ReviewThe neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis?
Graphical abstract
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)
- et al.
Breast milk butyrate as protective factor against food allergy
Dig. Liver Dis.
(2015) - et al.
Ageing and gut microbes: perspectives for health maintenance and longevity
Pharmacol. Res. SI Hum. microbiome health
(2013) - et al.
MHC peptides and the sensory evaluation of genotype
Trends Neurosci.
(2006) - et al.
The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids
J. Biol. Chem.
(2003) - et al.
Sodium butyrate inhibits histone deacetylation in cultured cells
Cell
(1978) - et al.
Valproic acid and other hdac inhibitors induce microglial apoptosis and attenuate lipopolysaccharide- induced dopaminergic neurotoxicity
Neuroscience
(2007) - et al.
HDAC inhibitor sodium butyrate reverses transcriptional downregulation and ameliorates ataxic symptoms in a transgenic mouse model of SCA3
Neurobiol. Dis.
(2011) - et al.
Prebiotic digestion and fermentation
Am. J. Clin. Nutr.
(2001) Inhibition of histone deacetylase activity by butyrate
J. Nutr.
(2003)- et al.
The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism
J. Lipid Res.
(2013)
Intestinal inflammation in a murine model of autism spectrum disorders
Brain. Behav. Immun.
Altered gut microbiota and activity in a murine model of autism spectrum disorders
Brain. Behav. Immun.
Cross-feeding between bifidobacteria and butyrate-producing colon bacteria explains bifdobacterial competitiveness, butyrate production, and gas production
Int. J. Food Microbiol.
D-lactate in human and ruminant metabolism
J. Nutr.
Cocaine-induced metabolic activation in cortico-limbic circuitry is increased after exposure to the histone deacetylase inhibitor, sodium butyrate
Neurosci. Lett.
Interactions of innate and adaptive immunity in brain development and function
Brain Res.
Targeting the correct HDAC(s) to treat cognitive disorders
Trends Pharmacol. Sci.
High doses of the histone deacetylase inhibitor sodium butyrate trigger a stress-like response
Neuropharmacology
Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington’s disease
J. Biol. Chem.
Tributyrin, a stable and rapidly absorbed prodrug of butyric acid, enhances antiproliferative effects of dihydroxycholecalciferol in human colon cancer cells
J. Nutr.
Structure-activity relationship between carboxylic acids and T cell cycle blockade
Life Sci.
SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter
Life Sci.
Ketone body synthesis in the brain: possible neuroprotective effects. Prostaglandins Leukot
Essent. Fat. Acids
Innate and adaptive immunity in the development of depression: an update on current knowledge and technological advances
Prog. Neuropsychopharmacol. Biol. Psychiatry
MHC-correlated mate choice in humans: a review
Psychoneuroendocrinology
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.
Butyric acid is synthesized by piglets
J. Nutr.
Functional evolution of mammalian odorant receptors
PLoS Genet.
GPR41 and GPR43 in obesity and inflammation – protective or causative?
Front. Immunol.
Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut
Nat. Rev. Immunol.
Uptake and metabolism of the short-chain fatty acid butyrate, a critical review of the literature
Curr. Drug Metab.
New insight into butyrate metabolism
Proc. Nutr. Soc.
Mechanisms and dynamics of protein acetylation in mitochondria
Trends Biochem. Sci.
Phylogenetic relationships of butyrate-producing bacteria from the human gut
Appl. Environ. Microbiol.
Two routes of metabolic cross-feeding between Bifidobacterium adolescentis and butyrate-producing anaerobes from the human gut
Appl. Environ. Microbiol.
Immunogold cytochemistry identifies specialized membrane domains for monocarboxylate transport in the central nervous system
Neurochem. Res.
Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians
PLoS One
Nutritional and environmental consequences of dietary fibre in pig nutrition: a review
Base
Feed your tregs more fiber
Science
The pharmacology and function of receptors for short-chain fatty acids
Mol. Pharmacol.
Histone deacetylase inhibitors up-regulate the expression of tight junction proteins
Mol. Cancer Res. MCR
Regulation of monocarboxylate transporter 1 (MCT1) promoter by butyrate in human intestinal epithelial cells: involvement of NF-kappaB pathway
J. Cell. Biochem.
Butyrate, neuroepigenetics and the gut microbiome: can a high fiber diet improve brain health?
Neurosci. Lett.
Histone deacetylases: salesmen and customers in the post-translational modification market
Biol. Cell Auspices Eur. Cell Biol. Organ
The gut microbiota influences blood-brain barrier permeability in mice
Sci. Transl. Med.
Mammalian social odours: attraction and individual recognition
Philos. Trans. R. Soc. B Biol. Sci.
Interactions among the MHC, diet and bacteria in the production of social odors in rodents
The role of short chain fatty acids in appetite regulation and energy homeostasis
Int. J. Obes.
Potential beneficial effects of butyrate in intestinal and extraintestinal diseases
World J. Gastroenterol. WJG
Inhibitor of protein synthesis blocks long-term behavioral sensitization in the isolated gill-withdrawal reflex of Aplysia
J. Neurobiol.
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