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. 2011 Sep 20;108(38):16050-5.
doi: 10.1073/pnas.1102999108. Epub 2011 Aug 29.

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

Javier A Bravo  1 , Paul Forsythe, Marianne V Chew, Emily Escaravage, Hélène M Savignac, Timothy G Dinan, John Bienenstock, John F Cryan
Affiliations

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

Javier A Bravo et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Effect of L. rhamnosus (JB-1) administration on behavior and stress-induced levels of corticosterone. (A) Stress-induced hyperthermia (SIH). There were no significant differences between L. rhamnosus (JB-1)-fed (n = 16) and broth-fed animals (n = 20). Elevated plus maze (EPM). Mice fed with the Lactobacillus (n = 16) entered significantly more times (***P < 0.001) into the open arms of the EPM apparatus in comparison with broth-fed mice (n = 20). (C) Forced swim test (FST). Animals fed with L. rhamnosus (JB-1) (n = 8) spent less time immobile (**P < 0.01) compared with broth-fed mice (n = 8). (B) Effect of L. rhamnosus (JB-1) on fear-related behaviors. On day 1, analysis revealed no differences in the learning curves between L. rhamnosus (JB-1)-fed mice (n = 16) and broth-fed control animals (n = 20). On day 2 (memory testing), L. rhamnosus (JB-1) treated animals displayed an enhanced memory towards cues (represented by the white boxes underneath the x axis. **P< 0.01 for cue no. 5 and *P < 0.05 for cue no. 6) and context (represented by the grey boxes underneath the x axis. *P < 0.05 for context 6). On day 3 (memory extinction), no differences were observed between the two treatment groups. (C) Effect of L. rhamnosus (JB-1) administration on stress-induced levels of corticosterone. Stress-induced corticosterone was measured in plasma 30 min after FST. Stress-induced levels of corticosterone are significantly lower in L. rhamnosus (JB-1)-fed mice compared with broth fed control animals (###P < 0.001).
Fig. 2.
Fig. 2.
Effect of L. rhamnosus (JB-1) administration on central GABAB1b mRNA expression. Mice fed with L. rhamnosus (JB-1) (n = 6) had higher levels of GABAB1b mRNA in the cingulate 1 (CG1) (A) and prelimbic (PrL) (B) cortices in comparison with broth fed control mice (n = 6). However, no differences between the two groups were observed in the infralimbic (IL) cortex (C). On the other hand, L. rhamnosus (JB-1) fed animals showed reduced levels of GABAB1b mRNA in the basolateral amygdala (BLA) (D), central amygdala (CeA) (E), locus coeruleus (LC) (F), dentate gyrus (DG) (G), cornus ammonis region 3 (CA3) (H), and cornus ammonis region 1 (CA1) (I) in comparison with broth fed mice. Values represent pixel density (*P < 0.05; **P < 0.01; ***P < 0.001).
Fig. 3.
Fig. 3.
Effect of L. rhamnosus (JB-1) administration on central GABAAα2 mRNA expression. Mice fed with L. rhamnosus (JB-1) (n = 6) had lower levels of GABAAα2 mRNA in CG1 (A) PrL (B), and IL (C) cortices. In addition, GABAAα2 mRNA was also reduced in the BLA (D) and CeA (E) of L. rhamnosus (JB-1) fed mice in comparison with broth fed animals. No differences in GABAAα2 mRNA between the two groups were observed in the LC (F). On the contrary, GABAAα2 mRNA is increased in the DG (G) of L. rhamnosus (JB-1) fed animals in comparison with broth control mice, but no differences were observed in CA3 (H) and CA1 (I). Values represent pixel density (*P < 0.05; ***P < 0.001).
Fig. 4.
Fig. 4.
Effect of vagotomy (Vx) on anxiety and depression-like behaviors and GABAA subunit expression of animals treated with L. rhamnosus (JB-1). (A) Sham/L. rhamnosus (JB-1) treated mice (n = 10) (white bars) spent more time in the central area of an open field arena in comparison with sham/broth animals (n = 10) (black bars). This behavior is reflected in the number of entries into the central area of the open field with sham/L. rhamnosus (JB-1) mice (n = 10) performing significantly more entries into this area than sham/broth treated animals. These behaviors are prevented by Vx. These differences are not due to an effect on locomotion, as the distance travelled within the open field is no different between the experimental groups. In the FST sham/L. rhamnosus (JB-1) (n = 10) mice spent less time immobile than sham/broth animals (n = 10) an effect prevented by Vx. (B) Sham/L. rhamnosus (JB-1) mice (n = 6) have significantly higher levels of GABAAα2 mRNA expression in the DG and CA3 areas in comparison with sham/broth animals (n = 6). No significant differences were observed in CA1 between the same experimental groups. Vx prevented any further effect of L. rhamnosus (JB-1) on hippocampal GABAAα2 mRNA expression in the DG CA3 and CA1. (C) Sham/L. rhamnosus (JB-1) (n = 6) mice have significantly lower levels of GABAAα1 mRNA in the DG, CA3, and CA1 in comparison with sham/broth (n = 6) animals. Vx prevented any effect of L. rhamnosus (JB-1) on hippocampal GABAAα1 mRNA expression in the DG, CA3, and CA1 areas in the two experimental groups. (*P < 0.05; ***P < 0.001).
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