The microbiota–gut–brain interaction in regulating host metabolic adaptation to cold in male Brandt’s voles (Lasiopodomys brandtii)


Gut microbiota play a critical role in orchestrating metabolic homeostasis of the host. However, the crosstalk between host and microbial symbionts in small mammals are rarely illustrated. We used male Brandt’s voles (Lasiopodomys brandtii) to test the hypothesis that gut microbiota and host neurotransmitters, such as norepinephrine (NE), interact to regulate energetics and thermogenesis during cold acclimation. We found that increases in food intake and thermogenesis were associated with increased monoamine neurotransmitters, ghrelin, short-chain fatty acids, and altered cecal microbiota during cold acclimation. Further, our pair-fed study showed that cold temperature can alter the cecal microbiota independently of overfeeding. Using cecal microbiota transplant along with β3-adrenoceptor antagonism and PKA inhibition, we confirmed that transplant of cold-acclimated microbiota increased thermogenesis through activation of cAMP–PKA–pCREB signaling. In addition, NE manipulation induced a long-term alteration in gut microbiota structure. These data demonstrate that gut microbiota-NE crosstalk via cAMP signaling regulates energetics and thermogenesis during cold acclimation in male Brandt’s voles.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Data availability

Raw sequence data are deposited in the NCBI Sequence Read Archive under accession PRJNA555499, PRJNA555506, PRJNA555511, and PRJNA555551.


  1. 1.

    McNab BK. The physiological ecology of vertebrates. Ithaca: Cornell University Press; 2002.

    Google Scholar 

  2. 2.

    Li XS, Wang DH. Photoperiod and temperature can regulate body mass, serum leptin concentration, and uncoupling protein 1 in Brandt’s voles (Lasiopodomys brandtii) and Mongolian gerbils (Meriones unguiculatus). Physiol Biochem Zool. 2007;80:326–34.

    CAS  PubMed  Google Scholar 

  3. 3.

    Zhang XY, Wang DH. Energy metabolism, thermogenesis and body mass regulation in Brandt’s voles (Lasiopodomys brandtii) during cold acclimation and rewarming. Horm Behav. 2006;50:61–9.

    CAS  PubMed  Google Scholar 

  4. 4.

    Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84:277–359.

    CAS  Google Scholar 

  5. 5.

    Heldmaier G, Steinlechner S, Rafael J. Nonshivering thermogenesis and cold resistance during seasonal acclimatization in the Djungarian hamster. J Comp Physiol B. 1982;149:1–9.

    Google Scholar 

  6. 6.

    Nicholls D, Locke R. Thermogenic mechanisms in brown fat. Physiol Rev. 1984;64:1–64.

    CAS  PubMed  Google Scholar 

  7. 7.

    Walter GC, Phillips RJ, McAdams JL, Powley TL. Individual sympathetic postganglionic neurons coinnervate myenteric ganglia and smooth muscle layers in the gastrointestinal tract of the rat. J Comp Neurol. 2016;524:2577–603.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Himms-Hagen J. Thyroid hormones and thermogenesis. Mammalian thermogenesis. Netherlands: Springer; 1983.

    Google Scholar 

  9. 9.

    Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev. 2014;94:355–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Uchida Y, Nagashima K, Yuri K. Fasting or systemic des-acyl ghrelin administration to rats facilitates thermoregulatory behavior in a cold environment. Brain Res. 2018;1696:10–21.

    CAS  PubMed  Google Scholar 

  11. 11.

    Cannon B, Nedergaard J. Thyroid hormones: igniting brown fat via the brain. Nat Med. 2010;16:965–7.

    CAS  PubMed  Google Scholar 

  12. 12.

    Contreras C, Nogueiras R, Diéguez C, Rahmouni K, López M. Traveling from the hypothalamus to the adipose tissue: the thermogenic pathway. Redox Biol. 2017;12:854–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Faith JJ, McNulty NP, Rey FE, Gordon JI. Predicting a human gut microbiota’s response to diet in gnotobiotic mice. Science. 2011;333:101–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–63.

    CAS  PubMed  Google Scholar 

  15. 15.

    Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K, Bäckhed HK, et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell. 2012;150:470–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Turnbaugh PJ, Backhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008;3:213–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Martinez-Guryn K, Hubert N, Frazier K, Urlass S, Musch MW, Ojeda P, et al. Small intestine microbiota regulate host digestive and absorptive adaptive responses to dietary lipids. Cell Host Microbe. 2018;23:458–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. 2005;307:1915–20.

    PubMed  Google Scholar 

  19. 19.

    Crawford PA, Crowley JR, Sambandam N, Muegge BD, Costello EK, Hamady M, et al. Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation. Proc Natl Acad Sci USA. 2009;106:11276–81.

    CAS  PubMed  Google Scholar 

  20. 20.

    Li Z, Yi CX, Katiraei S, Kooijman S, Zhou E, Chung CK, et al. Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit. Gut. 2018;67:1269–79.

    CAS  PubMed  Google Scholar 

  21. 21.

    Perry RJ, Peng L, Barry NA, Cline GW, Zhang DY, Cardone RL, et al. Acetate mediates a microbiome-brain-beta-cell axis to promote metabolic syndrome. Nature. 2016;534:213–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Donohoe DR, Garge N, Zhang X, Sun W, O’Connell TM, Bunger MK, et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 2011;13:517–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Psichas A, Sleeth ML, Murphy KG, Brooks L, Bewick GA, Hanyaloglu AC, et al. The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int J Obes. 2015;39:424–9.

    CAS  Google Scholar 

  24. 24.

    De Vedder F, Grasset E, Holm LM, Karsenty G, Macpherson AJ, Olofsson LE, et al. Gut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks. Proc Natl Acad Sci USA. 2018;115:6458–63.

    Google Scholar 

  25. 25.

    Lyte M. Microbial endocrinology: host-microbiota neuroendocrine interactions influencing brain and behavior. Gut Microbes. 2014;5:381–9.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Nagler CR, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161:264–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Zhao ZJ, Wang DH. Short photoperiod enhances thermogenic capacity in Brandt’s voles. Physiol Behav. 2005;85:143–9.

    CAS  PubMed  Google Scholar 

  28. 28.

    Bo TB, Zhang XY, Wang DH. Effects of cold acclimation on the structure of small intestinal mucosa and mucosal immunity-associated cells in Lasiopodomys brandtii. Acta Theriol Sin. 2018;2:158–65.

    Google Scholar 

  29. 29.

    Zhang XY, Sukhchuluun G, Bo TB, Chi QS, Yang JJ, Chen B, et al. Huddling remodels gut microbiota to reduce energy requirements in a small mammal species during cold exposure. Microbiome. 2018;6:103.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Wang JM, Wang DH. Comparison of nonshivering thermogenesis induced by dosages of norepinephrine from 3 allometric equations in Brandt’s voles (Lasiopodomys brandtii). Acta Theriol Sin. 2006;26:84–8.

    Google Scholar 

  31. 31.

    Dunphy-Doherty F, O’Mahony SM, Peterson VL, O’Sullivan O, Crispie F, Cotter PD, et al. Post-weaning social isolation of rats leads to long-term disruption of the gut microbiota-immune-brain axis. Brain Behav Immun. 2018;68:261–73.

    PubMed  Google Scholar 

  32. 32.

    Amato KR, Yeoman CJ, Kent A, Righini N, Carbonero F, Estrada A, et al. Habitat degradation impacts black howler monkey (Alouatta pigra) gastrointestinal microbiomes. ISME J. 2003;7:1344–53.

    Google Scholar 

  33. 33.

    Hosoda H, Kojima M, Matsuo H, Kangawa K. Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun. 2000;279:909–13.

    CAS  PubMed  Google Scholar 

  34. 34.

    Broglio F, Gottero C, Prodam F, Gauna C, Muccioli G, Papotti M, et al. Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. J Clin Endocrinol Metab. 2004;89:3062–5.

    CAS  PubMed  Google Scholar 

  35. 35.

    Toshinai K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T, et al. Des-Acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology. 2006;147:2306–14.

    CAS  PubMed  Google Scholar 

  36. 36.

    Mundinger TO, Cummings DE, Taborsky GJ. Direct stimulation of ghrelin secretion by sympathetic nerves. Endocrinology. 2006;147:2893–901.

    CAS  PubMed  Google Scholar 

  37. 37.

    Furness JB. Types of neurons in the enteric nervous system. J Auton Nerv Syst. 2000;81:87–96.

    CAS  PubMed  Google Scholar 

  38. 38.

    Chevalier C, Stojanović O, Colin DJ, Suarez-Zamorano N, Tarallo V, Veyrat-Durebex C, et al. Gut microbiota orchestrates energy homeostasis during cold. Cell. 2015;163:1360–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, et al. Host-gut microbiota metabolic interactions. Science. 2012;336:1262–7.

    CAS  PubMed  Google Scholar 

  40. 40.

    Velasco-Galilea M, Piles M, Viñas M, Rafel O, González-Rodríguez O, Guivernau M. et al. Rabbit microbiota changes throughout the intestinal tract. Front Microbiol. 2018;9:21–44.

    Google Scholar 

  41. 41.

    Li H, Qu JP, Li T, Wirth S, Zhang Y, Zhao X, et al. Diet simplification selects for high gut microbial diversity and strong fermenting ability in high-altitude pikas. Appl Microbiol Biotechnol. 2018;102:6739–51.

    CAS  PubMed  Google Scholar 

  42. 42.

    Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489:220–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006;124:837–48.

    CAS  PubMed  Google Scholar 

  44. 44.

    Bekele AZ, Koike S, Kobayashi Y. Phylogenetic diversity and dietary association of rumen Treponema revealed using groupspecific 16S rRNA gene-based analysis. FEMS Microbiol Lett. 2011;316:51–60.

    CAS  PubMed  Google Scholar 

  45. 45.

    Dai X, Tian Y, Li J, Su X, Wang X, Zhao S, et al. Metatranscriptomic analyses of plant cell wall polysaccharide degradation by microorganisms in cow rumen. Appl Environ Microbiol. 2014;81:1375–86.

    Google Scholar 

  46. 46.

    Mackie RI, Aminov RI, Hu W, Klieve AV, Ouwerkerk D, Sundset MA, et al. Ecology of uncultivated Oscillospira species in the rumen of cattle, sheep, and reindeer as assessed by microscopy and molecular approaches. Appl Environ Microbiol. 2003;69:6808–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Krause DO, Dalrymple BP, Smith WJ, Mackie RI, Mcsweeney CS. 16S rDNA sequencing of Ruminococcus albus and Ruminococcus flavefaciens: design of a signature probe and its application in adult sheep. Microbiology. 1999;145:1797–807.

    CAS  PubMed  Google Scholar 

  48. 48.

    Ziętak M, Kovatcheva-Datchary P, Markiewicz LH, Ståhlman M, Kozak LP, Bäckhed F. Altered microbiota contributes to reduced diet-induced obesity upon cold exposure. Cell Metab. 2016;23:1216–23.

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Martínez I, Perdicaro DJ, Brown AW, Hammons S, Carden TJ, Carr TP, et al. Diet-Induced alterations of host cholesterol metabolism are likely to affect the gut microbiota composition in hamsters. Appl Environ Microbiol. 2013;79:516–24.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Worthmann A, John C, Rühlemann MC, Baguhl M, Heinsen FA, Schaltenberg N, et al. Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis. Nat Med. 2017;23:839–49.

    CAS  PubMed  Google Scholar 

  51. 51.

    Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–31.

    PubMed  Google Scholar 

  52. 52.

    Li G, Xie C, Lu S, Nichols RG, Tian Y, Li L, et al. Intermittent fasting promotes white adipose browning and decreases obesity by shaping the gut microbiota. Cell Metab. 2017;26:672–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Royall D, Wolever TM, Jeejeebhoy KN. Clinical significance of colonic fermentation. Am J Gastroenterol. 1990;85:1307–12.

    CAS  PubMed  Google Scholar 

  54. 54.

    Byrne CS, Chambers ES, Morrison DJ, Frost G. The role of short chain fatty acids in appetite regulation and energy homeostasis. Int J Obes. 2015;39:1331–8.

    CAS  Google Scholar 

  55. 55.

    Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D Muir AL, et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem. 2003;278:11312–9.

    CAS  PubMed  Google Scholar 

  56. 56.

    Tazoe H, Otomo Y, Kaji I, Tanaka R, Karaki S, Kuwahara A. Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J Physiol Pharm. 2008;59:251–62.

    Google Scholar 

  57. 57.

    Kaji I, Karaki S, Tanaka R, Kuwahara A. Density distribution of free fatty acid receptor 2 (FFA2)-expressing and GLP-1-producing enteroendocrine L cells in human and rat lower intestine, and increased cell numbers after ingestion of fructo-oligosaccharide. J Mol Histol. 2011;42:27–38.

    CAS  PubMed  Google Scholar 

  58. 58.

    Chambers ES, Morrison DJ, Frost G. Control of appetite and energy intake by SCFA: what are the potential underlying mechanisms? Proc Nutr Soc. 2015;74:328–36.

    CAS  PubMed  Google Scholar 

  59. 59.

    Christiansen CB, Gabe MBN, Svendsen B, Dragsted LO, Rosenkilde MM, Holst JJ. The impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon. Am J Physiol Gastrointest Liver Physiol. 2018;315:G53–65.

    CAS  PubMed  Google Scholar 

  60. 60.

    Aukema HM, Davidson LA, Pence BC, Jiang YH, Lupton JR, Chapkin RS. Butyrate alters activity of specific cAMP-receptor proteins in a transgenic mouse colonic cell line. J Nutr. 1997;127:18–24.

    CAS  PubMed  Google Scholar 

  61. 61.

    Wang A, Si H, Liu D, Jiang H. Butyrate activates the cAMP-protein kinase A-cAMP response element-binding protein signaling pathway in Caco-2 cells. J Nutr. 2012;142:1–6.

    CAS  PubMed  Google Scholar 

  62. 62.

    Liu L, Wang Y, Fan Y, Li CL, Chang ZL. IFN-gamma activates cAMP/PKA/CREB signaling pathway in murine peritoneal macrophages. J Interferon Cytokine Res. 2004;24:334–42.

    PubMed  Google Scholar 

  63. 63.

    Luo X, Jia R, Zhang Q, Sun B, Yan J. Cold-induced browning dynamically alters the expression profiles of inflammatory adipokines with tissue specificity in mice. Int J Mol Sci. 2016;17:795.

    PubMed Central  Google Scholar 

  64. 64.

    Dong M, Yang X, Lim S, Cao Z, Honek J, Lu H, et al. Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis. Cell Metab. 2013;18:118–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Raybould HE. Gut chemosensing: interactions between gut endocrine cells and visceral afferents. Auton Neurosci. 2010;153:41–46.

    CAS  PubMed  Google Scholar 

  66. 66.

    Lopes JG, Sourjik V. Chemotaxis of Escherichia coli to major hormones and polyamines present in human gut. ISME J. 2018;12:2736–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Reigstad CS, Salmonson CE, Rainey JF, Szurszewski JH, Linden DR, Sonnenburg JL, et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J. 2015;29:1395–403.

    CAS  PubMed  Google Scholar 

  68. 68.

    Cogan TA, Thomas AO, Rees LE, Taylor AH, Jepson MA, Williams PH, et al. Norepinephrine increases the pathogenic potential of Campylobacter jejuni. Gut. 2007;56:1060–5.

    CAS  PubMed  Google Scholar 

  69. 69.

    Zhang XY, Zhang Q, Wang DH. Pre- and post-weaning cold exposure does not lead to an obese phenotype in adult Brandt’s voles (Lasiopodomys brandtii). Horm Behav. 2011;60:210–8.

    CAS  PubMed  Google Scholar 

  70. 70.

    Zhao ZJ, Wang DH. Effects of diet quality on energy budgets and thermogenesis in Brandt’s voles. Comp Biochem Physiol A Mol Integr Physiol. 2007;148:168–77.

    PubMed  Google Scholar 

  71. 71.

    Zhang XY, Lou MF, Shen W, Fu RS, Wang DH. A maternal low-fiber diet predisposes offspring to improved metabolic phenotypes in adulthood in an herbivorous rodent. Physiol Biochem Zool. 2017;90:75–84.

    PubMed  Google Scholar 

Download references


We appreciate the very helpful and constructive comments and suggestions from the three anonymous reviewers and the editor for improving the manuscript. We are grateful to Prof. Zuoxin Wang and Meghan Donovan from Department of Psychology and Program in Neuroscience, Florida State University for the comments and careful editing. We thank Jianfeng Wang from Beijing Nebula Medical Laboratory Co., Ltd. for helps in 16S rRNA gene sequencing and analyses. We also thank Prof. Jianxu Zhang and Dr. Yaohua Zhang for supplying some chemicals and technique, and thank all the members of Animal Physiological Ecology Group for their help in the experiments and discussions. This research was supported by the National Natural Science Foundation of China (Nos. 31770440 and 31772461), and the Beijing Natural Science Foundation (5172024).

Author information




X-YZ and D-HW designed the studies. T-BB and X-YZ conducted the experiments. T-BB, X-YZ, JW, and X-WQ performed the measurements of SCFAs and neurotransmitters. T-BB and X-YZ analyzed the data. TBB, X-YZ, and KD made the figures. T-BB, X-YZ, and D-HW wrote the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xue-Ying Zhang or De-Hua Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bo, T., Zhang, X., Wen, J. et al. The microbiota–gut–brain interaction in regulating host metabolic adaptation to cold in male Brandt’s voles (Lasiopodomys brandtii). ISME J 13, 3037–3053 (2019).

Download citation

Further reading


Quick links