The intestinal microbiota influences stress and cognitive performance

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

    The source of the article is available in its original and complete version here : https://academic.oup.com/nutritionreviews/article/73/suppl_1/28/1819270

    In summary

    Changes in the intestinal microbiota can modulate the peripheral and central nervous systems, resulting in altered brain function and suggesting the existence of a microbiota-brain intestinal axis.

    Diet can also alter the profile of the intestinal microbiota and, consequently, behaviour. The effects of bacteria on the nervous system cannot be separated from the effects on the immune system because the two are in constant two-way communication.

    Although the composition of the intestinal microbiota varies considerably from one individual to another, alterations in the balance and content of common intestinal microbes can affect the production of molecules such as neurotransmitters, e.g. gamma-amino butyric acid, and fermentation products, e.g. short-chain butyrate, propionate and acetate fatty acids.

    Short-chain fatty acids, which are pleomorphss, in particular butyrate, positively influence host metabolism by promoting glucose and energy homeostasis, regulating immune responses and epithelial cell growth, and promoting the functioning of the central and peripheral nervous systems.

    Introduction

    The intestinal microbiota is composed of thousands of billions of microbes that influence normal physiology and alter the host's susceptibility to disease. A growing body of animal evidence supports the concept that the intestinal microbiota influences emotional behaviour. Changes in the gut or intestinal microbiota and exposure to specific bacteria can modulate the peripheral and central nervous systems (CNS) in animals, resulting in altered brain function and suggesting the existence of an intestinal microbiota-brain axis.

    Animal studies show that intestinal bacteria influence brain chemistry and development. The enteric nervous system, including the sensory vagus nerve, appears to be able to differentiate between non-pathogenic and potentially pathogenic bacteria. This may play a key role in mediating the behavioural effects of intestinal microorganisms. Because the nervous system has constant two-way communication with the immune system, the effects of bacteria on our nervous system cannot be separated from the effects on the immune system. This type of crosstalk occurs regularly and can have profound neurological and immunological effects.

    PROBIOTICS AND HEALTH

    Although the composition of the intestinal microbiota varies considerably from one individual to another, changes in the balance of common intestinal microbes can affect the production of short-chain fatty acids (SCFAs), butyrate, propionate and acetate, which are products of intestinal bacterial fermentation that regulate intestinal adaptive immune responses and play a key role in CNS function. Butyrate has direct effects on the growth, maturation and function of intestinal epithelial cells, on immune system Treg cells (regulatory T cells that play a key role in the prevention of autoimmunity), and on the nervous system.

    A recent study also revealed that AGCCs, particularly butyrate, positively influence host 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 on body weight and glucose control induced by either AGCC or dietary fibre in normal mice are absent in mice deficient in intestinal gluconeogenesis, despite similar changes in the composition of the intestinal microbiota. This finding suggests that although diet is a major factor in determining the composition of the intestinal microbiota and production of CFAS in mice, there is a strong interaction with genotype that influences the results.

    An alteration of the intestinal microbiota may also be responsible for the pathophysiology of the colon. The poor adaptation of the intestinal microbiota to the host (dysbiosis) has been implicated in the increased incidence of inflammatory diseases such as inflammatory bowel disease. Patients with inflammatory bowel disease or irritable bowel syndrome experience reduced levels of Lactobacillus and Bifidobacterium species in the gut. Animal models indicate a role for bacteria in the adequacy of immune regulation and the development of gut inflammation. It is likely that the reduced number and diversity of normal beneficial commensals such as Lactobacillus and Bifidobacteria play an important role in allowing harmful microbes such as Citrobacter rodentium and Escherichia coli to access the epithelial surface.

    Encouraging results on immune response and stress

    Animals given B. fragilis or even PSA, which trigger beneficial immune responses, may be protected against experimental colitis. Probiotics may also improve stress-induced intestinal dysfunction, in part by normalizing hypothalamus - pituitary - adrenal axis activity (HPA).

    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 has shown that early exposure to the intestinal microbiota reduces exaggerated HPA responses in germ-free mice in adulthood, but not when administered to adult animals. Plasma levels of ACTH and corticosterone were higher in response to stress in germ-free mice compared to specific pathogen-free mice. Studies have shown similar results in normal, healthy mice and rats, i.e. feeding a probiotic may attenuate the HPA axis response to stress. Finally, it is important to recognize that stress itself has a major impact on the composition and function of the intestinal microbiota.

    Mice fed L. rhamnosus JB-1 for 28 days experienced changes in certain gamma amino butyric acid (GABA) receptors in different regions of the brain, increased anxiolytic behaviour and inhibition of corticosterone response to acute stress.23 These changes were consistent with benzodiazepine effects. However, neurochemical and behavioural effects were not found in vagotomized animals, indicating that the vagus nerve is a major communication pathway between such bacteria in the gut and brain.23 Screening for this type of enteric nervous system activity could potentially provide potential treatments for anxiety and stress.

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

    Improved learning and cognition

    It has also been shown that when animals are fed L. rhamnosus bacteria, effects can be observed not only on the local nervous system, but also systemically. Indeed, the intestinal microbiota can clearly influence brain chemistry and behaviour in mice independently of the autonomic nervous system, gastrointestinal neurotransmitters, or inflammation. Fecal transplants from NIH Swiss NIH mice free of specific pathogens, which are relatively non-anxious, to BALB/c mice, which are relatively anxious, showed surprisingly that the behavior of the animals depended on the source of fecal material/microbiota. Colonization of germ-free BALB/c mice with the NIH Swiss mouse microbiota increased exploratory behavior, suggesting a decrease in anxiety and an increase in hippocampal levels of brain-derived neurotrophic factor, which is important for growth, differentiation, and maturation of neurons. In turn, colonization of germ-free NIH Swiss mice with the microbiota BALB/c reduced exploratory behavior, suggesting an increase in anxiety. These changes were not affected by vagotomy.

    Diet can also alter the profile of the intestinal microbiota and, consequently, the behaviour of the host. Li et al. showed that altering the composition of rodent diets altered the spatial memory of recipients, indicating that nutrition and diet should be considered in such studies.

    Research with a mutant bacterium lacking PSA suggests that this component is necessary and sufficient for acute activation of intestinal sensory neurons, i.e. PSA can mimic the effects of the parent organism on the nervous system, just as it can mimic its immunological effects. Thus, the components of the bacteria may themselves have the ability to affect the functions of the nervous system. These results support the concept that the luminal contents of the intestine and the bacteria they contain are important factors in determining behaviour and even cognition in animals.

    RESEARCH ON HUMANS

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

    In a double-blind, randomized, placebo-controlled study, Messaoudi et al. administered a probiotic formula (L. helveticus and Bifidobacerium longum) to healthy women for 30 days, then assessed the beneficiaries' level of anxiety and depression and 24-hour urine-free cortisol levels. In female volunteers, daily administration of the probiotic formula alleviated psychological distress, as indicated in 3 behavioural assessments, and 24-hour urinary cortisol was reduced in treated women.

    Stress and anxiety

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

    A more recent clinical study was conducted in 23 healthy female volunteers without gastrointestinal or psychiatric symptoms. The women were randomly assigned to groups that received either a fermented milk product (Bifidobacterium animalis, Streptococcus thermophilus, L. bulgaricus and Lactococcus lactis) or a placebo, which consisted of an unfermented milk product adjusted for taste and texture, twice daily for 4 weeks. Consumption of the fermented milk product had a robust effect on the activity of the brain regions that control the central processing of emotions and sensations, as observed with functional magnetic resonance imaging before and after consumption of the fermented milk product.

    Autistic Disorders

    Some people diagnosed with Autism Spectrum Disorders also have a spectrum of gastrointestinal abnormalities. A recent study examined an animal model for neurodevelopmental autism in which pregnant mice were injected with viral mime (POLY I: C). This produced typical stereotypical autistic behaviours in the offspring that lasted into adulthood. Oral administration of B. fragilis to pregnant mice before and immediately after birth resulted in the development of significantly reduced autistic behaviours. In this model, the administration of PSA did not prevent all abnormalities. However, the results suggest that the incidence of viral infection during pregnancy may produce lasting effects, which are potentially reversible by oral administration of particular bacteria.

    The results of these clinical studies are consistent with those observed in rats and mice and suggest that communication between the intestinal microbiota and the brain is modifiable and may provide targets for treatment of patients with an increased stress response associated with intestinal dysbiosis.

    CONCLUSION

    Changes that occur in the microbial content of the gut as a result of ingesting probiotic bacteria or otherwise altering the balance of the intestinal microbiota can trigger a variety of mechanisms. These include effects on the immune, nervous and endocrine systems of the host, which in turn influence each other, demonstrating an important role of crosstalk between the gut and the host. Behaviour, mood and stress response can all be affected by the ingestion of probiotic bacteria. These data are very promising and have generated a great deal of popular and scientific interest. There is currently a significant gap between experimental and clinical data. The challenge now is to translate these animal findings into clinical applications. In the future, the composition, diversity and function of specific probiotics, combined with a more detailed knowledge of the composition of the intestinal microbiota, could potentially help develop more effective diets and drug therapies.

    Translated from English by Google Translate, verification and corrections by J. Frère. References for the studies cited in this article are available in the original version in English.