How did some species of frogs resist to the chytridiomycosis outbreak, a fungal infection which has decimated amphibian populations around the world? Could it be thanks to the presence, within their skin microbiota, of bacteria able to fight against the fungus Batrachochytrium dendrobatidis, which is responsible for this disease?

A therapeutic lead against aspergillosis?

To know for certain, researchers isolated several bacterial strains colonizing the skin of 7 species of frogs living in Panama, a country particularly affected by the epidemic. They then decided to investigate whether the bacterium B. dendrobatidis could stop the fungus development and if it could block the growth of Aspergillus fumigatus, a fungus causing over 80% of human aspergillosis. Their aim was to develop alternative therapies whose mechanisms of action would be different from that of standard antifungal agents.

Saving own skin ... thanks to the skin!

The bacterium Pseudomonas cichorii, which is present on the skin of frogs, holds first place as most potent antifungal thanks to the production of two active compounds, one of which has shown, in laboratory tests, a strong capacity to stop the growth of pathogenic fungi B. dendrobatidis and A. fumigatus. This finding still has to be confirmed in living organisms in order to prove that Pseudomonas cichorii truly prevents the development of the resulting diseases. Panamanian frogs could thus have escaped a massive extinction caused by a killer fungus thanks to their skin! Skin bacteria responsible for their survival could well be used to develop new natural remedies against human aspergillosis.

Breast milk is not sterile and the flora it hosts contributes to the development of newborns’ gut microbiota. But are all breast milk feeding techniques equally effective? To find out, an international team analyzed the composition of breast milk microbiota, either pumped or given directly from the breast, in 393 new mothers.

Impact of using a breast pump

The microbial composition of 393 breast milk samples, collected on average 3-4 months after birth, was matched to the breastfeeding mode of each mother and specific parameters (BMI, parity, delivery mode...) using several statistical methods. Bifidobacterium spp., bacteria involved in the maturation of the child’s immune system, were more abundant in the milk when it was given directly from the breast. Independently of other factors traditionally considered (mother BMI, delivery mode...), expressed breast milk feeding (defined as at least one feed with expressed milk in the previous two weeks), and especially with an electric breast pump, significantly reduced abundance and diversity of the milk’s microbiota. It also induced an increase in several families such as Enterobacteriaceae, Enterococcaceae, Stenotrophomonas and Pseudomonadaceae, of which some species are potential opportunistic bacteria. This observation suggests that environmental factors impact indirect breastfeeding.

Other factors to be considered

Results also indicate that in case of direct breastfeeding, the newborn itself regurgitates and contaminates the milk with its own oral microbiota (“retrograde inoculation” hypothesis), in a gender-specific manner. This is an additional argument supporting the idea of a shared mother-child contamination. Similarly, maternal factors could have an impact: ethnicity, BMI (able to modulate, among others, the amounts of fatty acids, hormones or oligosaccharides in the milk), delivery via C section (leading to decreased bacterial diversity and abundance in the milk), smoking, primiparity or multiparity, existence of an atopic field. And let’s not forget translocation of gut microorganisms towards the mammary glands, through the “entero-mammary pathway”. These findings could lead to potential avenues to improve milk microbiota, and consequently newborns’ intestinal flora, and implement prevention strategies for chronic diseases from an early age (allergies, respiratory infections. asthma...).

Many studies now confirm the existence of a correlation between gut dysbiosis (sidenote: Dysbiosis Generally defined as an alteration in the composition and function of the microbiota caused by a combination of environmental and individual-specific factors. Levy M, Kolodziejczyk AA, Thaiss CA, et al. Dysbiosis and the immune system. Nat Rev Immunol. 2017;17(4):219-232.   ) and schizophrenia based on known factors: the risk of developing the disease is 10 to 20 times higher when there was a prenatal infection; frequent gastrointestinal disorders associated with a dysbiosis in schizophrenic patients; as well as disruptions in the neurological, immune and hormonal systems, whose maturation is closely linked to the gut flora. Chinese researchers have thus compared the microbiota of healthy individuals to that of schizophrenic patients, before transferring imbalanced “schizophrenic” flora into microbiota-free mice.

The microbiota is related to the disease and its severity

The microbiota of schizophrenic patients is not only less abundant and less diverse, but there is also a predominance of 23 species (out of the 77 that have been identified); and the remaining 54 are underrepresented. This dysbiosis is specific to schizophrenia according to the authors, who have also identified a bacterial signature made up by 5 families. This signature is able to discriminate between healthy individuals and schizophrenic patients and it is different from the signature found in other psychiatric disorders (such as depression). Moreover, two large bacterial groups could be specifically correlated to the severity of schizophrenic symptoms.

Microbiota transplant and disease onset

Schizophrenia seems to be transferable to healthy microbiota-free mice through a gut microbiota transplant: the bacterial signature of human donors is found in recipient rodents who started to present behavior proper to schizophrenia: hyperactivity, decreased anxiety and depression. Abnormal variations in some neurotransmitter levels (chemical substances that allow neurons to send messages) were also observed, thus indicating that the gut-brain communication is altered. Researchers concluded that gut dysbiosis could play a role in the development of schizophrenia through this pathway. This discovery opens the way to new potential diagnostic and therapeutic strategies.

Crohn’s disease is an unpredictable and chronic disease, which progresses very variably from a patient to another. Although the causes of this inflammatory disease are not well known, it has been observed that patients’ gut microbiota seems to be less balanced than that of healthy subjects. But is it a cause of the disease, or a simple adaptation of the microbiota to an environment that has become inflammatory?

Two-year observational study

To get a clearer picture, a team of Israeli and American researchers monitored the microbiota of 45 patients in the remission phase of the disease. During this prospective observational study, the following tests were performed: analysis of gut microbiota, measurement of C-reactive protein (every 3 months) and fecal calprotectin levels, as well as endoscopic assessments (every 6 months). Results were compared to those of 17 patients in the inflammatory phase of the disease and to those of 22 control subjects. Objective: identifying whether flares are preceded by gut microbiota disruptions. To optimize the analytical process, the researchers used machine learning, a computer-based technology where analytical models are developed based on compiled data instead of prior programming.

Flares and microbiota instability

Results confirm that patients with Crohn’s disease have generally less abundant and more unbalanced microbiota (higher dysbiosis index) than healthy subjects. They mainly underline that in 27 out of the 45 patients who had a flare-up in the two-year follow-up period, they observed that this inflammatory phase was preceded by a significant decrease in the levels of some bacteria (Christensenellaceae and S24.7 families) and increase in others (Gemellaceae) compared to patients who remained in remission. Moreover, patients whose gut microbiota is more unstable in the resting phase of the disease are 11 times more likely to experiment an upcoming flare. Changes in the relative abundance of the three aforementioned taxa and global instability of the gut microbiota seem to precede flare‑ups, thus indicating that the gastrointestinal flora plays a role in flare pathogenesis. Despite the bias associated to machine learning (excessive individual variability compared to clinical factors), these results open the way to future tailored therapeutic options which could predict–and maybe one day prevent–upcoming flare-ups.

Diabetes mellitus prevention through regulation of blood sugar levels is mainly based on a diet containing less calories and less sugar. However, it seems that postprandial blood glucose levels (following food intake) do not only depend on the composition of ingested food: it varies from person to person based on individual parameters (physiological, genetic, or related to the gut microbiota).

With or without diabetes, all investigated!

According to an Israeli study conducted in 2015 with people with a predisposition to diabetes (overweight or obese), dietary interventions adapted to individual data (including gut flora) lower glucose levels more effectively than the standard model, which is exclusively based on low calorie and glucose intake. What about people without diabetes? American researchers from the Mayo Clinic tested the tailored model on 327 healthy adults from the Midwest region. While retaining their dietary habits (except breakfast which was normalized) participants had to wear a glucose meter in order to permanently monitor their blood glucose levels and a food tracking app recorded the nutritional values of their meals. All data were then compared to the predictions obtained through the tailored model and the standard model.

Microbiota and control of blood glucose levels

To some extent, the results of the Israeli study were confirmed: the same food can trigger very different glycemic responses from one person to another, while the response from the same individual over time remains relatively constant. Moreover, postprandial glucose levels predicted by the tailored model were closer to the data reported by participants than those predicted by the standard model. This difference could partly be explained by the composition of our gut microbiota, which could play a role in keeping glucose at normal levels (glucose homeostasis). All these findings tend to support a tailored dietary approach to prevent diseases associated with abnormally high blood sugar levels (hyperglycemia).

“One of the greatest threats against global health, food safety, and development.”

This is how the WHO characterizes antibiotic resistance, which leads to longer hospital stays, higher medical expenditure and increased mortality. Among potential solutions under investigation, fecal microbiota transplant (FMT) brings hope to the fight against multi-drug resistant bacteria but still raises questions regarding its safety, especially in immunocompromised patients.

10 immunocompromised patients were tested

A monocenter study was based on the retrospective analysis of 10 patients with blood disorders, undergoing a bone marrow transplant and who were (or had been) colonized by carbapenemase-producing or vancomycin-resistant bacteria which were classified as very high risk (eXDR, emerging extensively drug-resistant bacteria). The patients were about to receive an allogeneic (the donor is not the same person as the recipient) hematopoietic stem cell transplant (HSCT) following the treatment of their hematological cancer. The FMT was performed by enema or nasogastric tube, either before (for four patients) or after (for the remaining six who were still receiving immunosuppressants at the time of the procedure) the allograft.

Confirmed efficacy

In 7 out of 10 cases, investigators observed a significant decolonization of multi-drug resistant bacteria (3 successive bacterial cultures were negative). In 6 out of 10 patients, this decolonization persisted during the entire follow-up period (4-40 months). The three failures could be explained by methodological difficulties (antibiotics could not be suspended 72 hours after the FMT, the treatment period was too short, or the stool sample was too little...). Finally, when the first FMT was not able to eradicate multi-drug resistant bacteria, a second transplant turned out to be possible and effective in 2 out of 3 cases.

Proven safety

In all 10 patients, FMT was not associated to any major risk: one patient was constipated in the first days following the transplant; two others had transient, mild diarrhea. According to the researchers, none of the 3 reported deaths was attributable to the FMT. In two cases, the disease had progressed; and in the third case, the patient received two fecal transplants because of severe GVHD (sidenote: GVHD Graft-versus-host disease )  following the hematopoietic stem cell transplant, and the treatment with immunosuppressants led to the onset of a viral and fungal infection 6 months after the FMT. Consequently, in patients infected with multi-drug resistant bacteria, FMT seems to be an effective and safe solution, even in cases of severe immunosuppression.

Explain fecal transplantation to your patients with this dedicated content: 

About one third of the world’s annual plastic production ends up as land or marine pollutants, i.e. more than 100 million tons. Among this waste, plastic microparticles derived from cosmetics, petrochemical and clothing industries are a serious environmental issue. Smaller than 5 mm, they avoid filtration systems and are released into aquatic environments where it takes several centuries to break them down because of high salinity and low temperatures. As a result, they are colonized by all sorts of bacteria (sometimes toxic), before ending up in the stomach of sea organisms who are fooled by this false meal opportunity.

Singaporean coasts have been closely examined

Several studies have been carried out throughout the world to identify the nature of microorganisms proliferating on the surface of microplastics. What about Singapore? Do the waste polluting the most frequented beach waters have the same bacterial profile as that of immaculate beaches very rarely trampled by people? Two researchers for the University of Singapore decided to investigate. Fragments, fibers, foams, granulates, plastic films...: between April and July 2018, they collected and analyzed a total of 275 microplastic samples from three different beaches with different touristic affluence.

Human activity to blame

Not surprisingly, the more frequented the beach, the more polluted it was. But the nature of microplastics as well as that of bacterial species covering them were significantly different in each beach. This observation confirmed the impact of human activities on this pollution, also modulated by winds and tides. Good news: the ecosystem adapts to pollutants by promoting the development of bacterial species that are able to break them down. Bad news: it also allows for the emergence of pathogens, responsible for wound infections or gastrointestinal diseases. By inadvertently ingesting these microplastics, marine organisms could also trigger the accumulation and subsequent transfer of pathogenic agents into the food chain. The authors conclude that these two findings will have to be taken into account to meet the ecological and sanitary challenges caused by plastic pollution.

Intracranial aneurysm occurs in 2 to 6% of the world’s population. Some bacteria could have a protective role in this condition, and others a harmful one. This could explain why environmental factors (diet, lifestyle, physical activity, tobacco…) modulating the microbiota could have a greater impact on the risk of suffering an aneurysm than genetic factors.

Aneurysm induced in two types of mice

How did the researchers come to this conclusion? By inducing intracranial aneurysm in mice though the injection into the cerebrospinal fluid of elastase, an enzyme that degrades artery walls. In a first experiment, a group of mice received a cocktail of oral antibiotics (vancomycin, metronidazole, ampicillin, neomycin) three weeks before the injection of elastase, and until the end of the experiment, i.e. three weeks after the injection. Objective: destroying their gut microbiota. Meanwhile, a control group did not receive anything. In a second experiment, the administration of antibiotics was stopped one day before inducing the aneurysm, in order to exclude any direct antibiotics effect on the incidence of aneurysm.

Sharp fall of incidence rate

The results are indisputable: within three weeks from the injection of elastase, only 6% of mice treated with antibiotics suffered an aneurysm, compared to 83% for mice with an unaltered gut microbiota. Even when antibiotics were withdrawn the day before the injection (second experiment), aneurysm incidence was significantly lower: 28% of cases vs. 86% in controls. Moreover, inflammation was reduced in antibiotic-treated mice: less macrophages and less inflammation markers. These results suggest that the gut microbiota contributes to the pathophysiology of aneurysm through inflammation modulation. It should be noted that the total suppression of the microbiota is an artificial construct, thus it can only be concluded that the gut microbiota is involved in this process but whether it plays a beneficial or harmful role cannot be assessed.

Microbiota, potential biomarker for the risk of developing an aneurysm?

The gut microbiota could directly affect the pathophysiology of intracranial aneurysm; and from a clinical point of view, its profile could be a biomarker for the combined effects of environmental factors. However, we should not make hasty conclusions. A comparative analysis of the human gut microbiota of subjects with and without intracranial aneurysm is still necessary to identify the contribution of the microbiota to the pathophysiology of intracranial aneurysm.

“What about lupus?” Fans of House M.D. are familiar with the name of this uncommon disease. It gained its name due to the wolf shape that sometimes appears on the faces of people with lupus. However, lupus is not easily diagnosed because symptoms are not specific: fatigue, skin rashes, joint pain, hair loss, fever... or, in severe forms, damage to vital organs such as kidneys or heart. Which is why the team of the famous small-screen diagnostician often hesitates. But why are the symptoms so diverse? Because it is a disease related to a deregulation of the immune system which attacks the body’s own cells in different parts of the body, in flares. And the gut microbiota seems to be involved.

Microbiota crises and imbalances

Researchers were already aware that patients with lupus generally have reduced bacterial diversity in the gastrointestinal tract that is often combined with an imbalance in bacterial levels (i.e. “dysbiosis”), compared to healthy subjects. But until now, the microbiota of patients experiencing flares had rarely been characterized. It has now been done thanks to recent work carried out on around sixty women with lupus. The results indicated that periods of microbiota imbalance coincided with lupus flares.

Is Ruminococcus gnavus to blame?

Researchers were able to identify a bacterium, Ruminococcus gnavus, whose overabundance was correlated to the disease’s activity, especially in patients with kidney inflammation (or nephritis) and took place at the expense of beneficial bacteria known for their anti-inflammatory effect. This imbalance goes hand in hand with an alteration of the intestinal barrier, which exposes even more the immune system to gut bacteria, some of which turn out to be pathogenic. In the future, these preliminary findings give us hope that someday, House will be able to easily diagnose and monitor cases of lupus thanks to the development of a biomarker related to R. gnavus.