, Volume 236, Issue 5, pp 1653–1670 | Cite as

Identification and characterization of a novel anti-inflammatory lipid isolated from Mycobacterium vaccae, a soil-derived bacterium with immunoregulatory and stress resilience properties

  • David G. SmithEmail author
  • Roberta Martinelli
  • Gurdyal S. Besra
  • Petr A. Illarionov
  • Istvan Szatmari
  • Peter Brazda
  • Mary A. Allen
  • Wenqing Xu
  • Xiang Wang
  • László Nagy
  • Robin D. Dowell
  • Graham A. W. Rook
  • Laura Rosa Brunet
  • Christopher A. LowryEmail author
Original Investigation



Mycobacterium vaccae (NCTC 11659) is an environmental saprophytic bacterium with anti-inflammatory, immunoregulatory, and stress resilience properties. Previous studies have shown that whole, heat-killed preparations of M. vaccae prevent allergic airway inflammation in a murine model of allergic asthma. Recent studies also demonstrate that immunization with M. vaccae prevents stress-induced exaggeration of proinflammatory cytokine secretion from mesenteric lymph node cells stimulated ex vivo, prevents stress-induced exaggeration of chemically induced colitis in a model of inflammatory bowel disease, and prevents stress-induced anxiety-like defensive behavioral responses. Furthermore, immunization with M. vaccae induces anti-inflammatory responses in the brain and prevents stress-induced exaggeration of microglial priming. However, the molecular mechanisms underlying anti-inflammatory effects of M. vaccae are not known.


Our objective was to identify and characterize novel anti-inflammatory molecules from M. vaccae NCTC 11659.


We have purified and identified a unique anti-inflammatory triglyceride, 1,2,3-tri [Z-10-hexadecenoyl] glycerol, from M. vaccae and evaluated its effects in freshly isolated murine peritoneal macrophages.


The free fatty acid form of 1,2,3-tri [Z-10-hexadecenoyl] glycerol, 10(Z)-hexadecenoic acid, decreased lipopolysaccharide-stimulated secretion of the proinflammatory cytokine IL-6 ex vivo. Meanwhile, next-generation RNA sequencing revealed that pretreatment with 10(Z)-hexadecenoic acid upregulated genes associated with peroxisome proliferator-activated receptor alpha (PPARα) signaling in lipopolysaccharide-stimulated macrophages, in association with a broad transcriptional repression of inflammatory markers. We confirmed using luciferase-based transfection assays that 10(Z)-hexadecenoic acid activated PPARα signaling, but not PPARγ, PPARδ, or retinoic acid receptor (RAR) α signaling. The effects of 10(Z)-hexadecenoic acid on lipopolysaccharide-stimulated secretion of IL-6 were prevented by PPARα antagonists and absent in PPARα-deficient mice.


Future studies should evaluate the effects of 10(Z)-hexadecenoic acid on stress-induced exaggeration of peripheral inflammatory signaling, central neuroinflammatory signaling, and anxiety- and fear-related defensive behavioral responses.


10(Z)-hexadecenoic acid Bacteria Inflammation Interleukin 6 Lipid Macrophage Mycobacteria PPAR RNA-seq vaccae 



Cluster of differentiation


Central nervous system


Dendritic cell


Diagnostic and Statistical Manual of Mental Disorders (5th ed.)






Interferon regulatory factor






National Collection of Type Cultures


Nuclear factor kappa-light-chain-enhancer of activated B cells




Peroxisome proliferator-activated receptor


Posttraumatic stress disorder


Retinoic acid receptor


Transforming growth factor beta


Toll-like receptor


Regulatory T cell



We are grateful to Zachary D. Barger for proofreading the manuscript. We thank the University of Colorado Boulder BioFrontiers Institute Next-Gen Sequencing Core Facility, which performed the Illumina sequencing.

Author contributions

G.S.B. and P.A.I. isolated and synthesized 1,2,3-tri [Z-10-hexadecenoyl]glycerol. W.X. and X.W. developed a synthesis for 10(Z)-hexadecenoic acid and synthesized the compound. Experimental design was done by D.G.S., R.M., G.S.B., G.A.W.R., L.R.B., and C.A.L. L.N. and P.A.I designed the PPAR luciferase-based transfection assay experiments. In vivo screening and experimentation was performed by R.M. and L.R.B. In vitro experiments using freshly isolated murine peritoneal macrophages were performed by D.G.S. Transfections and reporter gene assays were performed by I.S. and P.B. RNA-seq data processing and analysis was done by D.G.S., R.D.D., and M.A.A. Experimental design and preparation of the manuscript were done by D.G.S., R.M., G.S.B., L.N., G.A.W.R., L.R.B., and C.A.L.

Funding information

This work was supported by the National Institute of Mental Health (grant number 1R21MH116263; CAL). Dr. Christopher A. Lowry is supported by the Department of the Navy, Office of Naval Research Multidisciplinary University Research Initiative (MURI) Award (grant number N00014-15-1-2809), Department of Veterans Affairs Office of Research and Development (VA-ORD) RR&D Small Projects in Rehabilitation Research (SPiRE) (I21) (grant number 1 I21 RX002232-01), Colorado Clinical & Translational Sciences Institute (CCTSI) Center for Neuroscience (grant number CNSTT-15-145), the Colorado Department of Public Health and Environment (CDPHE; grant number DCEED-3510), and the Alfred P. Sloan Foundation (grant number, G-2016-7077). Dr. Robin Dowell is supported by NSF Career MCB #1350915.

Compliance with ethical standards

All experimental protocols were consistent with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, Eighth Edition (The National Academies Press 2011), and the Institutional Animal Care and Use Committee at the University of Colorado Boulder approved all procedures. This work was covered under CU Boulder IACUC Protocol Numbers 2134-14MAY2018 and 2361-14MAY2018-DT. The research described here was conducted in compliance with The ARRIVE Guidelines: Animal research: reporting of in vivo experiments, originally published in PLOS Biology, June 2010 (Kilkenny and Altman 2010).

Conflict of interest

Christopher A. Lowry serves on the Scientific Advisory Board of Immodulon Therapeutics Ltd. Dr. Robin Dowell is a founder and scientific advisor of Arpeggio Biosciences.

Supplementary material

213_2019_5253_MOESM1_ESM.docx (799 kb)
ESM 1 (DOCX 798 kb)


  1. Adams VC, Hunt JRF, Martinelli R et al (2004) Mycobacterium vaccae induces a population of pulmonary CD11c+ cells with regulatory potential in allergic mice. Eur J Immunol 34:631–638. Google Scholar
  2. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorder (5th ed.). American Psychiatric Association, Arlington, VAGoogle Scholar
  3. Anders S, Huber W (2010) Differential expression analysis for sequence count data. Genome Biol 11:R106. Google Scholar
  4. Anders S, Pyl PT, Huber W (2015) HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics 31:166–169. Google Scholar
  5. Arteaga Figueroa L, Abarca-Vargas R, García Alanis C, Petricevich VL (2017) Comparison between peritoneal macrophage activation by Bougainvillea xbuttiana extract and LPS and/or interleukins. Biomed Res Int 2017:1–11. Google Scholar
  6. Baxter AJ, Scott KM, Vos T, Whiteford HA (2013) Global prevalence of anxiety disorders: a systematic review and meta-regression. Psychol Med 43:897–910Google Scholar
  7. Benko S, Love JD, Beládi M, Schwabe JWR, Nagy L (2003) Molecular determinants of the balance between co-repressor and co-activator recruitment to the retinoic acid receptor. J Biol Chem 278:43797–43806. Google Scholar
  8. Bensinger SJ, Tontonoz P (2008) Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 454:470–477. Google Scholar
  9. Blaser MJ (2017) The theory of disappearing microbiota and the epidemics of chronic diseases. Nat Rev Immunol 17:461–463Google Scholar
  10. Bloomfield SF, Rook GA, Scott EA et al (2016) Time to abandon the hygiene hypothesis: new perspectives on allergic disease, the human microbiome, infectious disease prevention and the role of targeted hygiene. Perspect Public Health 136:213–224. Google Scholar
  11. Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30:2114–2120. Google Scholar
  12. Böttger EC, Hirschel B, Coyle MB (1993) Mycobacterium genavense. Int J Syst Bacteriol 43:841–843.
  13. Burfeind KG, Zhu X, Levasseur PR, Michaelis KA, Norgard MA, Marks DL (2018) TRIF is a key inflammatory mediator of acute sickness behavior and cancer cachexia. Brain Behav Immun 73:364–374. Google Scholar
  14. Chan KL, Pillon NJ, Sivaloganathan DM, Costford SR, Liu Z, Théret M, Chazaud B, Klip A (2015) Palmitoleate reverses high fat-induced proinflammatory macrophage polarization via AMP-activated protein kinase (AMPK). J Biol Chem 290:16979–16988. Google Scholar
  15. Chen JD, Evans RM (1995) A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377:454–457Google Scholar
  16. Chinetti G, Fruchart JC, Staels B (2000) Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res 49:497–505Google Scholar
  17. Chinetti G, Fruchart JC, Staels B (2003) Peroxisome proliferator-activated receptors: new targets for the pharmacological modulation of macrophage gene expression and function. Curr Opin Lipidol 14:459–468. Google Scholar
  18. Choi JM, Bothwell ALM (2012) The nuclear receptor PPARs as important regulators of T-cell functions and autoimmune diseases. Mol Cell 33:217–222Google Scholar
  19. Chou S, Chedore P, Kasatiya S (1998) Use of gas chromatographic fatty acid and mycolic acid cleavage product determination to differentiate among Mycobacterium genavense, Mycobacterium fortuitum, Mycobacterium simiae, and Mycobacterium tuberculosis. J Clin Microbiol 36:577–579Google Scholar
  20. Coakley M, Ross RP, Nordgren M, Fitzgerald G, Devery R, Stanton C (2003) Conjugated linoleic acid biosynthesis by human-derived Bifidobacterium species. J Appl Microbiol 94:138–145.
  21. Committee for the Update of the Guide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research, Division on Earth and Life Sciences, National Research Council of the National Academies (2011) Guide for the Care and Use of Laboratory Animals. The National Academies Press, Washington D.C.Google Scholar
  22. Coyle MB, Carlson LDC, Wallis CK et al (1992) Laboratory aspects of Mycobacterium genavense, a proposed species isolated from AIDS patients. J Clin Microbiol 30(12):3206–3212Google Scholar
  23. Cryan JF, Dinan TG (2012) Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 13:701–712. Google Scholar
  24. Cryan JF, Dinan TG (2015) More than a gut feeling: the microbiota regulates neurodevelopment and behavior. Neuropsychopharmacology 40:241–242Google Scholar
  25. Cunningham C (2005) Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 25:9275–9284. Google Scholar
  26. Cunningham C (2013) Microglia and neurodegeneration: the role of systemic inflammation. Glia. 61:71–90. Google Scholar
  27. Cunningham C, Campion S, Lunnon K, Murray CL, Woods JFC, Deacon RMJ, Rawlins JNP, Perry VH (2009) Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry 65:304–312. Google Scholar
  28. Draper E, DeCourcey J, Higgins SC, Canavan M, McEvoy F, Lynch M, Keogh B, Reynolds C, Roche HM, Mills KHG, Loscher CE (2014) Conjugated linoleic acid suppresses dendritic cell activation and subsequent Th17 responses. J Nutr Biochem 25:741–749. Google Scholar
  29. Duan W, Croft M (2014) Control of regulatory T cells and airway tolerance by lung macrophages and dendritic cells. Ann Am Thorac Soc 11:S306–S313. Google Scholar
  30. Esposito G, Capoccia E, Turco F, Palumbo I, Lu J, Steardo A, Cuomo R, Sarnelli G, Steardo L (2014) Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation. Gut 63:1300–1312. Google Scholar
  31. Forsythe P, Sudo N, Dinan T, Taylor VH, Bienenstock J (2010) Mood and gut feelings. Brain Behav Immun 24:9–16. Google Scholar
  32. Foryst-Ludwig A, Kreissl MC, Benz V, Brix S, Smeir E, Ban Z, Januszewicz E, Salatzki J, Grune J, Schwanstecher AK, Blumrich A, Schirbel A, Klopfleisch R, Rothe M, Blume K, Halle M, Wolfarth B, Kershaw EE, Kintscher U (2015) Adipose tissue lipolysis promotes exercise-induced cardiac hypertrophy involving the lipokine C16:1n7-palmitoleate. J Biol Chem 290:23603–23615. Google Scholar
  33. Fox JH, Hassell JE, Siebler PH et al (2017) Preimmunization with a heat-killed preparation of Mycobacterium vaccae enhances fear extinction in the fear-potentiated startle paradigm. Brain Behav Immun 66:70–84. Google Scholar
  34. Frank MG, Fonken LK, Dolzani SD, Annis JL, Siebler PH, Schmidt D, Watkins LR, Maier SF, Lowry CA (2018) Immunization with Mycobacterium vaccae induces an anti-inflammatory milieu in the CNS: attenuation of stress-induced microglial priming, alarmins and anxiety-like behavior. Brain Behav Immun 73:352–363. Google Scholar
  35. Garn H, Bahn S, Baune BT, Binder EB, Bisgaard H, Chatila TA, Chavakis T, Culmsee C, Dannlowski U, Gay S, Gern J, Haahtela T, Kircher T, Müller-Ladner U, Neurath MF, Preissner KT, Reinhardt C, Rook G, Russell S, Schmeck B, Stappenbeck T, Steinhoff U, van Os J, Weiss S, Zemlin M, Renz H (2016) Current concepts in chronic inflammatory diseases: interactions between microbes, cellular metabolism, and inflammation. J Allergy Clin Immunol 138:47–56. Google Scholar
  36. Garton NJ, Christensen H, Minnikin DE et al (2002) Intracellular lipophilic inclusions of mycobacteria in vitro and in sputum. Microbiology 148:2951–2958. Google Scholar
  37. Gebert MJ, Delgado-Baquerizo M, Oliverio AM Webster TM, Nichols LM, Honda JR, Chan ED, Adjemian J, Dunn RR, Fierer N (2018) Ecological analyses of mycobacteria in showerhead biofilms and their relevance to human health. MBio 9:e01614–18.
  38. Guida F, Luongo L, Boccella S, Giordano ME, Romano R, Bellini G, Manzo I, Furiano A, Rizzo A, Imperatore R, Iannotti FA, D’Aniello E, Piscitelli F, sca Rossi F, Cristino L, di Marzo V, de Novellis V, Maione S (2017) Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: involvement of the CB2 receptor. Sci Rep 7:1–11. Google Scholar
  39. Gutzwiller MER, Reist M, Peel JE, Seewald W, Brunet LR, Roosje PJ (2007) Intradermal injection of heat-killed Mycobacterium vaccae in dogs with atopic dermatitis: a multicentre pilot study. Vet Dermatol 18:87–93. Google Scholar
  40. Hoyles L, Snelling T, Umlai UK, Nicholson JK, Carding SR, Glen RC, McArthur S (2018) Microbiome–host systems interactions: protective effects of propionate upon the blood–brain barrier. Microbiome. 6:55. Google Scholar
  41. Huang DW, Sherman BT, Lempicki RA et al (2009) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37:1–13. Google Scholar
  42. Ji Y, Wang Z, Li Z, Liu J (2010) Modulation of LPS-mediated inflammation by fenofibrate via the TRIF-dependent TLR4 signaling pathway in vascular smooth muscle cells. Cell Physiol Biochem 25:631–640. Google Scholar
  43. Kawasaki T, Kawai T (2014) Toll-like receptor signaling pathways. Front Immunol 5Google Scholar
  44. Kersten S (2014) Integrated physiology and systems biology of PPARα. Mol Metab 3:354–371. Google Scholar
  45. Kidani Y, Bensinger S (2012) Liver X receptor and peroxisome proliferator-activated receptor as integrators of lipid homeostasis and immunity. Immunol Rev 249:72–83. Google Scholar
  46. Kilkenny C, Altman DG (2010) Improving bioscience research reporting: ARRIVE-ing at a solution. Lab Anim 44:377–378. Google Scholar
  47. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL (2013) TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14:R36. Google Scholar
  48. Kishino S, Takeuchi M, Park S-B, Hirata A, Kitamura N, Kunisawa J, Kiyono H, Iwamoto R, Isobe Y, Arita M, Arai H, Ueda K, Shima J, Takahashi S, Yokozeki K, Shimizu S, Ogawa J (2013) Polyunsaturated fatty acid saturation by gut lactic acid bacteria affecting host lipid composition. Proc Natl Acad Sci U S A 110:17808–17813. Google Scholar
  49. Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, Devchand P, Wahli W, Willson TM, Lenhard JM, Lehmann JM (1997) Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci U S A 94:4318–4323. Google Scholar
  50. Kota BP, Huang THW, Roufogalis BD (2005) An overview on biological mechanisms of PPARs. Pharmacol Res 51:85–94Google Scholar
  51. Langgartner D, Lowry CA, Reber SO (2018) Old friends, immunoregulation, and stress resilience. Pflugers Arch - Eur J Physiol 471:237–269. Google Scholar
  52. Le Bert N, Chain BM, Rook G, Noursadeghi M (2011) DC priming by M. vaccae inhibits Th2 responses in contrast to specific TLR2 priming and is associated with selective activation of the CREB pathway. PLoS One 6:e18346.
  53. Leclercq S, Forsythe P, Bienenstock J (2016) Posttraumatic stress disorder: does the gut microbiome hold the key? Can J Psychiatr 61:204–213. Google Scholar
  54. Lee SO, Hong GW, Oh DK (2003) Bioconversion of linoleic acid into conjugated linoleic acid by immobilized Lactobacillus reuteri. Biotechnol Prog 19:1081–1084. Google Scholar
  55. Lee AJ, Cho KJ, Kim JH (2015) MyD88-BLT2-dependent cascade contributes to LPS-induced interleukin-6 production in mouse macrophage. Exp Mol Med 47.
  56. Lin JY, Tang CY (2007) Interleukin-10 administration inhibits TNF-alpha and IL-1beta, but not IL-6, secretion of LPS-stimulated peritoneal macrophages. J Food Drug Anal 15(1):48–54Google Scholar
  57. Locci A, Pinna G (2017) Neurosteroid biosynthesis down-regulation and changes in GABAA receptor subunit composition: a biomarker axis in stress-induced cognitive and emotional impairment. Br J Pharmacol 174:3226–3241Google Scholar
  58. Loscher CE, Draper E, Leavy O, Kelleher D, Mills KHG, Roche HM (2005) Conjugated linoleic acid suppresses NF-κB activation and IL-12 production in dendritic cells through ERK-mediated IL-10 induction. J Immunol 175:4990–4998Google Scholar
  59. Lowry CA, Hollis JH, de Vries A et al (2007) Identification of an immune-responsive mesolimbocortical serotonergic system: potential role in regulation of emotional behavior. Neuroscience 146:756–772. Google Scholar
  60. Lowry CA, Smith DG, Siebler PH, Schmidt D, Stamper CE, Hassell JE, Yamashita PS, Fox JH, Reber SO, Brenner LA, Hoisington AJ, Postolache TT, Kinney KA, Marciani D, Hernandez M, Hemmings SMJ, Malan-Muller S, Wright KP, Knight R, Raison CL, Rook GAW (2016) The microbiota, immunoregulation, and mental health: implications for public health. Curr Environ Health Rep 3:270–286. Google Scholar
  61. Lyte M (2014) Microbial endocrinology and the microbiota-gut-brain axis. Adv Exp Med Biol 817:3–24.
  62. Macovei L, McCafferty J, Chen T, Teles F, Hasturk H, Paster BJ, Campos-Neto A (2015) The hidden “mycobacteriome” of the human healthy oral cavity and upper respiratory tract. J Oral Microbiol 7:1–11. Google Scholar
  63. Maier SF (2003) Bi-directional immune-brain communication: implications for understanding stress, pain, and cognition. Brain Behav Immun 17:69–85Google Scholar
  64. Maier SF, Goehler LE, Fleshner M, Watkins LR (1998) The role of the vagus nerve in cytokine-to-brain communication. Ann N Y Acad Sci 840:289–300Google Scholar
  65. Merico D, Isserlin R, Bader GD (2011) Visualizing gene-set enrichment results using the cytoscape plug-in enrichment map. Methods Mol Biol 781:257–277. Google Scholar
  66. Miller AH, Raison CL (2016) The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 16:22–34Google Scholar
  67. Miller AH, Maletic V, Raison CL (2009) Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biol Psychiatry 65:732–41.
  68. Miyamoto J, Mizukure T, Park SB, Kishino S, Kimura I, Hirano K, Bergamo P, Rossi M, Suzuki T, Arita M, Ogawa J, Tanabe S (2015) A gut microbial metabolite of linoleic acid, 10-hydroxy-cis-12-octadecenoic acid, ameliorates intestinal epithelial barrier impairment partially via GPR40-MEK-ERK pathway. J Biol Chem 290:2902–2918. Google Scholar
  69. Moya-Camarena SY, Vanden Heuvel JP, Blanchard SG et al (1999) Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPARα. J Lipid Res 40:1426–1433. Google Scholar
  70. Nagy L, Kao HY, Love JD, Li C, Banayo E, Gooch JT, Krishna V, Chatterjee K, Evans RM, Schwabe JWR (1999) Mechanism of corepressor binding and release from nuclear hormone receptors. Genes Dev 13:3209–3216. Google Scholar
  71. Nugent NR, Tyrka AR, Carpenter LL, Price LH (2011) Gene-environment interactions: early life stress and risk for depressive and anxiety disorders. Psychopharmacology 214:175–196Google Scholar
  72. O’Donovan A, Cohen BE, Seal KH, Bertenthal D, Margaretten M, Nishimi K, Neylan TC (2015) Elevated risk for autoimmune disorders in Iraq and Afghanistan veterans with posttraumatic stress disorder. Biol Psychiatry 77:365–374. Google Scholar
  73. Ogawa J, Kishino S, Ando A, Sugimoto S, Mihara K, Shimizu S (2005) Production of conjugated fatty acids by lactic acid bacteria. J Biosci Bioeng 100:355–364. Google Scholar
  74. Ohue-Kitano R, Yasuoka Y, Goto T, Kitamura N, Park SB, Kishino S, Kimura I, Kasubuchi M, Takahashi H, Li Y, Yeh YS, Jheng HF, Iwase M, Tanaka M, Masuda S, Inoue T, Yamakage H, Kusakabe T, Tani F, Shimatsu A, Takahashi N, Ogawa J, Satoh-Asahara N, Kawada T (2018) A-linolenic acid–derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40. FASEB J 32:304–318. Google Scholar
  75. Okada H, Kuhn C, Feillet H, Bach J-F (2010) The “hygiene hypothesis” for autoimmune and allergic diseases: an update. Clin Exp Immunol 160:1–9. Google Scholar
  76. Pacífico C, Fernandes P, de Carvalho CCCR (2018) Mycobacterial response to organic solvents and possible implications on cross-resistance with antimicrobial agents. Front Microbiol 9.
  77. Paukkeri EL, Leppänen T, Sareila O, Vuolteenaho K, Kankaanranta H, Moilanen E (2007) PPARα agonists inhibit nitric oxide production by enhancing iNOS degradation in LPS-treated macrophages. Br J Pharmacol 152:1081–1091. Google Scholar
  78. Pestka S, Krause CD, Walter MR (2004) Interferons, interferon-like cytokines, and their receptors. Immunol Rev 202:8–32Google Scholar
  79. Pinna G (2018) Biomarkers for PTSD at the interface of the endocannabinoid and neurosteroid axis. Front Neurosci 12:482. Google Scholar
  80. Reber SO, Siebler PH, Donner NC, Morton JT, Smith DG, Kopelman JM, Lowe KR, Wheeler KJ, Fox JH, Hassell JE Jr, Greenwood BN, Jansch C, Lechner A, Schmidt D, Uschold-Schmidt N, Füchsl AM, Langgartner D, Walker FR, Hale MW, Lopez Perez G, van Treuren W, González A, Halweg-Edwards AL, Fleshner M, Raison CL, Rook GA, Peddada SD, Knight R, Lowry CA (2016) Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice. Proc Natl Acad Sci 113:3130–3139. Google Scholar
  81. Rohleder N (2014) Stimulation of systemic low-grade inflammation by psychosocial stress. Psychosom Med 76:181–189Google Scholar
  82. Roman-Nunez M, Cuesta-Alonso EP, Gilliland SE (2007) Influence of sodium glycocholate on production of conjugated linoleic acid by cells of Lactobacillus reuteri ATCC 55739. J Food Sci 72:140–143. Google Scholar
  83. Rook GAW (2009) Review series on helminths, immune modulation and the hygiene hypothesis: the broader implications of the hygiene hypothesis. Immunology 126:3–11. Google Scholar
  84. Rook GAW (2010) 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: Darwinian medicine and the “hygiene” or “old friends” hypothesis. Clin Exp Immunol 160:70–79. Google Scholar
  85. Rook GA (2013) Regulation of the immune system by biodiversity from the natural environment: an ecosystem service essential to health. Proc Natl Acad Sci 110:18360–18367. Google Scholar
  86. Rook GAW, Rosa Brunet L (2002) Give us this day our daily germs. Biologist (London) 49:145–149Google Scholar
  87. Rook GAW, Hamelmann E, Rosa Brunet L (2007) Mycobacteria and allergies. Immunobiology 212:461–473. Google Scholar
  88. Rosa Brunet L, Rook G (2008) United States Patent Application No. US 2008/0004341 A1. Retrieved from Accessed 05 May 2019
  89. Rusinova I, Forster S, Yu S, Kannan A, Masse M, Cumming H, Chapman R, Hertzog PJ (2013) INTERFEROME v2.0: an updated database of annotated interferon-regulated genes. Nucleic Acids Res 41:D1040–D1046. Google Scholar
  90. Sasso O, Russo R, Vitiello S, Raso GM, D’Agostino G, Iacono A, la Rana G, Vallée M, Cuzzocrea S, Piazza PV, Meli R, Calignano A (2012) Implication of allopregnanolone in the antinociceptive effect of N-palmitoylethanolamide in acute or persistent pain. Pain. 153:33–41. Google Scholar
  91. Scheuerbrandt G, Bloch K (1962) Unsaturated fatty acids in microorganisms. J Biol Chem 237:2064–2069Google Scholar
  92. Shacter E, Arzadon GK, Williams JA (1993) Stimulation of interleukin-6 and prostaglandin E2 secretion from peritoneal macrophages by polymers of albumin. Blood 82:2853–2864Google Scholar
  93. Smythies LE, Sellers M, Clements RH, Mosteller-Barnum M, Meng G, Benjamin WH, Orenstein JM, Smith PD (2005) Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest 115:66–75. Google Scholar
  94. Smythies LE, Shen R, Bimczok D, Novak L, Clements RH, Eckhoff DE, Bouchard P, George MD, Hu WK, Dandekar S, Smith PD (2010) Inflammation anergy in human intestinal macrophages is due to Smad-induced IκBα expression and NF-κB inactivation. J Biol Chem 285:19593–19604. Google Scholar
  95. Soroosh P, Doherty TA, Duan W, Mehta AK, Choi H, Adams YF, Mikulski Z, Khorram N, Rosenthal P, Broide DH, Croft M (2013) Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance. J Exp Med 210:775–788. Google Scholar
  96. Springer B, Kirschner P, Rost-Meyer G et al (1993) Mycobacterium interjectum, a new species isolated from a patient with chronic lymphadenitis. J Clin Microbiol 31:3083–3089Google Scholar
  97. Stamper CE, Hoisington AJ, Gomez OM et al (2016) The microbiome of the built environment and human behavior: implications for emotional health and well-being in postmodern western societies. Int Rev Neurobiol 131:289–323.
  98. Strickland D, Kees UR, Holt PG (1996) Regulation of T-cell activation in the lung: isolated lung T cells exhibit surface phenotypic characteristics of recent activation including down-modulated T-cell receptors, but are locked into the G0/G1 phase of the cell cycle. Immunology 87:242–249Google Scholar
  99. Suutari M, Laakso S (1993) The effect of growth temperature on the fatty acid composition of Mycobacterium phlei. Arch Microbiol 159:119–123Google Scholar
  100. Szatmari I, Pap A, Rühl R, Ma JX, Illarionov PA, Besra GS, Rajnavolgyi E, Dezso B, Nagy L (2006) PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med 203:2351–2362. Google Scholar
  101. Tay STL, Hemond HF, Polz MF et al (1998) Two new Mycobacterium strains and their role in toluene degradation in a contaminated stream. Appl Environ Microbiol 64:1715–1720Google Scholar
  102. Travar M, Petkovic M, Verhaz A (2016) Type I, II, and III interferons: regulating immunity to Mycobacterium tuberculosis infection. Arch Immunol Ther Exp 64:19–31Google Scholar
  103. Verme JL, Fu J, Astarita G et al (2005) The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol Pharmacol 67:15–19. Google Scholar
  104. Vichai V, Kirtikara K (2006) Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 1:1112–1116. Google Scholar
  105. Watkins LR, Maier SF, Goehler LE (1995) Cytokine-to-brain communication: a review & analysis of alternative mechanisms. Life Sci 57:1011–1026Google Scholar
  106. Wollenberg GK, DeForge LE, Bolgos G, Remick DG (1993) Differential expression of tumor necrosis factor and interleukin-6 by peritoneal macrophages in vivo and in culture. Am J Pathol 143:1121–1130Google Scholar
  107. Xu J, Storer PD, Chavis JA, Racke MK, Drew PD (2005) Agonists for the peroxisome proliferator-activated receptor-α and the retinoid X receptor inhibit inflammatory responses of microglia. J Neurosci Res 81:403–411. Google Scholar
  108. Yu HL, Deng XQ, Li YJ, Li YC, Quan ZS, Sun XY (2011) N-palmitoylethanolamide, an endocannabinoid, exhibits antidepressant effects in the forced swim test and the tail suspension test in mice. Pharmacol Rep 63:834–839. Google Scholar
  109. Zhang X, Goncalves R, Mosser DM (2008) The isolation and characterization of murine macrophages. Curr Protoc Immunol 14.
  110. Zuany-Amorim C, Sawicka E, Manlius C, le Moine A, Brunet LR, Kemeny DM, Bowen G, Rook G, Walker C (2002) Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 8:625–629. Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • David G. Smith
    • 1
    • 2
    Email author
  • Roberta Martinelli
    • 3
    • 4
  • Gurdyal S. Besra
    • 5
  • Petr A. Illarionov
    • 5
  • Istvan Szatmari
    • 6
  • Peter Brazda
    • 6
  • Mary A. Allen
    • 7
    • 8
  • Wenqing Xu
    • 1
  • Xiang Wang
    • 1
  • László Nagy
    • 6
    • 9
    • 10
  • Robin D. Dowell
    • 7
    • 8
  • Graham A. W. Rook
    • 3
  • Laura Rosa Brunet
    • 3
  • Christopher A. Lowry
    • 11
    • 12
    Email author
  1. 1.Department of Chemistry and BiochemistryUniversity of Colorado BoulderBoulderUSA
  2. 2.Department of Pathology, Anatomy, and Cellular BiologyThomas Jefferson UniversityPhiladelphiaUSA
  3. 3.Centre for Clinical Microbiology, Department of InfectionUCL (University College London)LondonUK
  4. 4.Merck Research Laboratories, MSDKenilworthUSA
  5. 5.School of BioscienceUniversity of BirminghamBirminghamUK
  6. 6.Department of Biochemistry and Molecular Biology, Faculty of MedicineUniversity of DebrecenDebrecenHungary
  7. 7.Department of Molecular, Cellular, and Developmental BiologyUniversity of Colorado BoulderBoulderUSA
  8. 8.BioFrontiers InstituteUniversity of Colorado BoulderBoulderUSA
  9. 9.MTA-DE “Lendület” Immunogenomics Research GroupUniversity of DebrecenDebrecenHungary
  10. 10.Department of MedicineJohns Hopkins University, Johns Hopkins All Children’s HospitalSaint PetersburgUSA
  11. 11.Department of Integrative Physiology, Center for Neuroscience, and Center for Microbial ExplorationUniversity of Colorado BoulderBoulderUSA
  12. 12.inVIVO Planetary Health, of the Worldwide Universities Network (WUN)West New YorkUSA

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