Mysteries of Healthy Gut

Mysteries of healthy gut, happy mind: gut-brain connection
Do you feel butterflies in your stomach when you want to give important speech to a large audience or right before examination or when you want to meet someone truly special in your life? This “butterfly feeling” is actually the result of communication between your gut and brain!

Autonomic nervous system (ANS) is a component of the peripheral nervous system that regulates involuntary or unconscious body functions such as heart rate, blood pressure, respiration, digestion, and sexual arousal [1]. Sympathetic and parasympathetic nervous systems are the major divisions of ANS. In the event of stress or emergency, the sympathetic (“fight-or-flight”) system is activated and becomes dominant while parasympathetic (“rest-and-digest”) system is suppressed. This increases heartbeat due to the release of hormone adrenaline into the bloodstream; triggers rapid release of glucose from the liver to be burned for quick energy; and reduces blood flow to the gut while redistribute it to muscles in the arms and legs that prime you for action (fight or flee in the presence of a threat). The reduced blood flow to the gut slows down digestion and causes the stomach’s sensory nerves to produce “butterflies” feeling in the stomach, giving you a signal that it is lacking of blood and oxygen to perform its job.

Gut microbiota is a key player in gut-brain connection
More recently, gut microbiota has emerged as a key player along the gut-brain connection (or gut-brain axis) which is a complex bidirectional communication between gastrointestinal tract and brain that involves enteric nervous system (ENS), sympathetic (prevertebral ganglia) and parasympathetic (vagus nerve) divisions of the ANS, and neuroendocrine and neuroimmune components of the central nervous system (CNS) [2].

ENS, another division of the ANS is a network comprising millions of neurons and glia within the wall of the bowel that is responsible for, blood flow, motility, uptake of nutrients, secretion, and inflammatory processes in the gastrointestinal tract [3]. It is often known as the “second brain” because of its neuron and glial diversity; neurotransmitter and receptor expression in the ENS that resembles that of the central nervous system; as well as complex and integrated circuits that permit the ENS to operate independently of brain and spinal cord [4-5].

Gut microbiota can modulate the gut-brain axis by communicating with ENS and CNS via vagus nerve after immunological priming of enteric glial cells [6]. The release of their active metabolites can also modify functional status for the components of ENS (e.g. excitability of enteric neurons) followed by signal transmission to CNS through vagus nerve [7]. The microbiota can also act on the CNS through the release of metabolites that can cross the blood-brain barrier [8]. Therefore, it is not surprised that one’s gut microbiota composition is related to neurobehavioral changes.

Gut health and development of mental health
Human exposure to external stimuli such as unhealthy diet, sedentary lifestyle, high stress environment, antibiotics intake and etc. are factors that can cause imbalance in gut microbiota (gut dysbiosis). Connection between gut dysbiosis and pathogenesis of mental illnesses have been evaluated in numerous studies. An altered fecal microbiota composition was found in patients with depression, where Enterobacteriaceae and Alistipes were over-represented while the level of Faecalibacterium was reduced [9]. Kelly et al. (2016) also suggested that alterations in the gut microbiota could play a causal role in the development of depression [10]. In the study, patients with depression showed reduced gut microbiota richness and diversity [10]. After microbiota-depleted rats were transplanted with fecal microbiota from depressed patients, they exhibited depressive phenotype, such as anhedonia and anxiety-like behaviours [10].

Hypothalamic-pituitary-adrenal (HPA) axis and mental health
The hypothalamic-pituitary-adrenal (HPA) axis is the main physiological system that mediates the body's stress response. Its hyperactivity or dysregulation is one of the most consistent biological findings in anxiety and depression [11].

Gut dysbiosis results in increased intestinal permeability, leading to the release of various mediators, such as pro-inflammatory cytokines, prostaglandins and microbial antigens that can pass through the blood-brain barrier and activate the HPA axis [12]. Prolonged activation of HPA axis can cause its dysfunction followed by hormonal dysregulation, which is a hallmark of several psychiatric conditions [13] as one becomes less resilient to stress.

Activation of vagal sensory neurons and mental health
Campylobacter jejuni and Citrobacter rodentium are both Gram-negative bacteria where the former is frequently isolated in poultry while the latter is a mouse pathogen [14-15]. Both bacteria can cause gastrointestinal conditions in human, such as colitis for C. rodentium, enteritis for C. jejuni and diarrhea for both [14-15].

Early infection with C. rodentium in mice model (by oral challenge) was found to induce anxiety-like symptoms that are likely mediated via vagal sensory neurons, as determined by significant increase in c-Fos immunoreactivity in the vagal sensory neurons of C. rodentium-treated mice, without increasing cytokines in the circulation [16]. Lyte et al. (1998) also reported that gastrointestinal infection with C. jejuni caused development of anxiety-like behavior in mice in the absence of systemic immune activation [17]. Goehler et al., (2005) later on found that oral inoculation with C. jejuni led to a significant increase in c-Fos expression in neurons bilaterally in the vagal ganglia, in the absence of elevated levels of circulating pro-inflammatory cytokines [18]. These studies indicated that early infection with some of the pathogenic bacteria such as C. rodentium and C. jejuni may directly induce anxiety-like symptoms through vagus nerve without systemic immune activation.

Psychobiotics modulate gut-brain axis and promote mental health
Psychobiotic is a new term to define probiotics that, when ingested in adequate amounts, produces a health benefit in patients with psychiatric illness [19]. Misra and Mohanty summarized some of the probiotics with psychotropic properties: Lactobacillus spp (L. acidophilus, L. casei, L. rhamnosus, L. helveticus, L. plantarum and etc.), Bifidobacterium spp (B. infantis, B. longum, B. bifidum, B. lactis and B. breve) and other species [20]. These beneficial bacteria can promote good mental health through the production of short-chain fatty acids (SCFAs) or neurotransmitters (such as GABA, serotonin, catecholamines and/or acetylcholine) [20]. Neurotransmitters are chemical substances that can influence neural signaling of gut-brain axis. Psychobiotics are also capable to stimulate the release of anti-inflammatory cytokines and curb the level of stress hormone (cortisol) [20].

Short-chain fatty acids (SCFAs): psychotropic microbial metabolites
Short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate interact with receptors on enteroendocrine cells and promotes indirect signaling to the brain via systemic circulation or vagal nerve through the secretion of neurotransmitters by gut such as γ-aminobutyric acid (GABA), and serotonin (5-HT) [21]. GABA and serotonin are the major inhibitory neurotransmitter in the brain that controls stress and decreased GABAergic or serotonergic activities has been implicated in anxiety and major depression [22-23].

In addition, SCFAs produced by probiotics can also regulate permeability of blood-brain barrier (BBB) that dictates the passage of circulating pro-inflammatory cytokines into the brain. According to Braniste et al. (2014), mice lacking of gut microbiota is associated with increased BBB permeability and reduced expression of tight junction proteins occludin and claudin-5 [24]. Treatment of germ-free mice with bacteria that produce SCFA decreased the permeability of the BBB [24]. Greene et al. (2020) also reported that BBB associated tight junction disruption and dysregulation is a common pathology observed across the major psychiatric disorders [25]. This is because expression of claudin-5 was found to be reduced in the hippocampus of individuals (human donor brain tissues) diagnosed with major depression or schizophrenia [25].

SCFA butyrate was also found to enhance gut barrier integrity in which its disruption can result in increased passage of pro-inflammatory stimuli and microbial antigens or toxins into the bloodstream and the brain, leading to mood-altering neuroinflammation [12, 26].

Furthermore, SCFAs such as butyrate can potentially reduce systemic inflammatory responses by modulating immune cell activity. This microbial metabolite butyrate can down-regulate inflammation by inhibiting the growth of pathobionts which are organisms associated with chronic inflammatory conditions [27-28]. It can also inhibit pro-inflammatory immune cells such as M1 macrophages and neutrophils whilst activating anti-inflammatory cells such as Regulatory T cells (Tregs) and M2 macrophages [27].

Conclusion
There are more and more studies to connect gut microbiota composition to mental health issues. Such connection is mediated by a gut-brain connection system (or gut-brain axis) in our body, which is a complex bidirectional communication system between gastrointestinal tract and brain. During the communication, our immune, hormonal and enteric nervous systems as well as vagus nerves are also taking part, giving us responses according to the conditions of the gut and brain. In a nutshell, emotional changes can affect your gut function and on the other way round, gut health can also affect your emotions.

It is also true that “you are what you eat” as an unhealthy gut (with gut dysbiosis and inflammation) can have great impacts on your mood and overall mental health because of gut-brain connection system. Having balanced diet and adhering to healthy lifestyle are the best strategies to manage mental well-being. However, it may be sometimes challenging for working adults to follow the healthy schedule everyday due to busy working schedule and hectic lifestyle. As such, you can also protect your gut microbiome and promote healthy gut-brain connection by taking probiotics.

References
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