Have you ever felt so worried that you can’t eat a thing? Or stress-binged an entire packet of biscuits while revising for an exam? If you have experienced an emotionally-driven digestion dilemma, it will come as no shock to you that your brain and your gut are engaged in a dialogue. In fact, your gut actually has an entire nervous system dedicated to it’s functioning, as well as central nerves which permit signals from your brain to reach the pit of your stomach. Although we know these systems communicate, interests lie in how much they influence each other. In this realm lies the emerging link between the composition of the microorganisms in the gut and neuropsychiatric disorders, namely anxiety and depression. Recent population studies of both conditions in humans indicate a difference, and therefore potential therapeutic target, in the gut microbiome - bringing a whole new meaning to your 'gut feeling'.
Gut feelings: Normal chat between your brain and belly
You may have felt that lurch in your stomach after realising you accidentally clicked ‘Reply All' with a cat meme on a full staff email. The anxiety-associated sinking feeling is produced from brain signalling to your gut. Although the gut has its only independent nervous system (the Enteric nervous system), the brain also connects to the digestive system through several pathways of neuron projections; with each pathway having individual origins in the brain and different chemical-mediated actions. Two of these pathways include the autonomic nervous system (ANS) and the hypothalamic pituitary axis (HPA). The ANS is responsible for those ‘automatic’ functions we don't even have to think about doing, such as breathing, heartbeat and controlling all that digestive movement you get after eating a bangin' meal. The HPA is responsible for regulating the levels of ‘stress’ hormones in your system, spiking following a tense sitch. The origins of these pathways in the brain are from the hormone centre (the hypothalamus) and the fear area (the amygdala), who both receive their directions from ‘high-thinking’ emotional brain regions such as the pre-frontal cortex. So although the gut mainly acts in an automatic manner, stress and emotions readily can impact the motion of the mucosa.
But what about you stomach talking to your brain? Your gut is able to reply to your brains actions and also signal *BRAND NEW INFORMATION*. One of these communication lines is sensory neuron afferents (*dendrites*) in the gut. Signalling to the brain via neuron projections can be stimulated by normal and abnormal gut movements (mechanical stimulation), the immune system and chemical changes within the digestive system; sending signals to the brain stem and spinal cord. This information is then relayed to various brain regions, for example, to the hypothalamus, which reports to higher cortical regions on the current state of the digestive system. Gut-mediated signalling is also received at behavioural and emotional centres such as the amygdala, the anterior cingulate cortex (thought to be responsible for complex cognitive processes like empathy & impulse control) and the orbitofrontal cortex (an area associated with decision making), as well as reward centres which can release dopamine in response to eating; generating a positive-association with this behaviour. Together, gut signalling can influence your state of mind and behaviour, not just how you digest your dinner.
Digestion-driven depression? Studies of the depression, anxiety and the gut microbiome
One major area of human biology research in recent years has been focused on the composition of the gut microbiome; thousands of different microorganisms responsible for protecting your health and fighting disease laying low in your stomach. Every individual has a distinct gut microbiome influenced by their genetics and environmental factors, and the composition of this microbiome can be altered by factors such as stress, diet and infections. However, alterations to the levels of certain species could potentially have a much great impact on human mental health than anticipated. It is thought gut microorganisms can influence signalling of neural afferents in the gut via the release of vitamins, neurotransmitters and metabolites, and specific bacterial species within the gut can impact the activity of specific brain regions and circuits. Mice bred to have no ‘germs’ in the gut display learning defects and reduced anxiety-like behaviour, highlighting the impact the gut microbiome can have on higher cognitive behaviours. Mouse models with symptoms mimicking depression and anxiety can have these symptoms lessened by treatment with specific gut bacterium (Lactobacillus Rhamnosus) and germ-free mice can have depressive symptoms induced when fed microbiome samples from human patients with depression. These studies along with a body of others promote the idea depression and anxiety in mammals can be impacted by the microorganisms in the gut.
So what about in humans with mental health conditions such as depression and anxiety? Recent population studies of both conditions drew correlations between gut microbiome composition and the mental health disorder in question. Researchers from KU Leuven-University compared the microbiome composition of over 2000 people and could relate the presence and levels of specific bacteria species with likelihood of the individual having depression. Individuals with high levels of Faecalibacterium and Coprococcus bacteria were described as having a higher quality of life, whereas lower levels of of Dialister and Coprococcus bacteria were noted in those with depression. Similar relationships were drawn in a review of studies which attempted to treat anxiety using microbiome-altering medication. The reviewers noted that over half of the 21 large-scale human studies conducted resulted in alleviation of anxiety symptoms. They pointed out that non-probiotic (e.g. dietary changes) interventions were more affective treatments than probiotic (giving more gut bacteria) supplementation. Together, these studies draw correlations with alterations to the microbiome and changes in mental health, with potential for specific micro-organism treatment or diet alterations as therapeutics dependent on the individual and the condition from which they are suffering.
Could modulations of the gut cut mental health?
From the above research, we could think of the gut microbiome as a world filled with trillions of individuals performing several thousand different occupations. Some of these occupations may be more beneficial to the world than others, so having more of these skilled individuals could promote a more prosperous environment, whereas other occupations which are not as useful are needed at lower numbers. However, if you lose too many of the important workers and gain a few million of those who are less helpful, your upset balance could lead to huge problems with optimal output. But, a key aspect of this scenario we need to full understand is which jobs are important and why. Although specific bacterial species have been linked with depressive and anxious symptoms, it still remains unclear how these species induce such complex states in the brain and it is unlikely they do so alone. Some gut bacteria are known to influence specific brain circuits and alterations to neurological processes, such as Lactobacillus' alteration to inhibitory neuron receptors, have been noted. Potentially, the recognition of the full neurological and health impact of these species could lead to the development of non-invasive mental health treatments targeting the gut by screening the gut microbiome and altering levels of specific bacterial species with the goal of lessening debilitating mental states.
The real work now will be to classify how many thousands of gut microorganisms alter neuronal or neural network functioning. This will require in-depth biological studies of individual and combinations of microorganisms as well as confirmation of results in large scale human studies. Once we have these answers, maybe we can truly go with our guts for mental health therapeutics.
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