Dr Thanh-Tam Pham - 10/07/2021

For the entire twentieth century, scientists could not see our gut microbes as the great majority of them could not be grown in the laboratory. Until the advent of automated gene sequencing techniques, we can identify classes of microbes and metabolites they produce.

The vast majority of microbes are not only harmless but are beneficial for our health and wellbeing. They obtain nutrients from their hosts and in exchange they help to keep the gut in balance and defend against intruders. But there is a small number of potentially harmful microbes as well. The symbiosis between the microbes and their hosts ensure optimal living conditions for themselves but also to stay in harmony with our gut environment. In exchange, the microbes provide us with essential vitamins, detoxify foreign chemicals and digest dietary fibres that our digestive system can’t break down or absorb and thus provide us with a substantial number of calories.

The gut has its own nervous system known as the enteric nervous system ENS or sometimes referred as the “second brain”. This contains as many nerve cells as are contained in the spinal cord.

There are more immune cells living in the wall of the gut than circulating in the blood or in the bone marrow. The gut- based immune defence system ensures that we can live with the gut microbiota in perfect harmony.

The lining of the gut is studded with a huge number of endocrine cells that can release up to 20 different types of hormones in the blood stream. The number of these endocrine cells if clumped together is greater than all the endocrine organs- gonads, thyroid, pituitary gland and adrenal glands- combined.

The gut is also the largest storage facility for serotonin in the body. Serotonin is a signaling molecule that plays a crucial role within the gut-brain axis.

The gut and the brain are closely linked through signaling pathways that include nerves, hormones and inflammatory molecules. Sensation information generated in the gut reaches the brain (gut sensations) and the brain send signals back to the gut to adjust its function (gut reactions).

There is a two way communication between the gut and the brain such as the immune system in the gut microbial signaling to the brain. There are specialized immune cells known as dendritic cells located just under the inner lining of the gut. Dendritic cells have “tentacles” extending into the gut’s interior where they can communicate directly with the gut microbes that live near the gut wall. When harmful bacteria are detected, they trigger an innate immune response to keep the bacteria in check. People eating a high animal fat diet have a relative increase in gram negative bacteria that are able to increase the leakiness of the gut to produce a chronic immune activation system. That is when inflammation, stress or excessive dietary fat has compromised the natural barriers that keep us separated from the trillions of microbes in our gut lumen. When the gut’s immune system detects microbes, it produce cytokines that can cause inflammation of the gut like in inflammatory bowel disease or in acute gastroenteritis. Once cytokines are generated in the gut, these signals can also be sent to the brain by binding to receptors on sensory nerve terminals of the vagus nerve. Cytokines may spill in the blood, cross the blood brain barrier and activate immune cells called microglial cells inside the brain. This signalling from the gut to the brain has been implicated in the development of neurodegenerative diseases such as Alzheimer’s.

Microbes are highly diverse and numerous and can digest substances that we cannot, thereby producing several hundred thousand metabolites that can go to the blood stream and can travel to many organs including the brain.

Some microbial metabolites can stimulate enterochromaffin cells in the gut wall to produce serotonin that can signal the brain via the vagus nerve. They can also alter sleep, pain sensitivity, overall wellbeing, anxiety and social behaviours.

In 2011, some researchers in Canada reported that gut microbes produce neurotransmitters that could change emotional behaviour in animal experiments.

Most patients with anxiety disorders, depression, IBS are particularly sensitive to stressful events, often experiencing a flare up of GI symptoms when they are under stress. The stress hormone norepinephrine can profoundly alter gut microbial behaviour, making them more aggressive and dangerous.

Positive emotions trigger the increase of endorphins, oxytocins, dopamine by the brain. Signals associated with happiness may improve gut microbial diversity, improve gut health and protect us from gut infections and other diseases.

Out gut microbiota allow us to generate personalised patterns of emotions primarily through the metabolites it produces. There are some 8 million microbial genes in the gut- 400 times more than the human genome. Humans differ very little from each other genetically, sharing more than 90 percent of our genes, but the assortment of microbial genes in our gut differs dramatically and only 5 percent of them are shared between any 2 individuals. The gut microbiome adds a new dimension of complexity and possibilities to our brain-gut emotion- generating process. The brain responds to various psychological influences, whereas the gut and its microbiome respond to what we eat, which medications we take, and to any infectious organisms. The entire system functions like a supercomputer which integrates vast amounts of information from within our bodies and from the outside world to generate optimal digestive and brain functions.

When we change the diet from high animal fat to plant based food, it can affect on the microbiome by favouring some of the bacteria’s growth but the bacteria can also adapt to the change of environment and produce different types of metabolites.

When we ingest a high animal fat diet, there is a low grade inflammation in the body. Inflammatory molecules are increased such as cytokines and lipopolysaccharide (LPS) which is a part of the cell wall of certain gram negative bacteria (E Coli,salmonella and other microbiota including Firmicutes and Proteobacteria)

Some studies have shown that some individuals find their stress level reduced by eating high fat and sugary foods “comfort foods”. Unfortunately, this food –induced stress reduction comes at a cost of weight gain and obesity.

Food addiction is caused by the effects of a high fat diet on food cravings.

Chronic high fat intake can compromise the hypothalamus’s ability to respond to satiety signals from the gut.

Disturbance and alterations in the gut microbiome are associated with a variety of diseases such as inflammatory bowel diseases, antibiotic –associated diarrhea and they may even play a role in autism spectrum disorders and neurodegenerative brain disorders like Parkinson’s disease. Gut microbiota have also been linked to depression. The serotonin signaling system was thought to be located exclusively in the brain but today we know that 95% of the body’s serotonin is in the gut specialised cells.

The microbiome changes during life stages. During birth, a baby born naturally is exposed to the mother’s vaginal microbiota, including the lactobacillus species, providing a key source of microbes to colonise the infant’s gut. Cesarian born infants are found to be colonised by microbes from the mother’s skin, from midwives, physicians and nurses and important beneficial bacteria such as bifidobacteria take longer to colonize their guts comparing to the vaginally born infants.

The microbiome is built under the influence of many early life factors such as diet, hygiene, siblings, pets, antibiotics…. However the gut bacteria are never static and lifestyle factors continue to influence this. The microbiome diversity varies over the lifetime of an individual. It is low in the first 3years of life when a stable gut microbiome is being established, reaches its maximum during adult life and tends to decline with age and with life style changes. By the time a person reaches 60 years old the bacteria are less diverse and beneficial bacteria like Lactobacillus and Bifidobacterium tend to lose ground and there is an increase in the enterobacteria population. These bacteria are opportunistic as they can cause an infection when given the opportunity like when the gut bacterial balance is disrupted by antibiotics.

This is a new emerging science that the microbiome plays an important part in our health. Studies have shown that by transferring faecal pellets from an “extrovert” mouse could change the behaviour of a “timid” mouse, making it behave like the gregarious donor mouse. In a similar experiment by transplanting microbes from an obese mouse makes a lean mouse to overeat.

Microbiome and autism.

Some parents of autistic children have claimed that changing a child’s diet or giving probiotics improves just not the digestive problems but also the behavioural symptoms. It was found that gut bacteria also manufacture bioactive compounds that help to orchestrate brain function and social development. Studies showed that children with ASD often have a mix of gut bacteria that is distinct from that of children without ASD. In lab animals, autism like symptoms arise when normal species of gut bacteria are absent.

Researchers at California Institute of Technology transfer microbes of ASD children into germ free mice. These mice socialize less, produce fewer vocal sounds and engaged in more repetitive behaviour.

A team in Arizona State University did microbiota transfer therapy to ASD children. Those children showed improvement in their gastrointestinal symptoms and behaviour.

The microbiome and Alzheimer’s disease.

Recent evidence suggests there is an interaction and influence of the gut microbiome upon the nervous system. Alterations in the composition of gut bacteria were seen in patients with Alzheimer’s compared to healthy controls.

The gut bacteria can influence the functioning of the brain and promote neurodegeneration through several pathways. They can modify the interaction between the immune system and the nervous system. Lipopolysaccharides, a protein located on the membrane of bacteria with pro-inflammatory properties, have been found in amyloid plaques and around vessels in the brains of Alzheimer patients. In addition, the microbiota produce metabolites short chain fatty acids and some like acetate and valerate were associated with large amyloid plaques, whereas butyrate were associated with less amyloid pathology.

When the microbiome becomes unbalanced (gut dysbiosis), there are symptoms like constipation, diarrhea, bloating, nausea, intestinal inflammation. Dysbiosis was found to be associated with neurological disorders such as Alzheimer’s, Parkinson’s and multiple sclerosis. Recent literature endorses the hypothesis that probiotic, prebiotic supplementation can alter Alzheimer’s symptoms and improve its associated disease biomarkers.

Microbiome and anxiety and depression

Recent observations revealed a link between mood disorders and changes in gut microbiota. Simply transferring the microbiota from an animal with mood disorders to an animal in good health was enough to bring about biochemical changes and depressive –like behaviour in the latter. Imbalance in the gut microbiome can cause a reduction in some metabolites and bioactive neurotransmitters that have psychiatric properties that can affect sleep, appetite, mood and cognition. A healthy gut microbiota contributes to normal brain function.

Increasing evidence suggests that modulation of gut microbiota could provide novel interventions for depression and anxiety. Probiotics containing Bifidobacteria species have been shown to reduce cortisol responses involved in anxiety and may reduce symptoms of depression.

Prebiotics and Probiotics may be potential treatment options for depression however more research is needed.


The Mind-Gut Connection by Emeran Meyer

Gut Microbiome and depression- Pathophysiology/Role of Pre and Probiotics by Dr Sanil Rege MBBS, MRCPsych, FRANZCP