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.

The first months of life are key to the bacterial colonization in our gastrointestinal tract and the development of our nervous system. Since the brain and the gut communicate, we can assume that the composition of our gut microbiota plays a key role in the development of our temperament.

Bacterial diversity: a prerequisite for good emotional health

To test this hypothesis, a team of researchers analyzed the gut microbiota of 301 babies at the age of two months and a half and later assessed their temperament at the age of six months. They used a questionnaire filled in by parents to describe the way their child expresses and regulates their emotions. We know that three factors impact bacterial diversity of newborns–delivery mode (vaginal or c-section), diet (breast milk or formula) and mother’s age–, while bacterial abundance is only dependent on the type of diet. This study reveals that greater diversity is related to lesser negative emotionality (fear, sadness) and to lesser fear reactivity, which are two personality traits that are predictive of subsequent psychological disorders.

Is temperament dictated by bacteria?

The study also revealed several specific associations between some bacterial genera and newborns’ temperament. Abundance of Bifidobacterium and Streptococcus and low content of Atopobium seem to be, for instance, associated to positive emotionality, which is a predictive marker of extroverted nature and good emotional regulation. On the contrary, negative emotionality seems to be associated to the Erwinia, Rothia and Serratia bacteria; the latter also being correlated to prenatal maternal stress. Fear reactivity proved to be specifically associated to an increased content of Peptinophilus and Atopobium bacteria. The authors point out that, even when their microbiota is the same, boys and girls do not have the same temperament, thus suggesting that the brain is differentially susceptible to the effects of gut microbiota based on gender.

Safeguarding mental health

Since personality traits can appear years before the development of psychological troubles, the authors believe that these results could have an impact on their early prevention in children. Provided, however, that a causal link is established, which is not the case in this study.

Acne is a true affliction dreaded by teenagers that affects up to 85% of the population aged between 11 and 30. This inflammatory skin disease, which may be more or less severe, affects several parts of the body, from the face to the back. Is it the skin microbiota’s fault? According to research it is, although the bacteria responsible for severe acne have not yet been identified. French researchers have thus led their own study...with surprising results!

Less abundant and diverse microbiota

The skin microbiota of 24 patients, collected from their back (severe acne area) and face (mild to moderate acne), was compared to that of 12 healthy volunteers. Compared to controls, the back of patients hosted less bacteria, and it had a higher content of Enterococcus, among others; and in their faces, staphylococci were significantly more abundant, contrary to bacteria from the Propionibacteriaceae family which were less abundant in people with acne but more abundant in healthy people. The Propionibacteriaceae family thus seems to be a marker of healthy skin... This is a true paradox since C. acnes, which was known to be one of the bacteria responsible for acne, is part of this family!

A matter of balance

Acne thus seems related to a disruption of the skin microbiota (or dysbiosis), and its severity to a decreased bacterial diversity and abundance. According to the authors, more than the overabundance of C. acnes, it is the imbalance between the Propionibacteriaceae and the staphylococci families, competing with each other, that induces changes in skin pH and triggers the inflammatory process. This discovery opens the way to the development of new anti-acne treatments based on the restoration of skin microbiota: the skin would have an improved quality and then be able to prevent colonization by opportunistic bacteria.

Lymphoid and epithelial tissues of the digestive tube are damaged following primary HIV-1 infection (human immunodeficiency virus-1). These alterations lead to chronic systemic and local inflammation, among others, as well as immune dysregulation, which are early development factors for age-related disorders (type 2 diabetes, cardiovascular diseases, fragility syndrome...). To study the impact of contamination over time, a Spanish team monitored for 9 to 18 months, using the shotgun sequencing method (sidenote:  Shotgun sequencing method is more accurate than 16S rARN. ) , the intestinal bacterial and viral composition of 49 subjects from Mozambique recently infected with HIV-1, as well as 54 control subjects. Results were then compared to that of 98 patients in chronic phase receiving an antiretroviral treatment (27) or not (71).

Increased adenovirus fecal excretion and ...

A fast increase in adenovirus fecal excretion was observed in patients recently infected. This situation persists during the chronic phase and is not resolved in patients under antiretroviral treatment. These viruses are rarely excreted in control subjects. Moreover, increased cytomegalovirus and enterovirus fecal excretion was observed in untreated chronic patients, suggesting that it is attributable to a prolonged immune deregulation.

... and decreased levels of anti-inflammatory bacteria

Gut bacterial composition also undergoes changes over time. Although the temporary decrease in abundance and diversity observed following the infection is not specific to VIH-1 contamination, a characteristic pattern has been observed in the chronic phase: drop in Akkermansia, Anaerovibrio, Bifidobacterium and Clostridium levels. This dysbiosis is, according to the scientific literature, associated to chronic inflammation, anergy of CD4+ T-cells and metabolic disorders, which are likely to worsen the patient’s condition. The researchers recommend that longitudinal studies be carried out on the effect of antiretroviral therapy to prevent or correct alterations of the gut microbiota, which are detrimental to people living with HIV-1.

Whether it is a simple cold or a more severe disease, acute respiratory infections are very frequent in the first years of life. Lower airways infections (especially pneumonia and bronchiolitis) are the main cause of hospitalization in children under 5 years old. But while some children get one infection after the other (5 to 7 per year) or catch severe forms, other are able to elude microbes. Of course, known risk factors (prematurity, daycare, age) can explain this difference in sensitivity, but only partially. Could their nasal microbiota play a role?

5 microbiota profiles

A team of Finnish researchers analyzed the results from a large study that included 839 healthy newborns who were monitored from birth to age two. Based on the samples from the nasal microbiota that were collected at the age of two months, 5 different profiles were identified, according to the dominant bacterial group: Moraxella (30.4%), Streptococcus (22.4%), Dolosigranulum (22.4%), Staphylococcus (17.9%) and Corynebacteriaceae (6.9%). The researchers observed that the frequency of acute respiratory infections depended on each of these profiles.

More Moraxella, more infections

Microbiotas dominated by Moraxella bacteria were less abundant and less diversified than the others, and were associated to a higher incidence of acute respiratory infections, especially lower airways infections, and to longer-lasting symptoms. Affected children also shared other factors: they were more likely to have siblings and to have mild respiratory symptoms as soon as two months old. This was also observed in children whose microbiota was dominated by Staphylococcus bacteria; on the contrary, children with a profile dominated by Corynebacteriaceae bacteria were less often ill.

Identifying at-risk children

Despite some limits acknowledged by the authors, this study still substantiates a link between nasal microbiota and incidence/severity of acute respiratory infections. Further studies are needed to elucidate the complex interactions between this ecosystem, immunity and these diseases in order to identify the children at a greater risk.

With nearly 25 million episodes per year, acute ischemic stroke is a major health challenge worldwide. Prognosis is currently very difficult to establish and could benefit from the identification of a risk factor for adverse progression. This observation led a Chinese team to develop the Stroke Dysbiosis Index (SDI), an index correlating stroke and gut dysbiosis. Its objective is to confirm the stroke and assess the severity of brain lesions as well as the risk of early complications.

Dysbiosis as a discriminating factor for stroke outcome

The SDI was designed based on the analysis of gut bacterial populations from 104 subjects who had an acute ischemic stroke, compared to 90 control subjects. The formula takes into account changes in levels of 18 bacterial genera. Among others, an increase in Enterobacteriaceae and Parabacteroides associated to a decrease in Faecalibacterium, Clostridiaceae and Lachnospira was observed in stroke patients whose SDI score was significantly higher than that of healthy subjects. The discriminative power of this model was validated with a second cohort of 83 stroke patients and 70 control subjects. A statistical method also demonstrated that SDI is a predictive indicator of both the severity of brain lesions and the risk of early complications.

Balanced microbiota = optimized recovery?

The second part of the study was performed in mice in order to clarify in vivo the relationship between gut microbiota and acute ischemic stroke sequelae. Middle cerebral artery occlusions were induced in animals who received fecal microbiota transplant from human patients with a low or high SDI. Result: brain damage worsened and levels of IL-17(proinflammatory cytokine)-producing g-δ T-cells increased in animals colonized by the bacteria typical of high-SDI pattern, compared to mice receiving transplants from patients with a low SDI. This proves that gut dysbiosis has a negative effect on the post-stroke prognosis. According to the team, the microbiota and its modulation through prebiotics or probiotics, are a therapeutic approach to be further explored in order to maximize the chances of recovery for post-stroke patients.

The ability of the gut microbiota to remotely communicate with organs such as the brain, liver or lungs has often been reported in the scientific literature, as well as associations between dysbiosis and some diseases. In this context, a Chinese team focused on the gut microbiota specificities of patients with tuberculosis (TB) caused by Mycobacterium tuberculosis.To describe them, the researchers compared the microbiota of 46 patients with TB to that of 31 control subjects, using shotgun sequencing (sidenote:  Shotgun sequencing method is more accurate than 16S rARN. ) .

Less diversified gut microbiota

First finding: the microbiota of patients with TB showed significantly lower bacterial abundance and diversity (Shannon index). It was also characterized by a decreased or increased presence of some species compared to the control group. In total, 23 species were less abundant in the microbiota of patients with TB, while 2 were more abundant (unclassified Coprobacillus and Clostridum bolteae).

Decreased SCFA metabolism

Another notable finding: among the 23 decreased bacterial species in patients with TB, 9 produce short-chain fatty acids (SCFA), components which are largely involved in inflammatory and immune responses. In particular, five butyrate-producing species (Roseburia inulinivorans, R. hominis, R. intestinalis, Eubacterium rectale and Coprococcus comes), two lactate- and acetate-producing species (Bifidobacterium adolescentis and B. longum) and two acetate- and propionate- producing species (Ruminococcus obeum and Akkermansia muciniphila) were found in decreased amounts. In line with these changes in bacterial composition, SCFA fermentation was significantly lower in patients with TB.

Identifying tuberculosis patients based on their microbiota?

Finally, based on modeling studies, the researchers characterized 3 bacterial species (Haemophilus parainfluenzae, R. inulinivorans and R. hominis) whose presence could discriminate between healthy and tuberculosis patients. The healthy and diseased states could also be distinguished by some genetic variations (SNP, Single Nucleotide Polymorphism) in the B. vulgaris species. As for several disorders affecting different body systems (type 2 diabetes, autism, etc.), tuberculosis seems to be associated to a dysbiosis of the gut microbiota. However, it is not yet possible to determine whether it is a cause or a consequence of the disease, since mechanistic data currently available from animal studies are compatible with both hypotheses.