reuteri to define functional probiotic features. PLoS One 6 e18783 21559529 PMC3084715

Cited by

Sorted by citations

Authors
Thomas, C. M., Hong, T., van Pijkeren, J. P., Hemarajata, P., Trinh, D. V., Hu, W., Britton, R. A., Kalkum, M., & Versalovic, J.
Affiliations
  • Baylor College of Medicine (US)
  • Beckman Research Institute (US)
  • Michigan State University (US)
Corresponding author
Versalovic, James
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-02-22
Volume
7
Issue
2
Pages
e31951
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0031951
PMC
PMC3285189
OpenAlex
W2092038168
Cited by
491
References
2
Citations by year
2026: 19 · 2025: 30 · 2024: 42 · 2023: 48 · 2022: 47 · 2021: 42 · 2020: 39 · 2019: 34 · 2018: 41 · 2017: 35 · 2016: 36 · 2015: 19 · 2014: 30 · 2013: 24 · 2012: 3
FWCI
37.38
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Funders
  • National Institutes of Health (DK56338)
  • National Institute of Allergy and Infectious Diseases (U19AI090872)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK56338, P30DK-56338, R01DK065075, DK065075, P30DK056338)
  • National Center for Complementary and Alternative Medicine (P30 DK56338)
  • National Center for Complementary and Integrative Health (R01AT004326)
Topics
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
  • Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
Keywords
Lactobacillus reuteri, histamine, histidine decarboxylase, histidine, histamine H2 receptor, cyclic AMP, pKa, TLR2, immunomodulation, gut microbiota, anti-inflammatory agents, bacterial metabolites
MeSH terms
Biological Assay, Chromatography, High Pressure Liquid, Fermentation, Histamine, Histidine, Histidine Decarboxylase, Humans, Lactobacillus, Magnetic Resonance Spectroscopy, Receptors, Histamine H2, Mass Spectrometry, Tumor Necrosis Factor-alpha, Mutagenesis, Cyclic AMP-Dependent Protein Kinases, Probiotics, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, Limosilactobacillus reuteri

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review