The second microbiota component that could be involved in IBD is the virome (viral component of the microbiota), made up of both eukaryote-infecting viruses and bacteriophages infecting bacterial cells, which are the most studied. In patients with IBD, a dysbiosis of this virome has been observed: loss of diversity in addition to a greater variability of gut viruses in patients with CD. A study conducted in the United States and United Kingdom in 2015 also revealed an increased abundance and diversity of the enteric virome in patients with CD or UC.⁷

Impact of bacteriophages on the bacterial microbiota

Bacteriophages are ten times more numerous than bacteria and are involved in the microbiota mechanism through the control of bacterial abundance and diversity, which leads to an either protective or harmful effect: in patients with CD, the expansion of Caudovirales bacteriophages is associated to a loss in bacterial diversity and could be involved in the bacterial dysbiosis and gut inflammation.⁸

Virome signature

While studies on the virome are rare, those focusing specifically on eukaryotic viruses are even more so. One of them compared the gut mucosa of healthy controls to that of treatment- naive young patients whose IBD had been diagnosed early,⁸ and suggested that some eukaryote-infecting viruses could be involved in the onset of gut inflammation and contribute to IBD pathogenesis, with a specific signature depending on the disease: more viruses from the Hepadnaviridae family compared to controls and patients with CD, and less Polydnaviridae and Tymoviridae in patients with UC; increased abundance of Hepeviridae (a family of viruses including HEV for instance) and less Virgaviridae in patients with CD compared to controls. These virome signatures could be acquired early in life (for instance through diet) and later increase host susceptibility to IBD.⁸

A double bacterial gut dysbiosis, characterized by a decrease in some beneficial strains and an increase in pathogenic strains, is associated to IBD. These composition abnormalities could be both the cause and the consequence of these disorders, thus inducing a vicious circle.

In patients with IBD, structural and functional alterations of the gut microbiota have been observed. The composition is also different in patient undergoing an acute episode compared to those in remission.²

Decrease in beneficial bacteria and increase in pathogens

First feature: decreased Firmicutes/ Bacteroidetes ratio. A decrease in somebeneficial bacteria from the Firmicutes phylum is observed, for instance, lower abundance of Faecalibacterium prausnitzii, a commensal bacterium with anti-inflammatory properties and whose decrease seems to be a marker of CD;³ reduced rate of Firmicutes, commonly observed in patients with IBD;⁴ significant decrease in Bacteroides fragilis (Bacteroidetes), a bacterium with proven protective effects in murine models of induced colitis.⁵ In patients undergoing an acute phase of IBD, there is also a lower abundance of Clostridium coccoides, Clostridium leptum, Faecalibacterium prausnitzii and Bifidobacterium.² Second feature: excess of potentially harmful microorganisms, especially Gammaproteobacteria and Actinobacteria. In one out of three patients with CD, the mucosa is invaded by a strain of Escherichia coli called AIEC (Adherent-invasive Escherichia coli).³ Contrary to other infectious agents, these strains are able to cross the intestinal mucus barrier, adhere to it, then invade the gut epithelial cells, and survive and replicate in macrophages. This leads to the secretion of large quantities of TNFα, which in turn causes inflammation.

Dysbiosis: cause or consequence of ibd?

This bacterial gut dysbiosis, which seems to be a marker of IBD, is suspected to play a role in its pathogenesis. A study conducted in mice genetically predisposed to UC revealed a two-way relation between this disease and gut dysbiosis.⁶ Bacterial dysbiosis could thus not only contribute to the onset of IBD, but also be a secondary consequence of gut inflammation. Different hypotheses were suggested to explain this dual phenomenon: some species from the Firmicutes phylum have anti-inflammatory properties and are major producers of short-chain fatty acids (SCFA)–especially butyrate–, which represent the main energy-producing substrate for colonocytes. Moreover, a decrease in the number of Firmicutes could trigger or intensify a local inflammation by decreasing the levels of anti-inflammatory cytokines (key regulators of mucosal immunity) and/ or by altering the colon barrier function through a deficit of SCFA.⁴

Why is the psychiatric field interested in the microbiota?

This interest is relatively new. It stems from studies published less than 10 years ago showing that some stress factors have an impact on the digestive barrier, making it more permeable, thus allowing gut bacteria to cross into the bloodstream. This phenomenon leads to the production of inflammatory molecules at the intestinal level, that would then travel to the brain and disrupt it. This inflammation impairs the synthesis of serotonin, a chemical messenger produced in the intestines and the central nervous system and involved in depression. Instead of producing serotonin, the body produces a toxic substance which destroys neurons and neural connections. We believe that the gut microbiota imbalance could trigger this cascade of events.

What is the link between microbiota and mood disorders?

Depressed individuals have an overrepresentation of some bacterial families, the presence of bacteria that are not found in healthy people, as well as bacterial species associated to an increase in the severity of the depressive episode. We also know that some gut bacteria synthesize dopamine and serotonin, two molecules responsible for regulating mood, among others. An imbalance of these bacteria would thus have an impact on the functioning of the brain. The disruption of the gut microbiota could thus be related to the onset of a depressive illness and/or symptom severity. This is why, my team and I are about to study the interest of the use of probiotics in depressed patients: we want to see if we can improve depression symptoms by modulating the microbiota.

From depression to addiction, is there only one step?

The link between gut microbiota and addiction should be studied. Nowadays, the research focus is mainly on alcohol dependency, which is known to alter the digestive barrier. A few years ago, in Belgium, scientists demonstrated that there is a correlation between alcohol consumption, dependency and microbiota: dependent patients who have a strong disruption of the digestive barrier are those who present the most severe anxiety and depression disorders and the strongest desire to drink. They are also the patients who are most at risk to relapse. Their intestinal flora is different from that of patients who are at low risk of relapsing French researchers have shown that apple pectin (a type of carbohydrate mainly found in the skin and seeds of apples) restores the digestive barrier in alcohol dependent rodents. This promising study is the first to demonstrate that diet can be a protective factor against addiction, although results are not yet applicable to humans.

Bipolar patients (as well as schizophrenics) have increased levels of antibodies against fungi (Saccharomyces cerevisiae and Candida albicans) that are naturally present in the gastrointestinal tract. The presence of a specific protein in the blood indicates that bacteria usually located in the intestines were able to migrate. Moreover, concentrations of anti- Saccharomyces cerevisiae antibodies are higher in treatment-naive patients than in those who are treated with antipsychotics. These observations strengthen the hypothesis of a link between disease and inflammation²⁶.

Is nutrition education an avenue to pursue?

Yes, without a doubt, according to some psychiatrists who rely on diet to reduce inflammation and restore gut microbiota balance²⁷. Actually, a link between Western diet (high intake of carbohydrates and fat) and a disruption of neural and inflammation activity has been demonstrated. On the contrary, Mediterranean diet is the example to follow: it could have a protective effect against bipolar disorders as well as depression. The same could be said of omega-3 intake.

It manifests itself by unusual sadness, loss of interest, inability to perform daily tasks, greater fatigue and is accompanied by an increase of cortisol levels²², and thus a disruption of stress response.

In animals, the absence of gut microbiota(or its disruption) is associated to depressive symptoms and to an imbalance of neurotransmitters (serotonin, dopamine, GABA...). Furthermore, inflammation-inducing molecules that are present in excess in the blood and produced by gut bacteria, seem directly related to the development of depression²³. Although there are few, studies made in humans seem to have brought to light a bacterial signature: very recently, researchers discovered for instance that low levels of some bacterial genera in the intestines (Coprococcus and Faecalibacterium) are related to a feeling of poor quality of life in depressed patients.

Balanced gut, balanced mind

The administration of some psychobiotics, such as Lactobacillus and Bifidobacteria (bacteria from the Firmicutes phylum that are present at low levels in affected people) could be beneficial and be used as a supplement to antidepressant and anxiolytic treatments currently used. Initial results are encouraging: prolonged use can relieve depressive symptoms and psychological distress, without causing adverse events²⁴.

Change your shopping list

It would seem that high-glucose transformed products could increase predisposition to depression. In depressed patients, prebiotics (mainly galacto-oligosaccharides found in red beans, chickpeas, artichokes...) could act positively by stimulating the increase of bifidobacteria²⁵. Opting for fruits, vegetables, fish (rich in omega-3 fatty acids) could restore the microbiota, regulate pro-inflammatory processes, and thus favorably impact mood. Turmeric could decrease cortisol levels in the saliva and increase gut flora diversity, resulting in positive effects on the state of mind and behavior

Among other factors is, once again, gut dysbiosis! It leads to an increase of intestinal permeability and a disruption of stress response, as well as an increase in inflammatory activity.

All roads lead to the microbiota¹⁵

Scientists agree that gut bacteria play a role in this process. But according to scientific studies, the microbiota could either have an anxiety-inducing effect or an anxiolytic effect¹⁶. The use of antibiotics– that disrupt and impoverish the gastrointestinal flora–could be associated to the onset of anxiety disorders, or conversely, to a decrease in anxiety in animals.

The flora is being explored “blindly”

In animal models, antibiotics seem to decrease anxiety during the treatment period. The drawback is that an early disruption of the gut microbiota by antibiotics could lead to behavioral changes that persist into adulthood^17,18. Some probiotic strains could also have an anxiolytic effect. Finally, fecal microbiota transplant could reduce anxiety levels¹⁹. All these results still have to be confirmed in humans.

What to eat to stay zen?

Fermented foods such as cheese, yogurts, kefir, kombucha or soy sauce are excellent sources of probiotics and prebiotics. They act as anti-inflammatory agents by strengthening the integrity of the intestinal barrier, improving the composition and function of gut bacteria, and stimulating immune cells in the digestive tract. Probiotics decrease frequency and severity of anxiety symptoms in rat models. In humans, they decrease cortisol levels in urine²¹. In healthy people with no psychiatric disorders, consumption of fermented milk leads to changes in brain activity in regions that are responsible for emotions and pain.

Healing - Body and mind²⁰

Psychobiotics are live microorganisms (bacteria, for instance) which, once ingested, produce a beneficial effect on the health of patients with psychiatric, psychological or neurological disorders.

In brief, they are probiotics that could have psychotropic properties and regulate the gut-brain axis by:

Symptoms appear early in life and include communication deficit, social communication and behavior disorders as well as repetitive behaviors. Compared to the general population, affected people are more subject to gastrointestinal disorders (diarrhea, abdominal pain, constipation), whose severity seems sometimes related to that of the disease’s symptoms.

Microbial “signatures”?

Autistic children seem to have a less diversified flora than other children: it has lower contents of bacteria known to be beneficial such as Bifidobacterium, and higher contents of others (Lactobacillus, Clostridium…). Moreover, autistic children intestines seem to host more Candida (especially Candida albicans) than usual. But this fungus produces ammoniac and toxins that can impact the brain’s functioning and exacerbate intestinal bacterial disorders.

Several risk factors

In animals, a high-fat maternal diet during pregnancy could be associated to an imbalance of the gut microbiota–called “dysbiosis”–and the onset of autistic disorders in their offspring. Children born through C-section who received many antibiotics also seem to have a higher risk of developing these disorders. The upside is that breastfeeding during the first 6 months of life (minimum) could decrease the risk of developing these disorders at a later age.

Microbiota: a therapeutic hope?

A few avenues are under investigation: probiotics for instance, which could improve gastrointestinal disorders and relieve autistic symptoms, similarly to some antibiotics. Despite a significant infectious risk, fecal transplant¹⁰ could also be useful to reduce autistic behaviors and associated gastrointestinal disorders⁷ in children and adolescents. Finally, diet is of great interest. The use of omega-3 supplements could improve behavior: a diet free of gluten or milk proteins as well as a high-fat low-carb diet (called “ketogenic”) could increase sociability as well as the ability to communicate and decrease stereotyped behaviors.

Research on the gut-brain axis is gradually revealing the processes used by gut bacteria to communicate with the brain. We now know that exchanges between brain and gut are based on 4 main pathways: neural, hormonal, immune, and metabolic. The two “organs” communicate through the vagus nerve which goes from the skull to the abdomen and plays a role in several vital functions such as heart rate. Patients who underwent a vagus nerve ablation are incidentally less likely to develop neurological disorders.

Gut-brain axis²: what is it?

Gut bacteria communicate with the brain by producing chemical molecules called “neurotransmitters” (serotonin, dopamine, GABA³…). These microbial molecules do not act directly on the brain, which is isolated and protected by a membrane called the blood-brain barrier. It appears that neurotransmitters produced by gut bacteria act on the cells lining the gastrointestinal wall in order to have them transmit their message to the central nervous system through the neurons of the gastrointestinal tract that are connected to the brain. Short chain fatty acids (SCFA) are biological substances, some of which have a beneficial and protective effect, produced by colon bacteria during the fermentation process of dietary fiber⁴. They play an important role in the communication between the two organs by acting directly on the brain.

Alternative routes

Other possible pathways are the immune system and the blood flow. Thanks to SCFA, gut bacteria can stimulate some white cells, which are responsible for defending our organism. Those white cells then produce chemical messengers (cytokines) that can cross the intestinal wall, move into the bloodstream, and cross the blood-brain barrier. They then act on the brain, mainly on regions involved in the regulation of stress response. The brain acts on the intestines by modulating secretions, motility and blood flow, and as such, it affects gut permeability⁵

Is there a link between microbiota and brain functions?

All studies conducted on animals show that gut bacteria impact brain development, throughout life: creation of new neurons in the brain, development of new neural connections⁶, involvement in the transmission rate of electrical signals delivered by neurons, memory, social behavior, regulation of stress hormone (cortisol)… Without bacteria, our brain would be distressed and more vulnerable to infectious agents or toxic molecules⁷.

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Alcoholic liver disease is associated to a high mortality rate and few therapeutic and prognostic innovations. The role of the gut-liver axis was recently brought to light in alcoholism complications, especially through the translocation of gut bacteria to the liver. Could fungal dysbiosis also play a role?

Proliferation of Candida

Based on a North American and European cohort, an international team studied the gut mycobiota of 59 patients with alcoholic hepatitis, 15 patients with problematic alcohol use (sidenote: In the study, problematic alcohol consumption in patients with alcoholic hepatitis was defined as over 50 g/day for men and 40 g/day for women in the last three months; non-problematic drinking is usually defined as under 20 g/day. )  (at different stages of liver damage), as well as 11 control subjects. A clear proliferation of Candida was observed in both groups of patients, as well as lower fungal diversity and abundance compared to the control group where Penicillium was dominant. Besides, a correlation between gut mycobiota and clinical parameters was established: Candida was associated to an increase in pericellular fibrosis, while Penicillium was associated to reduced inflammation and decrease in Mallory bodies (sidenote: Mallory bodies Residual clusters of microfilaments secondary to the toxicity of alcohol and its metabolites ) .

Higher immune response

Anti-Saccharomyces cerevisiae antibodies (ASCA) were measured to detect a potential immune response to fungal species, especially to Candida albicans. ASCA levels were significantly higher in the group of patients with alcoholic hepatitis compared to the two other groups: the authors believed that this could be explained by a combination of increased Candida levels and altered fungal phagocytosis. This combination leads to a higher immune response, contrary to subjects with alcohol abuse in whom phagocytosis is maintained. Moreover, ASCA levels and mortality rate were related: starting at 34 IU/ml, mortality at 90 and 180 days was significantly higher, regardless of other confounding factors such as corticosteroid or pentoxyfillin use (reference treatment), MELD score (sidenote: MELD score Model for end stage liver disease: reference prognostic score based on the INR (an index representative of prothrombin time), serum bilirubin and serum creatinine ) , or bacterial translocation rate.

New therapeutic options on the horizon

Other studies have shown that cirrhotic patients are exposed to an increased risk of developing fungal infections. Aspergillosis was a frequent and often mortal complication in patients with alcoholic hepatitis. According to the authors, the gut mycobiota is a potential therapeutic target that should be explored. The same applies to ASCA levels combined with the MELD score, which could improve diagnostic with regard to the mortality risk. Before that, these results need to be confirmed since the number of participants in this study was relatively low, and the use of antibiotics by some of them could have influenced the composition of their gut mycobiota.

Parkinson’s disease is a neurodegenerative disease affecting more than 1% of people over 60 worldwide. Its treatment produces very heterogeneous results in terms of efficacy and side-effects, depending on patients. Based on a study published in the journal Science, the gut microbiota could be the cause behind this variability.

Treatment with heterogeneous effects

The current treatment is based on a drug, levodopa (L-dopa), which, when metabolized in the brain, replaces dopamine that neural cells do not produce anymore. Problem: a significant part of L-dopa is transformed into dopamine in the intestines; however dopamine thus produced at the peripheral level cannot cross the blood-brain barrier and cannot reach the brain, which not only reduces the treatment’s efficacy but may also generate severe side-effects (gastrointestinal disorders and cardiac arrhythmias). Therefore, another molecule, carbidopa, is administered concomitantly in order to block this metabolization process: despite that, up to 56% of L-dopa does not reach the brain.

Interference of the gut microbiota

Although the interference of the gut microbiota with treatment’s efficacy was already suspected, its mechanism of action remained unclear until this study. The exploration of the bacterial metagenome first helped identify a species–Enterococcus faecalis–with tyrosine decarboxylase activity that degrades L-dopa into dopamine. The researchers then brought to light the conversion of dopamine into m-tyramine under the action of another enzyme–a molybdenum-dependent dehydroxylase–present in Eggerthella lenta. Differences in these microbial activities could potentially contribute to heterogeneous responses to L-dopa observed in patients, thus explaining its reduced efficacy and its side-effects observed in some of them.

Blocking the gut degradation of L-dopa

The researchers then tried to understand why carbidopa proved hardly effective to prevent the gut metabolization of L-dopa. Their conclusion was that although this molecule is indeed able to inhibit human decarboxylase involved in the metabolization of L-dopa, it turned out to have no effect on the decarboxylase present in E. faecalis in vivo. They then identified an inhibitor (AFMT (sidenote: AFMT (S)-α-fluoromethyltyrosine ) ) able to block the bacterial enzyme. The last phase of their works showed that the administration of standard treatment (L-dopa + carbidopa) combined with AFMT to gnotobiotic mice (sidenote: Gnotobiotic mice refers to laboratory animals in which only certain known strains of microorganisms are present )  colonized by E. faecalis, increases the serum concentration of L-dopa, thus demonstrating in vivo the inhibition of L-dopa degradation by the gut microbiota. This is a promising discovery (sidenote: Professor E. Balskus received the 2019 International Award of the Biocodex Microbiota Foundation for these works and as support for upcoming projects on this subject matter )  that could open the way to new therapies targeting the microbiota.