The gut microbiota influences stress and cognitive performance

This article supports our treatment protocol for children with symptoms of attention deficit with marked hyperactivity, autistic traits, or moderate to severe autism.

The full original source of this article is available here: https://academic.oup.com/nutritionreviews/article/73/suppl_1/28/1819270

Introduction

The gut microbiota is made up of trillions of microbes that influence normal physiology and alter the host's susceptibility to disease. A growing body of evidence in animals supports the idea that the gut microbiota influences emotional behaviour. Changes in the gut microbiota and exposure to specific bacteria can modulate the peripheral and central nervous systems (CNS) in animals, altering brain function and suggesting the existence of a microbiota–gut–brain axis.

Animal studies show that gut bacteria influence brain chemistry and brain development. The enteric nervous system, including the sensory vagus nerve, appears to be able to tell the difference between non-pathogenic and potentially pathogenic bacteria. This may play an essential part in mediating the effects of gut microorganisms on behaviour. Because the nervous system is in constant two-way communication with the immune system, the effects of bacteria on our nervous system cannot be separated from their effects on the immune system. This kind of crosstalk happens all the time and can have profound neurological and immunological effects.

PROBIOTICS AND HEALTH

Although the make-up of the gut microbiota varies considerably from one person to another, changes in the balance of common gut microbes can affect the production of short-chain fatty acids (SCFAs): butyrate, propionate and acetate. These are products of bacterial fermentation in the gut that regulate adaptive immune responses in the gut and play a key part in CNS function. Butyrate has direct effects on the growth, maturation and function of the epithelial cells lining the gut, on the immune system's Treg cells (regulatory T cells, which play a key part in preventing autoimmunity), and on the nervous system.

A recent study also found that SCFAs, particularly butyrate, had a positive influence on the host's metabolism by activating intestinal gluconeogenesis, in both insulin-sensitive and insulin-insensitive states, promoting glucose and energy homeostasis. Diets rich in non-digestible carbohydrates lower the pH in the proximal colon, which may be an important factor in butyrate production. Propionate and acetate have also been shown to promote satiety. The metabolic benefits for body weight and glucose control brought about by SCFAs or dietary fibre in normal mice are absent in mice lacking intestinal gluconeogenesis, despite similar changes in the make-up of the gut microbiota. This finding suggests that, although diet is a major factor in determining the make-up of the gut microbiota and SCFA production in mice, there is a strong interaction with genotype that influences the outcome.

An altered gut microbiota may also be responsible for disease processes in the colon. Poor adaptation of the gut microbiota to the host (dysbiosis) has been implicated in the rising incidence of inflammatory conditions such as inflammatory bowel disease. Patients with inflammatory bowel disease or irritable bowel syndrome have reduced levels of Lactobacillus and Bifidobacterium species in the gut. Animal models point to a role for bacteria in appropriate immune regulation and in the development of gut inflammation. It is likely that the reduced number and diversity of normal beneficial commensals, such as lactobacilli and bifidobacteria, play an important part in allowing harmful microbes such as Citrobacter rodentium and Escherichia coli to reach the epithelial surface.

Encouraging results on the immune response and stress

Animals given B. fragilis, or even PSA alone, which trigger beneficial immune responses, can be protected against experimental colitis. Probiotics can also improve stress-induced gut dysfunction, partly by normalising the activity of the hypothalamic–pituitary–adrenal (HPA) axis.

PROBIOTICS AND BEHAVIOUR

The microbiota influences stress

The HPA response to stress is programmed early in life (at least in rodents). A landmark study from Japan showed that early exposure to gut microbiota reduces the exaggerated HPA responses of germ-free mice in adulthood, but not when it is given to adult animals. Plasma levels of ACTH and corticosterone in response to stress were higher in germ-free mice than in specific-pathogen-free mice. Studies have shown similar results in normal, healthy mice and rats: feeding them a probiotic can dampen the HPA axis response to stress. Finally, it is important to recognise that stress itself has a major effect on the make-up and function of the gut microbiota.

Mice fed L. rhamnosus JB-1 for 28 days showed changes in certain gamma-aminobutyric acid (GABA) receptors in different regions of the brain, an increase in anxiolytic behaviour and an inhibition of the corticosterone response to acute stress.23 These changes were consistent with benzodiazepine-like effects. However, the neurochemical and behavioural effects were not found in vagotomised animals, which indicates that the vagus nerve is a major communication pathway between such bacteria in the gut and the brain.23 Screening for this kind of enteric nervous system activity could eventually lead to potential treatments for anxiety and stress.

Recent unpublished research shows that the amount of the neurotransmitters GABA and glutamate in the brain can be increased by feeding animals probiotic bacteria. However, the effects are limited, depend on timing and depend on the continued presence of the original probiotic.

Better learning and cognition

It has also been shown that when animals are fed the bacterium L. rhamnosus, effects can be seen not only on the local nervous system but also throughout the body. Indeed, the gut microbiota can clearly influence brain chemistry and behaviour in mice independently of the autonomic nervous system, gastrointestinal neurotransmitters or inflammation. Faecal transplants from specific-pathogen-free NIH Swiss mice, which are relatively unanxious, to BALB/c mice, which are relatively anxious, showed, surprisingly, that the animals' behaviour depended on the source of the faecal matter / microbiota. Colonising germ-free BALB/c mice with the microbiota of NIH Swiss mice increased exploratory behaviour, suggesting reduced anxiety, and increased hippocampal levels of brain-derived neurotrophic factor, which is important for the growth, differentiation and maturation of neurons. In turn, colonising germ-free NIH Swiss mice with BALB/c microbiota reduced exploratory behaviour, suggesting increased anxiety. These changes were not affected by vagotomy.

Diet can also change the profile of the gut microbiota and, as a result, the host's behaviour. Li et al. showed that changing the make-up of rodents' diet altered the spatial memory of the recipients, indicating that nutrition and diet need to be taken into account in such studies.

Research with a mutant bacterium lacking PSA suggests that this component is necessary and sufficient for the acute activation of sensory neurons in the gut: PSA can mimic the effects of the parent organism on the nervous system, just as it can mimic its immunological effects. Components of bacteria may therefore themselves be able to affect the functions of the nervous system. These results support the idea that the contents of the gut, and the bacteria they contain, are important factors in determining behaviour and even cognition in animals.

RESEARCH IN HUMANS

The strong evidence in animals of a direct link between the gut microbiota and the brain has led to the suggestion that the effect could be similar in humans. Bercik et al. suggested that gut dysbiosis could contribute to psychiatric disorders in patients with bowel disorders. To date, however, there is very little evidence in humans that probiotics will have the same neurochemical and behavioural effects seen in animals.

In a double-blind, randomised, placebo-controlled study, Messaoudi et al. gave a probiotic formula (L. helveticus and Bifidobacterium longum) to healthy women for 30 days, then assessed the participants' levels of anxiety and depression and their 24-hour urinary free cortisol. In the female volunteers, taking the probiotic formula daily reduced psychological distress, as shown in 3 behavioural assessments, and 24-hour urinary cortisol was lower in the women who received it.

Stress and anxiety

In another clinical pilot study, 39 patients diagnosed with chronic fatigue syndrome were selected to receive Lactobacillus casei Shirota or a placebo daily for 2 months. There was a significant reduction in anxiety symptoms in the treated group.

A more recent clinical study was carried out in 23 healthy female volunteers with no gastrointestinal or psychiatric symptoms. The women were randomly assigned to groups receiving either a fermented milk product (Bifidobacterium animalis, Streptococcus thermophilus, L. bulgaricus and Lactococcus lactis) or a placebo, a non-fermented milk product matched for taste and texture, twice a day for 4 weeks. Eating the fermented milk product had a robust effect on the activity of brain regions that control the central processing of emotions and sensations, as seen with functional magnetic resonance imaging before and after the fermented milk product was consumed.

Autistic disorders

Some people diagnosed with autism spectrum disorders also have a range of gastrointestinal abnormalities. A recent study looked at an animal model of the neurodevelopmental disorders of autism, in which pregnant mice were injected with a viral mimic (poly I:C). This produced typical stereotyped autistic behaviours in the offspring, which lasted into adulthood. Giving B. fragilis by mouth to pregnant mice before and immediately after birth led to the development of considerably fewer autistic behaviours. In this model, giving PSA did not prevent all the abnormalities. However, the results suggest that a viral infection during pregnancy can have lasting effects, which can potentially be reversed by giving particular bacteria by mouth.

The results of these clinical studies are consistent with those seen in rats and mice, and suggest that communication between the gut microbiota and the brain can be modified, and may provide targets for treating patients with a heightened stress response associated with gut dysbiosis.

CONCLUSION

The changes that occur in the microbial content of the gut after taking probiotic bacteria, or after altering the balance of the gut microbiota in some other way, can set off a variety of mechanisms. These include effects on the host's immune, nervous and endocrine systems, which in turn influence one another, showing that crosstalk between the gut and the host plays an important part. Behaviour, mood and the stress response can all be affected by taking probiotic bacteria. These findings are very promising and have attracted a great deal of public and scientific interest. There is currently a large gap between experimental and clinical data. The challenge now is to translate these animal findings into clinical applications. In future, the make-up, diversity and function of specific probiotics, combined with more detailed knowledge of the make-up of the gut microbiota, could potentially help to develop more effective diets and drug therapies.