Davide Casale

Beatrice Gregori

INTRODUCTION

Major Depressive Disorder(MDD)

Also known as clinical depression, unipolar depression, or unipolar disorder; or as recurrent depression in the case of repeated episodes, major depression is a mental disorder characterized by a pervasive and persistent low mood that is accompanied by low self-esteem and by a loss of interest or pleasure in normally enjoyable activities. Major depressive disorder is a disabling condition that adversely affects a person's family, work or school life, sleeping and eating habits, and general health. In the United States, around 3.4% of people with major depression commit suicide, and up to 60% of people who commit suicide had depression or another mood disorder.

The understanding of the nature and causes of depression has evolved over the centuries, though this understanding is incomplete and many aspects of depression are still the subject of discussion and research.

The aim of this report is to analyze the effects of the microbiome on the CNS, and, by doing that, understanding which are the connections between the brain-gut axis and the development of the disease, in order to explain how the use of probiotics can affect the evolution of the pathology.

MICROBIOTA AND BRAIN DEVELOPMENT

Gut-brain interactions likely begin soon during the growth. Even though the intestines were thought to be sterile while in utero, many studies confirm that actually a maternal-fetal transmission of bacteria happens during pregnancy: it occurs via amniotic fluid or umbilical cord blood.

The massive colonization, however, starts immediately after the delivery (mother’s health status, as well as the mode of the childbirth, vaginal or by caesarean section, will influence the population of bacteria that first take hold).

There are many other factors that affect the microbiota during the infancy of the child, such as breastfeeding, diet, antibiotics or the presence of siblings, because the microbiome lacks of stability throughout this first period, and it becomes relatively stable during childhood (while the brain continues to develop through adolescence into early adulthood).

The composition of the microbiota (generally the most represented phyla are Firmicutes and Bacterioides) is crucial to a correct development of the organs, as it influences DNA-methylation and other epigenetic changes.

This important role of microbiota-brain interactions is supported by germ-free rodent studies in which it has been shown that the hypothalamic pituitary adrenal (HPA) axis develops abnormally in the absence of the normal gut microbes, leading to altered stress responsiveness and reduced hippocampal brain-derived neurotrophic factor (BDNF).

The observed abnormalities could then be ameliorated, at least in part, when the gastrointestinal tracts of the germ-free mice, with a sterile GI tract, were reconstituted with stool from conventionally raised mice or with the specific organism Bifidobacterium infantis.

The effects of gut microbiota on CNS function in humans. 2014

THE PATHWAYS OF MICROBIOTA -BRAIN INTERACTION

There is evidence for multiple pathways of communication from the intestinal microbiota to the CNS including vagal afferent nerves, immune and HPA (Hypotalamic-pituitary-adrenal) axis modulation, and production of active metabolic products.

In particular, the vagus is a major nerve made up of 80% afferent fibers, connecting peripheral organs (as well as the gut), with the CNS. It is widely known that visceral afferences can modulate behavior, cognition and emotions, and this specifical aspect was confirmed by the experiments carried out on mice infected by Campylobacter Jejuni (Lyte M, Varcoe JJ, Bayley MT, Anxiogenic effect of subclinical bacterial infection in mice in the absence of overt immune activation, 1998 )when mices with subclinical Campylobacter infection were compared with uninfected mice they displayed anxiety-like behavioral changes. This change occurred in the absence of observed increases in peripheral inflammatory cytokines, suggesting that the behavior change was due to neural activation, rather than via circulating inflammatory mediators. Later studies have confirmed that Campylobacter does activate vagal afferent pathways.

Furthermore, these studies on the Campylobacter infection demonstrated that the affected mice showed increased level of activity in anxiety-associated brain regions (such as the amygdala, the parabrachial nucleus, the stria terminalis and the nucleus of the solitary tract).

But the connection between the brain and the intestines is not only regulated by the vagal system: we must not underestimate the imporance of the HPA axis. In order to demonstrate the importance of this influence of the HPA on the microbiota, Sudo et al., almost a decade ago, (Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. 2004 ), carried out studies that demonstrated how germ-free mice have an overactive HPA in response to stress.

In addiction to these evidences about the role of the microbiota and the vagal fibers in the CNS stress regulation, also a top down action of the brain on the gut was shown by Unsal et al. in 2008 (The short-term effects of different doses of dexamethasone on the numbers of some bacteria in the ileum. 2008 ) when they treated a mice population with dexamethasone, a synthetic member of the glucocorticoid class of steroid drugs: the use of this drug altered the adherence of the bacteria to the mucosal surface, changed the bacterial population profile of the test animals and increased cellular permeability, leading to the development of inflammation.

Because of these results, it is possible to assert that the communication between brain and microbiome is both dynamic and bidirectional.

THE CONNECTION BETWEEN GUT -BRAIN AXIS AND MAJOR DEPRESSION

The proof of the existence of a double connection between the two systems, however, wasn’t sufficient to demonstrate a relation between the microbiome and the evolution of major depression, so, in 2013, Park and colleagues ( Altered colonic function and microbiota profile in a mouse model of chronic depression. 2013 ) the results of their work on olfactory bulbectomized mice. Bulbectomy was used to induce in the test subjects depression-like symptoms and behaviors: olfactory bulbectomy is one of the few animal models that respond to chronic antidepressant medication and has been widely used as a screening tool for modern therapeutics. Moreover, many of the biological hallmarks of depression often follow bilateral removal of the olfactory bulbs of rodents including neurochemical, neuroendocrine, and neuroimmune changes (altered reward processing, a key symptom of depression, is also observed).

The mice population developed, after the surgery, an overactive HPA axis (high level of CRF in the hypothalamus), in association with hyperlocomotion in the open field and, most importantly, a relevant change in the proportion of the phyla of the microbiota. Although this redistribution of the bacteria within the microbiota could be unrelated with the depression- and anxiety-related phenotype, the authors go on to show how the infusion of CRF produced a similar altered motility and reduced the diversity of the microbiota, too.

Thus together, these findings provided important insights into the relationship between microbiota and major depression.

It is important to notice, though, that the bulbectomy model is often criticized as it lacks overt construct validity despite high predictive validity; moreover, the mechanism as to how bulbectomy induces its effects is not clear as it is not due to simple anosmia and is thought to involve limbic degeneration. Indeed, some authors refer to it as a model of neurodegeneration instead of depression.

To overcome these uncertainties about the validity of the experiments about the connection between microbiota and CNS disease, such as major depression itself, many physicians tried various strategies, including the use of antibiotics as well as probiotics treatments.

In particular, probiotic studies are among the most carried out to support the theory of a relationship between the gut microbiome and behavior.

PROBIOTICS : A WAY TO CONTROL AND BALANCE THE BRAIN -MICROBIOTA INTERACTION ?

Probiotics are microorganisms that are administrated as dietory supplements or as food products, such as yogurts. Lately several of these bacteria have been tested for health benefits and the experiments showed some interesting results.

Bravo JA, Forsythe P, Chew MV et al. (Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. 2011 ) that animals fed with Lactobacillus Rhamnosus show reduced levels of anxiety on a wide range of behavioral measures and altered expression of central GABA receptors. In order to determine the mechanism of action, the animals underwent vagotomy, and that prevented the emergence of an anxiolytic effect from probiotics and the changes in GABA receptors expression.

But all these studies weren’t sufficient to give clinical validation to the use of probiotics to face the clinical problems given by the disease, so in 2013 K. Tillisch and her colleagues started a trial with the aim of converting pre-clinical data into possible therapeutic reality (Consumption of fermented milk product with probiotic modulates brain activity. 2013 ). Healthy women with no GI or phsychiatric symptoms were provided randomly with either fermented milk product containing B. Animalis, Streptococcus Thermophiles, L. Bulgaricus, or a non-fermented milk product or no intervention twice daily for four weeks. Probiotic intake was associated with reduced task-related response of a network containing affective, viscerosensory, and somatosensory cortices, and other studies (Davari et al., Probiotics treatment improves diabetes-induced impairment of synaptic activity and cognitive function: behavioral and electrophysiological proofs for microbiome-gut-brain axis. 2013 ) also proved that the ingestion of probiotics can lower the level of serum cortisol (hormone responsible of stress responses, typical of diseases like anxiety and depression).

CONCLUSION

To sum up, we can say that there is a lot to discover about the complex bond between microbiota and CNS, and of course a lot of work has still to be done in this direction, but, with a judicious and sensible use of the techniques available nowadays, this effort would allow a more complete understanding of the brain-gut axis miscommunication that underlies stress-related pathologies like major depression.