Enteric bacterial metabolites propionic and butyric acid modulate gene expression, including CREB-dependent catecholaminergic neurotransmission, in PC12 cells--possible relevance to autism spectrum disorders.

Bistra B Nankova,Raj Agarwal,Derrick F Macfabe,Edmund F La Gamma,Yoshiaki Tsuji

doi:10.1371/journal.pone.0103740

Bistra B Nankova, Raj Agarwal + Show 3 more

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https://doi.org/10.1371/journal.pone.0103740

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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.

Highlights

The gut microbiota - the diverse range of symbiotic gut bacteria and other microorganisms is involved in the regulation of multiple host metabolic pathways in both health and disease [1,2]
Given that PPA is a key fermentation product of autism spectrum disorders (ASD)-associated antibiotic resistant bacteria (Clostridia, Bacteriodetes, Desulfovibrio) [33] and modulates many ASD related biochemical processes, we have proposed that Short chain fatty acids (SCFA) represent a group of host microbiome metabolites that are plausibly linked to ASDs and can induce widespread effects on gut, brain, and behavior [3,4]
We demonstrate that PPA can induce tyrosine hydroxylase (TH) gene transcription over a wide dose range (0.1 mM to 10 mM) in PC12 cells, similar to the effects of butyric acid (BA) [63,75]

Summary

Introduction

The gut microbiota - the diverse range of symbiotic gut bacteria and other microorganisms is involved in the regulation of multiple host metabolic pathways in both health and disease [1,2]. The mutually beneficial relationship between the host and gut microorganisms arises in part from SCFAs which are produced from bacterial fermentation of some proteins and dietary fiber, the most abundant of which are acetate, BA and PPA [8]. These SCFA serve local functions in phenotypic reprogramming of colonic epithelial cells, as the principal energy substrate for epithelial cells, as tumor suppressor agents, in apoptotic cell death, and in gene regulation of anti-inflammatory processes both in vitro and in vivo [9,10,11,12,13,14,15]. Despite the difficulty in their measurement due to intracellular concentration and rapid metabolism, there is growing evidence that the potential systemic effects of SCFA (especially PPA and BA) on physiology and pathology may have been underestimated (rev. in [8,3])

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