Gut Microbiota & Depression

Research is revealing fascinating links between the type of bacteria we have in our guts (often referred to collectively as either microbiota or microbiome, although there are some technical differences1 ) and a whole range of health issues – from depression to diabetes, allergic reactions to Alzheimer’s. This article will look specifically at what current studies are uncovering in relation to the role played by microbiota in the increasing incidence of clinical depression and related conditions.

The total estimated number of people living with depression worldwide increased by 18.4% between 2005 and 2015 to 322 million, according to the 2017 report on depression and anxiety by the World Health Organisation (WHO)2 .

Could this increase in cases of depression, which is paralleled with an increase in the spread of the SAD (Standard American Diet), actually be related to dietary changes within populations – changes that directly alter the type and ratio of gut bacteria from those which promote and maintain human health to those that undermine human health?

The idea that psychological states, such as depression, can be caused by the food we eat may seem like a novel idea to some people; but if we can link depression to microbiome changes, then there can be little doubt that diet is implicitly involved in our psychological functions, via the trillions of bacteria that inhabit our guts. Some interesting research3 is looking at how the hormones in plants (such as auxins, cytokinins, and abscisic acid) not only govern important plant physiological traits but are important elements in their interactions with animal microbes4 and, by extension, with human physiological processes such as glucose assimilation, inflammation, and cell division.

To explore this possible relationship, we will look at recent studies which explore the possible connections between depression (and some other co-morbid conditions) and our microbiota. This blog aims to cover a lot of the latest (2017-18) research data in varying degrees of detail so that you have a good idea of the range of studies that are currently being conducted in this rapidly growing field of medical/nutritional science.

First, though, the following diagram5 is an interesting and useful overview of some of the systems and pathways that are involved in the microbiota-gut-brain axis.

Blog Contents

Visual overview of the microbiota-gut-brain axis

Key to the above diagram: (A) Microbiota–gut–brain (MGB) axis. Direct and indirect pathways support the bidirectional interactions between the gut microbiota and the central nervous system (CNS); involving endocrine, immune and neural pathways. On the afferent arm (blue arrows): (1) lymphocytes may sense the gut lumen and internally release cytokines which can have endocrine or paracrine actions, (2) Sensory neuronal terminals, such as on the vagus nerve may be activated by gut peptides released by enteroendocrine cells, (3) Neurotransmitters or its precursors produced as microbiota metabolites may reach the gut epithelium having endocrine or paracrine effects. (4) Centrally, after brainstem relays (e.g., nucleus tractus solitarii) a discrete neural network has been described consistently involving the amygdala (Am) and the insular cortex (IC) as main integrators of visceral inputs. Consistently hypothalamic (Hy) activation initiates the efferent arm (red arrows): (5) corticosteroids, release as results of the hypothalamic–pituitary–adrenal (HPA) axis activation, modulates gut microbiota composition. (6) Neuronal efferent activation may include the so called “anti-inflamatory cholinergic reflex” and/or sympathetic activation, both liberating classical neurotransmitters that may affect directly the gut microbiota composition.

Study 1 – Tryptophan, serotonin and the brain-gut axis

A January 2016 study6 looked at the role of the microbiota in the production of tryptophan and, thereby, serotonin in relation to alterations in psychological functions (such as mood, memory and concentration levels). Serotonin is often thought of as the “happiness hormone” (although it’s not technically a hormone) along with the related chemical dopamine. Low levels of serotonin have been associated with depression for a long time. The researchers in this study concluded that:

Low serotonin contributes to a lowered mood state…depleted serotonin causes cognitive impairments, with reports including deficits in verbal reasoning, episodic, and working memory, while conversely tryptophan supplementation has positive effects on attention and memory. Interestingly, emotional processing, the modification of memory that underlies emotion, is inhibited in subjects with depression, or has a high-risk to develop, after tryptophan depletion.

An influence of gut microbiota on behaviour is becoming increasingly evident, as is the extension to effects on tryptophan and serotonin metabolism. There is regulation of tryptophan and serotonin in the gut by the resident microbiota and recent studies show that low-to-no gut microbiota increases levels of tryptophan and serotonin and modifies central higher order behaviour.

“…The suggestion that the gut-microbiota has central influence opens up many new possibilities, especially with the suggestion from Mayer and colleagues [126] that the composition and metabolic activity of the gut microbiota may play a role in such brain disorders as autism, anxiety, and depression. Ongoing studies will, in time, evaluate these assertions and hopefully determine the mechanisms by which the gut microbiota affect mood and cognition.

The following diagram illustrates how the brain-gut axis is a bi-directional system of communication between the brain and the gastrointestinal tract, linking emotional and cognitive centres of the brain with peripheral control and function of the gut.

The brain-gut axis is a bi-directional system of communication between the brain and the gastrointestinal tract (GI tract). This links emotional and cognitive centres of the brain with peripheral control and function of the gut and its resident microbiota. 90% of serotonin is produced in the GI tract. Serotonin is a neurotransmitter that is itself derived from the essential amino acid tryptophan. Serotonin is a key element of this axis, acting as a neurotransmitter in the CNS (central nervous system) and in the ENS (enteric nervous system – one of the main divisions of the autonomic nervous system and consists of a mesh-like system of neurons that governs the function of the GI tract) that is present in the wall of the gut.

A. (in the diagram above) shows the neural communication between the gut and brain being via the vagus nerve, DRG (dorsal root ganglia) and via projections from the enteric nervous system to sympathetic ganglia and parasympathetic innervation of the gut.

B. (in the diagram above) shows Humeral (hormones, antibodies etc carried in the blood) communication being via release of bacterial factors, production of cytokines (proteins involved in cell signalling) and circulating hormones.

Study 2 – Kynurenine pathway metabolism and the gut-brain axis

Kynurenine is important in the production of serotonin. A January 2017 study7 looked at how its production was related to microbiota. It concluded that: “..gut microbiota influences CNS physiology, anxiety, depression, social behaviour, cognition and visceral pain.

There are further studies8 on the role of kynurenine and the microbiota-gut-brain axis.

Study 3 – Different microbiota bacteria related to MDD (major depressive disorder)

A small January 2017 study9 concluded that those people with MDD appear to have different bacteria in their guts from those people without MDD. The researchers commented that: “More phylum Firmicutes, less Bacteroidetes, and more genus Prevotella, Klebsiella, Streptococcus and Clostridium XI were found in MDD patients. The changes of the proportion of Prevotella and Klebsiella were consistent with Hamilton depression rating scale.

Additional studies and reviews10 are available on the link between microbiota and MDD.

A February 2018 study11 found that there were gender differences in the microbiota of patients with MDD. The researchers concluded that: “These results demonstrated that there were sex differences in gut microbiota in patients with MDD. The suitability of Actinobacteria and Bacteroidia as the sex-specific biomarkers for diagnosing MDD should be further explored.

Study 4 – Effects of antidepressant/ antimicrobial drugs on microbiota and hence MDD

A January 2017 review12 looked at how dysbiosis (also called dysbacteriosis – a term for a microbial imbalance) of gut microbiota was implicated in the development or exacerbation of mental disorders, such as major depressive disorder (MDD). The researchers concluded that: “MDD is associated with changes in gut permeability and microbiota composition. In this respect, antidepressant drugs present antimicrobial effects that could also be related to the effectiveness of these drugs for MDD treatment.” That is, the very drugs used to treat depression could be causing depression!

Additional reviews and studies13 look at how drugs can affect the microbiota and, thereby, the overall health of the individual:

Study 5 – Do probiotic supplements affect microbiota and psychological symptoms?

An April 2017 systematic review and meta-analysis14 was interested in how probiotic supplementation (microorganisms that are claimed to provide health benefits when consumed) can create a microbiota that can influence CNS function in order to create a positive effect on mood and psychological symptoms such as depression and anxiety. They point out that several human clinical trials have investigated this with inconsistent results. This is why a systematic review and meta-analytic approach was thought appropriate in order to examine whether or not probiotic consumption has an effect on psychological symptoms.

This meta-analysis suggested that supplementation with probiotics resulted in a statistically significant improvement in psychological symptoms compared with placebo. The researchers concluded that: “…probiotic consumption may have a positive effect on psychological symptoms of depression, anxiety, and perceived stress in healthy human volunteers.

A more recent March 2018 meta-analysis15 looked at whether probiotic supplementation was effective in altering mood. It concluded that: “…Probiotic supplementation has an overall insignificant effect on mood. Future studies should be conducted on more patients with clinically diagnosed depression.” [This was not to say that probiotics don’t work at all but, rather, that the limited studies covered by this meta-analysis (10 studies in total) do not demonstrate any significant benefits. I bring you back to the issue of reductionism vs wholism. Extracting so-called “active” ingredients from food (whether bacteria,  macro-micronutrients, phytochemicals, minerals or vitamins) and hoping that they will have the same effect on the body as they do when embedded within the whole food, is questionable to say the least, and has even been shown to be highly dangerous in some cases16 . In this context, I strongly advise you to watch Dr Greger’s video Culture Shock – Questioning the Efficacy & Safety of Probiotics.17 ]

Study 6 – Immune-inflammatory CNS & psychiatric disorders relate to the microbiota

This March 2017 study18 looked at how inflammatory processes lead to the activation of wider immune processes, such as CNS disorders and psychiatric conditions. They questioned the current emphasis of physiological/psychological medicine on current, non-biologically based classification systems for psychiatric and CNS disorders. They take an alternative view on the classically-conceived brain-associated disorders, and suggest that processes (such as Alzheimer’s disease and MDD) are thought of in connection with the gut.

The researchers comments that: “Alterations in the gut, including gut permeability and the composition of the microbiome, have now become an important target for treatment across an array of medical conditions, emphasizing the importance of targeting regulators of the immune system in developing novel treatments that are based on a more comprehensive and ‘wholistic’ understanding of currently poorly managed medical conditions, particularly psychiatric and CNS disorders.

There are additional studies19 relating to the role of probiotics. A November 2017 review20 looked at new opportunities for clinical interventions based on the modulation of existing gut microbiota by using probiotics.

Study 7 – Gut microbiota’s role in major depressive disorder (MDD) & comorbidities

This November 2016 study21 reviewed all publications on the PubMed/MEDLINE database up to May 1, 2016 for studies that investigated intestinal dysbiosis (also called dysbacteriosis – a term used for a microbial imbalance or maladaptation on or inside the body, such as an impaired microbiota) and bacterial translocation (‘leaky gut‘) in the pathophysiology (the disordered physiological processes associated with disease or injury) of MDD and other comorbidities (related conditions ) such as IBS, CFS (chronic fatigue syndrome), obesity, and type 2 diabetes.

They found that the composition of the gut microbiota is influenced by several factors, including diet. Gut dysbiosis plays a significant role in MDD, including but not limited to immune activation, oxidative and nitrosative stress, and neuroplasticity* cascades.

The researchers concluded that intestinal dysbiosis and leaky gut: “…may constitute a key pathophysiological link between MDD and its medical comorbidities.

*Neuroplasticity is the ability of the brain to change its structure and organisation as we learn. With every repetition of a thought or emotion, we reinforce a neural pathway – and with each new thought, we begin to create a new way of being. These small changes, frequently enough repeated, lead to changes in how our brains work. Neuroplasticity is the ‘muscle building’ part of the brain; the things we do often we become stronger at, and what we don’t use fades away. We literally become what we think and do. Younger people change easily; their brains are very plastic. As we age or with medical conditions such as depression22 , change doesn’t come as easily; the brain loses some of its plasticity and we become more fixed in how we think, learn, and perceive.23

Study 8 – Nutrition & mental diseases

This January 2017 review24 pointed out that, though the pathological mechanisms are not yet fully understood, certain nutrients and dietary patterns influence the microbiome (as well many other systems, including immune and inflammatory processes), and this in turn is related to the function of neurotransmitters like dopamine and serotonin.

The reviewers state that: “…traditional dietary patterns, such as the Mediterranean diet have a protective effect on mental health. Supplementation with long-chain polyunsaturated omega-3 fatty acids showed small to medium but significant effect sizes in meta-analyses from depression trials.

Study 9 – Stress during pregnancy, microbiota and depression

This August 2017 study25 reviews other recent studies demonstrating that exposure to stress changes the composition of the intestinal microbiota. In turn, these changes are associated with changes in social behaviour, anxiety, and depression. Immune responses were also shown to be altered by microbiota composition.

Stress during pregnancy was also related to the emergence of these disorders. Indeed, changes (for instance in immune responses) were not only seen in the mother but were also found in her female offspring when they become adults themselves – an in utero impact on neurodevelopment extending into adulthood was based on the links observed between factors related to the mother’s placenta and the offspring’s adult amygdala.

The reviewers added that: “…gastrointestinal microbial communities were different in adult females born from stressed vs. non-stressed pregnancies. Adult female offspring also demonstrated increased anxiety-like behavior and alterations in cognition, suggesting a critical window where stress is able to influence the microbiome and the intrauterine environment in a deleterious manner with lasting behavioral consequences [for the female offspring]. The microbiome may be a key link between the intrauterine environment and adult behavioral changes.

The effects of pre- and post-natal factors on the developing neonatal microbiota and the resulting health of the baby are discussed in a September 2017 review26 , which also looks at potential therapeutic approaches based on the manipulation of gut bacterial composition. Other studies27 also touch on matters related to the influences of maternal stress on prenatal development.

A September 2017 review28 looked at the overlooked role of melatonin and the melatonergic pathways in relation to the biological interactions of breast milk and gut development. The reviewers considered that this area: “…has significant theoretical and treatment implications, as well as being important to the prevention of a host of infant-, child- and adult-onset medical conditions.

An October 2017 randomised, double-blind, placebo-controlled trial29 looked at whether probiotics could help prevent symptoms of anxiety and depression through several in pregnant women. The probiotic used was Lactobacillus rhamnosus HN001. It was given in pregnancy and postpartum to women with symptoms of maternal depression and anxiety during the postpartum period. Another outcome the researchers were looking for was the incidence of eczema in the offspring at 12 months of age – not yet covered in this trial.

Results showed that mothers in the probiotic treatment group reported significantly lower depression/anxiety scores when compared with the placebo group.

The researchers concluded that women who received the probiotic: “…had significantly lower depression and anxiety scores in the postpartum period. This probiotic may be useful for the prevention or treatment of symptoms of depression and anxiety postpartum.

This November/December 2017 study30 looks at biological and environmental changes to maternal and newborn microbiomes in the postnatal period and considers how they can affect health outcomes for both mother and baby. Postpartum sleep deprivation and unmet dietary needs can alter commensal (“eating at the same table”) bacteria within the body and disrupt gut-brain communication. Growth of unwelcome pathogens, because of changes in the composition of the microbiome, can result from injury to the perineum (the external genitalia, orifices of the urethra and vagina, and the perineal muscles) and breast infections. Disruptions within the gut microbiome and gut-brain communication may lead to postpartum depression: “a potentially devastating” consequence. Postnatal newborn changes to the gut and skin microbiome materialise quickly after birth and are profoundly influenced by the mode of birth, the feeding method, and bathing and skin care practices. During the newborn period, infant microbiomes are highly vulnerable and susceptible to multiple influences. The authors consider the important role of maternal-newborn nurses who are important in assisting mothers and newborns to promote healthy microbiomes.

Additional reviews and studies31 look at the issue of pre- and postnatal stress on the mother and child.

Study 10 – Effects of diet, antibiotics, infections and genetics on microbiota

An August 2017 review32 considered how an altered gut microbiome has been associated with the pathophysiology of different diseases, including neuropsychiatric disorders. They looked at how environmental factors – diet, antibiotics, infections, and host-genotype – strongly influence the gut microbiome, modulating the risk for neuropsychiatric illness. Additionally, they look at early life disruption of the microbiome-gut-brain axis and how it has been associated with an increased risk of developing depression later in life – further suggesting a link between gut microbiome, neurodevelopment, and depression.

The following diagram is the reviewer’s outline of the microbiota-gut-brain axis:

Key to diagram: The MGB axis, including the hypothalamic–pituitary–adrenal (HPA) axis. The MGB axis is a bidirectional system that links the gastrointestinal tract with the brain. It is a complex system characterized by a neuroendocrine–immune communication. The gut microbiome influences the function of the brain by modulation of both immune and endocrine systems, HPA axis, neurotransmitter pathways, and growth factors. Alterations of this network—that includes numerous molecules and cells—may be the basis of pathological processes.

Another January 2018 study33 considered antibiotic-induced experimental dysbiosis in mice. They found that perturbation of microbiota was accompanied by a general inflammatory state. Behavioural changes, including increased immobility and reduced social recognition were observed, as well as changes in protein signalling, phosphorylation and neuronal firing in the hippocampus. In addition, changes in non-neuronal brain cells controlling emotional behaviour were detected. When probiotics were administered, most of these gut inflammatory, behavioural, biochemical and functional alterations ceased. Increased levels of Lachnospiraceae were significantly correlated with behavioural changes observed in the dysbiotic mice.

 Study 11 – The role of microbiota in autism, depression and Alzheimer’s disease

A February 2017 review34 reported on how gut microbiota profoundly influence many aspects of host (i.e. yours and my) physiology, including nutrient metabolism, resistance to infection and immune system development. Along with this, the gut-brain axis has a critical role for the gut microbiota in orchestrating brain development and behaviour, with the immune system emerging as an important regulator of these interactions. The reviewers concluded that gut microbiota and the immune system are implicated in the development of “psychiatric and neurodegenerative diseases, such as autism spectrum disorder, depression and Alzheimer’s disease.

A September 2017 review35 considered autism, bipolar disorder, schizophrenia, and major depressive disorder to have links with environmental factors such as diet, gut microbiota, and infections, observing that: “…microbes within the human gut may play a significant role in the regulation of various elements of “gut-brain axis,” via their influence on inflammatory cytokines and production of antimicrobial peptides that affect the epigenome through their involvement in generating short chain fatty acids, vitamin synthesis, and nutrient absorption.

Study 12 – Slowing cognitive decline in rats by regulating gut microbiota

This April 2017 study36 proceeded from the premise that microbiota can influence behaviour and modulate cognitive function through the “microbiota-gut-brain” axis.

The researchers altered the balance of gut microbiota to improve psychological-stress-induced diabetes-associated cognitive decline (PSDACD), finding that diabetic fatty rats with PSDACD exhibited behavioural and cognitive anomalies – increased anxiety- / depression-like symptoms and decreased learning and memory abilities. They identified two types of gut bacteria, that were reduced in quantity in the diseased rats compared with the control group – Roseburia (a genus of butyrate-producing, Gram-positive anaerobic bacteria) and Coprococcus (a genus of anaerobic cocci bacteria). They were able to reverse these symptoms by changing the rats’ diets in ways that would repopulate the gut with these bacteria.

Study 13 – Complex pathways involved in microbiota & host “partnership”

This November 2017 review37 looks at the complex networks and relationships that exist between the gastrointestinal microbiota and the host, considering how this “partnership” may affect brain health and disorders of the central nervous system (CNS). The form of communication is two-way (bidirectional) between the microbiota and the CNS and occurs through a number of pathways: autonomic, neuroendocrine, enteric, (relating to the intestines) and the immune system. Thus, hormones, neurotransmitters and immune processes can be implicated in disruptions of health.

The reviewers state that: “...the gut microbial community have already been implicated in multiple host diseases such as obesity, diabetes, and inflammation, while recent evidence suggests a potential role of the microbiota-gut-brain axis in neuropsychiatric disorders, such as depression and anxiety.” And they consider the role of microbiota in: “…novel gastrointestinal-based treatment options for the prevention and treatment of brain-based disorders such as anxiety and depression.”

Study 14 – Food matters: How the microbiota relates to anorexia nervosa

This September 2017 review38 considers how gut microbiota influences weight regulation and psychopathology in anorexia nervosa (AN) – one of the most common chronic illnesses in female adolescents that accounts for most deaths of all the psychiatric disorders. They point out that a “leaky gut”, where antigens (toxins or other foreign substances which induce immune responses in the body, especially the production of antibodies) get through the thin intestinal wall, was shown in an animal model of AN, and could be the underlying cause of the low-grade inflammation and increased risk of autoimmune diseases common in AN.

Starvation has a huge impact on gut microbiota, and diets that are used for re-nutrition based on animal products may support the growth of bacteria capable of triggering inflammation. [I will discuss the related and fascinating new research regarding gut enterotypes in the next blog.]

The reviewers state that: “…there is currently no empirically derived agreement on therapeutic re-nourishment in AN” and go on to consider how: “gut-brain interactions may be important for treatment regarding the determination of target weight, rapidity of weight gain, refeeding methods and composition of the diet which might all be of importance to improve long-term outcome of one of the most chronic psychiatric disorders of adolescence.”

An additional September 2017 review39 explained how gut dysbiosis is associated with brain dysfunction and with behavioural changes. In particular, they looked at the role of microbiota in DON-induced anorexia. Deoxynivalenol (DON) is one of the most important mycotoxins (any toxic substance produced by a fungus) in cereal-based foods or other food productions, produced by Fusarium species. Because of the high occurrence of DON in food combined with vast consumption of cereals and grain worldwide, the reviewers noted that DON-contaminated food is a very harmful factor for human and animal health. DON has been reported to induce anorexia at lower or chronic doses in animal models.

Other 2017/18 studies40 41 42 43 have looked at the role of gut microbiota, anorexia nervosa and eating disorders.

Study 15 – Alcohol and its changes to gut microbiota in mice

This April 2017 study44 looked at how gut microbiota may be involved in alcohol addiction. They exposed rats to vaporised ethanol and discovered that their microbiota changed – there were significant increases in some bacteria (genus Alistipes) and significant reductions in others (genera Clostridium IV and XIVb, Dorea, and Coprococcus).

The researchers commented that: “Pronounced and repeated findings have linked gut microbiome to stress, anxiety, and depression….These findings…align with previous research showing similar microbiota alterations in inflammatory states during alcoholic hepatitis and psychological stress.

Other 2017/18 studies40 45  have looked at the role of gut microbiota and the effects of alcohol use.

Study 16 – Gut microbiota appear to affect stress responses and cognitive functioning

A March 2017 review46 again pointed out how gut microbes are capable of producing most neurotransmitters found in the human brain. They consider that: “…certain bacteria may have an impact on stress responses and cognitive functioning.”

There are additional studies47 in this area of stress and the microbiota-gut-brain axis.

One interesting review48 looks at the links between gut microbiota, stress and the practice of meditation. The research team recommends; “the integration of meditation into conventional health care and wellness models. Concurrently, studies to explore the effects of meditation on human microbiota are warranted.”

Study 17 – Gut microbiota and faecal metabolic phenotype associated with depression

A May 2017 study49 confirmed that accumulating evidence supports the idea that gut microbiota affects not only gastrointestinal physiology but also central nervous system (CNS) function and behaviour through the microbiota-gut-brain axis. The researchers found that depression led to significant gut microbiota changes, at the phylum and genus levels in stressed (depressive) rats compared to controls. The bacterial genera Marvinbryantia, Corynebacterium, Psychrobacter, Christensenella, Lactobacillus, Peptostreptococcaceae incertae sedis, Anaerovorax, Clostridiales incertae sedis and Coprococcus were significantly decreased, whereas Candidatus Arthromitus and Oscillibacter were markedly increased in model rats compared with normal controls. There were also changes found in faecal metabolic phenotype* of depressive rats, including lower levels of amino acids, fatty acids, and higher amounts of bile acids, hypoxanthine and stercobilins. They concluded that: “These results showed that the gut microbiota was altered in association with fecal metabolism in depressive conditions.”

*Phenotype – the set of observable characteristics of an individual resulting from the interaction of its genotype (the genetic constitution of an individual organism) with the environment.

A November/December 2017 review50 pointed out that the composition of one’s gut microbiota is unique, dynamic, and influenced by the following factors:

  • genetics
  • diet
  • age
  • metabolism
  • medication use
  • stress
  • geography

A February 2018 study51 looked at the effectiveness of faecal transplants for those with major depressive disorder (MDD).

Study 18 – Treating depression with probiotics instead of antidepressants

A February 2017 review52 pointed out that antidepressants have been traditionally used because it has been considered that this was the only route available in order to alter neurotransmitter activity in the brain and thus improve symptoms of depression. Recent advances in treating psychiatric disorders by altering the gut microbiome have made probiotics (bacteria that are consumed) an interesting alternative.

They concluded that: “The evidence for probiotics alleviating depressive symptoms is compelling but additional double-blind randomized control trials in clinical populations are warranted to further assess efficacy.”

Further 2017/18 studies and reviews have looked into the role of probiotics in relation to major depressive disorder (MDD) and bipolar disorder (BD)53 .

Study 19 – Treating depression with prebiotics

This 2017 study54 looked at whether prebiotics (non-digestible food ingredients that promote the growth of beneficial bacteria in the intestines) rather than probiotics (the bacteria themselves) modify behaviour across domains relevant to anxiety, depression, cognition, stress response, and social behaviour in mice.

They concluded that their research data: “…strongly suggest a beneficial role of prebiotic treatment for stress-related behaviors. These findings strengthen the evidence base supporting therapeutic targeting of the gut microbiota for brain-gut axis disorders, opening new avenues in the field of nutritional neuropsychopharmacology.”

[The researchers used specific prebiotics, such as fructooligosaccharides (FOS) and galactooligosaccharides (GOS). There are two approaches to prebiotics – one which separates the active ingredients from the food itself and sells it as a tablet or drink, and the other which relies on just eating the foods themselves which contain the prebiotics in a natural state (often called “functional foods”). A 2003 ScienceDirect article55 discusses this matter in more detail. For further advice on pre- and probiotics, Dr Greger56 has some articles and videos on the subject, and Dr Michael Klaper57 is an excellent source, too – recommending that the following are the “good” bacteria we want to see listed on any probiotic products:

  • Lactobacillus acidophilus
  • Lactobacillus plantarum
  • Lactobacillus. salivarius
  • Lactobacillus. bulgaricus
  • Lactobacillus casei
  • Lactobacillus bifidus
  • Lactobacillus rhamnosus
  • Bifidobacteria longum]

An April 2018 randomised trial58 considered the effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder (MDD). They report that: “Overall, 8 weeks of probiotic supplements to subjects with MDD resulted in an improvement in BDI score compared with placebo whereas no significant effect of prebiotic supplementation was seen.

Study 20 – Bifidobacterium & resistance to stress factors

In this April 2017 study59 three types of mice were exposed to stresses and their responses monitored in order to see if anything changed in the type of bacteria they had in their gut microbiota. There was a marked appearance of Bifidobacterium in mice which were resilient to stress, whereas mice in the control and susceptible groups had Bifidobacterium levels below the detection limit.

When oral Bifidobacterium was given, it significantly increased the number of resilient mice within the groups as a whole.

The researchers concluded that: “…Bifidobacterium may confer resilience to CSDS [chronic social defeat stress]. Therefore, supplementation of Bifidobacterium may prevent the onset of depression from stress in humans. In addition, supplementation of Bifidobacterium may prevent or minimize relapse from remission induced by inflammation and/or stress in depressed patients.

[Once again, we see the three topics of depression, inflammation and the gut microbiota-brain axis being linked together.]

A similar November 2017 study60 looked at chronic social defeat stresses in male mice. The researchers concluded that there were: “…changes in the mRNA expression of interleukin (IL)-1β and IL-6 [glycoproteins produced by leucocytes for regulating immune responses] within the prefrontal cortex were associated with elevated abundance of Flavobacterium spp. [see list61 of some “opportunistic bacteria below] and reduced abundance of Turicibacter spp., which were also strongly correlated to social avoidance severity. Although at this time a causal connection cannot be inferred, these results point to the possibility that specific clusters of bacterial communities in cecum contents may be linked to vulnerability to social deficits stemming from prolonged social stressor experiences.

Other studies62 63 look at the role of the microbiota in social stress/social stress defeat models.

Study 21 – Gender differences in gut microbiota & obesity

The idea that our gender can affect the type of microbiota within our guts is an interesting concept and has been explored to some extent in a study mentioned above25 which looked at the effect of in utero stress on female offspring in adulthood.

In this September 2017 study64 , it was pointed out that obesity is associated with a high prevalence of mood disorders such as anxiety and depression. The gut microbiota can be influenced by both stress and a high fat diet. In their experiments, the researchers induced obesity in mice using a high fat diet, and then the mice were stressed using a “chronic unpredictable mild stress protocol”.

The composition of the gut microbiota and the high-anxiety behaviours were measured. The researchers found that their results: “…revealed distinct gender differences in the impacts of obesity and stress on anxiety-like behaviors, activity levels, and composition of the gut microbiota.”

The results showed differences in the microbiota between male and female mice when responding to stress. The most most striking result was how similar the microbiota were of stressed female mice, whether or not they were obese. Specifically, stress in non-obese female mice caused the gut microbiota to more closely resemble the microbiota produced by the long-term consumption of a high fat diet, even though the non-obese female mice had no weight gain. Male mice did not show the same effect.

The researchers concluded by emphasising: “…the importance of considering gender as a biological variable in studies on the role of gut microbiota in obesity-related mood disorders.

A February 2018 review65 addresses the shared biological mechanisms in obesity and depression. A March 2017 review66 looked at the interplay between the gut-brain axis, obesity and cognitive function.

Study 22 – Reversing depression with a single bacterium supplementation in mice

This September 2017 study67 noted that diet-induced obesity has revealed that obese animals are prone to anxious and depressive-like behaviours. The researchers wanted to see if adding a single bacterium (Bifidobacterium pseudocatenulatum CECT 7765) could affect the regulating the gut-brain axis so as to reverse these obesity-related neurological conditions.

A complex series of behavioural tests were performed both before and after administration of the bacteria to the obese stressed mice, and it was found that found that obese mice showed an amelioration in their anhedonia (an inability to feel pleasure in normally pleasurable activities, like eating or playing). Positive behavioural changes were paralleled by other physiological changes within endocrine and immune mediators of the gut-brain axis:

  • Reduction of obesity-associated hyperleptinemia (a consistent feature of obesity where the “hunger hormone” leptin, rather than for instance insulin in diabetes, is produced in high quantities but resistance to it has developed)
  • Restoration of leptin signalling
  • Fat mass loss
  • Restoration of the obesity-induced reductions in adrenaline in the hypothalamus
  • Reduction in the obesity-induced upregulation of TLR2 protein or gene expression in the intestine and hippocampus
  • Restored alterations of 5-HT levels in the hippocampus

In summary, the results may be taken to suggest that administering bacteria (such as B. pseudocatenulatum CECT 7765) into the diet could replace or supplement current pharmaceutical/psychiatric interventions for those suffering from depressive behaviour comorbid with obesity.

Study 23 – Microbiota , schizophrenia & antipsychotic drug induced weight gain

A February 2018 review68  looked at how gut microbiota could both affect psychiatric conditions such as schizophrenia and interact with the drugs used to treat these conditions. some of these pharmaceuticals may alter microbiota and potentially contribute to adverse effects of the drug. Whilst other studies have described the relationship of microbiota to psychiatric disorders such as depression and anxiety, very few reports to date have looked at the role of the microbiome in schizophrenia. This review examined the evidence surrounding gut microbiota in schizophrenia and the potential for antipsychotics to alter the gut microbiota and promote adverse metabolic events, including weight gain.

Additional studies and reviews69 70 have looked at the role of targeting microbiota as a means of treating schizophrenia.

Study 24 – Parkinson’s disease, depression and the “second brain”

A March 2017 study71 looked at how the signals released within the microbiota-gut-brain axis (involving the co-ordination of multiple factors, including vagal nerve activation, cytokine production, and the release of neuropeptides/neurotransmitters and short chain fatty acids) can penetrate the blood-brain barrier, thereby influencing the maturation and activation state of the microglia (vital immune cells in the brain). Once activated, microglia play a fundamental part in immune surveillance, synaptic pruning, and clearance of debris. They comment that: “Microbiota (the collective bacteria, viruses, fungi and other microorganisms that live in the digestive tract), sometimes referred to as the “second genome” or the “second brain,” may influence our health in ways that scientists are just now beginning to understand. Scientists now believe that the microbiota and all that it involves may be a way to treat any number of disorders, including Parkinson’s disease and depression.

The following is a diagram of the microbiota-gut-brain axis from their study

Key to diagram: Communication within the microbiota-gut-brain axis involves the co-ordination of multiple factors, including vagal nerve activation, cytokine production, neuropeptide/neurotransmitter release and short chain fatty acid release. When these signals penetrate the blood brain barrier, they influence the maturation and activation state of the microglia, key immune cells in the brain. Once activated, microglia play a fundamental part in immune surveillance, synaptic pruning, and clearance of debris. The HPA axis* by cortisol production can in turn suppress the activation state of brain microglia, as well as influence cytokine release and trafficking of monocytes from the periphery to the brain.

*The HPA (hypothalamic pituitary adrenal) axis is our central stress response system. it is defined as “…an eloquent and every-dynamic intertwining of the central nervous system and endocrine system.72

Another review73 in March 2018 looked at the links between ageing and both Parkinson’s disease and Alzheimer’s disease. The conclusion was that the risk of both of these conditions is linked to the reduction in the diversity of gut microbiota as we age. The following diagram partly illustrates the area of research in which they were involved.

Study 25 – Diabetes, depression & the microbiota-gut-brain axis

An August 2017 review74 looked at the shared relationship of the hypothalamic-pituitary-adrenal (HPA) and microbiota-gut-brain axes in association with depression and type 2 diabetes. They considered that both depression and diabetes are associated with dysregulation of these axes, and that therapeutic actions include psychotherapy, healthy eating, physical activity, good sleep, and certain anti-inflammatory or antidepressant medications.

Study 26 – The role of the peptide-microbiota link in depression & anxiety

In a January 2018 review75 ,  looks at the role that the relationship between the gut microbiota and peptides76 might play in anxiety and depression.

Intestinal bacteria & peptide hormones

It’s important to understand the role of bidirectional interactions in the context of the microbiota-gut-brain axis between intestinal bacteria and those peptide hormones that are released from the gut.77 . Not many people realise that the GI (gastrointestinal) tract is the largest endocrine organ in mammals, secreting dozens of different signalling molecules, including peptides.

Gut-brain communication

Indirect gut-brain communication can be enabled by gut peptides that are released into systemic circulation (see diagram), where they can then bind to cognate receptors on immune cells and vagus nerve terminals. Gut peptide concentrations are not only modulated by enteric microbiota signals, but also vary according to the composition of gut microbiota. [And, as we know from other studies, diet, exercise and other environmental factors can directly and indirectly affect the type of microbiota (health-promoting or health-compromising) that we have living within us.]

The reviewers consider the role of gut microbiota as a regulator of anxiety and depression, and explore the role of gut-derived peptides as signalling molecules in microbiome-gut-brain communication.

They consider that potential interactions between microbiota and gut hormones/endocrine peptides include the following:

  • neuropeptide Y78
  • peptide YY79
  • pancreatic polypeptide80
  • cholecystokinin81
  • glucagon-like peptide82
  • corticotropin-releasing factor83
  • oxytocin84
  • ghrelin85

The reviews conclude that these gut peptides are important regulators of microbiota-gut-brain signalling in health and stress-related psychiatric illnesses.

Study 27 – IBD, stress & the gut-brain axis

Whilst IBD (irritable bowel disease) and depression has been covered in greater detail elsewhere86 , this December 2017 review87 makes some interesting observations that are worth mentioning in the context of this blog. The reviewers state that: “…the brain-gut axis serves as a circuit that incorporates the human experience, the state of mind, the gut microbiome, and the immune response that ultimately drives the phenotypic expression of inflammatory bowel disease (IBD).

They consider the variety of biological pathways through which stress can play a deleterious role. These include the common feature of IBD, increased intestinal permeability, which is instrumental in facilitating intestinal translocation of bacteria from the intestines into the rest of the body – not something you want to happen.

In addition, they emphasise that stress has an important impact on symptoms in IBD. They go on to state that, although it’s important to pay attention to stress and psychiatric comorbidity, more clinical trials are needed in order to prove that stress actually triggers increased intestinal inflammation, so that direct management of IBD can be established and implemented.

Other studies and reviews88 have looked at the relationship between the microbiota-gut-brain axis and stress.

Study 28 – Lifespan seen to depend increasingly on the microbiota

This interesting paper89 starts from the hypothesis that we all have a common pathway from well-being and health to chronic disease and potentially an early death death, which comprises the following steps:

  • An unhealthy diet
  • A sedentary life style
  • Permanent exposure  to xenobiotics (a substance, typically a synthetic chemical, that’s foreign to the body)
  • Intestinal dysbiosis
  • Alteration of the intestinal mucus layer (especially that of the colon)
  • Disruption of the endothelial tight junctions
  • Metabolic endotoxemia (presence of endotoxins in the blood, which, if derived from gram-negative rod-shaped bacteria, may cause haemorrhages, necrosis of the kidneys, and shock.) plus resulting bacterial translocation
  • Inflammation
  • Exacerbation of the enteric nervous system (ENS) and consequent maladaptation and malfunctioning of the colon
  • Epigenetic manifestations (arising from non-genetic influences on gene expression)
  • Chronopathy (a deficiency of time sense and inability to manage time, to comply with schedules that might improve health – e.g. putting off until the future those positive changes that we know should be made now)
  • Premature death

The authors consider that if we want to maintain good health (or improve/reverse chronic diseases), we should aim for homeostatic balance within the intestinal microbiota (eubiosis – healthy/hygienic lifestyle in relation to the GI tract), most of which is located in the colon. They mention Lynn Margulis, who was one of the main scientists to highlight the importance of the role played by bacteria not only in the origin of all biological species now present on earth, but also on their role in global homeostasis. Bacteria do not rely on other living beings for their existence, while the latter depend completely on the former. Humans are no exception, and new evidence emerges each day about the pivotal role of intestinal microbiota in human health, disease and, in general, in well-being.

  • The authors also point out some interesting facts:
  • There are ~10 times more bacteria in the gut than human cells in every human being
  • The microbiome is ~100-150 times bigger that the human genome
  • There’s a clear link between intestinal microbiota and many of the most common chronic diseases, from obesity and diabetes to depression and Parkinson disease and different kinds of cancer.

A rather interesting implication of this theory is that we should all become “microbiota farmers” – , becoming more aware of our intestinal microbiota, monitoring it and and taking good care of it permanently.

The authors add that, as part of good life habits (healthy eating, physical exercise), we should probably undergo periodic seasons of fasting and colon cleansing, as it was common in older times.

Study 29 – Psychobiotics – a new way for treating mental illness?

This November 2017 review90  introduces for the first time (at least to my ears) the term “psychobiotics“. It is another term which describes what we have been talking about in this blog – namely, the new field in neuroscience that looks at the significant impact of gut microbiomes on mood and cognition.

The author notes how studies have shown that increase in the amount of good bacteria in the gut achieve the following:

  • curb inflammation
  • reduce cortisol level
  • reduce symptoms of depression and anxiety
  • lower stress reactivity
  • improve memory
  • lesson neuroticism and social anxiety

He continues with the comment that taking advantage of the endogenous beneficial gut bacteria or through the ingestion of probiotics can: “…function mechanistically as delivery vehicles for neuroactive compounds“.

Thus, he defines a psychobiotic as a live organism that, when ingested in adequate amounts, can produce a health benefit in patients suffering from psychiatric illness. Further study of probiotics: “…may open up the possibility of rearrangement of intestinal microbiota for effective management of various psychiatric disorders.”

A March 2018 review73 considered how reduction in gut microbiota diversity is one of the hallmarks of aging. The researchers consider that: “… the gut microbiota-brain axis still remains a fascinating target to be exploited to attenuate some of the most burdensome consequences of aging.

The following diagram gives an insight into the nature of their findings regarding microbial diversity, ageing, Parkinson’s disease, Alzheimer’s disease.

Study 30 – Neuromicrobiology – nociception & brain development

Another term used for this rapidly-expanding field of neuroscience is “neuromicrobiology”, used in this February 2018 review91 . Whilst the authors comment on medical conditions influenced of the microbiota-gut-brain axis that we have already covered above (such as autism spectrum disorders, Alzheimer’s disease, Parkinson’s disease, depression, and anxiety disorder), they also mention that gut microbes may be involved in nociception92 and brain development. They suggest that future efforts will be required in order to establish causal mechanisms for the observed associations, as well as efforts to: “…to engineer effective interventions to modulate the effects of the microbiome on the central nervous system.”

[Once again, the elephant in the room (dietary and other lifestyle factors that can be controlled by the individual without need for possibly costly pharmaceutical interventions – costly in terms of money and unwanted side-effects) goes unmentioned.]

Additional reviews and studies93 consider the role of gut microbiota in the development of the brain.

Study 31 – Nutritional psychiatry – where to next?

This March 2017 review94 , along with other reviews and studies95 96 97 98 99 100 101 102 103 104 105 106  , discuss the evolving field of nutritional psychiatry. [Something that could be argued has been going on unclassified as such for the whole of human and animal evolution.] The authors state that: “The nascent field of ‘Nutritional Psychiatry’ offers much promise for addressing the large disease burden associated with mental disorders. A consistent evidence base from the observational literature confirms that the quality of individuals’ diets is related to their risk for common mental disorders, such as depression. This is the case across countries and age groups. Moreover, new intervention studies implementing dietary changes suggest promise for the prevention and treatment of depression. Concurrently, data point to the utility of selected nutraceuticals as adjunctive treatments for mental disorders and as monotherapies for conditions such as ADHD.” [A resulting conflict between, on the one hand, “selecting” chemicals from foods and, on the other, consuming the whole food itself, in order to duplicate what consumption of the whole food itself has been shown to achieve, is discussed elsewhere107 .]

BBC News Article

Gut microbiota are becoming front page news – well almost! An interesting article108 appeared on the BBC News website entitled “How bacteria are changing your mood” by James Gallagher, Presenter of The Second Genome, BBC Radio 4, from which I borrowed the main photo.

Joe’s Comments

The above is an overview of some of the current research data on the relationship between the trillions of bacteria that live within our guts and the rest of our body and brain. The relationship is complex and we are just at the stat of the journey of discovery in this field. There are issues with probiotics that should warrant some caution if you are considering taking them; although there are indications that their use, along with prebiotics, has some therapeutic value.

My suggestions for the best way of ensuring you have the healthiest possible “friendly” bacteria within you are:

  • eat a diet completely or, at least, largely consisting of a wide variety of whole plant foods
  • avoid processed & junk foods
  • minimise or, ideally, eradicate all animal products from your diet
  • cut down added salt and sugar to negligible amounts or completely
  • cut out ALL added oils and fats
  • get lots of daily exercise
  • don’t smoke
  • drink little or, ideally, no alcohol
  • get plenty of sleep
  • do all you can to reduce stress in your day-to-day life

I will be writing additional blogs on the relationship of our microbiota to other health conditions, and also explaining why eating plants rather than animal foods is a healthier option for those tiny but mighty microbes within.


References

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  53.  Microbiota abnormalities and the therapeutic potential of probiotics in the treatment of mood disorders. Rios AC, Maurya PK, Pedrini M, Zeni-Graiff M, Asevedo E, Mansur RB, Wieck A, Grassi-Oliveira R, McIntyre RS, Hayashi MAF, Brietzke E. Rev Neurosci. 2017 Oct 26;28(7):739-749. doi: 10.1515/revneuro-2017-0001. Review. PMID: 28593878. []
  54.  Targeting the Microbiota-Gut-Brain Axis: Prebiotics Have Anxiolytic and Antidepressant-like Effects and Reverse the Impact of Chronic Stress in Mice. Burokas A, Arboleya S, Moloney RD, Peterson VL, Murphy K, Clarke G, Stanton C, Dinan TG, Cryan JF. Biol Psychiatry. 2017 Oct 1;82(7):472-487. doi: 10.1016/j.biopsych.2016.12.031. Epub 2017 Feb 24. PMID: 28242013. []
  55. ScienceDirect: Discussion of Prebiotics & Probiotics. []
  56. What is a good source of probiotics? Written By Michael Greger M.D. FACLM on November 8th, 2012. []
  57. Dr Michael Klaper: Q&A: PROBIOTICS PRINCIPLES. []
  58. Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: A randomized clinical trial. Kazemi A, Noorbala AA, Azam K, Eskandari MH, Djafarian K. Clin Nutr. 2018 Apr 24. pii: S0261-5614(18)30161-4. doi: 10.1016/j.clnu.2018.04.010. PMID: 29731182. []
  59. Bifidobacterium in the gut microbiota confer resilience to chronic social defeat stress in mice. Yang C, Fujita Y, Ren Q, Ma M, Dong C, Hashimoto K. Sci Rep. 2017 Apr 3;7:45942. doi: 10.1038/srep45942. PMID: 28368029. []
  60. Implications of the gut microbiota in vulnerability to the social avoidance effects of chronic social defeat in male mice. Szyszkowicz JK, Wong A, Anisman H, Merali Z, Audet MC. Brain Behav Immun. 2017 Nov;66:45-55. doi: 10.1016/j.bbi.2017.06.009. Epub 2017 Jun 17. PMID: 28629758. []
  61. Opportunistic Pathogens – Slides from slideshare.net. []
  62. Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model. Qu Y, Yang C, Ren Q, Ma M, Dong C, Hashimoto K. Sci Rep. 2017 Nov 16;7(1):15725. doi: 10.1038/s41598-017-16060-7. PMID: 29147024. []
  63. Possible role of the gut microbiota-brain axis in the antidepressant effects of (R)-ketamine in a social defeat stress model. Yang C, Qu Y, Fujita Y, Ren Q, Ma M, Dong C, Hashimoto K. Transl Psychiatry. 2017 Dec 18;7(12):1294. doi: 10.1038/s41398-017-0031-4. PMID: 29249803. []
  64. Gender-based differences in host behavior and gut microbiota composition in response to high fat diet and stress in a mouse model. Bridgewater LC, Zhang C, Wu Y, Hu W, Zhang Q, Wang J, Li S, Zhao L. Sci Rep. 2017 Sep 7;7(1):10776. doi: 10.1038/s41598-017-11069-4. PMID: 28883460. []
  65. Depression and obesity: evidence of shared biological mechanisms. Milaneschi Y, Simmons WK, van Rossum EFC, Penninx BW. Mol Psychiatry. 2018 Feb 16. doi: 10.1038/s41380-018-0017-5. [Epub ahead of print] Review. PMID: 29453413. []
  66. Interplay Between the Gut-Brain Axis, Obesity and Cognitive Function. Agustí A, García-Pardo MP, López-Almela I, Campillo I, Maes M, Romaní-Pérez M, Sanz Y. Front Neurosci. 2018 Mar 16;12:155. doi: 10.3389/fnins.2018.00155. eCollection 2018. Review. PMID: 29615850. []
  67. Bifidobacterium pseudocatenulatum CECT 7765 Ameliorates Neuroendocrine Alterations Associated with an Exaggerated Stress Response and Anhedonia in Obese Mice. Agusti A, Moya-Pérez A, Campillo I, Montserrat-de la Paz S, Cerrudo V, Perez-Villalba A, Sanz Y. Mol Neurobiol. 2017 Sep 18. doi: 10.1007/s12035-017-0768-z. PMID: 28921462. []
  68. The microbiome-gut-brain axis: implications for schizophrenia and antipsychotic induced weight gain. Kanji S, Fonseka TM, Marshe VS, Sriretnakumar V, Hahn MK, Müller DJ. Eur Arch Psychiatry Clin Neurosci. 2018 Feb;268(1):3-15. doi: 10.1007/s00406-017-0820-z. Epub 2017 Jun 17. Review. PMID: 28624847. []
  69. The role of microbiota in the pathogenesis of schizophrenia and major depressive disorder and the possibility of targeting microbiota as a treatment option. Lv F, Chen S, Wang L, Jiang R, Tian H, Li J, Yao Y, Zhuo C. Oncotarget. 2017 Sep 27;8(59):100899-100907. doi: 10.18632/oncotarget.21284. eCollection 2017 Nov 21. Review. PMID: 29246029. []
  70. Overview and systematic review of studies of microbiome in schizophrenia and bipolar disorder. Nguyen TT, Kosciolek T, Eyler LT, Knight R, Jeste DV. J Psychiatr Res. 2018 Apr;99:50-61. doi: 10.1016/j.jpsychires.2018.01.013. Epub 2018 Jan 31. Review. PMID: 29407287. []
  71. Gut Feelings on Parkinson’s and Depression.Dinan TG, Cryan JF.Cerebrum. 2017 Mar 1;2017. pii: cer-04-17. eCollection 2017 Mar-Apr. PMID: 28698775. []
  72. Integrative Therapeutics: The HPA Axis. []
  73. Of Microbes and Minds: A Narrative Review on the Second Brain Aging. Calvani R, Picca A, Lo Monaco MR, Landi F, Bernabei R, Marzetti E. Front Med (Lausanne). 2018 Mar 2;5:53. doi: 10.3389/fmed.2018.00053. eCollection 2018. Review. PMID: 29552561. [] []
  74. Shared Dysregulation of Homeostatic Brain-Body Pathways in Depression and Type 2 Diabetes. Hoogendoorn CJ, Roy JF, Gonzalez JS. Curr Diab Rep. 2017 Aug 16;17(10):90. doi: 10.1007/s11892-017-0923-y. Review. PMID: 28815394. []
  75. Anxiety, Depression, and the Microbiome: A Role for Gut Peptides. Lach G, Schellekens H, Dinan TG, Cryan JF. Neurotherapeutics. 2018 Jan;15(1):36-59. doi: 10.1007/s13311-017-0585-0. Review. PMID: 29134359. []
  76. Definition of peptides: Peptides, from which proteins are formed, are short chains of amino acid monomers (molecules that can be bonded to other identical molecules to form a polymer.) Naturally, they are smaller than proteins, which are also chains of amino acids. Peptide molecules are small enough to be synthesised from the constituent amino acids and therefore, by convention, are called peptides rather than proteins. Depending on the number of amino acids involved, peptides can be called dipeptides, tripeptides, tetrapeptides, etc. They are linked together by peptide bonds, to form longer chains of amino acids, and thus proteins. []
  77. Definition of peptide hormones: Peptide hormones are hormones whose molecules are peptides rather than with protein hormones whose molecules are proteins. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocrine system of animals, including humans. []
  78. Neuropeptide Y (NPY) is a neurotransmitter in the central and peripheral nervous system, which is stored mainly in the hypothalamus as the central site of appetite regulation. []
  79. Peptide YY is a hormone made in the small intestine. It helps to reduce appetite and limit food intake. []
  80. Pancreatic Polypeptide (PP) is a 36 amino acid peptide produced and secreted by PP cells (originally termed F cells) of the pancreas which are primarily located in the Islets of Langerhans. It is part of a family of peptides that also includes Peptide YY (PYY) and Neuropeptide Y (NPY). PP is rapidly released after a meal but remains elevated for 4-6 hours in humans with the Vagus nerve being the major stimulator. PP has effects on GI motility, metabolism and food intake. A potential role as a satiety factor comes from the observation that PP secretion is absent in obese children with Prader-Willi syndrome. Its primary action on the exocrine pancreas is to inhibit secretion in vivo by acting on receptors in the brain leading to inhibition of vagal output to the pancreas. []
  81. Cholecystokinin is a gut hormone released after a meal, which helps digestion and reduces appetite. []
  82. Glucagon-like peptide-1 (GLP-1) is an intestinally derived incretin hormone that potentiates the glucose metabolism-dependent secretion of insulin from β cells located within the islets of Langerhans. []
  83. Corticotrophin-releasing hormone is the main element that drives the body’s response to stress. It is also present in diseases that cause inflammation. Too much or too little corticotrophin-releasing hormone can have a range of negative effects. []
  84. Oxytocin is a hormone and a neurotransmitter that is involved in childbirth and breast-feeding. It is also associated with empathy, trust, sexual activity, and relationship-building. It is sometimes referred to as the “love hormone,” because levels of oxytocin increase during hugging and orgasm. It may also have benefits as a treatment for a number of conditions, including depression, anxiety, and intestinal problems. Oxytocin is produced in the hypothalamus, a part of the brain. Females usually have higher levels than males. []
  85. Ghrelin is produced by the stomach. Among its numerous functions, ghrelin increases appetite and stimulates the release of growth hormone. []
  86. Depression & IBD / Crohn’s Disease / Ulcerative Colitis []
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  88. Stress & the gut-brain axis: Regulation by the microbiome. Foster JA, Rinaman L, Cryan JF. Neurobiol Stress. 2017 Mar 19;7:124-136. doi: 10.1016/j.ynstr.2017.03.001. eCollection 2017 Dec. Review. PMID: 29276734. []
  89. The colon revisited or the key to wellness, health and disease. Gonzalez-Correa CA, Mulett-Vásquez E, Miranda DA, Gonzalez-Correa CH, Gómez-Buitrago PA. Med Hypotheses. 2017 Oct;108:133-143. doi: 10.1016/j.mehy.2017.07.032. Epub 2017 Jul 29. PMID: 29055387. []
  90. Psychobiotics: A new approach for treating mental illness? Misra S, Mohanty D. Crit Rev Food Sci Nutr. 2017 Nov 30:1-7. doi: 10.1080/10408398.2017.1399860. PMID: 29190117. []
  91. Neuromicrobiology: How Microbes Influence the Brain. de la Fuente-Nunez C, Meneguetti BT, Franco OL, Lu TK. ACS Chem Neurosci. 2018 Feb 21;9(2):141-150. doi: 10.1021/acschemneuro.7b00373. Epub 2017 Dec 28. PMID: 29220570. []
  92. Definition of nociception: Pain is termed nociceptive (nocer – to injure or to hurt in Latin), and nociceptive means sensitive to noxious stimuli. Noxious stimuli are stimuli that elicit tissue damage and activate nociceptors. … Nociceptors are free (bare) nerve endings found in the skin (Figure 6.2), muscle, joints, bone and viscera. []
  93. Current evidence linking diet to gut microbiota and brain development and function. Ceppa F, Mancini A, Tuohy K. Int J Food Sci Nutr. 2018 Apr 19:1-19. doi: 10.1080/09637486.2018.1462309. PMID: 29671359. []
  94.  Nutritional Psychiatry: Where to Next? Jacka FN. EBioMedicine. 2017 Mar;17:24-29. doi: 10.1016/j.ebiom.2017.02.020. Epub 2017 Feb 21. Review. PMID: 28242200. []
  95.  Can gut microbes play a role in mental disorders and their treatment? Latalova K, Hajda M, Prasko J. Psychiatr Danub. 2017 Mar;29(1):28-30. PMID: 28291971. []
  96.  The Microbiome and Host Behavior. Vuong HE, Yano JM, Fung TC, Hsiao EY. Annu Rev Neurosci. 2017 Jul 25;40:21-49. doi: 10.1146/annurev-neuro-072116-031347. Epub 2017 Mar 8. Review. PMID: 28301775. []
  97.  Gut-Brain Axis and Behavior. Martin CR, Mayer EA. Nestle Nutr Inst Workshop Ser. 2017;88:45-53. doi: 10.1159/000461732. Epub 2017 Mar 27. Review. PMID: 28346923. []
  98.  Blockade of interleukin-6 receptor in the periphery promotes rapid and sustained antidepressant actions: a possible role of gut-microbiota-brain axis. Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M, Hashimoto K. Transl Psychiatry. 2017 May 30;7(5):e1138. doi: 10.1038/tp.2017.112. PMID: 28556833.  []
  99. Depressed gut? The microbiota-diet-inflammation trialogue in depression. Koopman M, El Aidy S; MIDtrauma consortium. Curr Opin Psychiatry. 2017 Sep;30(5):369-377. doi: 10.1097/YCO.0000000000000350. Review. PMID: 28654462. []
  100. Recent developments in understanding the role of the gut microbiota in brain health and disease. Sherwin E, Dinan TG, Cryan JF. Ann N Y Acad Sci. 2017 Aug 2. doi: 10.1111/nyas.13416. [Epub ahead of print] Review. PMID: 28768369.))  ((A psychology of the human brain-gut-microbiome axis. Allen AP, Dinan TG, Clarke G, Cryan JF. Soc Personal Psychol Compass. 2017 Apr;11(4):e12309. doi: 10.1111/spc3.12309. Epub 2017 Apr 18. PMID: 28804508. []
  101. Influence of gut microbiota on neuropsychiatric disorders. Cenit MC, Sanz Y, Codoñer-Franch P. World J Gastroenterol. 2017 Aug 14;23(30):5486-5498. doi: 10.3748/wjg.v23.i30.5486. Review. PMID: 28852308. []
  102. The Microbiota-Gut-Brain Axis in Neuropsychiatric Disorders: Pathophysiological Mechanisms and Novel Treatments. Kim YK, Shin C. Curr Neuropharmacol. 2017 Sep 15. doi: 10.2174/1570159X15666170915141036. PMID: 28925886. []
  103. Nutritional psychiatry: the present state of the evidence. Marx W, Moseley G, Berk M, Jacka F. Proc Nutr Soc. 2017 Nov;76(4):427-436. doi: 10.1017/S0029665117002026. Epub 2017 Sep 25. PMID: 28942748. []
  104. The microbiome as a novel paradigm in studying stress and mental health. Liu RT. Am Psychol. 2017 Oct;72(7):655-667. doi: 10.1037/amp0000058. PMID: 29016169. []
  105. Pharmacogenomics in the treatment of mood disorders: Strategies and Opportunities for personalized psychiatry. Amare AT, Schubert KO, Baune BT. EPMA J. 2017 Sep 5;8(3):211-227. doi: 10.1007/s13167-017-0112-8. eCollection 2017 Sep. Review. PMID: 29021832. []
  106. Harnessing Gut Microbes for Mental Health: Getting From Here to There. Bruce-Keller AJ, Salbaum JM, Berthoud HR. Biol Psychiatry. 2018 Feb 1;83(3):214-223. doi: 10.1016/j.biopsych.2017.08.014. Epub 2017 Aug 30. Review. PMID: 29031410. []
  107. Wholism vs Reductionism  – Not Just a War of Words. []
  108. How bacteria are changing your mood []