Neurotransmitter modulation by the gut microbiota

doi:10.1016/j.brainres.2018.03.015

Brain Research

Volume 1693, Part B, 15 August 2018, Pages 128-133

https://doi.org/10.1016/j.brainres.2018.03.015 Get rights and content

Highlights

•
The human microbiota has been linked to numerous components of health and disease.
•
Gut bacteria can influence diseases of the enteric and central nervous systems.
•
Bacteria have the capability to produce or consume neurotransmitters.
•
Neurotransmitter modulation is a likely communication route along the gut-brain-axis.

Abstract

The gut microbiota – the trillions of bacteria that reside within the gastrointestinal tract – has been found to not only be an essential component immune and metabolic health, but also seems to influence development and diseases of the enteric and central nervous system, including motility disorders, behavioral disorders, neurodegenerative disease, cerebrovascular accidents, and neuroimmune-mediated disorders. By leveraging animal models, several different pathways of communication have been identified along the “gut-brain-axis” including those driven by the immune system, the vagus nerve, or by modulation of neuroactive compounds by the microbiota. Of the latter, bacteria have been shown to produce and/or consume a wide range of mammalian neurotransmitters, including dopamine, norepinephrine, serotonin, or gamma-aminobutyric acid (GABA). Accumulating evidence in animals suggests that manipulation of these neurotransmitters by bacteria may have an impact in host physiology, and preliminary human studies are showing that microbiota-based interventions can also alter neurotransmitter levels. Nonetheless, substantially more work is required to determine whether microbiota-mediated manipulation of human neurotransmission has any physiological implications, and if so, how it may be leveraged therapeutically. In this review this exciting route of communication along the gut-brain-axis, and accompanying data, are discussed.

Graphical abstract

Section snippets

The human gut microbiota

Recent work has connected the human microbiota – the trillions of bacteria that reside on or inside the body (Mayer et al., 2014) – to many components of health and disease. Of particular importance is the gut microbiota, the complex bacterial community located in the gastrointestinal (GI) tract. Incredibly, not only has the gut microbiota been found to be essential for maintaining metabolic and immune health (Lynch and Pedersen, 2016), but of relevance to this review, there is also amassing

Identifying mechanisms of communication along the Gut-brain-axis

An attractive and simple exploratory technique to determine whether the microbiota may be involved in a disease is to eliminate bacteria from an animal (either through treatment with a combination of broad-spectrum antibiotics, or use of germ free lines/facilities), and determine if end points in a model of interest change. Using this approach, a seminal 2004 study found that germ free mice exhibited an increased response to induced stress via the restraint model, and that this behavioral

Neurotransmitters and the microbiota

When considering how the microbiota may interact with the nervous system, perhaps the most obvious scenario would be through modulation of host neurotransmitters and/or related pathways. Indeed, bacteria have been found to have the capability to produce a range of major neurotransmitters (Table 1), so many in fact, it was proposed as its own field of study decades ago – microbial endocrinology (Lyte, 1993). Below is a summary of key data for a selection of neurogenic amines and amino acids, as

Prospectus

While accumulating evidence suggests the gut microbiota can influence the nervous system, more work is required to validate potential mechanisms. Modulation of neurotransmission seems to be a likely route of communication along the gut-brain-axis, and animal experiments that couple microbiome intervention with neurotransmitter receptor antagonists will further confirm these pathways. Additionally, as the majority of existing work has been performed in animals, there is a strong need for

Acknowledgements

I would like to thank Dr. Kim Lewis (Northeastern University, Boston, MA) for his continued support and feedback in discussing these topics.

Funding

This work was supported in part by the grant R01HG005824.

References (70)

M. Dahlin
The ketogenic diet influences the levels of excitatory and inhibitory amino acids in the CSF in children with refractory epilepsy
Epilepsy Res.
(2005)
N. Dey
Regulators of gut motility revealed by a gnotobiotic model of diet-microbiome interactions related to travel
Cell
(2015)
M.D. Gershon et al.
The serotonin signaling system: from basic understanding to drug development for functional GI disorders
Gastroenterology
(2007)
E.Y. Hsiao
Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders
Cell
(2013)
J.R. Kelly
Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat
J. Psychiatr. Res.
(2016)
P.J. Kennedy
Kynurenine pathway metabolism and the microbiota-gut-brain axis
Neuropharmacology
(2017)
S.H. Kim
Source and identification of histamine-producing bacteria from fresh and temperature-abused albacore
J. Food Prot.
(2001)
N. Komatsuzaki
Production of γ-aminobutyric acid (GABA) by Lactobacillus paracasei isolated from traditional fermented foods
Food Microbiol.
(2005)
J.M. Landete et al.
Biogenic amine production by lactic acid bacteria, acetic bacteria and yeast isolated from wine
Food Control
(2007)
E.S. Ogbonnaya
Adult hippocampal neurogenesis is regulated by the microbiome
Biol. Psychiatry
(2015)

J.M. Yano

Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis

Cell

(2015)

Y. Asano

Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice

Am. J. Physiol. Gastrointest. Liver Physiol.

(2012)

T. Bansal

Differential effects of epinephrine, norepinephrine, and indole on Escherichia coli O157:H7 chemotaxis, colonization, and gene expression

Infect. Immun.

(2007)

E. Barrett

gamma-Aminobutyric acid production by culturable bacteria from the human intestine

J. Appl. Microbiol.

(2012)

C. Benakis

Commensal microbiota affects ischemic stroke outcome by regulating intestinal gammadelta T cells

Nat. Med.

(2016)

K. Berer

Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination

Nature

(2011)

K. Berer

Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice

Proc. Natl. Acad. Sci. U.S.A.

(2017)

M. Berger et al.

The expanded biology of serotonin

Annu. Rev. Med.

(2009)

B. Bonaz et al.

The vagus nerve at the interface of the microbiota-gut-brain axis

Front. Neurosci.

(2018)

O. Borodovitsyna et al.

Noradrenergic modulation of cognition in health and disease

Neural Plast.

(2017)

V. Braniste

The gut microbiota influences blood-brain barrier permeability in mice

Sci. Transl. Med.

(2014)

J.A. Bravo

Ingestion of lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

Proc. Natl. Acad. Sci. U.S.A.

(2011)

P.D. Cani

Endocannabinoids–at the crossroads between the gut microbiota and host metabolism

Nat. Rev. Endocrinol.

(2016)

E. Cekanaviciute

Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models

Proc. Natl. Acad. Sci. U.S.A.

(2017)

Y.R. Cho et al.

Production of gamma-aminobutyric acid (GABA) by Lactobacillus buchneri isolated from kimchi and its neuroprotective effect on neuronal cells

J. Microbiol. Biotechnol.

(2007)

G. Clarke

The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner

Mol. Psychiatry

(2013)

G. Clarke

Minireview: gut microbiota: the neglected endocrine organ

Mol. Endocrinol.

(2014)

L.A. David

Diet rapidly and reproducibly alters the human gut microbiome

Nature

(2014)

G. De Palma

Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice

Sci Transl Med.

(2017)

R. Dhakal et al.

Production of gaba (gamma – Aminobutyric acid) by microorganisms: a review

Braz. J. Microbiol.

(2012)

R. Diaz Heijtz

Normal gut microbiota modulates brain development and behavior

Proc. Natl. Acad. Sci. U.S.A.

(2011)

S. Dover et al.

Utilization of -aminobutyric acid as the sole carbon and nitrogen source by Escherichia coli K-12 mutants

J. Bacteriol.

(1972)

D. Erny

Host microbiota constantly control maturation and function of microglia in the CNS

Nat. Neurosci.

(2015)

C. Feehily et al.

Role of glutamate metabolism in bacterial responses towards acid and other stresses

J. Appl. Microbiol.

(2013)

P.P. Freestone

Growth stimulation of intestinal commensal Escherichia coli by catecholamines: a possible contributory factor in trauma-induced sepsis

Shock

(2002)

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ReviewNeurotransmitter modulation by the gut microbiota

Highlights

Abstract

Graphical abstract

Section snippets

The human gut microbiota

Identifying mechanisms of communication along the Gut-brain-axis

Neurotransmitters and the microbiota

Prospectus

Acknowledgements

Funding

Epilepsy Res.

Cell

Gastroenterology

Cell

J. Psychiatr. Res.

Neuropharmacology

J. Food Prot.

Food Microbiol.

Food Control

Biol. Psychiatry

Cell

Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice

Am. J. Physiol. Gastrointest. Liver Physiol.

Differential effects of epinephrine, norepinephrine, and indole on Escherichia coli O157:H7 chemotaxis, colonization, and gene expression

Infect. Immun.

gamma-Aminobutyric acid production by culturable bacteria from the human intestine

J. Appl. Microbiol.

Commensal microbiota affects ischemic stroke outcome by regulating intestinal gammadelta T cells

Nat. Med.

Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination

Nature

Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice

Proc. Natl. Acad. Sci. U.S.A.

The expanded biology of serotonin

Annu. Rev. Med.

The vagus nerve at the interface of the microbiota-gut-brain axis

Front. Neurosci.

Noradrenergic modulation of cognition in health and disease

Neural Plast.

The gut microbiota influences blood-brain barrier permeability in mice

Sci. Transl. Med.

Ingestion of lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

Proc. Natl. Acad. Sci. U.S.A.

Endocannabinoids–at the crossroads between the gut microbiota and host metabolism

Nat. Rev. Endocrinol.

Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models

Proc. Natl. Acad. Sci. U.S.A.

Production of gamma-aminobutyric acid (GABA) by Lactobacillus buchneri isolated from kimchi and its neuroprotective effect on neuronal cells

J. Microbiol. Biotechnol.

The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner

Mol. Psychiatry

Minireview: gut microbiota: the neglected endocrine organ

Mol. Endocrinol.

Diet rapidly and reproducibly alters the human gut microbiome

Nature

Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice

Sci Transl Med.

Production of gaba (gamma – Aminobutyric acid) by microorganisms: a review

Braz. J. Microbiol.

Normal gut microbiota modulates brain development and behavior

Proc. Natl. Acad. Sci. U.S.A.

Utilization of -aminobutyric acid as the sole carbon and nitrogen source by Escherichia coli K-12 mutants

J. Bacteriol.

Host microbiota constantly control maturation and function of microglia in the CNS

Nat. Neurosci.

Role of glutamate metabolism in bacterial responses towards acid and other stresses

J. Appl. Microbiol.

Growth stimulation of intestinal commensal Escherichia coli by catecholamines: a possible contributory factor in trauma-induced sepsis

Shock

Review
Neurotransmitter modulation by the gut microbiota