title: Enteric bacterial metabolites propionic and butyric acid modulate gene expression, including CREB-dependent catecholaminergic neurotransmission, in PC12 cells--possible relevance to autism spectrum disorders.
abstract: Alterations in gut microbiome composition have an emerging role in health and disease including brain function and behavior. Short chain fatty acids (SCFA) like propionic (PPA), and butyric acid (BA), which are present in diet and are fermentation products of many gastrointestinal bacteria, are showing increasing importance in host health, but also may be environmental contributors in neurodevelopmental disorders including autism spectrum disorders (ASD). Further to this we have shown SCFA administration to rodents over a variety of routes (intracerebroventricular, subcutaneous, intraperitoneal) or developmental time periods can elicit behavioral, electrophysiological, neuropathological and biochemical effects consistent with findings in ASD patients. SCFA are capable of altering host gene expression, partly due to their histone deacetylase inhibitor activity. We have previously shown BA can regulate tyrosine hydroxylase (TH) mRNA levels in a PC12 cell model. Since monoamine concentration is known to be elevated in the brain and blood of ASD patients and in many ASD animal models, we hypothesized that SCFA may directly influence brain monoaminergic pathways. When PC12 cells were transiently transfected with plasmids having a luciferase reporter gene under the control of the TH promoter, PPA was found to induce reporter gene activity over a wide concentration range. CREB transcription factor(s) was necessary for the transcriptional activation of TH gene by PPA. At lower concentrations PPA also caused accumulation of TH mRNA and protein, indicative of increased cell capacity to produce catecholamines. PPA and BA induced broad alterations in gene expression including neurotransmitter systems, neuronal cell adhesion molecules, inflammation, oxidative stress, lipid metabolism and mitochondrial function, all of which have been implicated in ASD. In conclusion, our data are consistent with a molecular mechanism through which gut related environmental signals such as increased levels of SCFA's can epigenetically modulate cell function further supporting their role as environmental contributors to ASD.
authors.affiliation: New York Medical College, Department of Pediatrics/Maria Fareri Children's Hospital, Valhalla, New York, United States of America.
authors.forename: Bistra B
authors.initials: BB
authors.lastname: Nankova
authors.affiliation: New York Medical College, Department of Pediatrics/Maria Fareri Children's Hospital, Valhalla, New York, United States of America.
authors.forename: Raj
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: The Kilee Patchell-Evans Autism Research Group, Departments of Psychology (Neuroscience) and Psychiatry, Division of Developmental Disabilities, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Derrick F
authors.initials: DF
authors.lastname: MacFabe
authors.affiliation: New York Medical College, Department of Pediatrics/Maria Fareri Children's Hospital, Valhalla, New York, United States of America.
authors.forename: Edmund F
authors.initials: EF
authors.lastname: La Gamma
mesh_terms: D000818:Animals; D020148:Butyric Acid / Q000378:metabolism*; D002659:Child Development Disorders, Pervasive / Q000382:microbiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004755:Enterobacteriaceae / Q000502:physiology*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D054884:Host-Pathogen Interactions; D016716:PC12 Cells / Q000378:metabolism / Q000382:microbiology*; D011422:Propionates / Q000378:metabolism*; D051381:Rats; D009435:Synaptic Transmission; D015533:Transcriptional Activation; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D011422:Propionates; D020148:Butyric Acid; D014446:Tyrosine 3-Monooxygenase