Elsevier

Neurochemistry International

Volume 99, October 2016, Pages 110-132
Neurochemistry International

Review
The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis?

https://doi.org/10.1016/j.neuint.2016.06.011Get rights and content

Highlights

  • Butyrate is produced by specific bacteria, mainly in the colon, and is taken up by the host.

  • Butyrate affects multiple host physiological processes via specific transporters/receptors and as an HDAC inhibitor.

  • Supraphysiological doses of butyrate exert potent neuropharmacological effects, facilitating synaptic tagging and capturing.

  • Physiological levels of butyrate may influence the brain indirectly via regulating immune system and vagus nerve activity.

  • Microbiota-derived volatile butyrate may be involved in host behaviour including social communication.

Abstract

Several lines of evidence suggest that brain function and behaviour are influenced by microbial metabolites. Key products of the microbiota are short-chain fatty acids (SCFAs), including butyric acid. Butyrate is a functionally versatile molecule that is produced in the mammalian gut by fermentation of dietary fibre and is enriched in butter and other dairy products. Butyrate along with other fermentation-derived SCFAs (e.g. acetate, propionate) and the structurally related ketone bodies (e.g. acetoacetate and d-β-hydroxybutyrate) show promising effects in various diseases including obesity, diabetes, inflammatory (bowel) diseases, and colorectal cancer as well as neurological disorders. Indeed, it is clear that host energy metabolism and immune functions critically depend on butyrate as a potent regulator, highlighting butyrate as a key mediator of host-microbe crosstalk. In addition to specific receptors (GPR43/FFAR2; GPR41/FFAR3; GPR109a/HCAR2) and transporters (MCT1/SLC16A1; SMCT1/SLC5A8), its effects are mediated by utilisation as an energy source via the β-oxidation pathway and as an inhibitor of histone deacetylases (HDACs), promoting histone acetylation and stimulation of gene expression in host cells. The latter has also led to the use of butyrate as an experimental drug in models for neurological disorders ranging from depression to neurodegenerative diseases and cognitive impairment.

Here we provide a critical review of the literature on butyrate and its effects on multiple aspects of host physiology with a focus on brain function and behaviour. We find fundamental differences in natural butyrate at physiological concentrations and its use as a neuropharmacological agent at rather high, supraphysiological doses in brain research. Finally, we hypothesise that butyrate and other volatile SCFAs produced by microbes may be involved in regulating the impact of the microbiome on behaviour including social communication.

Introduction

The gastrointestinal tract is the main interface for interaction and nutrient exchange between an animal’s interior milieu and the outside world. This interface is colonized by a vast and complex microbial ecosystem, which symbiotically interacts with the host. During the last decade, evidence has rapidly accumulated, showing that this microbiota has extensive regulatory effects on host physiology and function of virtually all organ systems (Clarke et al., 2014). As such, central nervous system function and subsequently also human and animal behaviour is influenced by microbial presence, metabolism and activity (Collins et al., 2012, Cryan and Dinan, 2012, Mayer et al., 2014, Sampson and Mazmanian, 2015). The microbiota-gut-brain axis integrates various routes of communication, including endocrine, vagus nerve-dependent and immune signalling as well as direct action of microbial metabolites as signalling molecules in the brain (Clarke et al., 2014, El Aidy et al., 2014, Forsythe et al., 2014, Lyte, 2013, Selkrig et al., 2014, Stilling et al., 2014b). Among the most important and pleiotropic functional components of microbe-to-host signalling are short-chain fatty acids (SCFAs), small organic monocarboxylic acids with less than six carbon atoms, that are major microbial metabolites produced during anaerobic fermentation in the gut (Roy et al., 2006).

The C4 monocarboxylic acid butyric acid (IUPAC name: butanoic acid) is an SCFA that got its name from the Greek word for butter and is infamous for its strong smell of rancid milk or butter, where it is generated from butyric acid-containing triglycerides present in milk fat by lipase-catalysed hydrolysis (Reineccius and Heath, 2006). Contributing to the characteristics of body odour, it is also largely responsible for the smell of vomit and sweat, where it is produced from lipids (e.g. milk fat in the stomach or sebum secreted by sebaceous glands on the skin) by salivary or gastric lipases or bacteria-derived lipases (e.g. by members of Corynebacterium, Staphylococcus and Micrococcus genera) (Holt, 1971).

Butyric acid comes in two isoforms, known as n-butyric acid and iso-butyric acid (Fig. 1A). Since n-butyric acid concentrations are outnumbering iso-butyric acid concentrations approximately 5-to-8-fold in human faeces (Payne et al., 2011, Siigur et al., 1993), and only n-butyrate has some of the molecular/pharmacological characteristics discussed in this review, we will focus predominantly on n-butyric acid. We will further refer to it as butyrate as in solution with a pH > pKa (=4.82), butyric acid appears mainly in its deprotonated form (e.g. in blood of pH 7.4 almost all butyric acid dissociates to butyrate and H+ (ratio [A-]:[HA] = 380:1)). In the human colon, butyric acid contributes to the slight acidity with a typical pH of about 5.7–6.7 ([A-]:[HA] ratios approximately 7.6:1 to 76:1) (Fallingborg, 1999).

Butyrate, the anionic part of dissociated butyric acid and its salts, has been implicated in various host physiological functions including energy homeostasis, obesity, immune system regulation, cancer, and even brain function (Bourassa et al., 2016, Di Sabatino et al., 2005, Li, 2014). Yet, the molecular mechanisms mediating these functions may differ, ranging from metabolic effects to receptor signalling and enzymatic inhibition, and are not completely understood (Canani et al., 2011). Under physiological conditions, i.e. butyrate is only derived from fermentation of dietary fibre in the gut and reaches the circulation in variable μ-molar concentrations, butyrate mainly affects intestinal and adjacent tissues in a significant and mostly beneficial manner ((Canani et al., 2011, Hamer et al., 2008), see sections 5 Butyrate: an effector of immune system, barrier function & tumour growth, 3.1 Intestinal synthesis and concentrations – relevance to host metabolism and obesity, 3.2 Transport, circulation and turnover in the host). However, butyrate is also widely used as an experimental pharmacological compound, and more recently also in neuroscience research, often administered systemically at concentrations of 100–1200 mg/kg (Bourassa et al., 2016, Fischer et al., 2010). It is thus of particular interest to the field of microbiota-gut-brain axis research to understand how gut-derived butyrate influences brain function and behaviour.

In this review, we will summarize what is known about the biological relevance of butyrate with a focus on the gut microbiota as its prime source and the known and potential effects butyrate has on brain function and behaviour.

Section snippets

Biochemistry

Caecal and colonic fermentation of dietary fibre, carbohydrates and proteins are complex energy-releasing processes that occur under anaerobic conditions and are necessary for survival of many gut-colonising bacterial and fungal species. The main end-products of the different fermentation processes are the SCFAs acetate (C2), propionate (C3) and butyrate (C4), but also - to a lesser extent - so-called branched short-chain fatty acids (iso-butyrate, valerate and iso-valerate) (Fernandes et al.,

Intestinal synthesis and concentrations – relevance to host metabolism and obesity

As butyrate is – with few exceptions in tissues of goats, rabbits and piglets (Kien et al., 2000, Nandedkar et al., 1969, Nandedkar and Kumar, 1969) – almost exclusively produced by gut bacteria, or taken up with the diet, butyrate concentrations are highest in the gut lumen. Human faeces show substantial variability in faecal butyrate concentrations (McOrist et al., 2011) in the range of about 3.5–32.6 g/kg of butyrate, as well as ∼60 g/kg acetate and ∼10–20 g/kg propionate (Macfarlane and

Butyrate as an HDAC inhibitor

Histone deacetylases (HDACs or KDACs) are a family of proteins catalysing the removal of acetyl groups from lysine (‘K’) residues within a peptide chain. Acetylation of lysine in proteins is an important mechanism of intracellular signalling (Spange et al., 2009) and is most well-known to be occurring on nucleosomal histone proteins, where acetylation of the histone tails is associated with activation of transcription (Fig. 2A). More recently, acetylation of lysines has been initially found in

Butyrate: an effector of immune system, barrier function & tumour growth

Hippocrates famously noted that “all diseases originate in the gut”. Indeed, the gastrointestinal system offers an integrated interface for regulation of various body functions in health and disease. Strikingly, butyrate has been shown to interact with virtually all of these functions (Canani et al., 2011, Hamer et al., 2008).

As such, the gut epithelium is also the first line of defence against pathogens taken up with the diet. Due to the mutualistic nature of the majority of microbes in the

A role for butyrate in social communication?

Due to their intimate relationship with the host, microbes have been suggested to play important roles in establishing host social behaviours and particularly the evolution and development of mammalian social group living by mutual benefit to the fitness of both host and microbes (Lombardo, 2008, Montiel-Castro et al., 2013, Montiel-Castro et al., 2014, Stilling et al., 2014a, Troyer, 1984). However, it is not entirely clear how communication between individuals of a certain host species can be

Conclusions

The current literature points toward mainly positive effects of enhancing production of butyrate and other SCFAs in the gut. However, in light of the usually low peripheral concentrations of butyrate and specialised localization of transporters and receptors, it appears very unlikely that butyrate enters the brain in high enough concentrations to exert direct molecular effects, such as receptor binding or HDAC inhibition, or to become a feasible energy source under physiological conditions,

Acknowledgements

This publication has emanated from research conducted with the financial support of Science Foundation Ireland to the APC Microbiome Institute (Grant Number 12/RC/2273). RMS is supported by the Irish Research Council through a Government of Ireland Postdoctoral Fellowship (Grant Number GOIPD/2014/355).

References (248)

  • C.G.M. de Theije et al.

    Intestinal inflammation in a murine model of autism spectrum disorders

    Brain. Behav. Immun.

    (2014)
  • C.G.M. de Theije et al.

    Altered gut microbiota and activity in a murine model of autism spectrum disorders

    Brain. Behav. Immun.

    (2014)
  • L. De Vuyst et al.

    Cross-feeding between bifidobacteria and butyrate-producing colon bacteria explains bifdobacterial competitiveness, butyrate production, and gas production

    Int. J. Food Microbiol.

    (2011)
  • J.B. Ewaschuk et al.

    D-lactate in human and ruminant metabolism

    J. Nutr.

    (2005)
  • M. Febo et al.

    Cocaine-induced metabolic activation in cortico-limbic circuitry is increased after exposure to the histone deacetylase inhibitor, sodium butyrate

    Neurosci. Lett.

    (2009)
  • A.J. Filiano et al.

    Interactions of innate and adaptive immunity in brain development and function

    Brain Res.

    (2015)
  • A. Fischer et al.

    Targeting the correct HDAC(s) to treat cognitive disorders

    Trends Pharmacol. Sci.

    (2010)
  • H. Gagliano et al.

    High doses of the histone deacetylase inhibitor sodium butyrate trigger a stress-like response

    Neuropharmacology

    (2014)
  • G. Gardian et al.

    Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington’s disease

    J. Biol. Chem.

    (2005)
  • T. Gaschott et al.

    Tributyrin, a stable and rapidly absorbed prodrug of butyric acid, enhances antiproliferative effects of dihydroxycholecalciferol in human colon cancer cells

    J. Nutr.

    (2001)
  • K.M. Gilbert et al.

    Structure-activity relationship between carboxylic acids and T cell cycle blockade

    Life Sci.

    (2006)
  • N. Gupta et al.

    SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter

    Life Sci.

    (2006)
  • M. Guzmán et al.

    Ketone body synthesis in the brain: possible neuroprotective effects. Prostaglandins Leukot

    Essent. Fat. Acids

    (2004)
  • R. Haapakoski et al.

    Innate and adaptive immunity in the development of depression: an update on current knowledge and technological advances

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2016)
  • J. Havlicek et al.

    MHC-correlated mate choice in humans: a review

    Psychoneuroendocrinology

    (2009)
  • A. Kalda et al.

    Histone deacetylase inhibitors modulates the induction and expression of amphetamine-induced behavioral sensitization partially through an associated learning of the environment in mice

    Behav. Brain Res.

    (2007)
  • C.L. Kien et al.

    Butyric acid is synthesized by piglets

    J. Nutr.

    (2000)
  • K.A. Adipietro et al.

    Functional evolution of mammalian odorant receptors

    PLoS Genet.

    (2012)
  • Z. Ang et al.

    GPR41 and GPR43 in obesity and inflammation – protective or causative?

    Front. Immunol.

    (2016)
  • D. Artis

    Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut

    Nat. Rev. Immunol.

    (2008)
  • S. Astbury et al.

    Uptake and metabolism of the short-chain fatty acid butyrate, a critical review of the literature

    Curr. Drug Metab.

    (2012)
  • K.E. Bach Knudsen et al.

    New insight into butyrate metabolism

    Proc. Nutr. Soc.

    (2003)
  • J. Baeza et al.

    Mechanisms and dynamics of protein acetylation in mitochondria

    Trends Biochem. Sci.

    (2016)
  • A. Barcenilla et al.

    Phylogenetic relationships of butyrate-producing bacteria from the human gut

    Appl. Environ. Microbiol.

    (2000)
  • A. Belenguer et al.

    Two routes of metabolic cross-feeding between Bifidobacterium adolescentis and butyrate-producing anaerobes from the human gut

    Appl. Environ. Microbiol.

    (2006)
  • L. Bergersen et al.

    Immunogold cytochemistry identifies specialized membrane domains for monocarboxylate transport in the central nervous system

    Neurochem. Res.

    (2002)
  • E. Biagi et al.

    Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians

    PLoS One

    (2010)
  • J. Bindelle et al.

    Nutritional and environmental consequences of dietary fibre in pig nutrition: a review

    Base

    (2008)
  • J. Bollrath et al.

    Feed your tregs more fiber

    Science

    (2013)
  • D. Bolognini et al.

    The pharmacology and function of receptors for short-chain fatty acids

    Mol. Pharmacol.

    (2016)
  • M. Bordin et al.

    Histone deacetylase inhibitors up-regulate the expression of tight junction proteins

    Mol. Cancer Res. MCR

    (2004)
  • A. Borthakur et al.

    Regulation of monocarboxylate transporter 1 (MCT1) promoter by butyrate in human intestinal epithelial cells: involvement of NF-kappaB pathway

    J. Cell. Biochem.

    (2008)
  • M.W. Bourassa et al.

    Butyrate, neuroepigenetics and the gut microbiome: can a high fiber diet improve brain health?

    Neurosci. Lett.

    (2016)
  • A. Brandl et al.

    Histone deacetylases: salesmen and customers in the post-translational modification market

    Biol. Cell Auspices Eur. Cell Biol. Organ

    (2009)
  • V. Braniste et al.

    The gut microbiota influences blood-brain barrier permeability in mice

    Sci. Transl. Med.

    (2014)
  • P.A. Brennan et al.

    Mammalian social odours: attraction and individual recognition

    Philos. Trans. R. Soc. B Biol. Sci.

    (2006)
  • R.E. Brown et al.

    Interactions among the MHC, diet and bacteria in the production of social odors in rodents

  • C.S. Byrne et al.

    The role of short chain fatty acids in appetite regulation and energy homeostasis

    Int. J. Obes.

    (2015)
  • R.B. Canani et al.

    Potential beneficial effects of butyrate in intestinal and extraintestinal diseases

    World J. Gastroenterol. WJG

    (2011)
  • V.F. Castellucci et al.

    Inhibitor of protein synthesis blocks long-term behavioral sensitization in the isolated gill-withdrawal reflex of Aplysia

    J. Neurobiol.

    (1989)
  • Cited by (548)

    View all citing articles on Scopus
    View full text