In a striking display of trans-kingdom symbiosis, gut bacteria cooperate with their animal hosts to regulate the development and function of the immune, metabolic and nervous systems through dynamic bidirectional communication along the ‘gut–brain axis’. These processes may affect human health, as certain animal behaviours appear to correlate with the composition of gut bacteria, and disruptions in microbial communities have been implicated in several neurological disorders. Most insights about host–microbiota interactions come from animal models, which represent crucial tools for studying the various pathways linking the gut and the brain. However, there are complexities and manifest limitations inherent in translating complex human disease to reductionist animal models. In this Review, we discuss emerging and exciting evidence of intricate and crucial connections between the gut microbiota and the brain involving multiple biological systems, and possible contributions by the gut microbiota to neurological disorders. Continued advances from this frontier of biomedicine may lead to tangible impacts on human health.
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Cryan, J. F. et al. The microbiota–gut–brain axis. Physiol. Rev. 99, 1877–2013 (2019).
Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015). This important study demonstrates that the gut microbiota can modulate microglia immune programming mediated by SCFAs in mice.
Clarke, G. et al. The microbiome–gut–brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol. Psychiatry 18, 666–673 (2013).
Lyte, M. Microbial endocrinology and the microbiota–gut–brain axis. Adv. Exp. Med. Biol. 817, 3–24 (2014).
Sharon, G. et al. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell 177, 1600–1618.e17 (2019).
Martin, C. R., Osadchiy, V., Kalani, A. & Mayer, E. A. The brain–gut–microbiome axis. Cell. Mol. Gastroenterol. Hepatol. 6, 133–148 (2018).
Zheng, D., Liwinski, T. & Elinav, E. Interaction between microbiota and immunity in health and disease. Cell Res. 30, 492–506 (2020).
Dabke, K., Hendrick, G. & Devkota, S. The gut microbiome and metabolic syndrome. J. Clin. Invest. 129, 4050–4057 (2019).
Collins, J., Borojevic, R., Verdu, E. F., Huizinga, J. D. & Ratcliffe, E. M. Intestinal microbiota influence the early postnatal development of the enteric nervous system. Neurogastroenterol. Motil. 26, 98–107 (2014).
de la Cuesta-Zuluaga, J. et al. Age- and sex-dependent patterns of gut microbial diversity in human adults. mSystems 4, e00261–e00319 (2019).
David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).
Vich Vila, A. et al. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat. Commun. 11, 362 (2020).
Sender, R., Fuchs, S. & Milo, R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 164, 337–340 (2016).
Tierney, B. T. et al. The landscape of genetic content in the gut and oral human microbiome. Cell Host Microbe 26, 283–295.e8 (2019).
Szabo, G. Gut–liver axis in alcoholic liver disease. Gastroenterology 148, 30–36 (2015).
Dalile, B., Van Oudenhove, L., Vervliet, B. & Verbeke, K. The role of short-chain fatty acids in microbiota–gut–brain communication. Nat. Rev. Gastroenterol. Hepatol. 16, 461–478 (2019).
Schroeder, F. A., Lin, C. L., Crusio, W. E. & Akbarian, S. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol. Psychiatry 62, 55–64 (2007).
Sudo, N. et al. Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. J. Physiol. 558, 263–275 (2004). This seminal study shows that GF mice have alterations in the HPA axis relevant to stress and anxiety, and shows the impact of a probiotic on stress responses.
Ghatei, M. A., Ratcliffe, B., Bloom, S. R. & Goodlad, R. A. Fermentable dietary fibre, intestinal microflora and plasma hormones in the rat. Clin. Sci. 93, 109–112 (1997).
Aresti Sanz, J. & El Aidy, S. Microbiota and gut neuropeptides: a dual action of antimicrobial activity and neuroimmune response. Psychopharmacology 236, 1597–1609 (2019).
Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).
Wichmann, A. et al. Microbial modulation of energy availability in the colon regulates intestinal transit. Cell Host Microbe 14, 582–590 (2013).
Buckley, M. M. et al. Glucagon-like peptide-1 secreting L-cells coupled to sensory nerves translate microbial signals to the host rat nervous system. Front. Cell Neurosci. 14, 95 (2020).
Strandwitz, P. et al. GABA-modulating bacteria of the human gut microbiota. Nat. Microbiol. 4, 396–403 (2019).
Barrett, E., Ross, R. P., O’Toole, P. W., Fitzgerald, G. F. & Stanton, C. γ-Aminobutyric acid production by culturable bacteria from the human intestine. J. Appl. Microbiol. 113, 411–417 (2012).
Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015). This study reveals microbial regulation of 5-HT production from enterochromaffin cells in the gut by specific microbial molecules. Impacts on the brain or behaviour are not yet known.
Poutahidis, T. et al. Microbial symbionts accelerate wound healing via the neuropeptide hormone oxytocin. PLoS ONE 8, e78898 (2013).
Morris, G. et al. The role of the microbial metabolites including tryptophan catabolites and short chain fatty acids in the pathophysiology of immune-inflammatory and neuroimmune disease. Mol. Neurobiol. 54, 4432–4451 (2017).
Muller, P. A. et al. Microbiota modulate sympathetic neurons via a gut–brain circuit. Nature 583, 441–446 (2020). This seminal study uses neuronal tracing techniques to demonstrate modulation of neuronal pathways of the gut–brain axis by the gut microbiota.
Yoo, B. B. & Mazmanian, S. K. The enteric network: interactions between the immune and nervous systems of the gut. Immunity 46, 910–926 (2017).
De Vadder, F. et al. Gut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks. Proc. Natl Acad. Sci. USA 115, 6458–6463 (2018).
Kabouridis, P. S. et al. Microbiota controls the homeostasis of glial cells in the gut lamina propria. Neuron 85, 289–295 (2015).
Aktar, R. et al. Human resident gut microbe Bacteroides thetaiotaomicron regulates colonic neuronal innervation and neurogenic function. Gut Microbes 11, 1745–1757 (2020).
Obata, Y. et al. Neuronal programming by microbiota regulates intestinal physiology. Nature 578, 284–289 (2020).
Mao, Y.-K. et al. Bacteroides fragilis polysaccharide A is necessary and sufficient for acute activation of intestinal sensory neurons. Nat. Commun. 4, 1465 (2013).
Golubeva, A. V. et al. Microbiota-related changes in bile acid & tryptophan metabolism are associated with gastrointestinal dysfunction in a mouse model of autism. EBioMedicine 24, 166–178 (2017).
Fülling, C., Dinan, T. G. & Cryan, J. F. Gut microbe to brain signaling: what happens in vagus. Neuron 101, 998–1002 (2019).
Wang, F.-B. & Powley, T. L. Vagal innervation of intestines: afferent pathways mapped with new en bloc horseradish peroxidase adaptation. Cell Tissue Res. 329, 221–230 (2007).
Han, W. et al. A neural circuit for gut-induced reward. Cell 175, 887–888 (2018).
Kaelberer, M. M. et al. A gut–brain neural circuit for nutrient sensory transduction. Science 361, eaat5236 (2018).
Tan, H.-E. et al. The gut–brain axis mediates sugar preference. Nature 580, 511–516 (2020).
Bellono, N. W. et al. Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways. Cell 170, 185–198.e16 (2017).
Bonaz, B., Picq, C., Sinniger, V., Mayol, J. F. & Clarençon, D. Vagus nerve stimulation: from epilepsy to the cholinergic anti-inflammatory pathway. Neurogastroenterol. Motil. 25, 208–221 (2013).
Bravo, J. A. et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl Acad. Sci. USA 108, 16050–16055 (2011).
Sgritta, M. et al. Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder. Neuron 101, 246–259.e6 (2019).
Milby, A. H., Halpern, C. H. & Baltuch, G. H. Vagus nerve stimulation for epilepsy and depression. Neurotherapeutics 5, 75–85 (2008).
Abdel-Haq, R., Schlachetzki, J. C. M., Glass, C. K. & Mazmanian, S. K. Microbiome–microglia connections via the gut–brain axis. J. Exp. Med. 216, 41–59 (2019).
Luck, B. et al. Bifidobacteria shape host neural circuits during postnatal development by promoting synapse formation and microglial function. Sci. Rep. 10, 7737 (2020).
Thion, M. S. et al. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell 172, 500–516.e16 (2018).
Bollinger, J. L., Collins, K. E., Patel, R. & Wellman, C. L. Behavioral stress alters corticolimbic microglia in a sex- and brain region-specific manner. PLoS ONE 12, e0187631 (2017).
Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480.e12 (2016). This study is the first to demonstrate the importance of the gut microbiota for PD-like symptoms in a mouse model. Using a translational approach, transplantation of gut bacteria from individuals with PD into GF mice can replicate some PD-like motor symptoms.
Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013). This study implicates the gut microbiota in an animal model of ASD. Treatment at weaning with the human gut commensal B. fragilis is able to reverse core behavioural patterns of ASD in mice.
Yuan, N., Chen, Y., Xia, Y., Dai, J. & Liu, C. Inflammation-related biomarkers in major psychiatric disorders: a cross-disorder assessment of reproducibility and specificity in 43 meta-analyses. Transl. Psychiatry 9, 233 (2019).
Braniste, V. et al. The gut microbiota influences blood–brain barrier permeability in mice. Sci. Transl. Med. 6, 263ra158 (2014).
Grab, D. J. et al. Borrelia burgdorferi, host-derived proteases, and the blood–brain barrier. Infect. Immun. 73, 1014–1022 (2005).
Daneman, R. The blood–brain barrier in health and disease. Ann. Neurol. 72, 648–672 (2012).
Jiang, H. et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav. Immun. 48, 186–194 (2015).
Luna, R. A. et al. Distinct microbiome–neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder. Cell. Mol. Gastroenterol. Hepatol. 3, 218–230 (2017).
Kim, S. et al. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 549, 528–532 (2017).
Choi, J. G. et al. Oral administration of Proteus mirabilis damages dopaminergic neurons and motor functions in mice. Sci. Rep. 8, 1275 (2018).
Kelly, J. R. et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J. Psychiatr. Res. 82, 109–118 (2016).
Cekanaviciute, E. et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc. Natl Acad. Sci. USA 114, 10713–10718 (2017).
Walter, J., Armet, A. M., Finlay, B. B. & Shanahan, F. Establishing or exaggerating causality for the gut microbiome: lessons from human microbiota-associated rodents. Cell 180, 221–232 (2020).
Marin, I. A. et al. Microbiota alteration is associated with the development of stress-induced despair behavior. Sci. Rep. 7, 43859 (2017).
Baio, J. et al. Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveill. Summ. 67, 1–23 (2018).
Lenroot, R. K. & Yeung, P. K. Heterogeneity within autism spectrum disorders: what have we learned from neuroimaging studies? Front. Hum. Neurosci. 7, 733 (2013).
McElhanon, B. O., McCracken, C., Karpen, S. & Sharp, W. G. Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics 133, 872–883 (2014).
Coury, D. L. et al. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics 130, S160–S168 (2012).
Buie, T. et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics 125, S1–S18 (2010).
Tordjman, S. et al. Gene × environment interactions in autism spectrum disorders: role of epigenetic mechanisms. Front. Psychiatry 5, 53 (2014).
Kang, D.-W. et al. Microbiota transfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome 5, 10 (2017).
Strati, F. et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 5, 24 (2017).
Liu, F. et al. Altered composition and function of intestinal microbiota in autism spectrum disorders: a systematic review. Transl. Psychiatry 9, 43 (2019).
Son, J. S. et al. Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the Simons Simplex Collection. PLoS ONE 10, e0137725 (2015).
Zhang, M., Ma, W., Zhang, J., He, Y. & Wang, J. Analysis of gut microbiota profiles and microbe-disease associations in children with autism spectrum disorders in China. Sci. Rep. 8, 13981 (2018).
Desbonnet, L., Clarke, G., Shanahan, F., Dinan, T. G. & Cryan, J. F. Microbiota is essential for social development in the mouse. Mol. Psychiatry 19, 146–148 (2014).
Degroote, S., Hunting, D. J., Baccarelli, A. A. & Takser, L. Maternal gut and fetal brain connection: increased anxiety and reduced social interactions in Wistar rat offspring following peri-conceptional antibiotic exposure. Prog. Neuropsychopharmacol. Biol. Psychiatry 71, 76–82 (2016).
Leclercq, S. et al. Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior. Nat. Commun. 8, 15062 (2017).
Buffington, S. A. et al. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165, 1762–1775 (2016). Together with reference 45, this study demonstrates that a specific probiotic can improve social deficits in mice via the oxytocin pathway and vagus nerve, providing initial insights into gut–brain pathways that impact complex behaviours.
Kang, D.-W. et al. Long-term benefit of microbiota transfer therapy on autism symptoms and gut microbiota. Sci. Rep. 9, 5821 (2019).
Sandler, R. H. et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J. Child Neurol. 15, 429–435 (2000).
Rodakis, J. An n = 1 case report of a child with autism improving on antibiotics and a father’s quest to understand what it may mean. Microb. Ecol. Health Dis. 26, 26382 (2015).
de Theije, C. G. M. et al. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav. Immun. 37, 197–206 (2014).
Coretti, L. et al. Sex-related alterations of gut microbiota composition in the BTBR mouse model of autism spectrum disorder. Sci. Rep. 7, 45356 (2017).
Tabouy, L. et al. Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders. Brain Behav. Immun. 73, 310–319 (2018).
Needham, B. D. et al. Plasma and fecal metabolite profiles in autism spectrum disorder. Biol. Psychiatry https://doi.org/10.1016/j.biopsych.2020.09.025 (2020).
West, P. R. et al. Metabolomics as a tool for discovery of biomarkers of autism spectrum disorder in the blood plasma of children. PLoS ONE 9, e112445 (2014).
Emond, P. et al. GC-MS-based urine metabolic profiling of autism spectrum disorders. Anal. Bioanal. Chem. 405, 5291–5300 (2013).
Ming, X., Stein, T. P., Barnes, V., Rhodes, N. & Guo, L. Metabolic perturbance in autism spectrum disorders: a metabolomics study. J. Proteome Res. 11, 5856–5862 (2012).
Kałużna-Czaplińska, J., Żurawicz, E., Struck, W. & Markuszewski, M. Identification of organic acids as potential biomarkers in the urine of autistic children using gas chromatography/mass spectrometry. J. Chromatogr. B 966, 70–76 (2014).
Chao, O. Y., Yunger, R. & Yang, Y.-M. Behavioral assessments of BTBR T+Itpr3tf/J mice by tests of object attention and elevated open platform: implications for an animal model of psychiatric comorbidity in autism. Behav. Brain Res. 347, 140–147 (2018).
Smith, S. E. P., Li, J., Garbett, K., Mirnics, K. & Patterson, P. H. Maternal immune activation alters fetal brain development through interleukin-6. J. Neurosci. 27, 10695–10702 (2007).
Estes, M. L. & McAllister, A. K. Maternal immune activation: implications for neuropsychiatric disorders. Science 353, 772–777 (2016).
Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/results?cond=autism&term=microbiota&cntry=&state=&city=&dist (2020).
Santocchi, E. et al. Gut to brain interaction in autism spectrum disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters. BMC Psychiatry 16, 183 (2016).
Kong, X.-J. et al. Probiotics and oxytocin nasal spray as neuro-social-behavioral interventions for patients with autism spectrum disorders: a pilot randomized controlled trial protocol. Pilot Feasibility Stud. 6, 20 (2020).
Sichel, J. Improvements in gastrointestinal symptoms among children with autism spectrum disorder receiving the Delpro® probiotic and immunomodulator formulation. J. Prob. Health https://doi.org/10.4172/2329-8901.1000102 (2013).
Tysnes, O.-B. & Storstein, A. Epidemiology of Parkinson’s disease. J. Neural Transm. 124, 901–905 (2017).
Blandini, F., Nappi, G., Tassorelli, C. & Martignoni, E. Functional changes of the basal ganglia circuitry in Parkinson’s disease. Prog. Neurobiol. 62, 63–88 (2000).
Chen, H. et al. Meta-analyses on prevalence of selected Parkinson’s nonmotor symptoms before and after diagnosis. Transl. Neurodegener. 4, 1 (2015).
Cersosimo, M. G. & Benarroch, E. E. Pathological correlates of gastrointestinal dysfunction in Parkinson’s disease. Neurobiol. Dis. 46, 559–564 (2012).
Braak, H. et al. Pathology associated with sporadic Parkinson’s disease — where does it end? J. Neural Transm. Suppl. 70, 89–97 (2006).
Forsyth, C. B. et al. Increased intestinal permeability correlates with sigmoid mucosa α-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS ONE 6, e28032 (2011).
Kim, S. et al. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron 103, 627–641.e7 (2019).
Challis, C. et al. Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice. Nat. Neurosci. 23, 327–336 (2020).
Chai, X.-Y. et al. Investigation of nerve pathways mediating colorectal dysfunction in Parkinson’s disease model produced by lesion of nigrostriatal dopaminergic neurons. Neurogastroenterol. Motil. 32, e13893 (2020).
Parkinson, J. An essay on the shaking palsy. 1817. J. Neuropsychiatry Clin. Neurosci. 14, 223–236 (2002).
Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211 (2003).
Svensson, E. et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann. Neurol. 78, 522–529 (2015).
Barichella, M. et al. Unraveling gut microbiota in Parkinson’s disease and atypical parkinsonism. Mov. Disord. 34, 396–405 (2019).
Hasegawa, S. et al. Intestinal dysbiosis and lowered serum lipopolysaccharide-binding protein in Parkinson’s disease. PLoS ONE 10, e0142164 (2015).
Keshavarzian, A. et al. Colonic bacterial composition in Parkinson’s disease. Mov. Disord. 30, 1351–1360 (2015).
Scheperjans, F. et al. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov. Disord. 30, 350–358 (2015).
Weimers, P. et al. Inflammatory bowel disease and Parkinson’s disease: a nationwide Swedish cohort study. Inflamm. Bowel Dis. 25, 111–123 (2019).
Matheoud, D. et al. Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1–/– mice. Nature 571, 565–569 (2019).
Bedarf, J. R. et al. Functional implications of microbial and viral gut metagenome changes in early stage l-DOPA-naïve Parkinson’s disease patients. Genome Med. 9, 39 (2017).
Unger, M. M. et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat. Disord. 32, 66–72 (2016).
Maini Rekdal, V., Bess, E. N., Bisanz, J. E., Turnbaugh, P. J. & Balskus, E. P. Discovery and inhibition of an interspecies gut bacterial pathway for levodopa metabolism. Science 364, eaau6323 (2019).
Çamcı, G. & Oğuz, S. Association between Parkinson’s disease and Helicobacter pylori. J. Clin. Neurol. 12, 147–150 (2016).
van Kessel, S. P. et al. Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease. Nat. Commun. 10, 310 (2019). Together with reference 119, this interesting study links gut microbial enzymatic pathways that alter availability of l-dopa, a first-line drug used for PD.
Dawson, T. M., Golde, T. E. & Lagier-Tourenne, C. Animal models of neurodegenerative diseases. Nat. Neurosci. 21, 1370–1379 (2018).
Sampson, T. R. et al. A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice. eLife 9, e53111 (2020).
Yang, X., Qian, Y., Xu, S., Song, Y. & Xiao, Q. Longitudinal analysis of fecal microbiome and pathologic processes in a rotenone induced mice model of Parkinson’s disease. Front. Aging Neurosci. 9, 441 (2017).
Sun, M.-F. et al. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson’s disease mice: gut microbiota, glial reaction and TLR4/TNF-α signaling pathway. Brain Behav. Immun. 70, 48–60 (2018).
Ekstrand, M. I. et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc. Natl Acad. Sci. USA 104, 1325–1330 (2007).
Hsieh, T.-H. et al. Probiotics alleviate the progressive deterioration of motor functions in a mouse model of Parkinson’s disease. Brain Sci. 10, 206 (2020).
Castelli, V. et al. Effects of the probiotic formulation SLAB51 in in vitro and in vivo Parkinson’s disease models. Aging 12, 4641–4659 (2020).
The Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. Alzheimers Dement. 16, 391–460 (2020).
Cattaneo, A. et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol. Aging 49, 60–68 (2017).
Vogt, N. M. et al. Gut microbiome alterations in Alzheimer’s disease. Sci. Rep. 7, 13537 (2017).
Wang, X. et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res. 29, 787–803 (2019).
Minter, M. R. et al. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease. Sci. Rep. 6, 30028 (2016).
Dodiya, H. B. et al. Synergistic depletion of gut microbial consortia, but not individual antibiotics, reduces amyloidosis in APPPS1-21 Alzheimer’s transgenic mice. Sci. Rep. 10, 8183 (2020).
Mezö, C. et al. Different effects of constitutive and induced microbiota modulation on microglia in a mouse model of Alzheimer’s disease. Acta Neuropathol. Commun. 8, 119 (2020).
Mangalam, A. et al. Human gut-derived commensal bacteria suppress CNS inflammatory and demyelinating disease. Cell Rep. 20, 1269–1277 (2017).
Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108, 4615–4622 (2011).
Berer, K. et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc. Natl Acad. Sci. USA 114, 10719–10724 (2017).
McEwen, B. S. & Wingfield, J. C. The concept of allostasis in biology and biomedicine. Horm. Behav. 43, 2–15 (2003).
Silverman, M. N. & Sternberg, E. M. Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction. Ann. NY Acad. Sci. 1261, 55–63 (2012).
Gareau, M. G., Jury, J., MacQueen, G., Sherman, P. M. & Perdue, M. H. Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation. Gut 56, 1522–1528 (2007).
Savignac, H. M., Kiely, B., Dinan, T. G. & Cryan, J. F. Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterol. Motil. 26, 1615–1627 (2014).
Bercik, P. et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut–brain communication. Neurogastroenterol. Motil. 23, 1132–1139 (2011).
Bailey, M. T. & Coe, C. L. Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev. Psychobiol. 35, 146–155 (1999).
García-Ródenas, C. L. et al. Nutritional approach to restore impaired intestinal barrier function and growth after neonatal stress in rats. J. Pediatr. Gastroenterol. Nutr. 43, 16–24 (2006).
O’Mahony, S. M. et al. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol. Psychiatry 65, 263–267 (2009).
Jašarević, E. et al. The maternal vaginal microbiome partially mediates the effects of prenatal stress on offspring gut and hypothalamus. Nat. Neurosci. 21, 1061–1071 (2018).
World Health Organization. Depression and other common mental disorders: global health estimates (WHO, 2017).
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th edn (American Psychiatric Publishing, 2013).
Dowlati, Y. et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010).
Zheng, P. et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol. Psychiatry 21, 786–796 (2016).
Valles-Colomer, M. et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat. Microbiol. 4, 623–632 (2019).
De Palma, G. et al. Microbiota and host determinants of behavioural phenotype in maternally separated mice. Nat. Commun. 6, 7735 (2015).
Li, N. et al. Oral probiotics ameliorate the behavioral deficits induced by chronic mild stress in mice via the gut microbiota–inflammation axis. Front. Behav. Neurosci. 12, 266 (2018).
Pinto-Sanchez, M. I. et al. Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: a pilot study in patients with irritable bowel syndrome. Gastroenterology 153, 448–459.e8 (2017). This pilot human study demonstrates that probiotic administration of B. longum NCC3001 improves depression in a cohort of individuals with irritable bowel syndrome and modulates activity of areas of the brain that process emotions.
Kessler, R. C., Chiu, W. T., Demler, O., Merikangas, K. R. & Walters, E. E. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 617–627 (2005).
Lyte, M., Varcoe, J. J. & Bailey, M. T. Anxiogenic effect of subclinical bacterial infection in mice in the absence of overt immune activation. Physiol. Behav. 65, 63–68 (1998).
Goehler, L. E., Park, S. M., Opitz, N., Lyte, M. & Gaykema, R. P. A. Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: possible anatomical substrates for viscerosensory modulation of exploratory behavior. Brain Behav. Immun. 22, 354–366 (2008).
Bruch, J. D. Intestinal infection associated with future onset of an anxiety disorder: results of a nationally representative study. Brain Behav. Immun. 57, 222–226 (2016).
Neufeld, K. M., Kang, N., Bienenstock, J. & Foster, J. A. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23, 255–64, e119 (2011).
Diaz Heijtz, R. et al. Normal gut microbiota modulates brain development and behavior. Proc. Natl Acad. Sci. USA 108, 3047–3052 (2011). Together with references 44 and 143, this study is among the first in mice to demonstrate the effects of probiotics on anxiety-like behaviour, which may be dependent on the vagus nerve.
Davis, D. J., Bryda, E. C., Gillespie, C. H. & Ericsson, A. C. Microbial modulation of behavior and stress responses in zebrafish larvae. Behav. Brain Res. 311, 219–227 (2016).
Crumeyrolle-Arias, M. et al. Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology 42, 207–217 (2014).
Hoban, A. E. et al. The microbiome regulates amygdala-dependent fear recall. Mol. Psychiatry 23, 1134–1144 (2018).
Chu, C. et al. The microbiota regulate neuronal function and fear extinction learning. Nature 574, 543–548 (2019). This study discovers that gut bacteria are involved in fear extinction in mice, potentially through microbial metabolites.
Bercik, P. et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141, 599–609 (2011).
Messaoudi, M. et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br. J. Nutr. 105, 755–764 (2011).
Cowan, C. S. M., Callaghan, B. L. & Richardson, R. The effects of a probiotic formulation (Lactobacillus rhamnosus and L. helveticus) on developmental trajectories of emotional learning in stressed infant rats. Transl. Psychiatry 6, e823 (2016).
Bermudez-Martin, P. et al. The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota. Preprint at BioRxiv https://doi.org/10.1101/2020.05.18.101147 (2020).
Kang, D.-W. et al. Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe 49, 121–131 (2018).
Wang, Y. et al. Probiotics and fructo-oligosaccharide intervention modulate the microbiota–gut brain axis to improve autism spectrum reducing also the hyper-serotonergic state and the dopamine metabolism disorder. Pharmacol. Res. 157, 104784 (2020).
Blacher, E. et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature 572, 474–480 (2019).
Cirstea, M. S. et al. Microbiota composition and metabolism are associated with gut function in Parkinson’s disease. Mov. Disord. 35, 1208–1217 (2020).
Liu, B. et al. Vagotomy and Parkinson disease: a Swedish register-based matched-cohort study. Neurology 88, 1996–2002 (2017).
Perez-Pardo, P. et al. Role of TLR4 in the gut–brain axis in Parkinson’s disease: a translational study from men to mice. Gut 68, 829–843 (2019).
Peter, I. et al. Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease. JAMA Neurol. 75, 939–946 (2018).
Chen, S. G. et al. Exposure to the functional bacterial amyloid protein curli enhances α-synuclein aggregation in aged Fischer 344 rats and Caenorhabditis elegans. Sci. Rep. 6, 34477 (2016).
van de Wouw, M. et al. Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain–gut axis alterations. J. Physiol. 596, 4923–4944 (2018).
Allen, A. P. et al. Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Transl. Psychiatry 6, e939 (2016).
Dalile, B., Vervliet, B., Bergonzelli, G., Verbeke, K. & Van Oudenhove, L. Colon-delivered short-chain fatty acids attenuate the cortisol response to psychosocial stress in healthy men: a randomized, placebo-controlled trial. Neuropsychopharmacology https://doi.org/10.1038/s41386-020-0732-x (2020).
O’Leary, O. F. et al. GABAB(1) receptor subunit isoforms differentially regulate stress resilience. Proc. Natl Acad. Sci. USA 111, 15232–15237 (2014).
Desbonnet, L. et al. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 170, 1179–1188 (2010).
Kelly, J. R. et al. Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects. Brain Behav. Immun. 61, 50–59 (2017).
Ogbonnaya, E. S. et al. Adult hippocampal neurogenesis is regulated by the microbiome. Biol. Psychiatry 78, e7–e9 (2015).
Lu, J. et al. Effects of intestinal microbiota on brain development in humanized gnotobiotic mice. Sci. Rep. 8, 5443 (2018).
Hoban, A. E. et al. Regulation of prefrontal cortex myelination by the microbiota. Transl. Psychiatry 6, e774 (2016).
Gacias, M. et al. Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. eLife 5, e13442 (2016).
Codagnone, M. G. et al. Programming bugs: microbiota and the developmental origins of brain health and disease. Biol. Psychiatry 85, 150–163 (2019).
Rao, M. & Gershon, M. D. Enteric nervous system development: what could possibly go wrong? Nat. Rev. Neurosci. 19, 552–565 (2018).
Kaiser, T. & Feng, G. Modeling psychiatric disorders for developing effective treatments. Nat. Med. 21, 979–988 (2015).
S.K.M. is the Luis & Nelly Soux Professor of Microbiology at the California Institute of Technology (Caltech). His laboratory explores biological mechanisms by which the gut microbiota impacts immunological and neurological diseases, including research into mouse models of inflammatory bowel disease, autism spectrum disorder and Parkinson disease. The laboratory is supported by funding from the National Institutes of Health, the Department of Defense, the Heritage Medical Research Institute, the Michael J. Fox Foundation, Autism Speaks, Aligning Science Across Parkinson’s and other charitable organizations and individuals. L.H.M. is a postdoctoral scholar at Caltech and recipient of am American Parkinson’s Disease Association postdoctoral fellowship. H.L.S.IV is a postdoctoral scholar at Caltech and recipient of a Della Martin fellowship. The authors thank R. Abdel-Haq, J. Ousey and G. Sharon for constructive comments and N.J. Cruz and G. Tofani for assistance with the figures.
S.K.M. has financial interests in Axial Biotherapeutics, although not directly related to the contents of this article. All other authors declare no competing interests.
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The primary resident immune cells in the central nervous system, responsible for pathogen surveillance, immune protection and synaptic pruning. Microglia have been implicated in psychiatric and neurodegenerative disorders, largely in animal models.
A subtype of glial cells in the central nervous system that play an essential role in blood–brain barrier formation and function, among other activates such as interfacing with microglia and neurons.
Brain cells that regulate development of neurons and insulate neuronal axons through the formation of the protective myelin sheath.
The process of maintaining physiological functions necessary for survival of an organism.
The ability of the nervous system to change activity by reorganizing its structure and function.
DNA modifications that do not alter the sequence but can impact gene expression and biological outcomes.
- Brain-derived neurotrophic factor
(BDNF). A protein that has an important role in neuronal survival, growth and synaptic plasticity. Alterations in expression are associated with mood disorders.
- γ-Aminobutyric acid
(GABA). The main inhibitory neurotransmitter in the adult brain; crucial for synaptic plasticity and learning.
(5-Hydroxytryptamine (5-HT)). A neurotransmitter involved in controlling mood, social behaviour, gut motility and the sleep cycle.
- Blood–brain barrier
(BBB). A physical gatekeeper to separate the brain microenvironment from the rest of the body, formed by mural and microvascular endothelial cells connected by tight-junction proteins.
- Internal validity
A measure of the reliability of cause-and-effect relationships determined in a research setting. Internal validity can be improved with an experimental design including blind testing, unbiased analysis and appropriate statistical power.
- External validity
A measure of how translatable findings from one experimental setting can be to other experimental settings and to the rest of the world. External validity fails when confounding factors are not considered or controlled in research.
A physiological and neurological response to demands for change in response to real or perceived threats.
- Developmental windows
Crucial periods (for example, prenatal, early life and adolescence) in which dynamic changes in development and maturation of multiple physiological systems are susceptible to environmental factors, such as those of the microbiota.
Highly specialized contacts between nerve cells that are the connections underlying dynamic and complex neuronal systems networks.
- Oxytocin system
A key neuropeptide system that modulates social behaviour, bonding, mating and stress in animals. Known to be associated with symptoms of autism spectrum disorder.
- Face and construct validity
Face validity is achieved when a wide range of features present in human disorders, such as behaviour and circuit abnormalities, are reproduced in an animal model. Construct validity refers to mimicking a disease aetiology in animals, such as environmental or genetic risks for human disease.
A surgical procedure that severs the vagus nerve in one of several locations, disrupting signalling from various peripheral organs to the brain.
The active process of the body to maintain homeostasis in the face of stress.
A reduced capacity to experience pleasure.
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Morais, L.H., Schreiber, H.L. & Mazmanian, S.K. The gut microbiota–brain axis in behaviour and brain disorders. Nat Rev Microbiol 19, 241–255 (2021). https://doi.org/10.1038/s41579-020-00460-0