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

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BMI-23.39

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.

We already knew that top athletes’ microbiota differs from that of sedentary people, and that intense physical activity has a significant impact on the gut flora. 

But how does more moderate physical activity affect our health? Moreover, is the impact the same regardless of weight?

Several hundred volunteers enrolled

To answer these questions, researchers from Canada and European research institutes recruited 350 men and women aged between 38 and 65 and divided them into two groups: one made up of volunteers of normal weight (BMI (sidenote: Body Mass Index (BMI) Body Mass Index (BMI) assesses the corpulence of an individual by estimating the body fat mass calculated by a ratio between weight ((kg) and height squared (m2). https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmicalc.htm https://www.euro.who.int/en/health-topics/disease-prevention/nutrition/a-healthy-lifestyle/body-mass-index-bmi ) between 18.5 and 25) and the other of overweight people only (BMI between 25 and 30, i.e., not obese).

The scientists asked them what types of physical activity they performed on a daily basis: rather light (walking, washing up, cooking, etc.), moderate (brisk walking, gardening, cycling, badminton, etc.), or intense (heavy work, running, weight training, basketball, football, etc.).

They also recorded the number of hours devoted to these activities for each participant (less than 2.5 hours, between 2.5 and 8 hours, or more than 8 hours).

Lastly, the researchers collected stools from all participants in order to analyze their gut microbiota.

Health benefits for all, but more comprehensive benefits in slim people

The results showed that improvements in the diversity and richness of the microbiota are linked more to total hours of physical activity than to the intensity of that activity. Regardless of your weight, at least 2.5 hours of physical activity a week is enough to benefit your gut.

Despite this, only the normal-weight volunteers (BMI < 25) saw changes in bacterial composition. The more time these volunteers devoted to physical activity, the richer their microbiota became in:

• Actinobacteria, a group of bacteria known for multiple benefits to cardiometabolic health, e.g., lower cholesterol, the production of acetate – a short-chain fatty acid (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. )   –, the digestion of complex carbohydrates such as resistant starch;
• Collinsella, bacteria belonging to the Actinobacteria family, which protect against gut permeability and produce butyrate, another SCFA with anti-inflammatory properties.

Impact also depends on gender

Another finding was that in normal weight men, as well as overweight women, the greater the grip strength, the higher the abundance of Faecalibacterium prausnitzii, bacteria known for their anti-inflammatory properties and effects countering 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.   ) .

BMI and gender therefore play a role in how physical activity impacts the microbiota. This is another major advance in our understanding of how the gut-muscle axis works.

Though not as high-profile as space dog Laika, astronaut mice have taken part in a major Nasa research program.

The aim was to evaluate the effects of microgravity on bone homeostasis, with the ultimate goal of finding ways to mitigate the consequences of extended space travel. Spaceflight is associated with altered bone formation and increased bone resorption.

Recent studies have established a link between changes in the gut microbiota and bone diseases such as osteoporosis via effects on the immune system, endocrine regulation, vitamin and nutrient deficiencies, and energy metabolism through short-chain fatty acids (SCFAs). To better understand the mechanisms involved in bone health, the Rodent Research 5 mission assessed the influence of microgravity on the gut and oral microbiota of 20 female mice that spent 4.5 weeks (10 rodents) or 9 weeks (10 rodents) in the International Space Station (ISS). This is the equivalent of several years in space for Neil Armstrong, since human life expectancy is 30 to 40 times longer than that of these small rodents.

Effects of extended space travel

After 4.5 weeks in space, the rodents’ microbiota remained broadly similar in terms of diversity to that of 20 control rodents who stayed behind on Earth under identical conditions, except for microgravity. However, a more prolonged stay in the ISS (9 weeks) saw increased gut microbiota diversity, with a higher relative abundance of Firmicutes and a lower relative abundance of Bacteroidetes. More specifically, a longer stay in space led to an enrichment in Lactobacillus murinus (from the Firmicutes phylum) and Dorea sp. compared to the mice who had a 4.5-week stay. 
Moreover, compared with the rodents who remained on Earth, those that spent 9 weeks in space had enriched metabolic pathways associated with the production of lactic, malic and butyric acids, as well as glutathione and amino acids such as leucine and isoleucine.

Links with bone density

These metabolites are linked to bone mineral density in rodents. For example, glutathione promotes the survival of osteoblast precursors and thus bone regeneration, while leucine and isoleucine, two branched-chain amino acids, are actively imported into osteoblasts during chondrogenesis. 
From here it is only a short step to deducing that the microbiota and bodies of the mice are trying to compensate for bone loss during periods of microgravity. However, the researchers refuse to take this step until their hypotheses have been clearly confirmed by mechanistic studies. Nevertheless, the implications may be far-reaching: the identification of potential treatments, such as probiotic bacteria to help maintain bone health, may be beneficial to the health of astronauts in space, as well as that of ordinary earthlings suffering from osteopenia or osteoporosis.

Anorexia nervosa is an eating disorder that affects 1% of the population, with 95% of cases occurring in women. It is characterized by distortions of body image and obsessions with weight loss, leading to a drastic voluntary restriction of food intake.

This in turn leads to emaciation and health complications that can sometimes result in death. The causes of anorexia nervosa remain poorly understood, and its management is complicated, resulting in remission in less than half of cases. Previous studies involving a small number of patients had already associated a gut microbiota imbalance (dysbiosis) with the disorder. Does gut dysbiosis promote the development of the disease?

Profoundly disturbed gut microbiota in anorexic women

Researchers analyzed stool and blood samples taken from 77 women suffering from anorexia nervosa and 70 healthy women of the same age. They compared gut microbiota composition and blood metabolites (sidenote: Metabolites Small molecules produced during cellular or bacterial metabolism. For example, short-chain fatty acids are metabolites produced by intestinal microbiota during fermentation of non-digestible complex carbohydrates (fibers, etc.). 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.  Lamichhane S, Sen P, Dickens AM, et al An overview of metabolomics data analysis: current tools and future perspectives. Comprehensive analytical chemistry. 2018 ; 82: 387-413 ) between the two groups, and indeed found differences. For example, the gut microbiota of the women suffering from anorexia nervosa contained fewer bacteria from the genus Roseburia, which are considered beneficial to health. In addition, the greater the abundance of bacteria from the genus Clostridium, the more severe the anorexic symptoms, suggesting that these species are involved in the regulation of eating behavior.

Gut microbiota contributes to eating disorders

The researchers then transplanted fecal samples from women suffering from anorexia nervosa to germ-free (sidenote: Germ-free mice mice that have no microbes at all, raised in sterile conditions. )  mice. After three weeks of a 30% reduction in food intake (to mimic the eating behaviors of anorexic patients), the mice given fecal samples from anorexia nervosa patients had lost more weight and took longer to return to normal weight than the “control” mice. A functional analysis of the bacteria present in the mice’s feces then confirmed the role of the gut microbiota in controlling eating behavior.

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