Many new mothers experience the baby blues after giving birth. However, some mothers (and sometimes even their partners) may suffer from a much more severe and long-lasting form of depression known as postpartum depression. The precise causes of this disorder often remain unknown and only certain risk factors, such as genetic and/or environmental factors, have been identified. A recent study published in a scientific journal suggests the gut microbiota may also be involved.

Altered gut flora

Numerous studies have shown that changes to the gut microbiota may influence certain depressive disorders. In particular, there appears to be a link between anxiety in late pregnancy and gut microbiota imbalance. In this new study involving around sixty women, the composition of the gut microbiota of mothers suffering from postpartum depression showed alterations with respect to that of healthy women. In addition, the severity of depressive symptoms correlated with the presence of certain bacterial species.

Sex hormones at heart of problem

This gut imbalance (dysbiosis) may be caused by abnormal secretions of sex hormones. While female sex hormones (estrogen and progesterone) have already been implicated in the development of postpartum depression, this new study shows that they may play an important role in disrupting the gut microbiota of affected patients.

A new diagnostic and treatment avenue

These results may help scholars further explore the underlying causes of postpartum depression. While the scientific theories proposed in the study remain tentative, the microbiota characteristics identified may prove to be valuable diagnostic biomarkers or provide significant clues for future treatments.

A mind-boggling number of studies are published each month on the gut microbiota’s influence on brain function. Many of these studies focus on the role of gut microbiota imbalances in the onset or progression of Alzheimer’s disease (AD). The researchers in this study sought to identify the ways in which gut bacteria contribute to the disease, and more specifically to the accumulation of the dreaded amyloid deposits.

Uncovering the mechanisms at play in the gut-brain axis

To this end, they brought together around 90 individuals aged between 50 and 85, with or without AD, in order to study how the gut influences the brain. Analyses assessed the presence in their blood of: 1. molecules produced by bacteria from the gut microbiota; 2. inflammatory molecules; and 3. markers signaling the alteration of the gut barrier (allowing gut compounds to reach the bloodstream) and blood-brain barrier (allowing compounds to cross from the blood to the brain). The presence of amyloid deposits in the brain was also measured. The aim was to find associations between all these parameters in order to identify the mechanisms involved.

Bacterial and inflammatory compounds implicated

This search proved fruitful, with many strong associations found. For example, between amyloid deposits on the one hand and inflammation and presence in the blood of compounds from the gut microbiota on the other, or between these compounds and alterations to the permeability of the aforementioned barriers. An imbalance in the gut microbiota could therefore trigger an inflammatory mechanism capable of disrupting the body’s protective barriers, leading to the leakage of compounds into the brain and the potential formation of amyloid plaques. This finding opens the way to novel therapeutic approaches, such as the administration of a cocktail of beneficial bacteria (probiotics) to preserve the balance in the microbiota, particularly in at-risk individuals. The ingredients of this cocktail remain to be identified, however.

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The presence of a gut dysbiosis in patients suffering from Alzheimer’s disease has already been proven. So too has the microbiota’s involvement in the cerebral accumulation of amyloid beta proteins associated with the disease. This new study aimed to investigate the signaling pathways through which patients’ gut microbiota contributes to this amyloid pathology.

In search of correlations

The study involved 89 individuals aged between 50 and 85 with cognitive performance ranging from normal to cognitive impairment with memory loss (whether or not associated with the disease). Amyloid deposits were measured by PET-scan and quantified in the various areas of the brain, while blood levels of molecules produced by the gut microbiota (lipopolysaccharides–LPS–and short-chain fatty acids–acetate, propionate, valerate, butyrate), pro- and anti-inflammatory biomarkers (including interleukins–ILs) and biomarkers of endothelial dysfunction (cell adhesion molecules–CAMs) were also measured.

Bacterial mediators implicated

Regardless of the brain area, amyloid deposition was positively correlated with blood levels of LPS, acetate, valerate, certain pro-inflammatory cytokines (e.g. IL1b, IL6) and many CAMs (e.g. P-selectin, PECAM-1), but negatively correlated with butyrate and IL10 (anti-inflammatory) levels. Lastly, some biomarkers of endothelial dysfunction were positively correlated with acetate, valerate, IL1b and IL4 levels, but again negatively correlated with levels of butyrate and IL10. The authors interpreted these correlations as evidence of a direct and indirect association between blood parameters linked to gut dysbiosis and amyloid pathology.

Inflammation, barrier function and Alzheimer’s

Therefore, the reduction in butyrate levels associated with an increase in the levels of acetate, valerate and LPS may compromise the integrity of the gut barrier, cause and maintain low-level systemic inflammation, and alter the blood-brain barrier, ultimately allowing pro-inflammatory compounds facilitating the pathological cascade of Alzheimer’s disease to enter the central nervous system. While highlighting that no causal link could be established from their data, the authors emphasize that the strength of the associations found supports this pathophysiological hypothesis. Lastly, it may be possible to develop prevention strategies for Alzheimer’s based on enriching the microbiota with beneficial bacteria or metabolites, once the microbial signature associated with the disease has been clarified.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease that leads to the destruction of pancreatic β-cells. Studies in mice suggest that interactions between the gut microbiota and the innate immune system are involved in the development of the disease, the progression of which may be slowed by fecal microbiota transplantation (FMT).

Autologous versus allogenic transplantation

In a randomized controlled trial, patients recently diagnosed with T1DM received three FMTs by nasoduodenal tube at 0, 2 and 4 months, either from their own feces (autologous FMT, n=10) or from the feces of healthy donors (allogenic FMT, n=10). In the year following the first FMT, the researchers evaluated residual β-cell function (via C-peptide release in response to a test meal), as well as metabolic, immune and microbiota changes induced by the two types of FMT.

Pancreatic function preserved

Contrary to the researchers’ expectations, β-cell function was preserved in the autologous group one year after the first FMT. β-cell function deteriorated in the allogenic group, however, although less than in T1DM patients not treated within the first year of diagnosis (sidenote: Overgaard AJ, Weir JM, Jayawardana K, et al. Plasma lipid species at type 1 diabetes onset predict residual beta-cell function after 6 months. Metabolomics 2018;14:158; Lachin JM, McGee PL, Greenbaum CJ, et al. Sample size requirements for studies of treatment effects on beta-cell function in newly diagnosed type 1 diabetes. PLoS One 2011;6:e26471 ) . According to the researchers, the benefits of FMT may be more pronounced and long-lasting where immunological compatibility between donor and host is high.

Desulfovibrio piger involved?

Changes in the microbiota were found to be associated with certain metabolic and immune changes. In the duodenum, the presence of Prevotella spp. was inversely correlated with residual β-cell function. In the colon, Desulfovibrio piger became significantly more abundant following autologous FMT only. Its abundance was associated with improved residual β-cell function and increased levels of plasma 1-arachidonoyl-GPC (A-GPC), a microbial metabolite associated with increased C-peptide production. In addition, the abundance of D. piger was negatively correlated with levels of certain T cells involved in autoimmunity. What was the significance according to the authors? D. piger may inhibit autoimmunity by suppressing these T cells via the production of A-GPC. From the multiple correlations found, the researchers have identified mechanistic leads that will need to be further investigated to clarify the effects of FMT on T1DM. They have also newly identified the therapeutic potential of certain bacterial species.

As you probably know, Maya the Bee lives surrounded by her half-sisters, since the queen spends her life producing eggs to populate the hive. However, despite their genetic similarity, she and her sisters recognize each other by smell! What’s more, this study suggests that a bee’s scent–a signal of hive membership–is directly linked to the gut microbiota shared with its nestmates

Recognizing their own by smell

The honey bee’s body is covered with scent molecules. This allows the guards at the entrance to the hive to recognize hive members and stop intruders trying to sneak in and steal food. A research team has recently shown that the olfactory cues are based on shared characteristics of the gut microbiota (bacteria, fungi and viruses colonizing the digestive system), rather than genetic similarity. Bees from the same colony share several types of identical bacteria in the gut, giving them their common scent. Conversely, bees from a different colony, whose microbiota is home to distinct bacteria, emit a different scent.

Mechanisms involved

How to explain this influence of the microbiota? A number of theories have been put forward. According to one of them, the colony-specific scent is derived from the smell of the gut microbiota itself. However, this hypothesis seems unlikely as it goes against previous studies suggesting the involvement of molecules secreted by cells located under bees’ “skin”, to which the gut bacteria have no access. A second, more likely, theory suggests that the microbiota of honey bees quantitatively and qualitatively influences the production of scent molecules, for example, by providing their ingredients (or failing to do so). This scent recognition system is very useful to bees, but also has advantages for their gut bacteria: by rejecting bees with a distinct digestive flora, the hive also limits the entry of different bacteria, offering the organisms in the microbiota a quiet life, without competition.

Introversion, social anxiety... alcoholics display alterations in social behavior that may facilitate relapse. Alcohol consumption can lead to a dysbiosis of the gut microbiota, which in turn is known to be a modulator of social behavior in rodents. Hence the theory that the gut microbiota may be involved in the sociability problems associated with alcoholism. To test this hypothesis, a team of researchers transplanted (FMT ) into mice the microbiota of alcoholic patients suffering from a dysbiosis (reduced bacterial count, reduced content of Faecalibacterium prausnitzii and increased content of Lachnospiraceae), increased gut permeability and psychological disorders (anxiety, alcoholic impulses, impaired sociability, etc.).

Microbiota was enough to modify behavior

The results? The mice which received the transplant (FMT) showed a reduced interest in social interactions and more depressive-like behavior, as well as higher corticosterone levels, reflecting higher levels of stress. Disturbances of myelination and neurotransmission, as well as inflammation, were observed in the frontal cortex and striatum.

β-hydroxybutyrate, a metabolic mediator?

β-hydroxybutyrate (BHB), a ketone body produced by the liver that serves as an energy source for neurons may be involved in the behavioral and brain disorders observed. Reduced in the FMT mice, it is one of the metabolites distinguishing them from controls. Studies in other animal models and in humans supports the involvement of BHB. In mice, an increase in plasma BHB levels under the ketogenic diet improved social skills and myelination and reduced brain inflammation. In alcoholics, low plasma BHB levels were associated with higher levels of social anxiety, depression and alcohol craving, and lower white matter integrity (one of the determinants of which is myelination).

Is microbial ethanol involved?

But how would the microbiota influence plasma BHB levels? The microbiota of alcoholic patients produces ethanol, even with protracted alcohol withdrawal, an observation confirmed in FMT mice. The authors believe this alcohol may inhibit the Hmgcs2 enzyme and PPARα transcription factor, which are involved in the synthesis of BHB. Indeed, the expression of these two molecules is lower in FMT mice. Restoring the microbiota or ketone body metabolism is one clinical avenue that may result from this work: by favorably modulating the gut-brain axis, this may help limit relapse.

Atopic dermatitis (or atopic eczema) is a chronic inflammatory skin disease that starts in early childhood as eczema patches appearing during flare-ups. The disease disappears in most cases during adolescence. Changes in the skin microbiome have been associated with atopic dermatitis and its severity, with an overabundance of Staphylococcus aureus and S. epidermidis in lesions, and a reduced abundance of streptococci during inflammatory flare-ups. Furthermore, the nasal microbiota is suspected of acting as a bacterial reservoir and of maintaining self-contamination between the skin and the nose, although few data support this theory.

Nose and skin: two connected microbiomes?

A team of researchers analyzed samples taken from the nose and lesioned skin of children suffering from atopic dermatitis. While the skin lesions were almost exclusively colonized by staphylococci, these species were far from the majority in the nasal microbiome, which is more diverse and dominated by other bacteria (Moraxella, Corynebacterium, Dolosigranulum). However, these distinct compositions do not prevent the nasal and skin microbiomes from interacting, as indicated by the statistical association between the bacterial species in the nasal passages and those present on the skin. However, the mechanisms involved are not fully understood.

Two microbiomes associated with severity

In addition, the composition of the nasal and skin microbiomes, and particularly that of the skin microbiome, was found to be linked to the severity of the disease. This link is mainly due to the presence of staphylococci in both microbiomes, but other species also play a role, such as Moraxella in the nose. According to the authors, these results suggest that the skin and nasal microbiomes play a role in exacerbating the inflammation caused by atopic dermatitis. The authors call for further research in order to identify more precisely the species and various microbiomes involved in the disease.

Changes in the skin microbiome have been associated with atopic dermatitis (AD) and its severity. The nasal microbiota may also be involved: Staphylococcus aureus has been found five times more often in the nose of AD patients. The nostrils may be an important source of self-contamination and of bacterial propagation from the nose to the skin, or vice versa. A study has therefore focused on the relationship between skin and nasal microbiomes in children with AD, based on the severity of the disease.

Nose and skin: two connected microbiomes?

Using 16S-rRNA sequencing, the researchers first found distinct microbial communities in the nose (89 samples) and on the damaged skin (57 samples) of children with AD: while the nasal microbiome was dominated by Actinobacteria (Corynebacterium spp.), Proteobacteria (mainly Moraxella) and Firmicutes (Staphylococcus, Streptococcus and Dolosigranulum spp.), the skin lesions were dominated by staphylococci, and to a lesser extent by species belonging to the genera Pelomonas, Streptococcus and Janthinobacterium. However, correlations were found between the bacterial species in the nose and those on the skin, although the mechanisms involved are not fully understood (cross-transmission between the two niches?).

Microbiomes linked to disease severity

Most importantly, the compositions of the nasal and skin microbiomes, and particularly that of the skin microbiome, were both found to be linked to the severity of pediatric AD. This was so even after adjusting for confounding factors such as age, antibiotic use, and skin sample site. This link between the microbiomes and AD severity is mainly due to the presence of staphylococci in both niches, and of other species, such as Moraxella in the nose.

Distinguishing between bacterial presence and bacterial load

The study also showed that S. aureus was present in the skin lesions of one out of two patients–more often in severe forms (sidenote: Trend nevertheless statistically insignificant ) –but that its load (measured by quantitative PCR) was not associated with the severity of AD. Conversely, although the presence of S. epidermidis in the skin was not correlated with severity in 80% of the samples, its load was significantly higher in cases of severe AD. Even though this association does not demonstrate a causal link, the results suggest that the two microbial niches play a role in exacerbating inflammation caused by the disease. Hence the importance of exploring in future studies not only the role of microbial species in AD and their relationships with the host and other species, but also the interactions between the different microbial communities within the organism.

A strong weight of evidence supports the hypothesis of a link between gut dysbiosis and autism. For example, many ASD patients suffer from gut imbalances–such as a deficiency of Bifidobacterium longum and an excess of Clostridium spp. and Candida albicans–, which are thought to be associated with inflammation of the gut and increased permeability of the gut-blood barrier. In addition, gastrointestinal comorbidity and digestive enzyme deficiencies are more common in children with ASD. Despite this, the mechanisms involved and the contribution of the gut microbiota to the development of ASD remain poorly understood.

A novel pairing strategy

However, a decisive step forward may now have been taken. In a study published in Science Advances, a research team compared the gut microbiota of 39 children with ASD to that of 40 neurotypical children of the same age and gender. This first analysis revealed differences in 18 bacterial species between these two groups but could not explain the exact role of the gut microbiota in the development of the disease. To control for interindividual diversity of the microbiota, the researchers developed a strategy consisting of pairing each ASD patient to a control subject based on the metabolic profile of their microbiota. A novel cohort of 65 pairs was thus created, with a metagenomic analysis performed to identify the metabolic pathways that differed between the two groups.

Impaired intestinal microbial detoxification

Among the 96 metabolic pathways associated with ASD, five that are involved in intestinal detoxification were significantly deficient compared to the control subjects, as were 8 enzymes involved in the degradation of toxins contained in insecticides and food additives. The authors believe that these detoxification impairments in ASD children may contribute to mitochondrial dysfunction, which can affect all tissues, including brain tissue. Based on these data, the researchers constructed a diagnostic model capable of discriminating ASD children from control subjects with 88% accuracy.

Increased gut permeability

This finding may explain why children with ASD are so vulnerable to environmental toxins and suggests that the impaired gut detoxification process in ASD patients may be involved in the development of the disease. However, the reasons for deficiencies in microbial detoxification remain unclear. One hypothesis points to a gut dysbiosis which, by causing increased intestinal permeability, allows environmental toxins to enter the bloodstream. Among other effects, these toxins may alter the mitochondria in the brain. If confirmed, this hypothesis could pave the way for new therapeutic strategies aimed at restoring the microbial detoxification capabilities of ASD patients, according to the authors.

The use of antibiotics increased by 65% between 2000 and 2015. This new study reminds us that when eradicating pathogenic germs responsible for infections, antibiotics can also destroy beneficial bacteria in the gut microbiota, thereby causing an imbalance (dysbiosis) within this ecosystem, with potential short and long-term consequences.

Adverse effects on microbiota in the short and medium term...

The first thing to note is that antibiotics disrupt the balance existing in the gut microbiota. By eliminating certain bacteria, they allow other pathogens to occupy the free space and multiply. One consequence is antibiotic-associated diarrhea, which affects between 5% and 35% of patients but usually resolves spontaneously within a few days. However, some forms of diarrhea can be more severe and when caused by Clostridioides difficile they may even be fatal.

The second observation is that antibiotics are linked to a reduction in microbiota diversity. A return to equilibrium may take some time, with certain bacteria still absent after several months. Lastly, the repeated or inappropriate use of antibiotics leads bacteria to develop strategies to circumvent their effects. Bacteria can become antibiotic-resistant, thereby rendering treatments ineffective. The experts’ predictions are unsettling: unless drastic measures are taken to address the issue, the misuse of antibiotics could cause ten million deaths worldwide by 2050.

...with serious long-term consequences

Systemic use of antibiotics is still far too widespread among infants and children and is thought to be associated with the development of diseases later in life (obesity, asthma, allergies, inflammatory bowel disease). This battle is far from won and the scientific community is actively seeking new strategies to restore the gut microbiota, based on multiple modulation pathways (diet, probiotics, prebiotics).