The gut microbiota, HPA axis, and brain in adolescent-onset depression: Probiotics as a novel treatment

Abstract

Stress-associated disruptions in the development of frontolimbic regions may play a critical role in the emergence of adolescent-onset depression. These regions are particularly sensitive to Hypothalamic-Pituitary-Adrenal (HPA) axis signaling. The HPA axis is hyperactive in adolescent depression, and interventions that attenuate such hyperactivity hold promise as potential treatments. The Microbiome-Gut-Brain (MGB) axis is an important pathway through which stress dysregulates HPA-axis activity and thus exerts deleterious effects on the adolescent brain. Probiotic agents, which alter the gut microbiota composition by introducing bacterial strains with beneficial physiological effects, normalize aberrant HPA-axis activity and reduce depressive symptoms in both animal studies and adult clinical trials. While the potential utility of such agents in treating or preventing adolescent depression remains largely unexplored, recent data suggest the existence of an adolescent sensitive window during which probiotics may be especially efficacious in reducing depressive symptoms compared to effects observed in adult populations. In this review, we outline evidence that probiotic use may attenuate stress effects on frontolimbic development, providing a novel means of improving depressive symptoms among adolescent populations.

Keywords: Adolescent; Depression; HPA axis; MGB axis; Microbiota; Neurodevelopment; Probiotics; Stress.

Fig. 1

Effects of stress on Microbiota-Gut-Brain (MGB) axis, and the resulting impact of these effects on adolescent frontolimbic development. Red arrows indicate processes leading to physiological dysfunction. Red boxes indicate disturbance in normative processes. Red (+) indicate direct causes of HPA-axis hyperactivation. - Anatomical image adapted from Society for Neuroscience (2017) interactive brain model tool. - Abbreviations: PVN (Paraventricular nucleus of the hypothalamus); SCFA (Short-chain fatty acid); ACC (Anterior cingulate cortex); PFC (Prefrontal cortex); OFC (Orbitofrontal cortex); VS (Ventral striatum); TPJ (Temporoparietal junction); AI (Anterior insula). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

1. 1)

   HPA-axis activation by stress exposure leads to production of stress hormones (glucocorticoids, catecholamines), which: increase intestinal barrier permeability (“leaky gut”)(Zheng et al., 2013; Ait-Belgnaoui et al., 2012) and disturb the gut microbiota composition(Bailey et al., 2011; Jang et al., 2018; Galley et al., 2014; Gareau et al., 2007; Moussaoui et al., 2017; Marin et al., 2017; Bharwani et al., 2016).

2. 2)

   The disturbed microbiota composition:

   1. a)

      Increases local inflammatory signaling (e.g, bacterial production of inflammatory cytokines including IL-1, IL-6, and TNF-α, in addition to release of lipopolysaccharide [LPS] and peptidoglycan from bacterial cell walls)(Bailey et al., 2011; Jang et al., 2018);

   2. b)

      Produces fewer of the bioactive substances (SCFAs; e.g., butyrate, propionate)(Moussaoui et al., 2017; Bharwani et al., 2016) and neurotransmitters (e.g., serotonin, dopamine, norepinephrine)(Bharwani et al., 2016) necessary for functional gut-brain signaling (disrupting processes such as PFC synaptogenesis and myelination(Lynch et al., 2021), as well as hippocampal neurogenesis(Jang et al., 2018; Ait-Belgnaoui et al., 2014; Murray et al., 2020; Sudo et al., 2004; Liao et al., 2019; Wei et al., 2019; Liu et al., 2016));

   3. c)

      Interacts with initial stress hormone-driven effects to further increase intestinal barrier permeability, via multiple pathways including microbiota-induced epigenetic programming of the intestinal epithelium(Ansari et al., 2020).

3. 3)

   Disruptions in gut microbiota structure and function, and increased intestinal barrier permeability, interact synergistically to potentiate the down-stream effects of stress exposure on HPA-axis through multiple pathways:

   1. a)

      Inflammatory cytokines (IL-1, IL-6, and TNF-α) and microbial antigens (lipopolysaccharide [LPS]) enter the systemic circulation through the impaired intestinal barrier and penetrate the blood-brain-barrier, leading to subclinical neuroinflammation(Ait-Belgnaoui et al., 2012, 2014) which:

      1. i)

         directly enhance HPA-axis excitability (e.g., increased increased neuronal activity and synaptogenesis in the paraventricular nucleus (PVN)(Ait-Belgnaoui et al., 2014)), and

      2. ii)

         indirectly activate the HPA axis, by impairing function(Jang et al., 2018) of neural regions critical to HPA axis negative feedback mechanisms (such as the PFC and hippocampus)(Cruz-Pereira et al., 2020).

   2. b)

      Independent of penetration through the intestinal barrier, stress-associated gut microbiota changes can activate the HPA axis through direct effects on gastrointestinal vagal afferents (e.g., modulation of enteric neuron excitability via effects on ion channels(Kunze et al., 2009; Bercik et al., 2011)), which terminate in the nucleus tracTus solitarius (NTS) – and project to regions including the amygdala, hippocampus, ventral tegmental area, and paraventricular nucleus (PVN) of the hypothalamus(Fülling et al., 2019).

4. 4)

   Chronic HPA-axis activation leads to excessive glucocorticoid signaling, which influences dendritic and synaptic remodeling, myelination, and neurogenesis in regions expressing Glucocorticoid Receptors (GRs)(McEwen et al., 2015; Hall et al., 2015; Liston and Gan, 2011) – including the amygdala, hippocampus, and PFC(Raymond et al., 2018).

5. 5)

   Prolonged disruption of these neural processes (box i) during adolescence(van der Kooij et al., 2016; Rowson et al., 2019; Urban and Valentino, 2017; Urban et al., 2019; Makinodan et al., 2012) may lead to impaired development of neurocircuitry underlying long-term emotional regulatory and reward processes (box ii), increasing depression risk(Davey et al., 2008; Shaw et al., 2020; Ho and King, 2021; Vanes et al., 2020; Kircanski et al., 2019).

Fig. 2

Hypothesized model of the effects of probiotics on stress-associated Microbiota-Gut-Brain (MGB) axis dysfunction which, in turn, impact adolescent frontolimbic development and associated behaviors (e.g., depressive symptoms). Green arrows indicate normal physiological processes. Green boxes indicate normative function. Green (−) indicate attenuation of HPA-axis hyperactivity. - Anatomical image adapted from Society for Neuroscience (2017) interactive brain model tool. - Abbreviations: PVN (Paraventricular nucleus of the hypothalamus); SCFA (Short-chain fatty acid); ACC (Anterior cingulate cortex); PFC (Prefrontal cortex); OFC (Orbitofrontal cortex); VS (Ventral striatum); TPJ (Temporoparietal junction); AI (Anterior insula). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

1. 1)

   HPA-axis activation by stress exposure leads to production of stress hormones (glucocorticoids, catecholamines), which: increase intestinal barrier permeability (“leaky gut”)(Zheng et al., 2013; Ait-Belgnaoui et al., 2012) and disturb the gut microbiota composition(Bailey et al., 2011; Jang et al., 2018; Galley et al., 2014; Gareau et al., 2007; Moussaoui et al., 2017; Marin et al., 2017; Bharwani et al., 2016).

2. 2)

   Probiotic use populates the gut microbiota with beneficial bacterial strains, a process which:

   1. a)

      Reduces local and systemic release of inflammatory cytokines and microbial antigens(Jang et al., 2018; Murray et al., 2019; Liu et al., 2016);

   2. b)

      Normalizes synthesis of bioactive substances (e.g. SCFAs, neurotransmitters)(Erny et al., 2015; Keogh et al., 2021; Yadav et al., 2013; Srivastav et al., 2019) necessary for functional gut-brain signaling (facilitating processes such as PFC myelination, via restoration of microglia homeostasis(Erny et al., 2015), oligodendrocyte maturation(Hoban et al., 2016; Keogh et al., 2021));

   3. c)

      Restores the production of intestinal epithelial cell tight junction proteins, improving intestinal barrier function(Gareau et al., 2007; Fukui et al., 2018; Ait-Belgnaoui et al., 2012; Vanhaecke et al., 2017).

3. 3)

   Probiotics may attenuate HPA-axis hyperactivity through multiple pathways:

   1. a)

      Restoring intestinal barrier function(Gareau et al., 2007; Vanhaecke et al., 2017), thus preventing the entrance of inflammatory cytokines and microbial antigens into the systemic circulation, and reducing downstream subclinical neuroinflammation(Ait-Belgnaoui et al., 2012, 2014);

   2. b)

      Transmitting vagal afferent signals associated with the normalized microbiota, leading to normalized Paraventricular Nucleus (PVN) signaling and HPA-axis activity(Bercik et al., 2011; Bravo et al., 2011).

4. 4)

   Prevention of chronic HPA-axis activation prevents excessive glucocorticoid signaling(Ait-Belgnaoui et al., 2012, 2014; Liao et al., 2019; Wei et al., 2019; Liu et al., 2016), which normalizes dendritic and synaptic remodeling, myelination, and neurogenesis in regions expressing Glucocorticoid Receptors (GRs)(McEwen et al., 2015; Hall et al., 2015; Liston and Gan, 2011) – including the amygdala, hippocampus, and PFC(Raymond et al., 2018).

5. 5)

   Normalization of these neural processes (box i) during adolescence may lead to more appropriate development of neurocircuitry underlying long-term emotional regulatory and reward processes (box ii)(Davey et al., 2008; Shaw et al., 2020; Ho and King, 2021; Vanes et al., 2020; Kircanski et al., 2019), potentially reducing(Liao et al., 2019; Wei et al., 2019; Liu et al., 2016) or preventing(Kato-Kataoka et al., 2016a, 2016b; Takada et al., 2016; Nishida et al., 2017; Sawada et al., 2017) depressive symptoms.