“Twinkle, Twinkle, Little Star”, “Rock-a-Bye Baby”, ““Puff the Magic Dragon”... Every night, you go through your repertoire of lullabies to send your child off to sleep. All in vain. Far from falling asleep, your adorable tot claps its hands and feet, and its wide-open eyes plead to hear you sing. It even seems to want an “encore”! But at what point will your baby finally sleep all through the night? Great news: there are ways to make sure your baby sleeps like a log from dusk to dawn. These solutions seem to involve the gut microbiota, the community of microorganisms in the digestive system, whose composition evolves during the first years of life.

Sleep: bacteria involved from three months

Recent studies carried out on more than 160 infants have shown a link between an infant’s gut flora and its sleeping habits. Infants who slept more during the day had lower gut microbial diversity than those who saved their sleep for nighttime. Moreover, the quality of infants’ nighttime sleep seems to depend on the type of bacteria present in their gut and on the maturity of their gut microbiota. This effect is clear from three months.  This is an important discovery, since up till now these links had only been known in adults.

Influence on future behavior 

Furthermore, brain activity during sleep at six months appears to vary according to the bacteria in the gut. It also appears to predict gut microbial diversity at one year. In short, sleep and microbiota seem closely connected and develop together over time. Should parents of children who have difficulty sleeping be worried?

On the contrary, the authors of the study reassure us that: “Sleep and gut microbiota can be readily modified. Sleep can be tailored with behavioral interventions through educational and behavioral strategies by the parents. Gut microbial composition can be modified by diet or orally ingested prebiotics and probiotics added to infant formula.”

Antibiotic prophylaxis reduces the risk of serious infection in women during delivery by cesarean section by 60–70%². Administration before the incision and not after cord clamping can also reduce the incidence of endometritis and global maternal infectious morbidity³. This approach is now therefore widely recommended, but nevertheless exposes the child to antibiotics before birth, with potential repercussions for his or her health and newly-formed microbiota. Dutch researchers wanted to find out whether it further altered the bacterial colonization of children born by cesarean section.

Dysbiosis in the first month following cesarean birth

Like many others before them, the researchers observed major differences in intestinal flora during the first month of life between the children born by cesarean and those born by vaginal delivery. They recorded a lower Shannon index (relative richness and abundance of species) with a reduction in bacteria from the Bacteroides and Bifidobacterium genera, and an increase in the Proteobacteria phylum, especially Firmicutes. However, these differences resolved by the age of 3 years.

No effects of antibiotic administration prior to incision

The main finding of this study was the absence of any significant difference in composition of the gut microbiota in terms of bacterial phyla or genera between the two groups of children born by cesarean section, at any point between 1 day and 3 years. Although it included only a small group of women, this study suggests that antibiotic prophylaxis prior to incision does not cause any additional disruptions to the intestinal microbiota of children born by cesarean section.

Vaginal human papillomavirus (HPV) is the most common sexually transmitted infection (STI). It is usually asymptomatic. Most of the time, the body eliminates these viruses by itself. However, they can persist in some women, putting them at risk of infections that can lead to cervical cancer. The fourth most common type of cancer among women (sidenote: https://www.who.int/fr/news-room/fact-sheets/detail/human-papillomavirus-(hpv)-and-cervical-cancer ) , cervical cancer is currently incurable and represents a major public health concern.

Dysbiosis of the vaginal microbiota

The risk factors for persistent HPV infections are known: they consist of behavioral (vaginal douching, sexual intercourse) and biological (bacterial vaginosis, bacterial vaginosis, sexually transmitted infections) factors that disturb the vaginal microbiota (dysbiosis). To date, most studies have focused on the link between dysbiosis and precancerous or cancerous lesions of the cervix, but none on the identification of a microbial signature of persistent HPV infection that can be detected before lesions appear, thereby preventing progression to cancer.

Probiotics for prevention?

The analyses showed that HPV infection is associated with a disturbance of the vaginal microbiota, with differences observed between the NC group and groups P and C. The analyses also showed that HPV infection is characterized by depleted bacterial richness and lower bacterial diversity.  Current or past infection is associated with an increase in Firmicutes and Actinobacteriota, and a decrease in Proteobacteria. The authors believe that this dysbiosis facilitates infection by the virus, whereas an increased abundance of vaginal Proteobacteria is thought to stabilize the microbiota. While the vaginal microbiota of all three groups were dominated by lactobacilli, their abundance was even greater in patients who had eliminated the virus (group C) than in NC patients. The researchers also observed a greater abundance of lactobacilli or bifidobacteria species depending on the type of virus eliminated, suggesting that these bacteria have a protective effect against different types of viruses. 

These findings have yet to be confirmed, but the researchers conclude that they pave the way for the development of probiotics which can be used to treat HPV infection early, before malignant lesions of the cervix appear.

Long considered sterile, the uterine cavity is in fact home to a microbiota composed of bacteria. Although 100 to 10,000 times less numerous than the bacteria present in the vagina, uterine bacteria appear to be just as involved in reproductive health. So suggests a multicenter (13 centers located in Europe, America, and Asia), prospective, observational study that analyzed the composition of the endometrial microbiota of 342 infertile women taking part in IVF programs.

Double sampling of endometrial microbiota

Two samples were taken prior to embryo transfer to evaluate the composition of the endometrial microbiota: the endometrial fluid was aspirated from the uterine cavity and the endometrial mucosa was sampled via biopsy. The researchers then studied the relationship between the composition of the endometrial microbiota, analyzed using 16S RNA sequencing, and the outcome of IVF, namely pregnancy carried to term (41% of patients), biochemical pregnancy (8%), miscarriage (8%), or no pregnancy (42%).

Endometrial dysbiosis associated with IVF failure

The researchers observed an increased abundance of Lactobacillus (in fluid and mucosal samples) in patients who carried a pregnancy to term. Conversely, Lactobacillus depletion and the presence of specific pathogenic bacteria, such as Atopobium, Bifidobacterium, Chryseobacterium, Gardnerella, Haemophilus, Klebsiella, Neisseria, Staphylococcus, and Streptococcus, were associated with IVF failure or a pregnancy that did not result in a viable birth. Notably, Gardnerella and Klebsiella were over-represented in both the endometrial fluid and endometrial mucosa of patients whose IVF was unsuccessful.

Lactobacilli, a bulwark against pathogens?

These data point to the role of the endometrial microbiota in the success or failure of embryo implantation and/or the outcome of IVF. The researchers suggest that the outcome of IVF is influenced by the absence of pathogenic bacteria in the endometrium, rather than the presence of beneficial bacteria (such as lactobacilli). Lactobacillus may thus inhibit the colonization of the uterine cavity by pathogenic bacteria. However, further studies are needed to clarify the mechanisms by which these pathogenic bacteria work.

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Is it finally time for endometriosis patients, i.e., one in every 10 women of reproductive age (sidenote: Endometriosis, World Health Organization (2021 March). ) , to come out of the shadows and put an end to diagnostic error? As we enter into Endometriosis Awareness Month and with the announcement by French President Emmanuel Macron on January 11, 2022 of a national strategy (sidenote: https://www.elysee.fr/emmanuel-macron/2022/01/11/strategie-nationale-endometriose ) , the answer is hopefully yes.

Researchers have for some time harbored suspicions about some of our microbiota: not only the vaginal microbiota, which could be a useful predictor of severity, but also, according to one recent Chinese study, the gut microbiota as well as the peritoneal fluid (sidenote: Peritoneal fluid Fluid found in the peritoneal cavity, i.e., inside the membrane surrounding the abdominal organs. It acts as a lubricant, preventing friction between the organs during digestion. DiZerega GS, Rodgers KE, Peritoneal Fluid. The Peritoneum. 1992. pp 26-56 Springer New York ) as tools for confirming the diagnosis.

Peritoneum, gut, and cervix under the microscope 

According to their results, the communities of microbes living in the gut and peritoneum of women with endometriosis differ from those observed in women not affected by this condition. Endometriosis patients have fewer of certain types of protective bacteria (especially Ruminococcus) in the digestive tract, and in contrast an over-representation of pathogenic bacteria (especially Pseudomonas) in the peritoneal fluid. 

On the other hand, the composition of the cervical mucus is relatively similar between women with and without endometriosis.

The gut microbiota, a diagnostic tool? 

Could this difference in the microbiota of the gut and peritoneum in women with endometriosis be used to diagnose the condition earlier? That is the question! Crucially, could this be something thousands of women have until now only dreamed of: a more rapid diagnostic test based on an analysis of the microbiota? In fact, the discovery of an intestinal marker is particularly interesting because a simple stool sample is all that is needed to analyze the gut microbiota. A very promising idea...

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Bacteriophages, or simply “phages,” are the most abundant and varied biological agent on Earth. The natural predators of bacteria, they are ubiquitous in the earth, oceans... and the human intestinal microbiota, where they are the dominant type of virus. Intestinal bacterial dysbiosis, which is associated with gastrointestinal disorders such as Crohn's disease and Irritable Bowel Syndrome, goes hand in hand with compositional changes in the virome.

A century on, and they’re back in the spotlight

In the 1920s, experiments to assess the therapeutic potential of phages gave promising results in patients with shigellosis, dysentery, and cholera. This emerging field of research (sidenote: Summers WC. The strange history of phage therapy. Bacteriophage. 2012 Apr 1;2(2):130-133. ) was then cast aside with the arrival of antibiotics in the 1940s. Although a few studies, unfortunately badly documented ones, continued in Soviet countries, phages were relegated to the second division. However, recent concerns over multidrug-resistant infections, and a new understanding of how antibiotics impact the balance of the intestinal microbiota, have prompted a renewed scientific interest in phage therapy. Each species of phage usually targets a single species of bacteria, which means these viruses can provide a “precision” solution where broad-spectrum antibiotics fall short. Nevertheless, despite its great promise, the health care authorities have yet to authorize any phage-based therapy (except in very exceptional cases).

Antibiotic resistance, dysbiosis, targeted therapy: multiple potential uses 

In 2017, one particular case study (sidenote: Schooley RT, Biswas B, Gill JJ, et al. Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection. Antimicrob Agents Chemother. 2017 Sep 22;61(10):e00954-17.  ) attracted attention: a 68-year-old diabetic patient with pancreatitis complicated by a multidrug-resistant Acinetobacter baumannii infection regained full health in just five months thanks to phage therapy, after several failed attempts with antibiotics. Similar success stories have been reported with Pseudomonas aeruginosa (sidenote: Jennes S, Merabishvili M, Soentjens P, et al. Use of bacteriophages in the treatment of colistin-only-sensitive Pseudomonas aeruginosa septicaemia in a patient with acute kidney injury-a case report. Crit Care. 2017 Jun 4;21(1):129.  ) and Mycobacterium abscessus (sidenote: Dedrick RM, Guerrero-Bustamante CA, Garlena RA, et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med. 2019 May;25(5):730-733. ) , offering hope of a promising alternative for the treatment of multidrug-resistant bacterial infections. Phage therapy as a modulator of the intestinal microbiota is also of interest to scientists. A study in mice found that treatment with phages specific to Enterococcus faecalis, a bacterium associated with a poor prognosis in alcohol-related hepatitis, can improve the disease.

Seeking to overcome the challenges of clinical use 

Research now needs to look at ways to overcome the many questions posed by clinical practice. Is phage therapy always safe? Can it replace antibiotic treatment? What is the best method of administration and the right dose? What is their long-term effect on the microbiota and health in general? According to the authors, randomized, double-blind, placebo-controlled clinical trials are needed to legitimize the role of phage therapy, an age-old practice that could help overcome several of the challenges facing medicine today.

COPD (sidenote: https://www.who.int/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd). ) is a chronic respiratory disease characterized by increasing difficulty in breathing. In its “mild” stage, patients have limited respiratory discomfort. In the “very severe” stage, they are short of breath at the slightest effort – even when at rest – preventing normal activity. Today, we can slow the aggravation of COPD with anti-inflammatory drugs, bronchodilators (sidenote: Bronchodilators Drugs that reduce bronchial obstruction. https://www.who.int/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd) ) , and breathing exercises, but we do not know how to cure it. While smoking and pollution are major risk factors for the disease, its mechanisms remain poorly understood.

However, a link between gut microbiota imbalances and respiratory diseases such as allergic asthma or pneumonia has recently been discovered, part of what scientists refer to as the “gut-lung axis”. Could the gut-lung axis be involved in COPD?

A microbiota imbalance associated with inflammation in patients...

To answer this question, a team of Chinese researchers analyzed the gut microbiota of around a hundred COPD patients at various stages of severity and compared them with the microbiota of healthy subjects. They found that the gut flora of COPD patients differed from that of healthy subjects. Specifically, the bacterial species Prevotella, suspected of exacerbating inflammation, dominated their gut microbiota. In addition, they had lower levels of short-chain fatty acid (SCFAs) (sidenote: Short chain fatty acids (SCFA) Short chain fatty acids (SCFA) are a source of energy (fuel) for an individual’s cells. They interact with the immune system and are involved in communication between the intestine and the brain. Silva YP, Bernardi A, Frozza RL. The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication. Front Endocrinol (Lausanne). 2020;11:25. ) , especially the most severely affected patients. SCFAs are produced by bacteria in the microbiota from dietary fiber and are known for their anti-inflammatory properties.

... that increases vulnerability to pollution

The researchers then performed a fecal microbiota transplant from the participants to mice. Four weeks later, the lungs of the mice receiving the transplant showed strong inflammation and mucus hypersecretion. Knowing that COPD is accompanied by hypersensitivity to air pollutants, they then exposed the mice to fuel smoke for 20 weeks. The researchers found that the lung function of these mice deteriorated faster than that of unexposed mice.

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Despite being nature’s most abundant and diverse biological entities, phages are still poorly understood. Natural predators of bacteria, they are found everywhere in the soil, the oceans... and in the human gut microbiota, where they are the dominant type of virus. We live in perfect harmony with them all through our lives. Of even greater interest is that they have significant potential to treat certain gastrointestinal diseases.

Promising discovery subsequently forgotten 

On being discovered in 1915, phages immediately aroused great interest for their ability to destroy certain bacteria responsible for infections. What’s more, in a specific way: each phage species targets (i.e. infects) a single bacterial species only. Experiments conducted since the end of the 1920s have shown satisfactory results for phage-based treatments in patients suffering from dysentery or cholera. “Phage therapy” was a serious contender to fight certain bacterial infections causing havoc at the time, before antibiotics took over in the 1940s. More effective and practical, antibiotics relegated phages to mere curiosity status. On the other hand, they are still used for therapeutic purposes in some Eastern countries. However, such therapies are poorly documented scientifically.

Phages make a comeback 

Today, the increase in antibiotic resistance has become a global health threat. Another concern is the impact of antibiotics on the balance of the gut microbiota, whose importance for health is now known. As a result, phages are back in the spotlight. Phage therapy trials have resumed over the past twenty years. After a few false starts, a study published in 2017 has caused a considerable stir. A diabetic patient infected with multidrug-resistant bacteria and suffering from pancreatitis went on to recover after five months thanks to phage therapy, following several failed treatments with antibiotics. Further successes in infections involving multidrug-resistant germs have since been reported. Except for a few very rare exceptions and despite the considerable hopes they raise, no treatment involving phages has been authorized by the health authorities to date.

The potential of phage therapy is not limited to the treatment of bacterial infections. It may also be used to correct microbiota imbalances (“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.   ) ”) associated with certain gastro-intestinal diseases, even non-infectious ones. For example, a study in mice showed the potential of phages to destroy specific intestinal bacteria associated with a poor prognosis in alcoholic hepatitis. Lastly, phages give cause for hope in the field of “precision” medicine. They could be used as “carriers” to deliver powerful drugs (e.g. chemotherapy) directly to a specific area of the body, allowing the treatment to be delivered solely to the cells/bacteria that need it. This would reduce the passage of the drug into the bloodstream, thereby curbing side effects and toxicity for neighboring organs.

Research underway to make phages our allies 

At present, a huge field of research is opening up in the hope of answering many questions, a century after the discovery of phages. Is phage therapy always safe? Can it replace antibiotic treatment? What is the right mode of administration and the right dosage? What long-term effects does phage therapy have on the microbiota? In addition to these numerous medical questions, there are regulatory constraints, as well as a legal vacuum in some countries that is surprising to say the least. Indeed, phages are neither drugs, vaccines, nor medical devices... making them inaccessible at present. This means there is a lot of work ahead, but according to the authors, it’s worth it.

With over ten million people infected worldwide in 2019 (sidenote: Tuberculosis_WHO Oct 2021 ) (WHO, 2020), tuberculosis (TB) remains a major public health concern. This highly contagious infectious disease is caused by the bacterium Mycobacterium tuberculosis. According to a recent review, a number of studies have suggested the involvement of various microbiota.

Gut dysbiosis...

The gut microbiota is involved in the modulation of the host’s immune system. Studies have reported differences in gut microbiota composition between tuberculosis patients and healthy individuals, with specific intestinal signatures in TB patients (lower diversity, lower abundance of Bacteroides, etc.), which nevertheless vary according to the stage of the disease.

Moreover, some studies on mouse models suggest that a gut dysbiosis may reduce the efficacy of antitubercular drugs. This implies that rebalancing the gut microbiota with probiotics or postbiotics may reinforce the efficacy of these drugs. It may also improve host immunity against the bacteria responsible for tuberculosis. The in vitro and in vivo anti-tuberculosis activity of probiotics and postbiotics is evidence of their potential.

A gut-lung axis in TB

The gut and lung microbiota appear to be involved in the prevention, development, and treatment of tuberculosis. How? By affecting the number and function of immune cell subsets, by producing bacteriocins and bacteriolysins that restrict the growth of M. tuberculosis directly, and/or by influencing the bioavailability and pharmacokinetics of anti-TB drugs. Lastly, due to strong links between the gut microbiota and lung microbiota via a two-way dialogue, alterations in the former can affect the latter, and vice versa. Thus, by affecting host immune responses to M. tuberculosis, the gut-lung axis may play a key role in the prevention and treatment of TB.

The WHO has organized World AMR Awareness Week (sidenote: World Antimicrobial Awareness Week Global awareness week to promote the proper us of antimicrobials Explore https://www.who.int/campaigns/world-antimicrobial-awareness-week/2021 )  every year since 2015. The goal? To raise awareness among health professionals and the general public about the proper use of antimicrobials to fight antibiotic resistance (sidenote: Antimicrobial resistance ) . The authors have contributed new knowledge on the mechanisms by which antimicrobial resistance is spreading across the globe. Low- and middle-income countries generally have higher rates of antibiotic resistance than high-income countries. Moreover, the ability of resistance genes to spread via travel is context-dependent (sidenote: Resistance gene’s prevalence in the endemic region, specific bacteria harboring the gene, and presence of mobile genetic elements in the vicinity of the gene that may promote its spread ) . The researchers thus sought to evaluate whether international travel to countries with high levels of resistance to certain antibiotics can facilitate the dissemination of resistance genes to regions with lower rates.

International travel promotes acquisition of resistance genes

To confirm this hypothesis, the researchers created a group of 190 Danish travelers (average age: 50.7 years) from the COMBAT (Carriage Of Multiresistant Bacteria After Travel) cohort. The subjects were divided into four subgroups according to the high antibiotic resistance area they visited: Southeast Asia, South Asia, North Africa or East Africa. A fecal sample was collected from each participant immediately before and after their trip, with trips lasting from 1 week to 3 months.

The team combined shotgun sequencing, functional metagenomics, and statistical modeling tools to finely analyze the subjects’ gut resistome. Comparing the samples taken before and after travel, they found an increase in the number of antibiotic resistance genes after travel. Furthermore, the acquisition of resistance genes was found to be higher in travelers returning from Southeast Asia than in those returning from other destinations.

56 resistance genes acquired during travel

The researchers detected the acquisition of 56 resistance genes (and the loss of 4 genes) during travel, with those encoding proteins responsible for antibiotic efflux and antibiotic target modification the most common. These included classic and well-known resistance genes [bla_CTX-M family (β-lactam resistance gene), mcr-1 (colistin resistance gene), variants of tetX (tetracycline resistant gene), and qnr (fluoroquinolone resistance gene)], as well as genes previously unknown. The authors found that 6/56 acquired genes were associated with the destination, including 3/6 detected in travelers returning from Southeast Asia which were dfrA1 variants that confer resistance to trimethoprim. Furthermore, mobile genetic elements identified next to resistance genes may contribute to the high number of these genes acquired by subjects who traveled to Southeast Asia.

Better understanding the mechanisms involved in the spread of antibiotic resistance: with this goal in mind the Biocodex Microbiota Foundation has recently launched its International Grant for 2022 on the research theme entitled “Structure and Function of the Gut Microbiota Resistome”. A collective and multidisciplinary effort is being made to counter antibiotic resistance.