Gut Feelings

Over the last couple of months I’ve discussed the relationship between the bacteria in your gut and the brain, the bacteria’s influence on neurodevelopment, and how there’s really not as much bacteria in our bodies as we once thought. So how are researchers taking advantage of this interplay between bacteria and brain? Enter psychobiotics. This term has been coined to describe a class of probiotics that have the ability to modulate the gut-brain axis, imparting a beneficial effect on mood, and cognition. The idea here is to eventually employ these psychotropic bacteria in clinical settings to improve psychiatric symptoms in individuals. Now is this in the realm of possibility, or simply too good to be true? Let’s talk about that.

Probiotics are live microorganisms that, when administered in adequate amounts, confer a beneficial effect on the health of the host. Administering bacteria to provide health benefits is not a new concept and you’ve probably seen a variety of probiotics lining the shelves of your local grocery store. These products are highly regulated and have a number of characteristics. An ingested probiotic needs to be non-pathogenic, it must be able to survive in the human digestive system, and it needs to compete with indigenous bacteria and effectively colonize the intestinal tract.

The gut-brain axis is a bidirectional system of communication between the gut and the brain. The bacteria can act on a number of pathways such as tryptophan metabolism, metabolite production, and the vagus nerve, to exert their influence on the brain. (For a more in depth discussion on the gut-brain axis, check out my previous post). This pathway connecting the gut to the brain is the target for these so-called psychobiotics. By modulating the gut-brain axis, perhaps it is in turn possible to modulate brain function.

Several probiotics have been shown to impart beneficial effects to improve symptoms of anxiety and depression. For example, administration of Lactobacillus rhamnosus has been shown to reduce depression-related behaviour in mice, Bifidobacterium longum has had the effect of reducing anxiety-like behaviour in rats, and Bacteroids fragilis has even alleviated autism-like behaviour in mice models.

A particularly interesting example of a psychobiotic involves Lactobacillus plantarum. In a study published earlier this year in the journal Brain Research, researchers investigated the psychotropic effects of this bacterium. Sticking with the rodent theme, mice were subjected to early life stress in the form of maternal separation. The pups were pried away from their mothers between 2 and 14 days after birth. As you would expect, this is particularly stressful for the newborn pups. Maternal separation (MS) is frequently used to induce early life stress in mice and to investigate the pathophysiology of stress-related disorders.

Figure 1: To induce early life stress, newborn mice were separated from their mothers for 3 hours a day. This was done between 2 days and 14 days after birth.

The probiotic was administered to the mice for 4 weeks after which a series of tests were performed to evaluate the pychotropic potential of the bacteria.

Mice subjected to maternal stress often show a number of behavioural abnormalities including increased anxiety-like behaviour and increased depression-like behaviour. Chronic administration of the probiotic actually caused distinct alterations to behaviour of the mice. Mice had reduced depression-like behaviour and actually demonstrated increased locomotive behaviour when compared to control mice.

So what is behind this positive effect on behaviour? Although not entirely clear, the researchers have proposed a couple of possibilities.

Mice inflicted with early life stress had significant increases in serum IL-6 levels and decreases in IL-10 levels. Alterations to these cytokines have previously been implicated with stress-related disorders in humans. In a clinical study, patients with major depression demonstrated a higher ratio of IL-6 to IL-10, as well as a decrease in serum IL-10 levels, compared to patients without major depression. Treatment of the mice with the probiotic resulted in a reduction of serum IL-6 levels. Indeed in preclinical animal studies, reductions in this cytokine have been associated with reductions in depression-like behaviour.

Figure 2: The mice that underwent early life stress were split into two groups: a control group that was fed a saline solution and an experimental group that was fed the probiotic. After administration of the probiotic the mice in the experimental group were found to have decreased depression-like behaviour.

Furthermore, mice that were administered the probiotic had increased concentration of dopamine in their prefrontal cortex. The prefrontal cortex is an intricate structure that has been associated with stress responses, decision-making, and personality (you may remember the case of Phineas Gage). The researchers suggest that the abnormal behaviour in the early-stress mice may be in part due to alterations to dopamine in the prefrontal cortex. Thus by administering the probiotic, dopaminergic activity is increased, and behaviour is normalized.

This psychobiotic looks like the real deal right?

Well, it’s not that simple  Even with promising results like this, it is very difficult to translate from animal models to the clinic, even more so when the specific mechanism of action has yet to be resolved.  

Even when studies are done with humans, we run into some difficulties. Take this study for example. A multi-species probiotic was found to reduce negative thoughts related to sad mood in healthy participants. But we do need to consider a number of other factors that may have contributed to this. The researchers did not control diet during the trial, including the consumption of other probiotics. Similarly, it is likely that other aspects of the participants’ lifestyles or environment were playing a part.

So now we arrive at back at the original question. Do these psychotropic bacteria have a realistic capacity to positively influence cognition?

Maybe.

I know that’s probably not the answer you wanted to hear, but it is the most accurate one. This entire field is still in its infancy and if you’ve been following my blog, you know there is still so much we need to learn. The bacteria are having an impact on brain and behaviour – we just don’t know exactly how. Obviously more research needs to be done to elucidate these mechanisms. And more research is required in clinically diagnosed patients. This is a fascinating field of study that seemingly holds a lot of promise. Whether we’re going to start seeing psychobiotics along side conventional probiotics on store shelves, only time will tell.

- Babar

For more: http://www.sciencedirect.com/science/article/pii/S0006899315008628

We were all teenagers once and I think it’s safe to say adolescence is a trying time for all involved. During these formative years, individuals are exposed to a number of psychological stressors amid what is a crucial period for brain development and growth. Indeed many psychiatric disorders are often found to emerge during this time. 

A recent review by scientists in Ireland (shoutout to my old stomping grounds) looked at how alterations to the gut microbiota during adolescence may influence brain development and the subsequent onset of psychiatric illness. Most of the research regarding this has been carried out in rodent models such as germ-free mice. These mice exhibit abnormalities in their stress response which is usually accompanied by a number of behavioural defects. 

Now here’s the interesting part. 

The abnormal stress response can be reversed by the introduction of colonizing bacteria in the adolescent mouse. But, dysfunctions are not reversed if bacteria are introduced to the adult mouse. This implies that there may be a window during adolescence where the introduction of bacteria could have a tangible effect. This leads to the proposal that targeting this sensitive stage of development with pre- and probiotics may provide a potential method of improving teenage psychiatric health. This is an emerging area of study but I think it will be an exciting and promising avenue of future research!

Happy last full week of class!

I took some inspiration from one of my favourite YouTube series and this is what I came up with. Enjoy! 

Right now your body is teeming with bacteria. There are close to 40 trillion microbes in the human body – about as much as the number of human cells. Not only that, but the bacteria represent over 1000 different species and upwards of 7000 different strains. With all this microbial life, it’s no surprise that they play a big role in human health. The bacteria are involved in a number of functions including protection against pathogens, fermenting indigestible nutrients, and metabolizing drugs. Recently researchers have begun to discern the microbiota’s role in brain function and mental health.

An important network that bacteria can take advantage of, to exert their influence, is the gut-brain axis. This highway of sorts is a bidirectional system of communication that links the bacteria in your gut to your brain. The microbes can utilise a number of pathways including the neural, endocrine, and immune systems.

So how do these bacteria interact with the brain? Although concrete mechanisms have yet to be determined, some possibilities have been proposed.

Bacteria in the gut can produce short chain fatty acids (SCFAs) through the fermentation of polysaccharides. Certain SCFAs such as acetic acid and butyrate act as signalling molecules and have the ability to cross the blood-brain barrier. In doing so, they can modulate neurotransmission and behaviour. For example, butyrate treatment resulted in anti-depressive effects in rats and recent studies have even suggested that increasing levels of SCFAs may be related to the development of autistic behaviour in animal models.

It has also been proposed that the gut microbiota influence the expression of brain derived neurotrophic factor (BDNF). BDNF is a protein that is crucial for brain plasticity, memory, as well as neuronal health and growth. In one study, mice were administered antibiotics so as to create pseudo germ free mice. Along with the depleted microbiota, they found significant reductions in hippocampal BDNF, and this was concomitant with deficits in cognitive function.

Another noteworthy pathway involves serotonin. There is emerging evidence that suggests a role for the gut microbiota in the development and regulation of serotonergic neurotransmission. In the gastrointestinal tract, specialized endocrine cells, called enterochromaffin cells (ECs), synthesize serotonin. The ECs accomplish this by acting on the amino acid tryptophan. Tryptophan is converted to 5-hydroxytrptophan (5-HTP) by the enzyme tryptophan hydroxylase (TPH) and this intermediate is subsequently converted to serotonin by the enzyme aromatic amino acid decarboxylase (AAAD). 

Of course, serotonin is a neurotransmitter and therefore, is able to influence signalling in the central nervous system. As such, perturbations to the levels of this neurotransmitter have been associated with mood and anxiety disorders. Reduced levels of circulating serotonin are characteristic of germ-free mice when compared to conventional mice. Researchers have hypothesized that this is due to reduced expression of TPH. This may also explain why germ-free mice show elevated levels of tryptophan in circulation. A number of bacterial species are able to produce tryptophan and a handful are even able to synthesize serotonin. Because of this, the serotonergic system has become an attractive target for probiotic and prebiotic action. Indeed, administering certain species of bacteria has had anti-anxiety, and anti-depressive effects in mice. This lends support to the idea that probiotics and prebiotics have a potential therapeutic application for depression and other psychiatric conditions.

Figure 1. Enterochromaffin cells convert tryptophan to 5-hydroxytryptophan by the enzyme tryptophan hydroxylase (TPH). Aromatic amino acid decarboxylase (AAAD) converts this intermediate to serotonin which can then proceed to influence neurotransmission in the brain.

While we’re on the topic, Bell’s annual “Let’s Talk” event took place last month and one of the most striking statistics I came across was that 3 million Canadians are suffering from depression at this very moment. So depression is quickly becoming a more apparent issue in our communities and researchers are turning to the microbiota and bacteria’s role in this disorder.

One proposed mechanism for this interaction involves leaky gut. Leaky gut is the term given to the compromised state of the epithelial gut barrier. A healthy barrier is important as it allows the absorption of nutrients, electrolytes, and water, while preventing entry of macromolecules and pathogens. Interestingly, microbial balance can alter this permeability, and if compromised, the tight junctions in the mucosal gut barrier allow molecules to “leak” between the GI tract and the bloodstream.

One such molecule that enters circulation as a result is bacterial lipopolysaccharide (LPS). LPS is an example of a microbe-associated molecular pattern (MAMP). Think of them as ID tags that allow the molecule to be recognized by certain receptors. The LPS can circulate in the bloodstream and bind to toll-like receptors (TLRs) triggering an immunological and inflammatory response. These receptors are a type of transmembrane protein and are expressed in a number of immune, epithelial, and endothelial cells, including glial cells in the central nervous system. The TLRs dimerize through binding of the LPS and this leads to recruitment of the adaptor protein myD88. This in turn, mediates a signalling pathway that activates a series of kinases, eventually leading to activation of the NF-κB transcription factor and the production of inflammatory cytokines. 

It has even been noted that elevated serum levels of antibodies against elevated LPS are present in patients with chronic depression. This has led to the development of an animal model where administration of LPS induces behavioural phenotypes characteristic of depression. Furthermore, the phenotype is actually reversed by anti-depressants. This suggests there is potential for treating depression by targeting LPS activation of toll-like receptors.

Figure 2. Leaky gut leads to the release of lipopolysaccharides (LPS) that can bind to and activate toll-like receptors (TLRs), leading to the production of inflammatory cytokines.

Although the mechanisms by which microbiota influence brain function have not explicitly been determined, the research does suggest that perturbations to the microbial composition can lead to adverse health effects later on in life. The findings also promote the idea that bacteria in our gut are actively communicating with our brain. In doing so, it opens the door for potential modulation of the gut-brain axis, giving hope of new therapeutic options to those 3 million Canadians battling depression and millions more suffering from similar illnesses.

-Babar

Learn more about the gut-brain axis here.

Obesity has a high comorbidity with mental health problems and although it is a stretch to say that obesity causes mental illness, researchers are looking to related factors such as gut microbiota to better understand this relationship. The following paper looks at how a change in diet leads to alteration of the gut microbiota and in turn, adverse neurobehavioral effects. Specifically, the researchers investigated whether obese-type microbiota would still have an impact in non-obese mice. They subjected conventional, non-obese mice to antibiotic treatment before transplanting microbiota from donors that were on either a high fat diet (HFD) or a control diet. The recipient mice went through a number of neuropsychological tests and analysis was performed on blood, brain, and intestine samples. It turns out that changes to microbiota composition that are induced by high fat diets are able to significantly disrupt cognitive behaviour in the absence of obesity. This also lends support to the idea that modulation of the microbiota may have potential therapeutic effects for neuropsychiatric disorders. Now that’s an exciting thought!

The whole article is pretty interesting and easy to follow so I would definitely recommend checking it out. Even if it’s just to see why the researchers opted to use conventional mice rather than germ-free mice. 

- Babar

Meet Elaine Hsiao. An assistant professor at UCLA, featured on Forbes 30 under 30, she researches the microbiome and strives to find links between the gut and the brain. 

Some of her most exciting research is regarding the microbiota and autism. Okay, so what do bacteria in your gut have to do with autism, a disorder of the brain? In her 2013 paper, Hsiao attempted to elucidate this. When “autistic” mice were treated with Bacteroids fragilis they showed improved communication, as well as reduced anxious, and obsessive behaviours. Sounds pretty good so far right? Unfortunately, the mice retained their social deficits. This was quite a significant drawback because social deficiencies are characteristic of autism spectrum disorders. 

Although this probiotic-to-be turned out to be a flop, the study did suggest a link between the gut microbiome and the brain and it paved the way for further research in the field. If you’re more of a visual learner, Hsiao also did a Ted Talk where she describes some of her work. So take a break from “Making a Murderer” and give it a watch!

Hello everyone!

My name is Babar (yes, like the elephant) and I am in the fourth and final year of my biochemistry degree at UNB. I was born in Pakistan and grew up in Ireland where I developed a love for potatoes, sports, and a good cup of tea. I spent the best part of fourteen years on the Emerald Isle before moving across the pond to New Brunswick. After getting over the fact that everyone here drives on the wrong side of the road, I have definitely grown fond of the people, places, and even weather of the maritimes.

I enjoy playing sports and in the past I’ve played such sports as hurling and cricket but my true love is soccer. I play and watch as much of the beautiful game as I can and I am a massive Arsenal fan - they WILL win the league this year. 

My fellow proctors and I during Orientation Week. I’ve been fortunate enough to spend my undergrad living in the best house on campus. 

Okay so enough about me, let’s get to the science! My blog is centered around two things: bacteria and mental health. At first glance these two terms may seem mutually exclusive but it turns out that the bacteria in your body can actually have an effect on your mental health! That’s kind of a bizarre thought right?

Mental health is something that is relevant to all of us and it is something that I have become more and more interested in over the last number of years. During this time we have seen a lot of awesome mental health initiatives pop up on campus, for example Mental Health Awareness Week and the My Definition campaign and this interest in the subject has also been reflected in the scientific community. Most of the research regarding microbiota and mental health has been carried out in the last one or two years! This is an emerging field but a very exciting and promising one. Over the course of the semester, I’ll be navigating through the new research and looking at things like the gut-brain axis and psychobiotics!

I look forward to exploring this field and sharing what I learn with you all! Hopefully I’ve piqued your interest and you’ll decide to join me on this journey!