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.

No more age- or weight-based triaging for Covid-19 patients admitted to the hospital. In the future, measuring the abundance of two bacterial species in the oropharyngeal microbiota could become the gold standard, thanks to its superior reliability. These are the claims made by a German team who believe this microbiota plays a crucial role, since it regulates host immunity, homeostasis of the mucous membranes, and defense against pathogens. However, previous studies have been less conclusive. Most likely because the majority focused on patients with severe Covid-19, where numerous intervening factors (e.g., antibiotic therapy, invasive mechanical ventilation, etc.) could also have altered the diversity and composition of the microbiota samples.

When antibiotics and ventilation disrupt the oropharyngeal microbiota 

This cross-sectional, multi-center clinical study (7 German centers) therefore adapted its methodology: oropharyngeal swabs were taken from 72 healthy adults, 112 patients with non-SARS-CoV-2 infections (mild upper respiratory tract infections or critical pneumonia), and patients with mild, moderate or severe Covid-19 (n=36, 37 and 65). The total study population was 322 participants aged 21 to 93 years.

The results? Broad-spectrum antibiotics and invasive mechanical ventilation appear to destabilize the oropharyngeal microbiota: there is a loss of diversity and severe dysbiosis in Covid-19 patients admitted to the hospital with moderate or severe disease, or when the sampling is performed during prolonged hospitalization.

Two bacterial species can predict mortality

The most important finding was that samples harvested promptly after admission (to avoid alteration due to hospital care) have a signature predictive of Covid-19 mortality, according to artificial intelligence models (machine learning). A lower abundance of two bacterial genera, Neisseria (and more specifically the species Neisseria subflava) and Haemophilus (species Haemophilus influenzeae, parainfluenzae and pittmaniae) considerably increase the risk of death. And this predictive model is more reliable than models based on clinical variables such as age, sex, or obesity. The underlying mechanisms have not yet been explained, but it is possible that these bacteria regulate innate immune response and cytokine production.

Tuberculosis is a highly contagious infectious disease that affects over 10 million people around the world (sidenote: Tuberculosis_WHO Oct 2021 )  (WHO, Oct 2021). Although cases are becoming rarer in developed countries thanks to vaccination programs, tuberculosis remains a major public health problem. What is more, the Covid-19 pandemic has reversed years of progress worldwide in the fight against tuberculosis, and for the first time in over a decade, the tuberculosis death rate has risen, according to the 2021 World Health Organization (WHO) Global Tuberculosis Report (sidenote: Tuberculosis deaths rise for the first time in more than a decade due to the COVID-19 pandemic _WHO Oct 2021 ) . Much collateral damage is being sustained by the microbiota in our gut and lungs, which are heavily involved in this infection.

Disruptions to the gut microbiota 

The first microbiota in the line of fire is our intestinal flora, which works closely with our immune cells throughout our lives. Tuberculosis stops this microbiota from operating at full capacity; it loses its diversity and certain bacteria begin to dwindle, while others become more abundant. This imbalance of certain bacterial species (dysbiosis) could even be characteristic of the stages of disease progression.

In addition, based on results from animal models, these disruptions to the gut microbiota make tuberculosis drugs less effective. Hence the idea, not yet validated, of restoring balance to the gut microbiota using probiotics and postbiotics (sidenote: Postbiotics A preparation of inanimate microorganisms and/or their components that confers a health benefit on the host. Salminen S, Collado MC, Endo A, et al. The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics. Nat Rev Gastroenterol Hepatol. 2021 Sep;18(9):649-667. ) . The aim is to increase the efficacy of the tuberculosis drugs and strengthen the patient’s immune defenses against the bacteria responsible for TB.

Intestinal and pulmonary troops uniting against infection

Although in different locations, the gut and lung microbiota do not appear to work in isolation. These two microbiota communicate closely and their diversity changes in tandem: the gut microbiota contributes to the pulmonary immune response, and the lung infection in turn affects the composition of the gut microbiota. They are therefore not just two microbiota, but an intestinal/pulmonary unit with a role to play in TB infection and treatment. This could therefore justify a new treatment approach.

Recommended by our community

Have you ever heard the word “dysbiosis”? Or about the benefits of probiotics for your health? Did you know that your gut microbiota is a good indicator of longevity? Or that your vaginal microbiota consists of hundreds of bacteria that help maintain a healthy vaginal environment? Curious and experts, will find the answers to these questions. 

A hub designed around three major health topics, built around personalized journeys:

Information written by scientists about Microbiota become accessible for everyone through news, physician interviews, thematic folders, infographics, developed content and even through stories on the mobile version. 

About the Microbiota Institute 

The Biocodex Microbiota Institute is an international scientific institution that aims to foster health through spreading knowledge about the human microbiota. To do so, the Institute addresses both healthcare professionals and the general public to raise their awareness about the central role of this still little-known organ of the body. 

^BMI-21.47

Available in 7 languages (English, French, Spanish, Russian, Polish, Turkish, and Portuguese), this online international hub offers you the latest scientific news and data about microbiota including the Institute’s exclusive content such as Microbiota magazine, thematic folders, continuing medical education (CME) courses and interviews with experts. 

A useful and trustful partner for HCPs 

In a dedicated section for HCPs, you will also find practical and educational infographics such as: “What are probiotics?” or “what you need to know about the 6 microbiota of the human body?”, that you can easily download and share with your patients. Care to share other information with your patients? Invite them to discover the lay public section of the website through dedicated online journeys, where they can find updated, useful and understandable content. 

Stay tuned, stay up to date! 

Also available on this hub, congress calendars where you can find the next events about microbiota. And after your journey on the website, don’t forget to register online to receive the “Microbiota Digest”, a monthly newsletter with the latest news about microbiota. Want to share a publication? To follow a Conference live-tweet (WGO, ESPGHAN, etc.)? Or browse through Microbiota Institute’s new Twitter account (@Microbiota_Inst) designed to reach the widest community of health professionals who want to be up to date with the latest information on the microbiota field. By providing healthcare professionals with the latest scientific news and data, but also a variety of educational tools and services, Biocodex Microbiota Institute’s website aims to help healthcare professionals improve their patient’s understanding of their conditions on an everyday basis. 

About the Microbiota Institute 

The Biocodex Microbiota Institute is an international scientific institution that aims to foster health through spreading knowledge about the human microbiota. To do so, the Institute addresses both healthcare professionals and the general public to raise their awareness about the central role of this still little-known organ of the body. 

^_BMI-21.46 

Searching for a link between the gut microbiota and autism has been a hot topic in recent years. It is true that the gut is our “second brain” and that some neuropsychiatric conditions such as depression are associated with imbalances in intestinal flora. Moreover, mice transplanted with intestinal bacteria from people with autism develop “autistic behavior.” This population is also prone to digestive problems. It may therefore seem an obvious step to assume that autistic spectrum disorders are due to changes in the gut microbiota, and that autism can be treated by rebalancing the gut.

Dysbiosis and autism: an exaggerated link?

However, Australian researchers believe this is one step too far, despite some studies that appear to show characteristic changes to the gut microbiota in autistic children. Having looked at all publications on this topic, they believe that there is no evidence of a causal link between the intestinal flora and autism. With differing protocols, often based on small population sizes, and rarely accounting for “confounding” factors such as diet that can also alter the intestinal microbiota, and inconsistent in their microbial analysis results... these studies do not, according to this new review, make a convincing argument.

These researchers rolled up their sleeves and conducted a vast study of the intestinal microbiota in 247 children (99 diagnosed with autism and 148 not). They analyzed the bacterial species present in the samples, also taking into account stool consistency and other factors known to alter the gut microbiota such as diet, sex, and age. They concluded that an autism diagnosis is not significantly associated with the composition of the intestinal microbiota.

Intestinal flora disruptions due to a lack of variation in the diet

On the other hand, the study revealed that the composition of the intestinal microbiota in these autistic children was very strongly correlated with diet, stool consistency, and age. A narrower range of interests and repetitive behavior are typical traits of autism. Many autistic children prefer to eat the same food at every meal, or are put off by certain tastes, smells and textures, explains one of the authors.

These results suggest therefore that autism leads to a less varied diet (and therefore one of poorer quality), resulting in a loss of diversity in the gut microbiota and, in turn, softer stools. Widely reported in the media, this article goes against the tide of theories about a link between the gut microbiota and autism. Nevertheless, the authors believe that nutritional measures could help rebalance gut microbiota in autistic children and relieve their gastrointestinal disorders, while also improving their overall health.

Recommended by our community

For several years, the scientific community has shown a keen interest in the possibility of a link between gut microbiota and autistic spectrum disorders. There is clearly an increasing volume of evidence of associations between the gut microbiota and certain neuropsychiatric conditions. Moreover, mice studies appear to have shown that fecal transplantation from autistic patients triggers “autistic behaviors.” Finally, people with autism commonly suffer from gastrointestinal disorders. Spurred on by this array of evidence, several teams have sought to highlight the major role, perhaps even a causal one, that intestinal dysbiosis might play in autism. This would allow us to better understand, diagnose, and even treat autistic spectrum disorders by targeting the microbiota.

Dysbiosis and autism: an exaggerated link?

However, by looking at all the studies and meta-analyses already conducted on this topic, an Australian research team believes that this conclusion is somewhat premature. With differing methods, often based on small population sizes, subject to certain bias and rarely accounting for confounding factors such as diet and age, and inconsistent in their microbial analysis results... these studies do not, according to this team, make a convincing argument.

The researchers therefore conducted a metagenomics study of the intestinal microbiota in 247 Australian children (99 diagnosed with autism and 148 not). Their analysis included several other factors known to alter the gut microbiota such as dietary, clinical, genetic, psychometric, and demographic elements. They found that the composition of the gut microbiota of these children showed only negligible differences between the autism and non-autism groups. Only an abundance of the species Romboutsia timonensis appears to be linked to autistic spectrum disorders. In addition, they were unable to reproduce the results of studies claiming to have established a link between certain microbiota species (e.g., Prevotella and Bifidobacterium) and autism.

Lack of microbiota diversity associated with a lack of variation in the diet

On the other hand, the study did find changes in the composition of the gut microbiota of autistic children that correlated with diet, stool consistency, and age. Certain autistic traits, such as a narrower range of interests, repetitive behaviors, and clear sensory preferences, could affect their diet. According to the research team, autism leads to a diet that is less varied, and therefore of poorer quality. This contributes to a reduced diversity of the intestinal microbiota, which in turn results in softer stools indicative of digestive problems.

Widely reported in the media, this article goes against the tide of theories about a link between the gut microbiota and autism. However, the authors believe that dietary measures could help rebalance gut microbiota in autistic children and thus relieve their gastrointestinal disorders while improving their general health.

Some are morning people, others prefer the evening. But what makes us an early bird or a night owl? Recent scientific research suggests that bacteria in the gut may influence our biological clock, with early birds and night owls shown to have very different gut microbes.

Early to bed vs. late to bed: specific microbiota

An analysis of the gut microbiota of 91 individuals has shown a greater abundance of the bacterial genus Alistipes in the gut microbiota of early sleepers. These people generally have bowel movements in the morning, eat a healthy diet (rich in fruit, vegetables, and fiber), and drink water regularly.

On the other hand, night owls have a greater quantity of Lachnospira in their gut. They go to the toilet in the evening, following a day of unhealthy food (e.g. rich in sugars) washed down with soda. The bacteria in our digestive tract produce molecules that act on our own body. These molecules cause a set of chemical reactions (known as metabolic pathways) which lead to the production of certain compounds (e.g. glucose) and/or the degradation of others. Three metabolic pathways were found to be significantly more common in early sleepers.

The authors therefore propose that certain human metabolic pathways are activated by specific bacterial fatty acids involved in the regulation of our sleep. This may be the missing link between all these data: a given diet has a specific microbiota, which secretes molecules that influence the rhythm of the host’s sleep.

Improving night owls’ health

The scope of these observations is important, going beyond the mere issue of harmony in families with both early and late sleepers. Indeed, night owls are more likely to develop:

...and other chronic diseases.

This research suggests it may be possible to improve their health by altering their diet and, therefore, their gut microbiota. This may help the night owls go to bed with the early birds.