Neuronal programming by microbiota regulates intestinal physiology


Neural control of the function of visceral organs is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence, and is often dysregulated in gastrointestinal disorders1. Luminal factors, such as diet and microbiota, regulate neurogenic programs of gut motility2,3,4,5, but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor aryl hydrocarbon receptor (AHR) functions as a biosensor in intestinal neural circuits, linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons that represent distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles that are controlled by the combined effects of host genetic programs and microbial colonization. Microbiota-induced expression of AHR in neurons of the distal gastrointestinal tract enables these neurons to respond to the luminal environment and to induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr, or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in the enteric neurons of mice treated with antibiotics partially restores intestinal motility. Together, our experiments identify AHR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits to maintain gut homeostasis and health.

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Fig. 1: Programming of the enteric neuron transcriptome by microbiota.
Fig. 2: Microbiota- and ligand-dependent activation of AHR signalling.
Fig. 3: AHR signalling in enteric neurons regulates intestinal peristalsis.

Data availability

All RNA-seq data are available at Gene Expression Omnibus (GEO) under accession number GSE140293. Source Data for Figs. 2, 3 and Extended Data Fig. 15, 7 are provided with the paper. All datasets analysed during the current study are presented in this manuscript, or are available from the corresponding authors upon reasonable request.

Code availability

The source code and installation instructions for colonic migrating motor complex evaluation and Ca2+ imaging can be found at (Ca2+ imaging analysis source code) and (installation instructions and user guide). For more information, please contact The code related to the RNAscope signal quantification is available at GitHub (


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We thank the Crick Science Technology Platforms, the University of Bern FACSLab and the Bern Clean Mouse Facility for expert support; R. Lasrado and S.-H. Chng for assistance with tissue dissection; M. Shapiro for bioinformatic input; C. Schiering for useful advice; all members of the Pachnis laboratory for insightful comments on the manuscript and discussions; and M. D’Amato for insightful comments on the manuscript. Y.O. was supported by an EMBO long-term fellowship (ALTF 1214-2015), travel grants from Boehringer Ingelheim Fonds and the Society for Mucosal Immunology (SMI); he is currently supported by an HFSP postdoctoral fellowship (LT000176/2016). This work was supported by the Medical Research Council (MRC) and The Francis Crick Institute (which receives funding from the MRC, Cancer Research UK and the Wellcome Trust). V.P. was also funded by BBSRC (BB/L022974) and the Wellcome Trust (212300/Z/18/Z).

Author information

Y.O. and V.P. conceived the study and together with B.S. and A. J. Macpherson designed the experiments. Á.C., A.C.B.-F., C.F., M.G.d.A., B.Y., M.R.M., W.B. and B.Y. helped with the experiments. Á.C. performed the RNAscope in situ hybridization experiments; T.F. helped with the quantification of RNAscope data; M.G.d.A. and B.Y. helped to organize experiments with germ-free and exGF mice; A.C.B.-F., W.B. and P.V.B. provided help with the spatiotemporal mapping experiments and the analysis. C.F. carried out and analysed the Ca2+ imaging experiments with help from W.B. and P.V.B. A.H. prepared the cDNA library for the bulk nRNA-seq. S.B. performed bioinformatics analysis. S.H. performed statistical analysis. R.L. generated ChAT-TVA-mCherry mice. Y.O. generated the AAV-CaMKII-eGFP-KASH construct with help from A. J. Murray. V.P. and Y.O. wrote the manuscript with help from B.S. and A. J. Macpherson, and contributions from all authors.

Correspondence to Yuuki Obata or Vassilis Pachnis.

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The authors declare no competing interests.

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Peer review information Nature thanks John Cryan, Michael D. Gershon, Sven Petterson and Harry Sokol for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 AAV-based transcriptional profiling of enteric neurons.

ag, Representative images of myenteric ganglia from mice injected with the AAV9-CaMKII- eGFP-KASH vector. Colon (a) and small intestine (bg) myenteric-plexus preparations were immunostained with antibodies against eGFP (ag), PGP9.5 (a, b), S100β (c), SOX10 (d), nNOS and calretinin (CALR) (e), nNOS and calbindin (CALB) (f), and VIP and ChAT (g). Data represent two independent experiments. Scale bars, 100 μm (a, b) and 30 μm (cg). h, Percentage of PGP9.5+ enteric neurons (mean ± s.d.) in the proximal small intestine and colon expressing eGFP, following intravenous administration of the AAV9-CaMKII-eGFP-KASH vector. n = 1,308 colon neurons and 784 small-intestine neurons from 3 mice. i, FACS plots indicating the gating parameters for the isolation of muscularis externa nuclei (gated on DAPI) from the colon (left) and small intestine (right) of mice injected intravenously with AAV9-CaMKII-eGFP-KASH. j, k, Peripherin (red) and eGFP (green) whole-mount immunostaining of the colon (j) and small intestine (k) of mice injected with AAV9-CaMKII-eGFP-KASH mice following dissection of the muscularis externa. The identification of an intact submucosal plexus demonstrates that our transcriptomic analysis is specific for myenteric neurons. Images represent two independent experiments. Scale bars, 100 μm. l, Volcano plots showing mean log2-transformed fold change (x axis) and significance (−log10(adjusted P value)) of differentially expressed genes between eGFP+ and eGFP nuclei isolated from the colon (left) and small intestine (right) of mice injected with AAV9-CaMKII-eGFP-KASH vector. Coloured dots indicate genes specific to enteric neurons (Ret, Chat, Camk2a, Elavl3, Elavl4, Nos1 and Tubb3) in red, glial cells (Sox10, Gfap, Cdh19, Entpd2, S100b and Plp1)41 in blue and muscular macrophages (Itgam, Cd163, H2-Ab1, Mrc1 and Retnla)42 in green. n = 4 mice (Crick). m, Principal component analysis of the transcriptomes of eGFP+ (neuronal) and eGFP (non-neuronal) nuclei isolated from the muscularis externa of the colon and small intestine of mice injected with AAV9-CaMKII-eGFP-KASH vectors. Segregation of nuclear transcriptomes according to their neuronal versus non-neuronal origin and anatomical location along the gut. n = 4 mice (Crick). Source data

Extended Data Fig. 2 Differential expression of enteric-neuron-specific genes in myenteric neurons from the small intestine and colon of SPF and germ-free mice.

a, b, Representative images of myenteric ganglia (outlined by dotted line) from small intestine (left) and colon (right) of SPF (a) and germ-free (b) mice hybridized with the indicated fluorescence RNAscope probes and counterstained for the pan-neuronal marker HuC/D. Ret (positive control for RNAscope detection) is expressed in neurons of myenteric ganglia of both the small intestine and the colon. Pou3f3, Pde1c, Pantr2, Ano5, Unc5d and Col25a1 are expressed at higher levels in colonic versus small intestine neurons in both SPF (a) and germ-free (b) mice. Data represent three independent experiments. Transcripts per kilobase million (TPM) values (mean ± s.d.) for each transcript in small intestine and colon neurons from SPF (a) and germ-free (b) mice. n = 8 SPF and 3 germ-free mice. Scale bars, 30 μm. Source data

Extended Data Fig. 3 Molecular and neurochemical characterization of colonic neurons in germ-free mice.

a, TPM values (mean ± s.d.) for neuronal gene markers Elavl4, Uchl1, Prph, Chat, Vip, Nos1, Calb2 and Nefm in the muscularis externa of the colon of SPF and germ-free mice. n = 4 SPF and 3 germ-free mice. bf, Immunostaining of colonic myenteric ganglia from germ-free (top) and SPF (bottom) mice with VIP, CALR and HuC/D (b), CALR, nNOS and TuJ1 (c), VIP, nNOS and CALB (d), PGP9.5, ChAT and TuJ1 (e) and peripherin and NF-M (f). Scale bars, 30 μm. Data represent three independent experiments. Source data

Extended Data Fig. 4 Microbiota-dependent expression of AHR in colonic neurons.

a, TPM values (mean ± s.d.) for AHR transcripts in neuronal and non-neuronal nuclear preparations from muscularis externa from colon and small intestine of SPF and germ-free mice. n = 4 (SPF) and 3 (germ-free) mice. b, c, Myenteric ganglia immunostained for KIT (which identifies interstitial cells of Cajal) and AHR (b) or SOX10 (enteric glial cells) and AHR (c). AHR+ cells are distinct from intestitial cells of Cajal and enteric glia. Scale bars, 30 μm. df, Immunostaining of neurons from the colon of wild-type mice for AHR (df) and the neuronal markers peripherin and NF-M (d), calbindin and nNOS (e), and calretinin and HuC/D (f). AHR signal was detected in all subtypes of myenteric neurons (arrowheads). Scale bars, 30 μm. g, Immunostaining of neurons from the colon of ChAT-mCherry-TVA reporter mice for mCherry (red), AHR (green) and HuC/D (blue). Arrowhead indicates an enteric neuron positive for ChAT and AHR. Scale bar, 30 μm. h, i, Immunostaining of myenteric ganglia from the jejunum (h) and ileum (i) with the pan-neuronal marker peripherin (blue) and AHR (red). Scale bar, 30 μm. j, k, Representative images of enteric ganglia from duodenum (j) and colon (k) hybridized with RNAscope probe for Ahr (green). Dotted line defines the borders of myenteric ganglia. Scale bar, 30 μm. l, Quantification (mean ± s.d.) of RNAscope signal per neuron is shown (two-sided non-parametric Mann–Whitney U-test). n = 91 small-intestine and 254 colon neurons from 6 mice. mo, Immunostaining of ganglia from the colon of control (m), antibiotic-treated (n) and microbiota-colonized, antibiotic-treated (o) mice with peripherin (blue) and AHR (red). Small panels show signal for AHR (top) and peripherin (bottom). n = 3 mice for each condition. Scale bars, 30 μm. p, q, Representative images of enteric ganglia from the colon of control (p) and antibiotic-treated (q) mice hybridized with RNAscope probe for Ahr (green). Dotted line defines the borders of myenteric ganglia and arrows indicate positive cells. Scale bars, 30 μm. r, Quantification (mean ± s.d.) of RNAscope signal per neuron is also shown (two-sided non-parametric Mann–Whitney U-test). n = 518 neurons from 4 control and 468 neurons from 4 antibiotic-treated mice. Data represent two (j, k, mq) or three (bi) independent experiments. Source data

Extended Data Fig. 5 AHR-dependent gene expression and effects on colon myenteric neurons.

a, The top 30 genes upregulated in colonic neurons by AHR-ligand treatment (AHR-induced CUEGs) were identified on the basis of fold-change criteria (log2-transformed fold change = 2 < maximum). b, Cyp1a1::cre;Rosa26eYFP reporter mice were intraperitonially injected with 3MC five days before GFP immunostaining. CYP1A1 induction in response to ligand-activated AHR signalling is expected to induce expression of eYFP. c, d, Immunostaining of myenteric ganglia from the colon (c) and small intestine (d) of 3MC-treated Cyp1a1::cre;Rosa26 mice for peripherin (red), HuC/D (blue) and eGFP (green). Scale bars, 100 μm. Data represent three independent experiments. eg, Live calcium imaging of colonic myenteric plexus preparations from Wnt1::cre;Rosa26-GCaMP6f mice. Electrically stimulated Ca2+ transients in enteric neurons under control conditions (e) or in the presence of the ML-133 blocker21 (10 μM) (f). Data represent four independent experiments. The greyscale images depict a proximal colon myenteric plexus preparation in which enteric neurons were stimulated by a single electrical pulse (top panels) or an electrical pulse train (1 s, 20 Hz; bottom panels) via a focal electrode positioned on an internodal strand leading into the myenteric ganglion in the field of view. Left, baseline before stimulation. Middle, peak GCaMP6f fluorescence of the same ganglion upon electrical stimulation. Scale bars, 20 μm. Right, Ca2+ transients of individual enteric neurons (indicated by colour-coded arrows shown in the middle panels) induced by electrical stimulation. The electrical stimulus was applied at 10 s as marked by the black arrows. Comparison of the average maximal GCaMP6f fluorescence amplitudes of neuronal Ca2+ responses (mean ± s.e.m.) under control conditions (e) or the presence of ML-133 (f) upon single pulse (top) (n = 457 neurons) and pulse train (bottom) (n = 526 neurons) electrical stimulation is shown in g (two-sided paired t-test). h, i, Myenteric ganglia from colon of control (h) and antibiotic-treated (i) mice hybridized with the Kcnj12 RNAscope probe. Dotted line defines the borders of myenteric ganglia and arrows indicate Kcnj12-expressing cells. Scale bars, 30 μm. Data represent two independent experiments. j, Quantification of RNAscope signal (mean ± s.e.m.) shown in h and i (two-sided non-parametric Mann–Whitney U-test). n = 421 neurons from 4 control and 468 neurons from 4 antibiotic-treated mice. Abx, antibiotics. k, l, Myenteric ganglia from colon of SPF mice hybridized with the Ahr (green) (k)and Kcnj12 (blue) (l) RNAscope probes and immunostained with HuC/D (data not shown). Dotted line defines the borders of myenteric ganglia and arrows indicate AHR- and KCNJ12-expressing neurons. Scale bars, 30 μm. Data represent two independent experiments. m, Scatter plot shows positive correlation in RNAscope signal for Ahr (k) and Kcnj12 (l) in myenteric neurons (F-test). n = 1,037 neurons from 3 mice. n, o, Immunostaining of myenteric ganglia from control (Ahr+/+;Rosa26eYFP injected with the AAV9-CaMKII-Cre vector) (n) and AhrEN-KO (o) mice for AHR (red) and eYFP (green). Note the lack of overlap between green and red signal in the case of AhrEN-KO (o). Data are representative of two independent experiments. Scale bars, 30 μm. p, Percentage of AHR+ neurons in myenteric ganglia of control (Ahr+/+;Rosa26eYFP mice injected with the AAV9-CaMKII-Cre vector) and AhrEN-KO mice. Random images were acquired from the colon of each biological replicate (n = 9 for control, n = 13 for AhrEN-KO), and the average percentage (mean ± s.d.) of AHR+ HuC/D + cells among the total population of HuC/D+ neurons was calculated (two-sided Student’s t-test). Source data

Extended Data Fig. 6 Deletion of Ahr does not alter the organization and composition of myenteric ganglia.

a, Immunostaining of muscularis externa preparations from the colon of control (top) and AhrEN-KO (bottom) mice with nNOS, eYFP and HuC/D (left) or peripherin, eYFP and VIP (right). Scale bars, 30 μm. b, Immunostaining of muscularis externa preparations from the colon of wild-type (top) and Ahr−/− (bottom) mice with PGP9.5 and HuC/D (left), VIP, peripherin and HuC/D (middle) and PGP9.5 and nNOS (right). Scale bars, 100 μm. Data represent three independent experiments.

Extended Data Fig. 7 Intravenous administration of AAV vectors does not elicit an inflammatory response or intestinal dysmotility.

a, Cross-sections from the colon of wild-type (top), wild-type infected with AAV9-CaMKII-Cre (middle) and Ahr fl/fl (bottom) mice stained with Alcian blue–PAS (left) or haematoxylin and eosin (H&E) (right). Data represent two independent experiments. b, Graph (mean ± s.d.) shows that administration of AAV-CaMKII-Cre vector into wild-type mice is not sufficient to alter intestinal transit time. n = 3 (wild type), 4 (WT + AAV) or 3 (Ahr fl/fl) mice. Statistical test is a two-sided non-parametric Mann–Whitney U-test. Scale bars, 50 μm. Source data

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Obata, Y., Castaño, Á., Boeing, S. et al. Neuronal programming by microbiota regulates intestinal physiology. Nature 578, 284–289 (2020).

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