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

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 stressrelated disorders such as anxiety and depression.brain-gut axis | irritable bowel syndrome | probiotic | fear conditioning | cognition T here is increasing evidence suggesting an interaction between the intestinal microbiota, the gut, and the central nervous system (CNS) in what is recognized as the microbiome-gut-brain axis (1-4). Studies in rodents have implicated dysregulation of this axis in functional bowel disorders, including irritable bowel syndrome. Indeed, visceral perception in rodents can be affected by alterations in gut microbiota (5). Moreover, it has been shown that the absence and/or modification of the gut microflora in mice affects the hypothalamic-pituitary-adrenal (HPA) axis response to stress (6, 7) and anxiety behavior (8, 9), which is important given the high comorbidity between functional gastrointestinal disorders and stress-related psychiatric disorders, such as anxiety and depression (10). In addition, pathogenic bacteria in rodents can induce anxiety-like behaviors, which are mediated via vagal afferents (9, 11).GABA is the main inhibitory neurotransmitter of the CNS, the effects of which are mediated through two major classes of receptors-the ionotropic GABA A receptors, which exist as a number of subtypes formed by the coassembly of different subunits (α, β, and γ subunits; ref. 12), and the GABA B receptors, which are G protein coupled and consist of a heterodi...

Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling

“…[61] Confirming this pathway, the behavioral and neural www.advancedsciencenews.com www.bioessays-journal.com actions of certain probiotic strains are abolished if the vagus nerve is severed (a procedure known as a vagotomy). [4,62] From the NTS, there are both direct and indirect noradrenergic projections to the amygdala (see Figure 3). [61] Thus, visceral information collected by the vagus nerve may ultimately influence amygdala activity.…”

Probiotics drive gut microbiome triggering emotional brain signatures

“…1 , 2 The ‘gut-brain axis‘ had already been studied before this field of research gained new momentum a decade ago with the characterization of the gut microbiome. 3 Although the underlying molecular mechanisms remain elusive, the gut microbiota has been shown to modulate behavior and brain processes, including pain perception, 2 stress responsiveness, 4 prefrontal myelination, 5 and brain biochemistry.…”

“…3 Although the underlying molecular mechanisms remain elusive, the gut microbiota has been shown to modulate behavior and brain processes, including pain perception, 2 stress responsiveness, 4 prefrontal myelination, 5 and brain biochemistry. 1 Experimental manipulation of the gut microbial community composition was shown to be able to modify the host's neural function. For example, chronic ingestion of a probiotic Lactobacillus strain by BALB/c mice altered gamma amino butyric acid (GABA) expression in brain regions associated with emotional processing, and this was accompanied by reduced anxiety and depression-like behavior.…”

“…For example, chronic ingestion of a probiotic Lactobacillus strain by BALB/c mice altered gamma amino butyric acid (GABA) expression in brain regions associated with emotional processing, and this was accompanied by reduced anxiety and depression-like behavior. 1 The gut microbiota was found to influence the process of myelination in frontal brain regions, suggesting a role of gut microbiota in higher-order cognitive functions, in addition to emotional processing. 5 …”

Designing synbiotics for improved human health

“…Some Lactobacillus species, in particular, are thought to deplete systemic pro‐inflammatory Th17 immune cells through the production of tryptophan metabolites, which activate the aryl hydrocarbon receptor (AHR; Zelante et al ., 2013). Many of their other downstream effects on host health have yet to be elucidated, but there are indications that certain Lactobacillus species may affect brain (Bravo et al ., 2011), reproductive (Linhares et al ., 2011) and epithelial barrier function (Levkovich et al ., 2013). Ongoing research on the diverse and understudied members of the human gut microbiota likely will propel pharmaceutical investment in clinically relevant probiotics and synbiotics.…”