Each year, tens of thousands of tons of antibiotics are used for healthcare purposes in humans, animals, and plants, a portion of which is released into the environment. Antibiotics are thus found not only in wastewater, but also in rivers, the sea, and soil, enabling environmental bacteria to acquire resistance genes that can then be transferred to other bacteria. Bacterial cells and genetic material can aerosolize and, due to air turbulence, rise into the atmosphere, travel long distances, and then become part of the water cycle.

Proof of a “resistome” in the clouds

A French and Canadian research team assessed the quantity of antibiotic resistance genes in clouds at the Puy de Dôme meteorological observatory in France’s Massif Central, at an altitude of 1,465 meters. Twelve samples were taken with a high-flow vacuum between September 2019 and October 2021, revealing an average concentration of around 5,400 copies of resistance genes per cubic meter of air (measured by flow cytometry). The 33 resistance genes found correspond to the main antibiotic families in use today: quinolones, sulfonamides, tetracyclines, aminoglycosides, glycopeptides, β-lactam antibiotics, and macrolides. Of these, 29 were detected at least once, and 6 were observed in at least 75% of samples. 

Rather than varying with the seasons, the distribution of these genes varied according to the geographical origin of the air masses. Resistance genes for the quinolone family, antibiotics strongly implicated in antibiotic resistance and whose use has been restricted in Europe since 2018, were more abundant in high marine clouds. Resistance genes for the sulfonamide and tetracycline families were more abundant in clouds formed over continental surfaces, perhaps due to their widespread use in livestock farming.

The atmosphere is a major highway for resistome dissemination

Considering the average concentration of resistance genes in clouds according to the study (5,400/m3 of air), the researchers estimate that clouds permanently carry around 2.53 × 1021 copies of resistance genes worldwide. Thus, each year, between 1.29 × 1025 and 2.06 × 1026 resistance genes may be transported by clouds, with a very large quantity of these genes (2.2 ×1024) falling to earth through precipitation (and a fraction remaining evaporated in the atmosphere). 

This study has found the atmosphere to be one of the routes by which antibiotic resistance factors are disseminated worldwide. Studies that pinpoint the sources of bacterial emissions may limit their dispersal^.2 

Infographics to share with your patients

The fact that bacteria adapt to resist antibiotics is a natural evolutionary phenomenon. But the massive use of these drugs to treat human, animal and plant infections has greatly amplified it. And every year, a good proportion of the tons of antibiotics used end up in the environment, namely in soil, rivers, oceans, etc. Resistant bacteria can develop there, transmit their resistance genes to other bacteria and disperse with the wind and reach high altitudes. Although the atmosphere is not a suitable environment for their survival, fragments and genetic material can still reach the clouds, travel from one continent to another and return to dry land through rain.

Clouds vacuumed up into test tubes

At the Puy-de-Dôme weather station located at an altitude of 1,465 meters in the French Massif Central, Franco-Canadian researchers spent two years taking 12 "cloud samples" with a special vacuum cleaner aimed at nimbus and cumulus clouds. For each sample, they measured the quantity of bacteria and 33 resistance genes corresponding to the main antibiotics used today. Of these, 29 were detected at least once and 6 were observed in at least 75% of the samples. The clouds contained an average of 8,000 bacteria mainly of plant origin, of which 5 to 50% could be alive and potentially active, and over 20,000 copies of antibiotic resistance genes per milliliter of water.^1,2

The researchers found that the distribution of these genes varied according to the geographical origin of the air masses sampled. For example, genes for resistance to quinolones (antibiotics whose use has been restricted for several years due to the antibiotic resistance they promote) were more abundant in high ocean clouds. Sulfonamide and tetracycline resistance genes were more prevalent in clouds formed over continental surfaces, perhaps due to their widespread use in livestock farming.

Reservoirs of antibiotic resistance genes hovering over our heads

The researchers extrapolated their measurements to the total volume of clouds around the earth, assuming that all would have the same concentration of antibiotic resistance genes. The results showed that every year, around 70 trillions of trillions (1024) of these genes pass through the clouds, of which around 3% could potentially fall back down to the earth's surface.

This study highlights the role of the atmosphere as one of the routes by which antibiotic resistance factors are disseminated worldwide. Additional studies to pinpoint the sources of bacterial emissions could help limit their dispersion.

The symptoms of ulcerative colitis, i.e., bloody diarrhea, abdominal pain, cramps, tenesmus and fatigue, have a major impact on the quality of life of patients. Altered gut microbiota may lie at the root of the problem. However, this same microbiota is influenced by diet. That is why this randomized controlled trial was set up by researchers and clinicians at the University of British Columbia, Canada. They assessed the effectiveness of the Mediterranean diet in treating symptoms, inflammation and gut microbiota. The adults recruited (65% women, median age 47) either adopted a Mediterranean diet for 12 weeks, with advice from a dietitian (15 patients), or continued with their usual diet (13 patients, control group).

Preventing ulcerative colitis relapses 

At the end of the 12-week study, the Mediterranean diet was well tolerated and reduced the frequency of attacks. Although all patients (except one experiencing a benign episode) were in remission at the start, slight activity was observed in one-third of the patients in the Mediterranean group while almost half of the patients in the control group suffered from a mild-moderate attack. The Mediterranean diet also helped to reduce fecal calprotectin levels which predict impending relapses and measure intestinal inflammation: 20% of patients on this diet had levels above 100 μg/g compared with 75% of those in the control group. 

Improved gut microbiota

Microbiota analysis also showed the benefits of the Mediterranean diet, with an increased presence of protective bacteria, notably Firmicutes (Ruminococcus spp., Flavonifractor spp., Clostridium M, Blautia A, and Lactococcus spp.), as well as a decrease in potentially pathogenic bacteria such as Veillonella dispar, Veillonella obetsuensis, Prevotella copri, Streptococcus australis, and biofilm-forming species. The researchers also observed a significant increase in fecal secretory immunoglobulin A (sIgA) after 12 weeks on the Mediterranean diet. This sIgA plays an essential role in maintaining mucosal homeostasis as it binds to pathogenic bacteria and prevents them from gaining access to the intestinal epithelium. Fecal secretory immunoglobulin A could thus explain the negative association between opportunistic pathobionts and the Mediterranean diet.

More short-chain fatty acids

Lastly, the Mediterranean diet coincided with an increase in the production of short-chain fatty acids (SCFAs), known for their immunomodulatory properties and role in promoting intestinal homeostasis, with observed higher levels of total SCFAs as well as butyric, acetic and valeric acids.

As such, the well-tolerated Mediterranean diet appears to be a reasonable and healthy dietary model that can be an option for ulcerative colitis patients in remission to prevent relapses, in addition to their standard medical treatment.

Rich in legumes (lentils, beans, chickpeas, etc.), whole grains, fruits, vegetables, nuts, seeds and olive oil, the Mediterranean diet (sidenote: Mediterranean diet Rich in fruit, vegetables, cereals, oilseeds (nuts) and fish, and low in red meat, saturated fats and dairy products. Lăcătușu CM, Grigorescu ED, Floria M, et al. The Mediterranean Diet: From an Environment-Driven Food Culture to an Emerging Medical Prescription. Int J Environ Res Public Health. 2019 Mar 15;16(6):942. ) is also characterized by moderate consumption of fish, poultry and dairy products and low consumption of processed foods and red meat. This particularly healthy diet involves a high intake of dietary fiber and beneficial compounds (notably the famous polyphenols found in grapes, nuts and olives) and a better balance of fats (fewer saturated fatty acids). It provides health benefits to its followers, including patients suffering from ulcerative colitis (sidenote: Ulcerative colitis Ulcerative colitis is a chronic disease of the large intestine (colon) characterized by inflammation (redness and swelling) and ulcers (sores) along the lining of the colon, which can cause abdominal pain, cramping, bleeding and diarrhea. Along with Crohn’s disease, ulcerative colitis is one of the chronic inflammatory bowel diseases (CIBD) that affect 10 million people worldwide. (source: Canadian Digestive Health Foundation).   ) (a real intestinal nuisance), based on the results of a recent clinical study. And this was not just any trial, but a randomized (sidenote: Randomized trial Study in which the products tested are distributed randomly, between the participants. ) controlled trial (sidenote: Controlled trial a study in which participants are given either a test product (capsule containing the active compound) or a placebo (control capsule not containing the active compound), thus allowing for comparison. ) , i.e., the Holy Grail of studies offering the highest level of evidence of a possible effect.

Reducing the frequency of ulcerative colitis relapses

In practice, this study, carried out by researchers at the University of British Columbia, compared the effects of a typical Western diet (low in fruit, vegetables and legumes, high in meat, etc.) and a Mediterranean diet, in patients suffering from ulcerative colitis. And what did the results show? The Mediterranean diet seems to reduce the frequency of attacks for patients in remission and lessen the severity of relapses. A mild resumption of the disease was observed in one out of three patients after three months on the Mediterranean diet, while almost half of the patients who maintained their usual Western diet had the disease return with mild to moderate activity.

_{Sources (sidenote: Source : World Gastroenterology Organisation Global Guidelines, 2015 )}

The protective effect of gut microbiota 

What accounts for such a protective effect? The most likely reason involves the gut microbiota. The Mediterranean diet goes hand in hand with the growth of protective bacteria that produce more health-promoting short-chain fatty acids (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. ) and reduce the number of potentially pathogenic bacteria. Secretions from the mucous membranes lining the intestine could play a role. Amplified by the Mediterranean diet, these secretions are thought to prevent pathogenic bacteria from gaining access to the intestinal epithelium.

These results encourage ulcerative colitis patients to take advantage of periods of remission of their disease to adopt a Mediterranean diet. This dietary boost is well tolerated during these lulls but should not replace their medical treatment!

Infographic to share with your patients

Accrediting training on probiotics

Latest news about probiotics

Extract of thematic folders about probiotics

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Advising a patient to "take probiotics" is not necessarily sufficient for a patient looking for a probiotic for a specific disorder ³. However, an American study found that 40% of primary care professionals who recommend probiotics to their patients let them choose their own product ⁴. Although it is now generally accepted that probiotics contribute to healthy gut microbiota, experts agree that the vast majority of probiotic effects are strain-dependent ^5,6.

It is therefore important to ensure that the strain is effective in terms of the targeted health need or disease ⁷. To do this, it is necessary to check that the product characteristics and information (strain, dosage, formulation) match in every respect those used in the clinical trials that proved the benefit ascribed to the product ³. As such, particular attention should be paid to the following:

• clear reference to the genus, species and probiotic strain contained in the product and the associated indication ^8,9 ;
• product dosage ^3,8 ; 
• clinical proof of the efficacy of the probiotic strain in the therapeutic area with which it is associated. at a dosage similar to and not lower than the one used in the clinical trial ⁸. 

Other factors should also be taken into account when choosing a probiotic, such as :

• formulation type ^3,8 ;
• remaining viability up to the expiration date, not from the date of manufacture ⁸;
• product quality resulting from manufacturer requirements, i.e., quality controls and, preferably, certification by an independent body ^8,9 .

Informing your patient

An infographic entitled "What are probiotics?” is provided below. It is designed to help you inform patients about probiotic-based products and facilitate your discussions during consultations.

The Biocodex Microbiota Institute recommends the ISAPP website which also provides health professionals and consumers with resources on probiotics. (in English): https://isappscience.org/for-clinicians/resources/

In the field of gastroenterology, you will find information on clinically proven indications for adults and children on the following websites: World Gastroenterology Organisation (WGO) and American Gastroenterological Association (AGA).

See the other pages in our series dedicated to probiotics

Recommended by our community

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Definition of probiotics and a brief modern history 

Probiotics are “live microorganisms which when administered in adequate amounts confer a health benefit on the host”. The first definition by the Food and Agriculture Organization (FAO) and the World Health Organization (WHO) in 2002 ² was slightly rewritten by a consensus of experts in 2014 ³.

Since time immemorial, nutritional and therapeutic advantages have been attributed to fermented foods. But it was only from 1906, following Louis Pasteur’s work, that the effects of microorganisms on health, linked to lactic fermentation, were scientifically explored ⁴. Consequently, the Russian Elie Metchnikoff associated the longevity of rural Bulgarians with the regular consumption of fermented milk with Bacillus bulgaricus ⁵ . When the pediatrician Henri Tissier observed the paucity of “bifidus” bacteria in the diarrhea of children, he suggested that these bacteria could restore their intestinal flora ⁶ . The probiotics “boom” in science started at the end of the 1980s ⁷ , with the advent of molecular biology. Vitally important progress has since been made in the characterization of probiotic microorganisms and the demonstration of their health benefits ^{8 9} .

Zooming in on microorganisms: what are probiotics? 

As a reminder, microorganisms are living beings that are invisible to the naked eye and include the following ¹⁰:

• All prokaryote unicellular organisms (a single cell without a nucleus): These include bacteria, of which numerous species live in all environments, including the human body^10,11 , but also Archaea, which resist in extreme conditions and are thought to be the first forms of life on earth ^12,13 .
• Certain eukaryote uni- or multicellular microorganisms (one or more cells with a nucleus): These comprise microscopic fungi, including yeasts and molds¹⁴ , but also microalgae and protozoa^15,16 .
• Viruses: Whether they belong to the world of the living is still under debate: they are not cells and they can only replicate in a host cell ^10,17 .

The microorganisms most commonly used as probiotics are :

• Lactic bacteria, include the genera Lactobacillus and Bifidobacterium as well as Lactococcus, Streptococcus and Enterococcus  ^5,18 .
• More rarely, other bacteria, such as Clostridium and Escherichia Coli ¹⁹.
• Yeasts, such as Saccharomyces boulardii, isolated from the skin of lychees and mangosteens ²⁰ , or even Kluyveromyces ²¹ .

Probiotics are classified by genus, species (sometimes also sub-species) and their strain number according to international nomenclature ²² . For example: Lactobacillus (genus) casei (species), then a series of numbers and/or letters (strain). A strain is differentiated from other microorganisms of the same species because it is genetically unique and has specific physiological properties ¹⁸.

Health benefits of probiotics

The efficacy of specific strains of probiotics has been clinically demonstrated for different indications.

A mode of action for each strain

A probiotic exerts a beneficial effect on the microbiota by maintaining the equilibrium, favoring its reconstruction during and after an episode of dysbiosis or preventing certain clinical situations that disrupt the microbial ecosystem ⁴⁵ . The mode of action is strain-dependent, and cannot be extrapolated to the species or the genus ⁴⁶ .

Each probiotic acts according to its own physiological properties and/or on ^46,47 :

Learned societies, such as the World Gastroenterology Organisation (WGO), the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN), and the International Scientific Association of Probiotics and Prebiotics (ISAPP) regularly issue opinions and recommendations on the use of probiotics.

See the other pages in our series dedicated to probiotics

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In studies of the gut microbiota, fungi have long been overlooked, with the focus instead falling on bacteria, the main microorganisms found in the gut. We still have a limited understanding of how fungi interact with bacterial communities in the gut microbiota and of how antibiotics impact the gut mycobiota. French researchers have tried to shed some light on the matter by studying the effect of amoxicillin/clavulanic acid (AMC) on bacteria and fungi in the gut microbiota of mice and infants.

Unexpected, antibiotic-dependent fall in gut fungal load 

Their study on conventional mice showed, as expected, that AMC administered for ten days reduced the amount of bacteria present in the feces and gut. Far more surprising, the treatment also greatly reduced the overall fungal population compared to controls. A “cocktail” of broad-spectrum antibiotics (ampicillin, metronidazole, neomycin, and vancomycin [VA]...), had the same impact. However, mice that received a fecal microbiota transplant (FMT) from healthy adult humans showed a response in their mycobiota that was antibiotic-dependent: the fungal load was again lower with amoxicillin/clavulanic acid but increased with VA. In parallel, the researchers analyzed 19 gut microbiota samples from 7 infants aged 2 to 4 months treated for otitis media with amoxicillin. This antibiotic, which is very similar to AMC, also reduced the bacterial and fungal load during treatment.

Bacterial and fungal balance transformed by amoxicillin/clavulanic acid

The researchers found that the alpha and beta diversity of the fungal population in the feces of conventional mice treated with AMC had decreased, but that the share of Aspergillus, Cladosporium, and Valsa had increased compared to untreated mice. Bacterial alpha-diversity had also decreased, but differential analysis revealed a shift in bacterial families in the gut microbiota after treatment, with an increase in Enterobacteriaceae.

Suspecting a link between the increase in this bacterial family and the reduction in fungal load, the researchers isolated 13 bacteria from the feces of mice treated with AMC and coincubated them with S. cerevisiae. Nine of them inhibited the growth of this yeast, all of which were Enterobacteriaceae. These Enterobacteriaceae, and in particular E. hormaechei, also reduced the growth of Candida albicans. In addition, when colistin, an antibiotic that targets Enterobacteriaceae, was administered to the mice that had received a human FMT, the mice’s gut fungal abundance increased. After further in vitro and in vivo tests to observe the interactions between gut bacteria and fungi, the researchers concluded that Enterobacteriaceae were at least partly involved in the dysbiosis of the gut mycobiota caused by AMC. Several mechanisms could be at play, including competition for certain nutrients between these bacteria and fungi. 

A change of paradigm? 

Although carried out on mice and a small cohort of infants, this study challenges the preconceived idea that all antibiotics promote the proliferation of fungi in the gut microbiota. Amoxicillin/clavulanic acid, a widely prescribed antibiotic, decreases the overall abundance of the gut fungal population and remodels gut microbiota composition in terms of fungal and bacterial species. The study also reveals the close links between bacteria and fungi in the gut microbiota via the complex alterations in the balance of their populations that antibiotics can provoke. Confirmation of these results on larger cohorts may lead to changes in medical practice, particularly in situations where the mycobiota plays a significant role in patient health.

We are not all equal in the face of depression: women are twice as affected as men, probably due to hormonal differences. It has been shown in mice that the decrease in estradiol levels leads to a depressive syndrome. Estradiol is excreted into the digestive system via bile and partially reabsorbed. However, previous studies have shown that the passage of steroid hormones in contact with our digestive microbiota could affect their serum level. To find out more about the mechanisms involved, a Chinese team monitored 91 depressed women in their thirties and 98 other women without depression.

The role of microbiota

The results showed that estradiol levels were significantly lower (54 pg/mL vs 95 pg/mL) in depressed women. And their microbiota could be responsible for this: in vitro, after 2 hours, the microbiota of 5 depressed women was capable of degrading 77.8% of the 100 mg/L of estradiol added, compared to only 19.3% for the microbiota of 5 women without depression. Further, transplanting this “depressive microbiota” into mice was enough to decrease the rodents’ serum estradiol levels and morale.

Focus on Klebsiella aerogenes

The cause of this degradation is believed to be the bacterium Klebsiella aerogenes. A gavage experiment confirms this: mice consuming K. aerogenes exhibited reduced estradiol levels and depressive syndromes; the administration of an antibiotic to which the bacterium is sensitive was sufficient to suppress symptoms. Everything therefore seems to indicate that K. aerogenes degrades estradiol. Moreover, the bacterium can express the gene encoding the estradiol-degrading enzyme. And in depressed women, this bacterium and this enzyme are found to be more abundant. But K. aerogenes may not be the only gut bacterium capable of producing this enzyme. Other bacteria, such as Bacteroides thetaiotaomicron and Clostridia, could also be involved.

Targeting the bacteria

These preliminary findings could open up new treatment pathways to reduce depression in women: estrogen replacement therapy. The authors believe that the estradiol-degrading bacteria in the intestine, or even the enzymes expressed by these bacteria, could therefore constitute much better targets.

Nature is such that women, despite having no specific hormonal issues, are subject to an endless cycle of hormonal ups and downs from puberty to menopause. 
And that can lead to some drastic mood changes. One of the hormones involved is estradiol, which increases during the first half of the cycle and decreases in the second half. That explains why sex drive peaks during ovulation (when the hormone is at its peak) and morale tends to be rock solid during pregnancy (record levels). Conversely, women may feel blue during the second half of their cycle. But that’s not all. In premenopausal women suffering from depression, estradiol levels in the blood have been found to be almost half those of women of the same age with a sunny outlook. And the painstaking work of a Chinese team seems to have resulted in the naming of a culprit responsible for these depressive disorders: the gut microbiota Klebsiella aerogenes.

When microbiota degrades our hormones

Bear in mind that, in healthy individuals, estradiol is a hormone secreted in our digestive system via bile, which we then reabsorb. However, when it travels through the gut, the hormone comes into contact with our local microbiota. Some bacteria, especially K. aerogenes, are thought to have the ability to produce a molecule, called 3b-hydroxysteroid dehydrogenase (3b-HSD), an enzyme which chemically cuts estradiol and degrades it.

The 91 premenopausal women in their 30s with depression who agreed to take part in the trial were found to have a higher prevalence of both the bacteria and enzyme in their gut flora, compared to 98 women of the same age without depression. And if we mix their gut microbiota with estradiol in vitro (sidenote: In vitro Refers to an experiment performed in a test tube, outside a living organism. )  the microbiota degraded ¾ of the hormone in just two hours… while microbiota from women without depression destroyed four times less. Lastly, gavaging mice with microbiota from premenopausal women with depression, or simply K. aerogenes bacteria, was sufficient to cause depression-like behaviors in rodents.

Getting to the root of the problem

This work, which highlights the involvement of microbiota in depression in premenopausal women and how it operates, could have implications for the treatment provided to women with depression and their health. They are currently prescribed hormone replacement therapy, which comes down to increasing their estrogen levels. However, the cause of these health problems, i.e., bacteria found in the gut microbiota which are responsible for degrading the hormone, are not addressed. That’s why there is a risk of relapse when treatment is withdrawn. The authors believe that we need to get to the root of the problem, by directly targeting the bacteria that degrade estradiol in the gut, or even the enzymes expressed by those bacteria.