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).

The oropharyngeal microbiota (OM) normally comprises a wide variety of bacteria that help maintain a balanced local environment. Some illnesses and drugs such as proton pump inhibitors (PPIs) can disturb this balance, thereby allowing opportunistic pathogens to colonize the oropharyngeal tract. Microaspiration of these pathogens during hospitalization can lead to colonization of the lower respiratory tract, increasing the risk of nosocomial pneumonia. Early detection of oropharyngeal disturbance may be a means to reduce incidence. A team of researchers studying the occurrence of the disturbance during hospitalization has identified patient characteristics associated with the disorder.

Oropharyngeal disturbance increases with length of hospital stay

Oropharyngeal samples were collected from 134 hospital patients within 24 hours of admission, on day 3 of hospitalization, and then every four days for the remainder of their stay. The samples were analyzed by conventional bacterial culture and MALDI-TOF (matrix-assisted laser desorption/ionization time-of-flight) mass spectrometry, with the pathogens then classified into three categories: respiratory tract pathogens, gut microbiota species and yeasts. In 89% of the patients, the swab collected at admission showed a balanced OM. The authors found that a significant proportion of patients developed an OM disturbance during their stay, and that the number of patients with the disorder increased with the length of stay.

Antibiotics and PPIs responsible for disturbance

The prescription of antibiotics during hospitalization appears to be associated with this imbalance. Similarly, PPI and antibiotic use prior to hospitalization are predictive of an OM disturbance consisting of colonization by bacterial species from the gut microbiota. The study found that the risk of nosocomial pneumonia increased in patients treated with PPIs or antibiotics prior to hospitalization. Conversely, patients admitted to hospital on a short-term basis had a lower risk of oropharyngeal colonization by gut pathogens. These results underline the need for vigilance in the management of patients with risk factors associated with OM disturbance. Patients admitted to hospital with ongoing antibiotic or PPI treatment may well benefit from more aggressive physiotherapy aimed at maximizing lung aeration and minimizing aspiration. In this way, early detection of an OM disturbance may reduce the incidence of nosocomial pneumonia.

While Covid-19 usually produces respiratory symptoms, a significant proportion of patients suffer from gastrointestinal disorders such as diarrhea, vomiting or abdominal pain. In a review of 35 studies involving 6,686 Covid-19 patients, 29 of the studies showed a 4% prevalence of gastrointestinal symptoms and a 19% prevalence of liver function abnormalities. These symptoms were more severe with increased viral load. In addition, approximately 10% of patients had gastrointestinal symptoms only, and no respiratory symptoms.

A deregulation of ACE2 in the gut

To link bowel disorders to Covid-19, the researchers investigated the role of ACE2 (receptor for the SARS CoV-2 Spike protein (sidenote: The Spike protein, or S protein, is the key that allows SARS-CoV-2 to enter human cells ) ) in gut inflammation. Highly expressed in the gut, its function is to control the absorption of dietary amino acids such as tryptophan, which plays an important role in immunity. Indeed, several preclinical studies suggest that gut ACE2 is an essential regulator of gut inflammation. In an ACE2 knockout (sidenote: ACE2 knockout mouse An ACE2 knockout mouse is a mouse model in which the ACE2 gene is absent )  mouse model, the absence of the ACE2 gene leads to more severe colitis (sidenote: A sodium dextran sulphate (DSS)-induced colitis model ) . In another model (animals treated with an antihypertensive drug (sidenote: Angiotensin receptor blocker (ARB) ) ) with stress-induced inflammation, increased ACE2 expression correlated with reduced inflammation. Therefore, an ACE2 deficiency increases gut’s susceptibility to inflammation.

A lasting gut dysbiosis?

Furthermore, the digestive tract takes longer to excrete SARS-CoV-2 than the respiratory tract. SARS-CoV-2 RNA persists in the stool in over half of patients even after a negative nasopharyngeal swab test and up to 33 days after symptomatic healing of a lung lesion. A study on 15 patients also showed persistence of gut dysbiosis well beyond infection, with a loss of beneficial species in most patients. Exposure to SARS-CoV-2 may therefore be associated with long-lasting harmful effects on the gut microbiota.

According to the authors, by down-regulating gut ACE2, SARS-CoV-2 may modify the gut microbiota and increase systemic inflammation, which may explain the multiple organ failure observed in Covid-19.

As the sixth leading cause of cancer death, esophageal cancer remains highly lethal, with five-year survival rates of 15%-20%. Esophageal squamous cell cancer (ESCC) is the most common subtype of the disease. Current treatments include neoadjuvant chemotherapy (sidenote: Neoadjuvant chemotherapy To reduce tumor size prior to surgery )  (NAC) followed by esophageal resection. Although patients who respond favorably to NAC have a better chance of survival, most tumors develop NAC resistance. Understanding the mechanisms behind NAC resistance is therefore key to improving treatment response and, accordingly, patient survival.

What role does Fusobacterium nucleatum play in tumors?

The composition of the gut microbiota has already been shown to influence responses to certain cancer treatments such as immunotherapy and chemotherapy. In addition, intratumoral Fusobacterium nucleatum levels have recently been shown to be associated with reduced survival and/or increased recurrence rates in colorectal cancer and in ESCC. This encouraged researchers to assess, for the first time, the prognostic value of intratumoral F. nucleatum levels in ESCC patients and their ability to predict NAC response. The study was carried out in 551 Japanese subjects from two independent cohorts.

Predictive marker of reduced survival rate...

First finding: tumor tissue has higher levels of F. nucleatum compared to adjacent healthy tissue. In addition, intratumoral F. nucleatum levels are associated with both the stage of tumor progression and a reduction in relapse-free survival (RFS). The link between F. nucleatum and reduced survival is observed even in early-stage patients, suggesting that this bacterial species may promote tumor aggressiveness. Intratumoral F. nucleatum levels may therefore serve as a prognostic biomarker.

... and poor responses to chemotherapy

Lastly, analyses in a subgroup of 101 patients receiving NAC showed that patients with increased levels of F. nucleatum had a lower response to tumor treatment. Although the mechanisms likely to explain the role of F. nucleatum in increased tumor resistance remain speculative (activation of metabolic pathways leading to cell autophagy?; deactivation of chemotherapeutic substances?), the researchers point out a promising therapeutic avenue: improving responses to chemotherapy via an antibiotic therapy targeting F. nucleatum. More work to follow.

The microbial world present in the air, soil and plants is considered critical for our health. Certain theories suggest that low exposure to green spaces and to the microorganisms found in them has contributed to the contemporary rise in obesity, diabetes mellitus, and allergies. Therefore, a better understanding of the interactions between man and nature, and especially between microbiota and environment, seems key to fighting these non-communicable diseases. To this end, a team of scientists evaluated the impact of green spaces on the composition and diversity of the skin and nasal flora of three individuals following visits to urban green spaces in three different countries, Australia, India, and the UK.

Green spaces increase microbial diversity

During their walks, the participants took soil, leaf, and air samples in order to analyze the bacteria in the environment. They also took samples from their nose and skin before and after each exposure to the environment so as to assess the impact of green spaces on their microbiota. The analysis revealed that the skin flora had changed following the walk: it was richer in bacteria, more diverse and closer to that of the soil, evidence that environmental bacteria had colonized the skin. Furthermore, the composition of the nasal microbiota was similar to that of air samples.

Transient changes?

Even more interesting was the overall similarity between the changes in microbial diversity and composition in the three countries visited, even though many factors known to influence the composition of the microbiota, such as pollution, humidity, or diet, differed between these three countries. It is not yet known how long these changes in the flora last, but previous studies suggest that most environmental bacteria transferred to humans disappear after 2 hours, with less common types potentially persisting for up to 24 hours on the skin. Further research is required to establish whether there are any health benefits from these microbial changes, but in the meantime, feel free to roll around in the grass!

As part of World Antimicrobial Awareness Week (18-24 November 2020), the WHO encouraged the general public, health workers and decision-makers to adopt best practices in order to avoid the emergence and spread of antimicrobial resistance. While antibiotics were one of the major therapeutic advances of the 20th century, they can also have an adverse impact on the body’s various microbiota. Although the short-term effects of some classes of antibiotics on the gut microbiota are well known, the long-term effects are not yet fully understood. This study compared the impact of 15 classes of antibiotics on the composition of the gut microbiota up to four years after the last dose.

“Large scale” study

The composition of the gut microbiota of 1413 participants (median age: 62.6 years) who had previously taken antibiotics was analyzed by 16S rRNA sequencing. The time elapsed from the last dose of antibiotics to the day of sampling was categorized as follows: 0-12, 12-24, 24-48 and >48 months. The results were adjusted for certain confounding factors (sex, age, BMI, diabetes mellitus, concomitant medications such as statins, PPIs, corticosteroids, etc.).

Impact of macrolides and lincosamides

The most significant and prolonged impact on the gut microbiota was observed for macrolides and lincosamides: decrease in Shannon ratio that lasted for 4 years after the last administration, and significant change in bacterial community structure (Bray-Curtis diversity ratio). A significant loss of diversity was also observed one year after use of beta-lactams.

Impact of antibiotics with high anti-anaerobic activity

The results also revealed that antibiotics with high anti-anaerobic activity (penicillin/beta-lactamase inhibitor combinations, imidazole derivatives and lincosamides) had a greater and longer-lasting impact on the gut microbiota than other classes: the Firmicutes/Bacteroidetes ratio significantly shifted in favor of Firmicutes up to one year after administration, while this ratio significantly shifted in favor of Bacteroidetes up to two years after taking antibiotics with no anti-anaerobic activity.

Therefore, macrolides and lincosamides are associated with an acute and long-lasting dysbiosis of the gut microbiota. These effects differ in strength and duration depending on the class of antibiotic used. According to the authors, these findings should be considered when prescribing antibiotics.