In recent years, many studies have examined the link between gut dysbiosis and depression, a condition that affects more than 300 million people worldwide. Two new studies have confirmed the gut microbiota’s role in the disease.

The endocannabinoid system: the link between depression and the gut microbiota

In a study carried out by the Pasteur Institute, CNRS and INSERM, naive mice received a fecal microbiota transplant (FMT) from either healthy mice or mice with depression induced by unpredictable chronic mild stress (UCMS). The researchers then analyzed the gut microbiota, the metabolism of polyunsaturated fatty acids and neurogenesis in the hippocampus (a brain region heavily involved in the development of depressive symptoms). According to the study, the symptoms of the UCMS mice (reduced hippocampal neurogenesis, mood disorders) had been transferred to the FMT mice. Metabolomic analysis of the FMT mice revealed an altered fatty acid metabolism characterized by deficits in lipid precursors of endogenous cannabinoids. This resulted in impaired activity of the brain’s endocannabinoid system, which is thought to have induced depression. Increasing endogenous cannabinoids, either via the pharmacological blockade of the enzymes that degrade them or through diet, reduced depressive symptoms in the mice that received the FMT from the UCMS mice. This increase in endogenous cannabinoids also led to a recovery in neurogenesis in the hippocampus of these mice. Lastly, a gut microbiota dysbiosis characterized by a decrease in Lactobacilli abundance was observed in both the UCMS (donor) and FMT (recipient) mice. Complementing the dietary intake of the FMT mice with a strain of Lactobacilli was sufficient to increase both endogenous cannabinoid brain levels and hippocampal neurogenesis, thus alleviating mood disorders. This work in mice provides a new mechanistic scenario for the gut microbiota’s involvement in depression via the endogenous cannabinoid system. The study also suggests that dietary interventions or the use of probiotics may be an effective means to fight against the symptoms of this disease.

Gut biomarkers: towards more accurate diagnosis?

In a second study, Chinese and American researchers identified 3 bacteriophages, 47 bacterial species and 50 metabolites whose fecal abundance differed between a first cohort of 118 patients with untreated major depressive disorder (MDD) and 118 healthy controls (HC). The analysis of a second, validation cohort (38 treated MDD patients vs. 38 HC) showed that 6 biomarkers (2 bacteria, 2 phages and 2 metabolites) made it possible to discriminate between MDD patients and healthy controls in both cohorts with an accuracy of more than 90%. Lastly, the researchers showed that levels of fecal GABA and its relevant metabolites were consistently decreased in MDD patients relative to HC. These findings suggest that fecal GABA levels in the patients with MDD may be modulated by a panel of gut microbes, which in turn may be collectively implicated in the development of MDD. These findings provide new directions to uncover the pathogenesis of MDD. They also help improve MDD diagnosis, which is currently incomplete and subject to misdiagnosis, by focusing on the gut microbiota.

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The gut microbiota is populated by various microorganisms which synthesize compounds called metabolites that are essential for the proper functioning of the human body. Over the last decade, researchers have established links between microbiota imbalances and various diseases, including major depressive disorder (MDD), a psychiatric disorder with significant social consequences. A recent study has confirmed this link and has gone one step further by using the gut microbiota as a diagnostic tool.

A more precise map of the microbiota

Lacking easily measurable biomarkers and based solely on patient interviews, MDD diagnosis is often incorrect or incomplete. In order to get an accurate picture of the gut microbiota in depression, the researchers studied bacteria, viruses, and their metabolites in the stool of a hundred MDD patients and a hundred healthy controls. They identified 3 bacteriophages (viruses that infect bacteria), 47 bacterial species and 50 fecal metabolites that showed notable differences in abundance between MDD patients and healthy controls. According to the researchers, these biomarkers may serve as a complementary tool in the diagnosis of depression, alongside clinical interviews. The analysis of a second cohort showed that these biomarkers made it possible to identify the MDD patients in both cohorts with an accuracy of more than 90%.

Gut-brain axis at the heart of depression?

This mapping also revealed that GABA (a neurotransmitter which decreases brain activity) was found in lower quantities in the stool of MDD patients. According to the researchers, this decrease may be modulated by the altered bacterial composition of MDD patients’ microbiota and may be involved in the development of MDD. The authors speculate that the decrease in gut GABA levels in MDD patients may be correlated with the dysregulation of GABA function in the brain. This hypothesis would seem to confirm the role of the gut-brain axis in major depressive disorder. The study therefore provides new hope for the diagnosis of MDD.

Despite their high fat and caloric content, avocados may help us lose weight. Their secret is their richness in fiber and monounsaturated fatty acids (MUFA), which increase satiety and reduce fat levels in the blood. But how does the consumption of avocados impact the bacteria in the gut microbiota and the products that result from the fermentation of ingested food, particularly in obese or overweight people (sidenote: Overweight is defined as a body mass index (BMI) of 25-30; obesity corresponds to a BMI of >30. ) ?

An avocado a day for three months

To answer this question, a team of researchers followed 157 adults aged 25 to 45 who were overweight (sidenote: Overweight is defined as a body mass index (BMI) of 25-30; obesity corresponds to a BMI of >30. ) or obese, but otherwise healthy, for 12 weeks. The subjects were divided into two groups. All were given a meal prepared by the researchers once a day, instead of breakfast, lunch, or dinner. Only one group received a meal containing an avocado, the caloric content of which was matched in the other group. With the exception of the avocado, meal ingredients were >90% similar. For their other meals, the participants were instructed to maintain their usual eating habits and daily serving sizes.

More fat in the stool, less in the body

Results: participants in the avocado group reported MUFA (“good fat”) consumption that was ~20 g higher than the control group, while dietary fiber consumption was 14 g higher. The participants also had a daily caloric surplus of 300 kcal. Despite this, by the end of the study, they had not put on a single ounce. At the same time, their gut microbiota had diversified and was enriched in bacteria able to break down fiber. In addition, their stool contained diminished bile acid concentrations (molecules secreted by the digestive system which make it possible to absorb fats) and more fats. The authors conclude that by modifying the gut microbiota, avocados influence the host metabolism and increase fat excretion. They are already considering new dietary approaches to improve the health of the increasing number of overweight or obese people.

A major cause of death and serious morbidity in premature infants born before 32 weeks of gestation,NEC is a complex gastrointestinal disease. The underlying mechanisms remain poorly understood, with diagnosis difficult due to a lack of specific symptoms and tests. On the other hand, certain human milk oligosaccharides (HMO (sidenote: Human Milk Oligosaccharide ) ), including disialyllacto-N-tetraose (DSLNT), appear to have a protective role. Hence this study assessing interactions between maternal HMO profiles and the development of the infant’s gut microbiota on the one hand, and their association with NEC on the other.

Breast milk: a critical oligosaccharide threshold

Only one oligosaccharide–DSLNT–had a lower concentration in the breast milk received by the 33 infants with NEC compared with that given to the 37 matched controls. A threshold level of 241 nmol/ml was able to predict NEC in these children (sensitivity and specificity of 0.9) and in a validation cohort 100% of NEC children, but only 60% of controls, were correctly classified. However, the cohort studied was very homogeneous, with an over-representation of Caucasian populations. In addition, the observed threshold may be influenced by genetic, geographical, ethnic or seasonal factors, underlining the need for complementary multicenter trials.

Delayed microbiota development

In addition, stool metagenomic sequencing (n=644) of a subgroup of 48 infants (sidenote: Sequencing limited to 48 infants for cost reasons, since many samples were taken for each child )  (14 NEC infants, 34 controls) showed a lower relative abundance of Bifidobacterium longum and a higher relative abundance of Enterobacter cloacae in the NEC infants. Microbiota development was affected by a low concentration of DSLNT in breast milk, which seems to delay the transition of the microbiota towards the types of microbial communities generally observed in older infants, but is also associated with a lower relative abundance of Bifidobacterium spp., a bacterium generally associated with good health in premature infants.

Biomarkers and probiotics on the horizon?

In sum, an analysis of the data confirms the possibility of identifying infants at risk of NEC based on the composition of the breast milk they receive, with this criterion superseding to a certain extent metagenomic profiles of the microbiome. Combining these two criteria (composition of breast milk (sidenote: The concentration of DSLNT in breast milk remains relatively stable over time )  and pre-disease metagenome) makes it possible to discriminate healthy children from NEC children with an accuracy of 87.5%.

These findings offer potential targets for biomarker development, disease risk stratification and microbiota modulation strategies that could prevent infant NEC. However, further work is still required, including that needed to understand the underlying mechanisms, i.e. does DSLNT act by modulating the microbiota alone, or does it work directly on the host by modifying the immune response and reducing inflammation that leads to necrosis?

From the outset of the Covid-19 pandemic, some patients have reported digestive symptoms, particularly diarrhea. This has prompted researchers to study patients’ gut microbiota to see whether the bacteria, fungi and viruses living in the gut impact our immune defenses. The results of a new study in Hong Kong seem to validate the link between the gut microbiota and the disease. However, further studies will be required to confirm these findings, which were obtained in the heat of the action in early 2020 and suffer from several methodological flaws.

Dysbiosis in Covid-19 patients

The study focused on relatively young Covid-19 patients (average age: 36.4 years) mostly with mild forms of the disease (47 mild cases, 45 moderate cases, 5 severe cases and 3 critical cases (sidenote: 34% of patients were taking antibiotics and 31% had comorbidities (hypertension, hyperlipidemia, allergies, etc.) ) ). What does it reveal? Firstly, these patients presented an imbalance of the gut flora (dysbiosis) that was not present in healthy patients. It was depleted in certain bacteria beneficial to the regulation of immunity. Second, the more severe the case and the higher the levels of inflammation markers in the patient’s blood, the greater the dysbiosis. It therefore seems as if the gut microbiota plays a role in regulating the disease by modulating inflammatory processes. However, this mechanism remains to be confirmed. The study does not clarify whether the dysbiosis is the cause or consequence of the severity of the symptoms observed.

Dysbiosis persists after virus clearance

Another observation of the researchers was that this gut dysbiosis, which seems to increase with antibiotic treatments, persists even after the virus has been eliminated from the body. This led to the tentative hypothesis that the gut flora imbalance may contribute to the persistent symptoms observed in some patients.

Although Covid-19 is primarily a respiratory illness, recent work has pointed to the involvement of the gut microbiota in the disease. A new study conducted in early 2020 appears to confirm this hypothesis. The study involved 100 Covid-19 patients from two Hong Kong hospitals (average age: 36.4; 47 mild cases, 45 moderate cases, 5 severe cases and 3 critical cases) and 78 controls recruited before the pandemic. The aim was to find a link between the gut microbiota and disease severity, and to evaluate the persistence of any dysbiosis after virus clearance.

Gut dysbiosis in Covid-19 patients

The gut microbiota composition of 87 patients whose stools were collected during hospitalization showed a dysbiosis (more species from the Bacteroidetes phylum, fewer from the Actinobacteria phylum) compared to that of controls, which, according to the authors, was irrespective of any antibiotic treatment. This dysbiosis appeared to be linked to Covid-19 severity; and antibiotic therapy–received by 34% of patients–was the second most important factor in the severity of the disease. Certain immunomodulatory bacteria (Faecalibacterium prausnitzii, Bifidobacterium bifidum) were negatively correlated with severity after adjusting for antibiotic use and patient age. Despite this, the design of the study (heterogeneous clinical management, 31% of patients with comorbidities, etc.) prevents confirmation at this stage of the results obtained.

An associated immune response

The dysbiosis was also correlated with higher concentrations of inflammatory cytokines and other blood markers (sidenote: C-reactive protein, lactate dehydrogenase, aspartate aminotransferase and gamma-glutamyl transferase ) . Gut microbiota composition may be associated with the magnitude of immune response to Covid-19 and subsequent tissue damage and could thus play a role in regulating disease severity. However, according to the authors, another explanation is possible: the dysbiosis may simply be a response to patients’ health and immune states, rather than having any direct involvement in disease severity.

Persistent dysbiosis even after virus clearance

In addition, the gut microbiota composition of 27 patients surveyed up to 30 days after virus clearance differed from that of the controls: more B. dentium and Lactobacillus ruminis, less Eubacterium rectale, Ruminococcus bromii, F. prausnitzii and B. longum. This difference was observed whether the patients had received antibiotics or not (14 received antibiotics, 13 did not), although antibiotic treatment tended to accentuate it. According to the authors, this dysbiosis may contribute to the persistence of symptoms. However, a longer follow-up (e.g., 3 months to 1 year after virus clearance) is needed to confirm this link.

Asphalt, detergents, antibiotics, and processed foods are the flipside of modern society: the skin and gut microbiota that contribute to our health and immunity suffer the consequences. Under attack and poorly renewed due to insufficient contact with microbial diversity, these microbiota may go off-balance, which could explain today’s explosion in immune system diseases. What if all that’s needed to restore our microbiota is to replace the asphalt with nature? So suggests a Finnish study involving 75 toddlers aged 3 to 5. The study’s approach was original: the researchers integrated more green spaces into urban daycare centers (gravel covered with grass, forest floor, peat blocks for climbing, plants) in order to observe the effects of this microbe-rich environment.

Contact with nature boosts microbiota

The results were conclusive. After only 28 days of spending 90 minutes per day outdoors, the 36 Finnish children in the four ‘nature-boosted’ daycare centers saw their skin microbiota strengthened, with increased diversity and a greater abundance of certain beneficial bacteria. The change made their skin flora comparable to that of 23 other children who throughout the year attend daycare centers that bring them on daily trips to the forest. The same trend was observed in the gut: the microbiota of children in the nature-boosted centers saw rapid increases in the abundance of bacteria that produce beneficial fatty acids.

Immunity: the power of biodiversity!

Better still, the children’s immune systems evolved towards a less inflammatory profile. Everything thus seems to suggest that introducing nature into daycare centers is beneficial to toddlers’ immune systems: contact with microorganisms from the soil and plants builds their defenses in a balanced manner. We no longer have any reason to stop our children from digging in the earth or rolling around in the grass: it’s good for them!

The third most common cause of cancer-related death in the United States, with a survival rate of 9% at 5 years, PDAC is a dreaded form of cancer. Previous studies have shown that the tumor microbiota of PDAC patients contains bacteria normally present in the upper gastrointestinal tract thought to have migrated from the duodenum. If this is the case, the duodenal fluid could be a representative biospecimen for determining microbiome profiles of patients with PDAC or at risk of developing PDAC. Hence this monocenter case-control study comparing the bacterial and fungal profiles of duodenal fluid collected from patients undergoing a duodenal endoscopy, including 134 normal pancreas (controls), 98 patients with pancreatic cyst(s) and 74 patients with PDAC.

Dysbiosis in PDAC patients

The duodenal fluid of PDAC patients had higher levels of bacterial and fungal DNA than that of controls, even after adjusting for age, tobacco use and PPI (sidenote: Proton Pump Inhibitors )  use. In addition, PDAC patients had reduced microbial diversity, with the Bifidobacterium genus more abundant. Furthermore, Fusobacterium, Rothia and Neisseria were more abundant among PDAC patients whose survival was short.

The effect of PPIs should not be overlooked: in the controls, regular PPI use reduced microbiome diversity. PPI treatments were also associated with an increase in predominantly oral bacteria such as Streptococcus or Fusobacterium, with the latter linked to several types of cancer, including PDAC.

Alteration of the mycobiome

Duodenal fluid bacterial profiles were not significantly different between controls and patients with pancreatic cyst(s). On the other hand, the mycobiomes of these two groups did differ: patients with pancreatic cyst(s) had fewer Basidiomycota and Malassezia and more Ascomycota. At the same time, the PDAC patients had a lower abundance of Saccharomyces than the patients with pancreatic cyst(s).

Stratifying the cancer risk?

The study therefore suggests different duodenal fluid bacterial and fungal profiles for PDAC patients, patients with pancreatic cysts and those with a normal pancreatic function. These characteristic dysbioses open up the possibility of defining profiles that better stratify the risk of pancreatic cancer in patients under pancreatic surveillance. Broader studies that include other populations and regions will be required to draw definitive conclusions.

With many city dwellers currently considering leaving the city for the countryside, an article on the protective effect against asthma of growing up on a farm appears to support this choice. The authors had previously demonstrated a protective role for microorganisms coming from inside the home. In this new study, they focus on a key period in childhood development: the first year of life. Even before toddlers blow out their first candle, exposure to the outdoor environment shapes the development of their gut microbiota. This process may have long-term consequences, including the risk of developing asthma.

Farm 1, asthma 0

To test their hypothesis, the researchers followed a population of nearly 1,000 children living in rural areas of Europe, half of whom were born on farms, and 8% of whom became asthmatic between the ages of 0 and 6. Stool samples were taken at 2 and 12 months, with changes in the gut microbiome assessed over this period.

The fields’ secret: a more mature microbiome

The results confirm it: spending our first year on a farm reduces the risk of developing asthma later in childhood. But why? 19% of the farm’s protective effect seems to be linked to a more mature gut microbiome. The researchers also identified certain bacterial groups that were particularly involved. These are thought to produce a beneficial compound, butyrate, known for its anti-inflammatory properties. At the same time, while no specific bacterium stood out based on its protective effect, some did appear to be associated with an increased risk of asthma.

These results support the idea of a communication axis between the gut and the lungs, similar to the well-known gut-brain axis. They also encourage the use of preventive measures for respiratory and allergic diseases during the first year of life. In addition, they might further incite certain urban families to return to nature or at least to adopt a less overly hygienic lifestyle.

Persistent infection with high-risk human papillomavirus (HPV) is a leading cause of cervical dysplasia and cervical cancer. In recent years, numerous studies have suggested that a dysbiosis of the cervicovaginal microbiota may be closely related to persistent HPV infection, altered local immunity, and cervical intraepithelial neoplasia. A new study confirms this hypothesis.

Microbial signature of persistent HPV infection

In this new study, the cervicovaginal microbiota of 15 women was analyzed via 16S rRNA gene sequencing, and HPV genotyping was performed. Six of the women showed persistent infection (infection with the same HPV type for more than 12 months), four showed transient infection (infection cleared in less than 12 months) and five were HPV-negative. The three groups showed significant differences in the composition of the cervicovaginal microbiota. In the healthy women and those with transient infection, the Lactobacillus genus predominated, whereas women with persistent infection had a more diverse cervicovaginal microbiota. A statistical analysis revealed 36 bacteria to be associated with transient or persistent infection status, with these bacteria having the potential to serve as biomarkers. Among them, and in line with previous studies, the genera Acinetobacter, Prevotella and Pseudomonas were correlated with persistent infection. On the other hand, Lactobacillus iners was correlated with transient infection.

An increase in immunosuppressive cells

The women with persistent HPV infection had significantly higher concentrations of IL-6 and TNF-α in their cervical secretions and a higher number of regulatory T cells and myeloid-derived suppressor cells in their peripheral blood. Cervicovaginal dysbiosis may therefore create an inflammatory microenvironment, leading to an accumulation of immunosuppressive cells, which may in turn lead to the development of cancer.

Towards earlier diagnosis

The results of this study suggest that changes in the cervicovaginal microbiota may be linked to persistent HPV infection. However, it is not known whether dysbiosis induces persistence of the infection or vice versa. Despite this, the identification of a microbial signature for persistent HPV infection may allow earlier diagnosis, ultimately leading to earlier intervention to eradicate the infection and reduce the likelihood of developing malignant cervical lesions.