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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 Sep 20; 108(38):16050-5
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08 Sep 2011
George Breese
F1000 Pharmacology & Drug Discovery
University of North Carolina at Chapel Hill,
Chapel Hill, NC, USA.
F1000 Pharmacology & Drug Discovery
University of North Carolina at Chapel Hill,
Chapel Hill, NC, USA.
Mary Katherine Kelm
F1000 Pharmacology & Drug Discovery
University of North Carolina at Chapel Hill,
Chapel Hill, NC, USA.
F1000 Pharmacology & Drug Discovery
University of North Carolina at Chapel Hill,
Chapel Hill, NC, USA.
New Finding
DOI: 10.3410/f.13131956.14459054
This paper provides evidence that probiotics, which affect the bacterial microflora in the gut, can affect anxiety- and depression-like behavior and GABA receptor expression through a mechanism dependent on the vagus nerve.
One of the most interesting aspects of this paper is that these experiments were...Continue reading
One of the most interesting aspects of this paper is that these experiments were...Continue reading
This paper provides evidence that probiotics, which affect the bacterial microflora in the gut, can affect anxiety- and depression-like behavior and GABA receptor expression through a mechanism dependent on the vagus nerve.
One of the most interesting aspects of this paper is that these experiments were done in normal, healthy animals, extending the usefulness of these findings for future therapeutic interventions. As this effect appears strain-dependent, future work should include testing additional probiotics, including those that are already commercially available.
One of the most interesting aspects of this paper is that these experiments were done in normal, healthy animals, extending the usefulness of these findings for future therapeutic interventions. As this effect appears strain-dependent, future work should include testing additional probiotics, including those that are already commercially available.
Disclosures
None declared
Add Comment
Breese G and Kelm M: F1000Prime Recommendation of [Bravo JA et al., Proc Natl Acad Sci U S A 2011, 108(38):16050-5]. In F1000Prime, 08 Sep 2011; DOI: 10.3410/f.13131956.14459054. F1000Prime.com/13131956#eval14459054
16 Sep 2011
New Finding
DOI: 10.3410/f.13131956.14628067
The message conveyed by this paper sounds revolutionary because it presents direct experimental evidence that long-term treatment of mice with the probiotic Lactobacillus rhamnosus has a significant impact on brain neurochemistry and behaviour.
Probiotics such as L. rhamnosus are living bacteria...Continue reading
Probiotics such as L. rhamnosus are living bacteria...Continue reading
The message conveyed by this paper sounds revolutionary because it presents direct experimental evidence that long-term treatment of mice with the probiotic Lactobacillus rhamnosus has a significant impact on brain neurochemistry and behaviour.
Probiotics such as L. rhamnosus are living bacteria that can inhabit the gut and modify the intestinal microbiome in such a way that the health of the host is promoted. As the current paper shows, the beneficial effects of probiotics are not restricted to the gut but can extend to the brain. Thus, stress-induced activation of the hypothalamus-pituitary-adrenal (HPA) axis and stress-induced enhancement of anxiety- and depression-related behaviour are counteracted by L. rhamnosus treatment. An intriguing neurobiological aspect of this action is the involvement of the vagus nerve and region-dependent alterations in gamma-aminobutyric acid (GABA) receptor expression.
The current paper adds significantly to the emerging view that the intestinal microbiome is an important factor in regulating brain set points of well-being. Importantly, the data show that strengthening of microbiota homeostasis in the gut by a probiotic bacterium has a positive impact on behaviour and its neurobiological basis. This contention is consistent with a number of recent observations that attest to the relevance of the gut microbiota-brain axis. For instance, antibiotic-induced dysbiosis in the intestinal microbiome has an adverse impact on brain neurochemistry and behaviour {1}, which is a corollary to the present observations. It has, in addition, been found that the presence of commensal gut microbiota during a critical window of time is required for normal brain development and synaptogenesis {2}. Memory is impaired in germ-free mice, and exposure to stress combined with Citrobacter rodentium infection causes prolonged memory dysfunction, an effect that can likewise be prevented by probiotics {3}.
One question that all these observations are posing relates to the pathways whereby the intestinal microbiota signals to the brain. Several possibilities come to mind: constituents of the microbiota themselves {4}, circulating cytokines, gut hormones and sensory neurons. The current paper by Bravo et al. provides an important answer to this enigma. It is the vagus nerve that serves as an important link between the microbiota and the brain. How vagal nerve fibres, 90% of which are sensory and afferent in nature, are activated by microbiota is one of the next questions to be tackled. As I have pointed out in a review {5}, the afferent vagus nerve is a component of the gut-brain axis that subserves functions that have not yet been thought of.
Another question relates to the neurobiological effects in the brain whereby intestinal microbiota alters behaviour. Antibiotic-induced dysbiosis of the intestinal microbiome has been found to alter cerebral levels of brain-derived neurotrophic factor {1}. The present paper focuses on the HPA axis and on GABA, one of the universal inhibitory transmitters in the brain. Bravo et al. found region-dependent alterations in the expression of GABAA and GABAB receptors and hypothesize that these alterations may be relevant to the changes in anxiety-related behaviour evoked by probiotic treatment.
The current study is important in that it shows that prolonged (28 days) treatment of healthy, normal mice with a probiotic has a substantial impact on emotional-affective behaviour and stress coping. As such, it provides an experimental model to identify the mediators, receptors and signalling mechanisms that underlie the beneficial effect of probiotics on brain function. It also provides a translational model to examine how quickly the beneficial effect of probiotics may set in and how long it lasts once probiotic treatment has been stopped. The authors rightly point out that, on the basis of their observations, microbial-based strategies may be developed for the adjunctive treatment of stress-related psychiatric disorders.
Probiotics such as L. rhamnosus are living bacteria that can inhabit the gut and modify the intestinal microbiome in such a way that the health of the host is promoted. As the current paper shows, the beneficial effects of probiotics are not restricted to the gut but can extend to the brain. Thus, stress-induced activation of the hypothalamus-pituitary-adrenal (HPA) axis and stress-induced enhancement of anxiety- and depression-related behaviour are counteracted by L. rhamnosus treatment. An intriguing neurobiological aspect of this action is the involvement of the vagus nerve and region-dependent alterations in gamma-aminobutyric acid (GABA) receptor expression.
The current paper adds significantly to the emerging view that the intestinal microbiome is an important factor in regulating brain set points of well-being. Importantly, the data show that strengthening of microbiota homeostasis in the gut by a probiotic bacterium has a positive impact on behaviour and its neurobiological basis. This contention is consistent with a number of recent observations that attest to the relevance of the gut microbiota-brain axis. For instance, antibiotic-induced dysbiosis in the intestinal microbiome has an adverse impact on brain neurochemistry and behaviour {1}, which is a corollary to the present observations. It has, in addition, been found that the presence of commensal gut microbiota during a critical window of time is required for normal brain development and synaptogenesis {2}. Memory is impaired in germ-free mice, and exposure to stress combined with Citrobacter rodentium infection causes prolonged memory dysfunction, an effect that can likewise be prevented by probiotics {3}.
One question that all these observations are posing relates to the pathways whereby the intestinal microbiota signals to the brain. Several possibilities come to mind: constituents of the microbiota themselves {4}, circulating cytokines, gut hormones and sensory neurons. The current paper by Bravo et al. provides an important answer to this enigma. It is the vagus nerve that serves as an important link between the microbiota and the brain. How vagal nerve fibres, 90% of which are sensory and afferent in nature, are activated by microbiota is one of the next questions to be tackled. As I have pointed out in a review {5}, the afferent vagus nerve is a component of the gut-brain axis that subserves functions that have not yet been thought of.
Another question relates to the neurobiological effects in the brain whereby intestinal microbiota alters behaviour. Antibiotic-induced dysbiosis of the intestinal microbiome has been found to alter cerebral levels of brain-derived neurotrophic factor {1}. The present paper focuses on the HPA axis and on GABA, one of the universal inhibitory transmitters in the brain. Bravo et al. found region-dependent alterations in the expression of GABAA and GABAB receptors and hypothesize that these alterations may be relevant to the changes in anxiety-related behaviour evoked by probiotic treatment.
The current study is important in that it shows that prolonged (28 days) treatment of healthy, normal mice with a probiotic has a substantial impact on emotional-affective behaviour and stress coping. As such, it provides an experimental model to identify the mediators, receptors and signalling mechanisms that underlie the beneficial effect of probiotics on brain function. It also provides a translational model to examine how quickly the beneficial effect of probiotics may set in and how long it lasts once probiotic treatment has been stopped. The authors rightly point out that, on the basis of their observations, microbial-based strategies may be developed for the adjunctive treatment of stress-related psychiatric disorders.
References
1.
The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.
Gastroenterology 2011 Aug; 2(141):599-609, 609.e1-3
PMID: 21683077
2.
Normal gut microbiota modulates brain development and behavior.
Proc Natl Acad Sci USA 2011 Feb 15; 7(108):3047-52
PMID: 21282636
3.
Bacterial infection causes stress-induced memory dysfunction in mice.
Gut 2011 Mar; 3(60):307-17
PMID: 20966022
4.
Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity.
Nat Med 2010 Feb; 2(16):228-31
PMID: 20081863
5.
Holzer P, "The role of the vagus nerve in afferent signaling and homeostasis during visceral inflammation." In: "Neurogenic Inflammation in Health and Disease. Neuroimmune Biology, Volume 8." Jancsó G (ed) Amsterdam: Elsevier, 2009:321-38 [ISBN:978-0444532299].
Disclosures
None declared
Holzer P: F1000Prime Recommendation of [Bravo JA et al., Proc Natl Acad Sci U S A 2011, 108(38):16050-5]. In F1000Prime, 16 Sep 2011; DOI: 10.3410/f.13131956.14628067. F1000Prime.com/13131956#eval14628067
20 Sep 2011
New Finding
DOI: 10.3410/f.13131956.14628073
This exciting paper shows that oral administration of Lactobacillus rhamnosus JB-1 alters GABA receptor expression in the brain, as well as anxiety and depression-related behaviour in healthy mice.
The paper adds to recent findings describing the importance of intestinal bacteria in the bidirectional...Continue reading
The paper adds to recent findings describing the importance of intestinal bacteria in the bidirectional...Continue reading
This exciting paper shows that oral administration of Lactobacillus rhamnosus JB-1 alters GABA receptor expression in the brain, as well as anxiety and depression-related behaviour in healthy mice.
The paper adds to recent findings describing the importance of intestinal bacteria in the bidirectional communication of the gut-brain axis and, on the other hand, adds to the already long list of physiological and immunological effects associated with this bacterium. The authors concluded that the strain JB-1 differs genetically from other L. rhamnosus isolates. Limited evidence so far indicates that not all Lactobacilli affect the enteric nervous system, and it will be highly interesting and rewarding to confirm the strain dependency and to identify the bacterial factors that are involved.
The paper adds to recent findings describing the importance of intestinal bacteria in the bidirectional communication of the gut-brain axis and, on the other hand, adds to the already long list of physiological and immunological effects associated with this bacterium. The authors concluded that the strain JB-1 differs genetically from other L. rhamnosus isolates. Limited evidence so far indicates that not all Lactobacilli affect the enteric nervous system, and it will be highly interesting and rewarding to confirm the strain dependency and to identify the bacterial factors that are involved.
Acknowledgments
This paper was brought to my attention by Klaus Tähkä.
Disclosures
None declared
Korhonen T: F1000Prime Recommendation of [Bravo JA et al., Proc Natl Acad Sci U S A 2011, 108(38):16050-5]. In F1000Prime, 20 Sep 2011; DOI: 10.3410/f.13131956.14628073. F1000Prime.com/13131956#eval14628073
30 Nov 2011
Eamonn Quigley
F1000 Pharmacology & Drug Discovery
The Methodist Hospital, Weill Cornell Medical College,
Houston, TX, USA.
F1000 Pharmacology & Drug Discovery
The Methodist Hospital, Weill Cornell Medical College,
Houston, TX, USA.
New Finding
DOI: 10.3410/f.13131956.14748066
This paper demonstrates the ability of an orally administered commensal bacterium, Lactobacillus rhamnosus, to modulate emotional behaviour and produce alterations in central GABA expression. The impact of the bacterium on behaviour and GABA expression was lost following vagotomy suggesting that these...Continue reading
This paper demonstrates the ability of an orally administered commensal bacterium, Lactobacillus rhamnosus, to modulate emotional behaviour and produce alterations in central GABA expression. The impact of the bacterium on behaviour and GABA expression was lost following vagotomy suggesting that these effects are vagally mediated.
While the concept of the brain-gut-axis has been widely employed to provide a framework to advance our understanding of what are referred to as 'functional gastrointestinal disorders', such as irritable bowel syndrome (IBS) and functional dyspepsia, the extension of this construct to include the gut microbiota, the microbiota-gut-brain axis, has been much more recent {1}. The basis for the latter is derived from disparate experimental findings as well as clinical observations such as the occurrence of post-infectious IBS, the description of alterations in the microbiota in IBS as well as reports of therapeutic benefits from interventions that modulate the microbiota (antibiotics, prebiotics and probiotics {2}). This study, from Bravo and colleagues, takes these ideas one step further by not only demonstrating the behavioural and neurochemical impact of the administration of a single commensal organism, L. rhamnosus, but also, and this is what is most novel about this paper, suggesting that the vagus represents a major conduit of this particular microbiota-gut-brain conversation. While the central role of the vagus in visceral sensation is well known and its anti-inflammatory effects well documented {3}, the description of the vagus as the vehicle for communication between the microbiota provides a vital link in completing the microbiota-gut-brain axis. It is important to note that others have demonstrated that a more global modification of the microbiota, by oral antibiotics, impacts on animal behaviour and brain expression of a neurotrophic factor but through a vagally-independent mechanism {4}. The concept of the microbiota-gut-brain axis is further supported by observations on behaviour and brain neurochemistry in the germ-free animal effects that are reversed by the administration of a normal microbiota {5}. The microbiota-gut-brain axis appears to be a reality and now joins microbiota influences on systemic immune and metabolic function as yet another manifestation of the impact of the 'forgotten organ' on homeostasis. These findings also provide a potentially new therapeutic target in these challenging disorders.
While the concept of the brain-gut-axis has been widely employed to provide a framework to advance our understanding of what are referred to as 'functional gastrointestinal disorders', such as irritable bowel syndrome (IBS) and functional dyspepsia, the extension of this construct to include the gut microbiota, the microbiota-gut-brain axis, has been much more recent {1}. The basis for the latter is derived from disparate experimental findings as well as clinical observations such as the occurrence of post-infectious IBS, the description of alterations in the microbiota in IBS as well as reports of therapeutic benefits from interventions that modulate the microbiota (antibiotics, prebiotics and probiotics {2}). This study, from Bravo and colleagues, takes these ideas one step further by not only demonstrating the behavioural and neurochemical impact of the administration of a single commensal organism, L. rhamnosus, but also, and this is what is most novel about this paper, suggesting that the vagus represents a major conduit of this particular microbiota-gut-brain conversation. While the central role of the vagus in visceral sensation is well known and its anti-inflammatory effects well documented {3}, the description of the vagus as the vehicle for communication between the microbiota provides a vital link in completing the microbiota-gut-brain axis. It is important to note that others have demonstrated that a more global modification of the microbiota, by oral antibiotics, impacts on animal behaviour and brain expression of a neurotrophic factor but through a vagally-independent mechanism {4}. The concept of the microbiota-gut-brain axis is further supported by observations on behaviour and brain neurochemistry in the germ-free animal effects that are reversed by the administration of a normal microbiota {5}. The microbiota-gut-brain axis appears to be a reality and now joins microbiota influences on systemic immune and metabolic function as yet another manifestation of the impact of the 'forgotten organ' on homeostasis. These findings also provide a potentially new therapeutic target in these challenging disorders.
References
1.
The microbiome-gut-brain axis: from bowel to behavior.
Neurogastroenterol Motil 2011 Mar; 3(23):187-92
PMID: 21303428
2.
Gut microbiota and the role of probiotics in therapy.
Curr Opin Pharmacol 2011 Dec; 6(11):593-603
PMID: 21996283
3.
Physiology and immunology of the cholinergic antiinflammatory pathway.
J Clin Invest 2007 Feb; 2(117):289-96
PMID: 17273548
4.
Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.
Gastroenterology 2010 Dec; 6(139):2102-2112.e1
PMID: 20600016
5.
Normal gut microbiota modulates brain development and behavior.
Proc Natl Acad Sci USA 2011 Feb 15; 7(108):3047-52
PMID: 21282636
Disclosures
Eamonn Quigley is a co-principal investigator with some of the authors of this paper on other projects, but had no involvement in this particular project.
Quigley E: F1000Prime Recommendation of [Bravo JA et al., Proc Natl Acad Sci U S A 2011, 108(38):16050-5]. In F1000Prime, 30 Nov 2011; DOI: 10.3410/f.13131956.14748066. F1000Prime.com/13131956#eval14748066
F1000Prime Recommendations, Dissents and Comments for [Bravo JA et al., Proc Natl Acad Sci U S A 2011, 108(38):16050-5]. In F1000Prime, 19 May 2013; F1000Prime.com/13131956
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There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(Aα2) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(Aα2) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.
PMID: 21876150
