Faecal bile acids are natural ligands of the mouse accessory olfactory system
Open accessAbstract
The accessory olfactory system (AOS) guides behaviours that are important for survival and reproduction, but understanding of AOS function is limited by a lack of identified natural ligands. Here we report that mouse faeces are a robust source of AOS chemosignals and identify bile acids as a class of natural AOS ligands. Single-unit electrophysiological recordings from accessory olfactory bulb neurons in ex vivo preparations show that AOS neurons are strongly and selectively activated by peripheral stimulation with mouse faecal extracts. Faecal extracts contain several unconjugated bile acids that cause concentration-dependent neuronal activity in the AOS. Many AOS neurons respond selectively to bile acids that are variably excreted in male and female mouse faeces, and others respond to bile acids absent in mouse faeces. These results identify faeces as a natural source of AOS information, and suggest that bile acids may be mammalian pheromones and kairomones.
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.
Integrity signals
Registry
Cites
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.
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?
The murine olfactory system is capable of discriminating between male and female feces based on sex-dependent differences in the fecal composition of bile acids.
“the murine olfactory system is capable of discriminating between male and female feces, based on sex-dependent differences in the fecal composition of bile acids (Doyle et al., 2016)”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Doyle et al., 2016
The Results section reports that accessory olfactory bulb neurons discriminate between male and female BALB/cJ faecal extracts and identifies a sex-dependent difference in the bile acid CDCA. The Discussion says CDCA signalling *may* underlie that discrimination, while acknowledging that other ligands may contribute. The claim presents bile-acid differences as the established basis for discrimination, which goes beyond the paper's conclusion. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSome olfactory neurons fire exclusively in response to either primary or secondary bile acid application.
“some olfactory neurons were firing exclusively in response to either primary or secondary bile acid application.”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Doyle et al., 2016
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
A novel family of genes encoding putative pheromone receptors in mammals
Dulac, C., & Axel, R. (1995) · Cell · doi:10.1016/0092-8674(95)90161-2 · Cited by 1,001 · see citing works
Bile acids as regulatory molecules
Hylemon, P. B., Zhou, H., Pandak, W. M., Ren, S., Gil, G., & Dent, P. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r900007-jlr200 · Cited by 694 · see citing works
Ultrasensitive pheromone detection by mammalian vomeronasal neurons
Leinders-Zufall, T., Lane, A. P., Puche, A. C., Ma, W., Novotny, M. V., Shipley, M. T., & Zufall, F. (2000) · Nature · doi:10.1038/35015572 · Cited by 576 · see citing works
Encoding pheromonal signals in the accessory olfactory bulb of behaving mice
Luo, M., Fee, M. S., & Katz, L. C. (2003) · Science · doi:10.1126/science.1082133 · Cited by 365 · see citing works
Molecular organization of vomeronasal chemoreception
Isogai, Y., Si, S., Pont-Lezica, L., Tan, T., Kapoor, V., Murthy, V. N., & Dulac, C. (2011) · Nature · doi:10.1038/nature10437 · Cited by 317 · see citing works
A map of pheromone receptor activation in the mammalian brain
Belluscio, L., Koentges, G., Axel, R., & Dulac, C. (1999) · Cell · doi:10.1016/s0092-8674(00)80731-x · Cited by 293 · see citing works
Responses of vomeronasal neurons to natural stimuli
Holy, T. E., Dulac, C., & Meister, M. (2000) · Science · doi:10.1126/science.289.5484.1569 · Cited by 275 · see citing works
Flagged first, then by citations
Research works printed but not linked: 63
- Munger S. D., Leinders-Zufall T. & Zufall F. Subsystem organization of the mammalian sense of smell. Annu. Rev. Physiol. 71, 115– 140 (2009). 18808328
- Dulac C. & Torello A. T. Molecular detection of pheromone signals in mammals: from genes to behaviour. Nat. Rev. Neurosci. 4, 551– 562 (2003). 12838330
- Stowers L., Holy T. E., Meister M., Dulac C. & Koentges G. Loss of sex discrimination and male-male aggression in mice deficient for TRP2. Science 295, 1493– 1500 (2002). 11823606
- Haga-Yamanaka S.. Integrated action of pheromone signals in promoting courtship behavior in male mice. eLife 3, e03025 (2014). 25073926 PMC4107909
- Brennan P. A. & Keverne E. B. Neural mechanisms of mammalian olfactory learning. Prog. Neurobiol. 51, 457– 481 (1997). 9106902
- Papes F., Logan D. W. & Stowers L. The vomeronasal organ mediates interspecies defensive behaviors through detection of protein pheromone homologs. Cell 141, 692– 703 (2010). 20478258 PMC2873972
- Kimoto H., Haga S., Sato K. & Touhara K. Sex-specific peptides from exocrine glands stimulate mouse vomeronasal sensory neurons. Nature 437, 898– 901 (2005). 16208374
- Ferrero D. M.. A juvenile mouse pheromone inhibits sexual behaviour through the vomeronasal system. Nature 502, 368– 371 (2013). 24089208 PMC3800207
- Chamero P.. Identification of protein pheromones that promote aggressive behaviour. Nature 450, 899– 902 (2007). 18064011
- Leinders-Zufall T.. MHC class I peptides as chemosensory signals in the vomeronasal organ. Science 306, 1033– 1037 (2004). 15528444
- Liberles S. D.. Formyl peptide receptors are candidate chemosensory receptors in the vomeronasal organ. Proc. Natl Acad. Sci. USA 106, 9842– 9847 (2009). 19497865 PMC2690606
- Riviere S., Challet L., Fluegge D., Spehr M. & Rodriguez I. Formyl peptide receptor-like proteins are a novel family of vomeronasal chemosensors. Nature 459, 574– 577 (2009). 19387439
- Spehr M.. Essential role of the main olfactory system in social recognition of major histocompatibility complex peptide ligands. J. Neurosci. 26, 1961– 1970 (2006). 16481428 PMC6674934
- Roberts S. A.. Darcin: a male pheromone that stimulates female memory and sexual attraction to an individual male's odour. BMC Biol. 8, 75 (2010). 20525243 PMC2890510
- Nodari F.. Sulfated steroids as natural ligands of mouse pheromone-sensing neurons. J. Neurosci. 28, 6407– 6418 (2008). 18562612 PMC2726112
- Ben-Shaul Y., Katz L. C., Mooney R. & Dulac C. In vivo vomeronasal stimulation reveals sensory encoding of conspecific and allospecific cues by the mouse accessory olfactory bulb. Proc. Natl Acad. Sci. USA 107, 5172– 5177 (2010). 20194746 PMC2841925
- Spehr M., Hatt H. & Wetzel C. H. Arachidonic acid plays a role in rat vomeronasal signal transduction. J. Neurosci. 22, 8429– 8437 (2002). 12351717 PMC6757791
- Turaga D. & Holy T. E. Organization of vomeronasal sensory coding revealed by fast volumetric calcium imaging. J. Neurosci. 32, 1612– 1621 (2012). 22302803 PMC3342671
- Herrada G. & Dulac C. A novel family of putative pheromone receptors in mammals with a topographically organized and sexually dimorphic distribution. Cell 90, 763– 773 (1997). 9288755
- Pantages E. & Dulac C. A novel family of candidate pheromone receptors in mammals. Neuron 28, 835– 845 (2000). 11163270
- Ryba N. J. & Tirindelli R. A new multigene family of putative pheromone receptors. Neuron 19, 371– 379 (1997). 9292726
- Matsunami H. & Buck L. B. A multigene family encoding a diverse array of putative pheromone receptors in mammals. Cell 90, 775– 784 (1997). 9288756
- Meeks J. P., Arnson H. A. & Holy T. E. Representation and transformation of sensory information in the mouse accessory olfactory system. Nat. Neurosci. 13, 723– 730 (2010). 20453853 PMC2930753
- Dulac C. & Wagner S. Genetic analysis of brain circuits underlying pheromone signaling. Annu. Rev. Genet. 40, 449– 467 (2006). 16953793
- Arnson H. A. & Holy T. E. Chemosensory burst coding by mouse vomeronasal sensory neurons. J. Neurophysiol. 106, 409– 420 (2011). 21525370 PMC3129729
- Rodriguez I., Feinstein P. & Mombaerts P. Variable patterns of axonal projections of sensory neurons in the mouse vomeronasal system. Cell 97, 199– 208 (1999). 10219241
- Meeks J. P. & Holy T. E. An ex vivo preparation of the intact mouse vomeronasal organ and accessory olfactory bulb. J. Neurosci. Methods 177, 440– 447 (2009). 19073215 PMC2709076
- Kimoto H. & Touhara K. Induction of c-Fos expression in mouse vomeronasal neurons by sex-specific non-volatile pheromone(s). Chem. Senses 30, (Suppl 1): i146– i147 (2005). 15738083
- Turley S. D., Schwarz M., Spady D. K. & Dietschy J. M. Gender-related differences in bile acid and sterol metabolism in outbred CD-1 mice fed low- and high-cholesterol diets. Hepatology 28, 1088– 1094 (1998). 9755247
- Hagey L. R., Vidal N., Hofmann A. F. & Krasowski M. D. Evolutionary diversity of bile salts in reptiles and mammals, including analysis of ancient human and extinct giant ground sloth coprolites. BMC Evol. Biol. 10, 133 (2010). 20444292 PMC2886068
- Hofmann A. F., Hagey L. R. & Krasowski M. D. Bile salts of vertebrates: structural variation and possible evolutionary significance. J. Lipid Res. 51, 226– 246 (2010). 19638645 PMC2803226
- Moschetta A.. A phylogenetic survey of biliary lipids in vertebrates. J. Lipid Res. 46, 2221– 2232 (2005). 16061950
- Hammen G. F., Turaga D., Holy T. E. & Meeks J. P. Functional organization of glomerular maps in the mouse accessory olfactory bulb. Nat. Neurosci. 17, 953– 961 (2014). 24880215 PMC4327767
- Fu X.. A molecular code for identity in the vomeronasal system. Cell 163, 313– 323 (2015). 26435105 PMC4642884
- Hsu F. F.. Structural characterization of sulfated steroids that activate mouse pheromone-sensing neurons. Biochemistry 47, 14009– 14019 (2008). 19053227 PMC2664627
- Chiang J. Y. Bile acids: regulation of synthesis. J. Lipid Res. 50, 1955– 1966 (2009). 19346330 PMC2739756
- Griffiths W. J. & Sjovall J. Bile acids: analysis in biological fluids and tissues. J. Lipid Res. 51, 23– 41 (2010). 20008121 PMC2789783
- Turley S. D., Spady D. K. & Dietschy J. M. Regulation of fecal bile acid excretion in male golden Syrian hamsters fed a cereal-based diet with and without added cholesterol. Hepatology 25, 797– 803 (1997). 9096579
- Dawson P. A. & Karpen S. J. Intestinal transport and metabolism of bile acids. J. Lipid Res. 56, 1085– 1099 (2015). 25210150 PMC4442867
- Hofmann A. F. & Hagey L. R. Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades. J. Lipid Res. 55, 1553– 1595 (2014). 24838141 PMC4109754
- Hagey L. R. & Krasowski M. D. Microbial biotransformations of bile acids as detected by electrospray mass spectrometry. Adv. Nutr. 4, 29– 35 (2013). 23319120 PMC3648736
- Haga S.. The male mouse pheromone ESP1 enhances female sexual receptive behaviour through a specific vomeronasal receptor. Nature 466, 118– 122 (2010). 20596023
- Botham K. M. & Boyd G. S. The metabolism of chenodeoxycholic acid to beta-muricholic acid in rat liver. Eur. J. Biochem. 134, 191– 196 (1983). 6861760
- Kaur A. W.. Murine pheromone proteins constitute a context-dependent combinatorial code governing multiple social behaviors. Cell 157, 676– 688 (2014). 24766811 PMC4051225
- Arnson H. A. & Holy T. E. Robust encoding of stimulus identity and concentration in the accessory olfactory system. J. Neurosci. 33, 13388– 13397 (2013). 23946396 PMC3742926
- Mayer E. A., Knight R., Mazmanian S. K., Cryan J. F. & Tillisch K. Gut microbes and the brain: paradigm shift in neuroscience. J. Neurosci. 34, 15490– 15496 (2014). 25392516 PMC4228144
- Wagner S., Gresser A. L., Torello A. T. & Dulac C. A multireceptor genetic approach uncovers an ordered integration of VNO sensory inputs in the accessory olfactory bulb. Neuron 50, 697– 709 (2006). 16731509
- Dietschi Q., Assens A., Challet L., Carleton A. & Rodriguez I. Convergence of FPR-rs3-expressing neurons in the mouse accessory olfactory bulb. Mol. Cell. Neurosci. 56, 140– 147 (2013). 23664818
- Kuipers F., Bloks V. W. & Groen A. K. Beyond intestinal soap--bile acids in metabolic control. Nat. Rev. Endocrinol. 10, 488– 498 (2014). 24821328
- Russell D. W. Fifty years of advances in bile acid synthesis and metabolism. J. Lipid Res. 50, S120– S125 (2009). 18815433 PMC2674696
- Copple B. L. & Li T. Pharmacology of bile acid receptors: Evolution of bile acids from simple detergents to complex signaling molecules. Pharmacol. Res. 104, 9– 21 (2016). 26706784 PMC4900180
- Li T. & Chiang J. Y. Bile acid signaling in metabolic disease and drug therapy. Pharmacol. Rev. 66, 948– 983 (2014). 25073467 PMC4180336
- Philipp B. Bacterial degradation of bile salts. Appl. Microbiol. Biotechnol. 89, 903– 915 (2011). 21088832
- Buchinger T. J., Li W. & Johnson N. S. Bile salts as semiochemicals in fish. Chem. Senses 39, 647– 654 (2014). 25151152
- Huertas M.. Olfactory sensitivity to bile fluid and bile salts in the European eel (Anguilla anguilla), goldfish (Carassius auratus) and Mozambique tilapia (Oreochromis mossambicus) suggests a 'broad range' sensitivity not confined to those produced by conspecifics alone. J. Exp. Biol. 213, 308– 317 (2010). 20038666
- Doving K. B., Selset R. & Thommesen G. Olfactory sensitivity to bile acids in salmonid fishes. Acta Physiol. Scand. 108, 123– 131 (1980). 7376910
- Ridlon J. M., Kang D. J. & Hylemon P. B. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 47, 241– 259 (2006). 16299351
- Boillat M.. The vomeronasal system mediates sick conspecific avoidance. Curr. Biol. 25, 251– 255 (2015). 25578906
- Li J., Ishii T., Feinstein P. & Mombaerts P. Odorant receptor gene choice is reset by nuclear transfer from mouse olfactory sensory neurons. Nature 428, 393– 399 (2004). 15042081
- Zariwala H. A.. A Cre-dependent GCaMP3 reporter mouse for neuronal imaging in vivo. J. Neurosci. 32, 3131– 3141 (2012). 22378886 PMC3315707
- Hendrickson R. C., Krauthamer S., Essenberg J. M. & Holy T. E. Inhibition shapes sex selectivity in the mouse accessory olfactory bulb. J. Neurosci. 28, 12523– 12534 (2008). 19020044 PMC6671729
- Holekamp T. F., Turaga D. & Holy T. E. Fast three-dimensional fluorescence imaging of activity in neural populations by objective-coupled planar illumination microscopy. Neuron 57, 661– 672 (2008). 18341987
- John C.. A liquid chromatography-tandem mass spectrometry-based method for the simultaneous determination of hydroxy sterols and bile acids. J. Chromatogr. A 1371, 184– 195 (2014). 25456597
Cited by
Sorted by citations
Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286 · see citing works
- Authors
- Doyle, W. I., Dinser, J. A., Cansler, H. L., Zhang, X., Dinh, D. D., Browder, N. S., Riddington, I. M., & Meeks, J. P.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- The University of Texas at Austin (US)
- Corresponding author
- Meeks, Julian P.
- Venue
- Nature Communications
- Published
- 2016-06-21
- Volume
- 7
- Issue
- 1
- Pages
- 11936-11936
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4919516
- OpenAlex
- W2468548481
- Cited by
- 52
- References
- 7
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 7 · 2023: 5 · 2022: 3 · 2021: 9 · 2020: 5 · 2019: 4 · 2018: 9 · 2017: 1
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Texas System
- National Institutes of Health
- National Institute on Deafness and Other Communication Disorders (R00DC011780)
- National Institute of Neurological Disorders and Stroke (T32NS069562)
- Topics
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Life Sciences › Agricultural and Biological Sciences › Insect Science › Insect Pheromone Research and Control
- Health Sciences › Nursing › Nutrition and Dietetics › Biochemical Analysis and Sensing Techniques
- Keywords
- accessory olfactory system, vomeronasal organ, bile acids, vomeronasal sensory neurons, pheromones, kairomones
- MeSH terms
- Action Potentials, Animals, Bile Acids and Salts, Feces, Female, Ligands, Male, Mice, Inbred BALB C, Neurons, Olfactory Bulb, Pheromones, Sex Factors, Tissue Culture Techniques, Mice, Single-Cell Analysis
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