Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction (DGBI), which are also known as functional bowel disorders (FBD). It causes chronic abdominal pain and transit disorders leading to a significant deterioration in quality of life. ¹ Many patients associate IBS with their diet, thus justifying dietary approaches, sometimes empirical, in an attempt to reduce symptoms. A systematic review ² examined the effect of one such approach, a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs).

Effect limited to bifidobacteria

This meta-analysis included 9 randomized controlled trials involving a total of 403 patients. Apart from a clear reduction in the abundance of bifidobacteria, this dietary approach had inconsistent or minimal effects on microbiota composition and metabolism. It had no clear impact on microbiota diversity, which the authors consider reassuring, since higher diversity is considered a hallmark of gastrointestinal health, while lower diversity is associated with disease states. 

The diet did not have any clear effect on bacterial load either, even though it supposedly works by reducing the availability of fermentable carbohydrates in the colon, limiting the major substrates available for bacterial proliferation. 
Fecal concentrations of SCFAs were also unaffected. However, since most SCFAs produced are absorbed in the colon, the fecal concentration may not be reflective of the luminal concentration.

A reversible anti-bifidogenic effect

The anti-bifidogenic effect of the low-FODMAP diet is a cause for concern. Bifidobacteria have immunomodulatory and anticancer properties (animal studies) and a lower abundance of bifidobacteria has been associated with a greater severity of IBS symptoms in humans. However, according to the authors, this concern should be put into perspective, at least for short-term diets (3 to 4 weeks): a recent trial showed a restoration of bifidobacteria abundance upon completion of the diet, while bifidobacteria supplementation was sufficient to reduce the anti-bifidogenic effect.
Thus, three to four weeks on a low-FODMAP diet induces a dysbiosis limited to bifidobacteria, without implications for the composition and functioning of the gut microbiota. According to the authors, this alleviates concerns about the safety for the colonic microbiota of a short-term low-FODMAP diet. However, the effects of long-term interventions are not yet known.

Could the answer lie in the tight junctions?

A second publication ³ has contributed further to this issue. To establish potential causal relations between specific microbial taxa and their functional impact on host tissues, an Israeli team infused mouse digestive tract cultures into solutions containing microbiota samples collected from IBS patients who had successfully followed a low-FODMAP diet for six weeks. In patients who benefited from this diet (3 out of 10), bifidobacteria, and particularly Bifidobacterium adolescentis, were less present in the gut microbiota as the diet progressed (at three weeks and then at six weeks). More importantly, ex vivo cultures show that the post-diet microbiota (lower in bifidobacteria) modulates the intestinal expression of genes involved in inflammatory and neuromuscular processes and in the tight junctions between cells of the digestive wall. In addition, the team identified B. adolescentis as a potent disruptor of intestinal epithelium tight junction integrity and of gut barrier functions. In low-FODMAP diets, the reduced presence of B. adolescentis may result from lower fructose availability. This finding therefore leads us to wonder about the reverse situation, i.e. Western diets rich in fructose that are associated with gut barrier deterioration, low-grade inflammation, and endotoxemia: could the observed pathological consequences of excess fructose consumption be mediated, at least in part, by dysbiotic B. adolescentis overgrowth?

To start, a frequently asked question: what is infertility?

Prof. Ina Schuppe-Koistinen: According to the WHO, infertility is a disease of the male or female reproductive system defined by the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse ¹. The methods used to estimate its frequency varies across research studies, and this variation makes it difficult to understand and estimate the magnitude of the problem. However, the World Health Organization (WHO) estimates that the Infertility affects approximately 15% of all couples of reproductive age worldwide, this having an impact on their families and communities ^1,2 but this figure masks considerable variation within and between countries. Infertility can be primary or secondary. Primary infertility is when a pregnancy has never been achieved and secondary infertility is when at least one prior pregnancy has been achieved.

Is a treatment currently available to help couples?

I.S.-K.: Infertility is treated with assisted reproduction technologies (sidenote: Assisted Reproduction Technologies (ART) ART includes all fertility treatments in which either eggs or embryos are handled. In general, ART procedures involve surgically removing eggs from a woman’s ovaries, combining them with sperm in the laboratory, and returning them to the woman’s body or donating them to another woman. They do NOT include treatments in which only sperm are handled (i.e., intrauterine—or artificial—insemination) or procedures in which a woman takes medicine only to stimulate egg production without the intention of having eggs retrieved. ) (ART), such as in vitro fertilization (IVF) that have been available for more than three decades, with more than 5 million children born worldwide. However, these technologies are still largely unavailable, inaccessible and unaffordable in many parts of the world, particularly in low and middle-income countries.

Which role plays the vaginal microbiota in infertility?

I.S.-K.: In addition to healthy reproductive organs, a successful pregnancy relies on a functional crosstalk between the immune system and expression of hormones enabling fertilization and implantation of the semi-foreign embryo, while at the same time preventing entry and colonization of pathogens (sidenote: Pathogens A pathogen is a microorganism that causes, or may cause, disease. Pirofski LA, Casadevall A. Q and A: What is a pathogen? A question that begs the point. BMC Biol. 2012 Jan 31;10:6. ) . A healthy vaginal microbiota is dominated by Lactobacillus (sidenote: Lactobacilli Rod-shaped bacteria whose main characteristic is the production of lactic acid, from where they get the name “lactic acid bacteria”.  Lactobacilli are present in the oral, vaginal and gut microbiota of humans, but also in plants and animals. They are found in fermented foods, such as dairy products (e.g. certain cheeses and yoghurts), pickles, sauerkraut, etc. Lactobacilli are also found in probiotics, with certain species recognized for their beneficial properties.   W. H. Holzapfel et B. J. Wood, The Genera of Lactic Acid Bacteria, 2, Springer-Verlag, 1st ed. 1995 (2012), 411 p. « The genus Lactobacillus par W. P. Hammes, R. F. Vogel Tannock GW. A special fondness for lactobacilli. Appl Environ Microbiol. 2004 Jun;70(6):3189-94. Smith TJ, Rigassio-Radler D, Denmark R, et al. Effect of Lactobacillus rhamnosus LGG® and Bifidobacterium animalis ssp. lactis BB-12® on health-related quality of life in college students affected by upper respiratory infections. Br J Nutr. 2013 Jun;109(11):1999-2007. ) species that helps protect against pathogens by producing lactic acid and other molecules that kill pathogens. By that, a vaginal microbiota dominated by Lactobacillus species is important for fertility.

There are a number of studies that associate high levels of inflammatory cells and raised inflammation markers in the vagina and uterus of women with unexplained infertility. Several studies link the vaginal microbiota as driver of local inflammation executed by both compounds produced by the vaginal microbes and inflammatory host response factors ^3,4. With other words, a dysbiotic vaginal microbiota contributes to an inflammatory state that has a negative impact on fertility. 
Finally, several studies have demonstrated an association between the microbiota and diseases and infections influencing fertility, such as bacterial vaginosis, cervical cancer, polycystic ovary syndrome and endometriosis. More research on how the microbiota influences fertility is vital ⁵.

What about bacterial vaginosis?

I.S.-K.: Bacterial vaginosis is a common cause of vaginal inflammation and discomfort in women of reproductive age. In bacterial vaginosis the healthy vaginal microbiota is overtaken by less favorable bacteria. Although the composition of the bacteria in bacterial vaginosis varies between individuals, there are some species such as Gardnerella, Atopobium, Snethia, Megasphera, Dialister and others, that are found most frequently ⁶. The microbial composition of bacterial vaginosis has been linked to various pregnancy outcomes including pre-term birth, and can also affect the semen microbiota after intercourse, which in term could affect sperm quality or motility. The link to infertility is not fully established but data suggests that bacterial vaginosis is leading to reduced fertility ⁷.

Does a perturbation of the vaginal flora have an impact on the outcome of assisted reproductive technology procedures?

I.S.-K.: Studies have shown that a healthy vaginal microbiota with certain Lactobacillus species during assisted reproductive technology procedures may have a positive impact on success while women with bacterial vaginosis have poorer results.

May gut health through intestinal microbiota affect the fertility?

I.S.-K.: The microbiota of the female reproductive tract accounts for approximately 10% of the body’s total microbial population. The vast majority of human microbes are found in the gut. They are highly connected to our health and do not only influence the intestinal milieu but also other organs in the body. Vaginal microbes are mainly derived from the gut, although those mechanisms are not well understood yet. As gut microbes metabolize the female sex hormone estrogen, they are directly affecting female physiology and reproductive health. Therefore, a healthy gut microbiome is not only important for good health but also fertility.

What about men: could the men genital microbiota play a role in fertility?

I.S.-K.: Again, there are few studies that have looked at the microbiome in the male reproductive system ⁹. The male genital mucosa contains a bacterial composition that is similar to adjacent anatomical sites with bacterial species as Prevotella, Staphylococcus, Corynebacterium, and Anaerococcus and is affected by sexual intercourse. Male circumcision seems to influence the penile microbiome. More studies and research are needed to understand the role of the male genital microbiome for fertility.

Any advices to improve fertility considering microbiota plays a role?

I.S.-K.: Most important is to live a healthy life when trying to get pregnant. Environmental and lifestyle factors such as smoking, excessive alcohol intake and stress can affect fertility as well as under- or overweight. A healthy lifestyle also includes a diet that makes your microbiota thrive in the gut and vagina. My advice is to eat a diet rich in vegetables and fruits to feed your microbiota with fibres. Fermented foods like yoghurt, kefir, kimchi or sauerkraut will provide you with the important lactobacilli species that support your fertility.

Women should avoid hygiene habits that influence the sensitive skin in the vulva. Don’t use soap and products that contain perfumes, you don’t have to wash your vagina as it cleanses itself with a natural discharge. Washing would only destroy the vaginal microbiota in the vagina.

Discover Prof. Ina Schuppe Koistinen's interview:

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Adolescence is a time when various mood disorders, including major depressive disorder (MDD), can occur. In recent years, many studies have examined the link between intestinal dysbiosis and depression. The problem is that most of these studies have been conducted in adults. An international team of scientists has therefore focused on adolescents and more specifically on the effects of sport on the intestinal microbiota of adolescents suffering from "subthreshold depression". This "borderline" depressive syndrome - which only meets part of the criteria for a major depressive syndrome - would affect 20 to 30% of adolescents and would be reflected by the presence of at least 2 symptoms characteristic of depression described by the manual of mental disorders (a depressed mood, fatigue, weight loss or gain, agitation or psychomotor slowing, feelings of guilt, etc.), for at least 15 days. These individuals have a 40% risk of eventually developing MDD.

Depressed schoolchildren put to the test

The researchers recruited 25 middle school students aged 12 to 14 years with submental depression and randomly assigned them to 2 groups: 

• a group running at a moderate pace (50 to 70% of maximum heart rate) 30 minutes a day, 4 days a week;
• a placebo group doing group activities (reading, singing and games) once a fortnight.

After 3 months of experimentation, the stools of all the volunteers were collected and analyzed by sequencing of the rRNA16S gene.
Results published in Psychiatry Research show that adolescents in the running group had significantly fewer depressive symptoms, whereas those in the reading and games group showed no improvement.

A signature of the intestinal microbiota

Analysis of the microbiota shows that, compared to the placebo group, the young runners had an increase in the relative abundance of certain bacteria:
Coprococcus and Blautia, bacteria that produce butyrate, 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. ) (SCFA) known for its health benefits, thanks to its anti-inflammatory action for example Dorea, and Tyzzerella: bacterial genera whose link with depression is not yet fully established. However, Tyzzerella had already been identified in smaller quantities in women suffering from postpartum depression.

Enrichment of certain metabolic pathways

Analysis of the runners metabolic pathways revealed that those involving defense and signal transduction mechanisms were strongly enriched, which could explain in part the antidepressant effect of running. 
The researchers also note that pathways associated with neurodegenerative diseases - some of which are known to be similar to those of major depressive syndrome - were depleted in runners.
While the results of this study need to be confirmed by a larger study, they represent a new step in understanding the function of the gut-brain axis and its role in mood disorders.

Inform and educate to better diagnose. In keeping with its mission to raise awareness about the microbiota’s importance for health, the Biocodex Microbiota Institute will be actively involved in IBS Awareness Month this April, with exclusive content aimed at healthcare professionals and the general public.

Educating and training healthcare professionals

IBS certification training course, infographics to share with patients, expert videos, thematic paper, the latest scientific news... Biocodex Microbiota Institute provides healthcare professionals with customized tools and content to improve their day-to-day practice and quickly become experts on IBS.

A checklist to improve IBS diagnosis

IBS affects around 10% of the world’s population, but 75% of those affected by the disease remain undiagnosed. Most IBS patients share a bumpy care path: failure to diagnose, a lack of reliable information, unsuccessful treatments, inappropriate or even harmful dietary changes. This is why three internationally renowned gastroenterologists (Professor Jean-Marc Sabaté, Professor Jan Tack, and Dr. Pedro Costa Moreira), with the support of the Biocodex Microbiota Institute, have developed a quick guide to improve IBS diagnosis. This practical and innovative tool provides an easy-to-use checklist to differential diagnosis (diagnostic criteria, IBS subtypes, checklist of warning signs, etc.) and to improving communication with patients. Available in three formats, this guide can be downloaded from the health professional section of the Biocodex Microbiota Institute website.

Living with IBS: patients’ stories 

Meet Mihai, Jennifer, and Aline. They all suffer from irritable bowel syndrome and speak openly about how the disease has changed their lives. To mark IBS Awareness Month, the Biocodex Microbiota Institute is launching “Patient Stories”, a series of video testimonials from patients suffering from chronic diseases. The first episodes of the series are dedicated to IBS and were produced with the support of the French Association of Irritable Bowel Syndrome Patients (APSSII).

A public health issue

Not well known among the general public, diagnosed late by healthcare professionals, and sometimes misunderstood by patients themselves, irritable bowel syndrome is a complex chronic disease and a public health problem. With this holistic awareness campaign, the Biocodex Microbiota Institute intends to actively encourage all stakeholders (patients and health professionals, as well as family members, caregivers, health authorities, and the general public, etc.) to get a better understanding of the disease itself, and the latest research advances pointing to the role played by the gut microbiota.

^BMI-23.13

Irritable bowel syndrome (IBS) is a functional disorder caused by multiple factors and in which dysbiosis of the gut microbiota plays an important pathophysiological role. It is associated with a higher prevalence of depression, emphasizing a pathogenesis that involves disturbance of the gut-brain axis. The Rome IV classification distinguishes 4 subtypes of IBS: diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), mixed-type (IBS-M) and unclassified (IBS-U). While dietary factors appear to aggravate IBS symptoms, dietary interventions that modulate gut microbiota, such as the low FODMAPs diet, can actually alleviate them. Nonetheless, we would gain a lot from better understanding the links between gut microbiota, depression and diet in these different subtypes of IBS.

Each IBS subtype has its own signature

Chinese researchers used data from the American Gut Project to match 942 subjects with different IBS subtypes (IBS-D, IBS-C, IBS-U) with 942 control subjects of similar age, sex, BMI, geographic origin and diet. On comparing their gut microbiota, they found that bacterial diversity in subjects with IBS-D and IBS-U was lower than in the control subjects. While there were lower levels of certain genera in all IBS subjects, such as Bifidobacterium and Faecalibacterium, this trend was reversed in the case of others depending on the subtype. For example, there were more Subdoligranulum, Dorea and Eubacterium hallii in IBS-D, but less in IBS-C. Amounts of certain opportunistic pathogens, more abundant in IBS subjects than in the controls, also differed according to subtype. The study identified a total of 101 bacterial genera associated with the different subtypes of IBS.

Metabolic alterations related to symptoms

The scientists also observed various functional alterations of gut microbiota in IBS subjects depending on the subtype: IBS-D subjects produced more hydrogen sulfide, known to induce diarrhea, while an increase in palmitoleate biosynthesis was demonstrated in IBS-C subjects, the product of which binds to calcium, conductive to stool hardness. In addition, there were fewer beneficial Bifidobacterium, Sutterella and Butyricimonas bacteria in the gut microbiota of subjects with IBS also suffering from depression, and more Proteus, shown in animal studies to damage neurons. The short-chain fatty acid (SCFA) production pathway, a reduction in which has already been correlated with depression, was reduced compared to IBS subjects without depression.

Age, sex, diet: an overview of IBS influencers

In this study, the subjects with the most severe gut dysbiosis were women, younger subjects with IBS-D and older subjects with IBS-C. Certain dietary factors also had a significant impact on the gut microbiota and symptoms associated with IBS. Lactose from milk worsened symptoms and red wine improved symptoms in all subjects with IBS, while examples of foods that tended to normalize gut microbiota included cheese and whole grains in IBS-C subjects, fruit in IBS-D and IBS-C subjects, and eggs in IBS-D subjects.

Combined, these analyses reveal the unique characteristics of gut microbiota associated with different subtypes of IBS. It highlights the importance of taking a personalized approach to gut microbiota modulation to optimize therapeutic outcomes.

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Encouraging teenagers with depressive episodes to run regularly may prevent them from developing full-blown depression. A new study points to a link between the protective effect of physical activity and the changes it induces in gut microbiota.

Move your body to fight depression

The scientists achieved this result by conducting a study on 25 adolescents between the ages of 12 and 14 with “subthreshold depression.” This type of depression is characterized by the presence, for 2 weeks or more, of at least 2 significant symptoms of depression described in the Manual of Mental Disorders : 

• a depressed mood,
• fatigue,
• weight loss or gain,
• agitation or psychomotor slowing,
• feelings of guilt,
• etc. 

It is associated with a 40% risk of one day developing a major depressive disorder (MDD). 
The adolescents enrolled in the study were assigned randomly to two groups: in one, they were asked to run for half an hour at moderate intensity 4 days a week; in the other, they participated in games, singing and reading every 2 weeks. Before and after the 3 months of experimentation, the stools of all participants were collected and analyzed to establish the composition of the gut microbiota.

Moving and running to (positively) influence your gut microbiota

The results indicate a significant improvement in depressive symptoms in the group of runners, compared to no change in the group that played games and read. Running also induced clear changes in the adolescents’ gut microbiota. 
Those who ran had more Coprococcus and Blautia, two bacterial genera that produce butyrate, 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. ) (SCFA) known for its health benefits (e.g. anti-inflammatory protection in the intestines).

They also had more Dorea and Tyzzerella, bacterial genera that do not yet have a fully established link to depression.

Parkinson’s disease is a significant cause of disability and death. The prevalence of the disease has doubled in the past 25 years, with an estimated 8.5 million people affected as of 2019². The disease’s etiology remains poorly understood, but it may be caused by a combination of genetic susceptibility and environmental factors. Parkinson’s disease is a neurodegenerative disorder that is now considered both a movement disorder and a multi-systemic disease. The connection between the disease and the digestive system has long been established, with symptoms including constipation (generally the earliest sign), a compromised gut barrier, and inflammation.

The hypothesis that an enteric bacterial neurotoxin triggers the disease (Braak’s hypothesis) is gaining increasing scientific support. However, all studies focusing on the gut microbiota have given mixed results due to the use of cohorts of limited size and low-resolution sequencing technology.

Largest study of gut microbiome to date 

A research team in the US put together a cohort of unprecedented size, including 490 Parkinson’s patients and 234 neurologically healthy controls. About 50 variables were analyzed, such as the presence of digestive disorders, medication intake, and diet.  The participants’ gut microbiome was analyzed via deep shotgun sequencing. 
Unsurprisingly, constipation was much more common in the Parkinson’s group. At the microbiome level, up to 30% of the species, bacterial genes, and signaling pathways were altered in the Parkinson’s patients. 55 species were more abundant in the Parkinson’s patients, including Bifidobacterium dentium, Actinomyces oris, Streptococcus mutans, and Lactobacillus fermentum, while 29 others were depleted, including Roseburia, Eubacterium, Ruminococcus, and Faecalibacterium prausnitzii, species known to produce short-chain fatty acids (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. )

Major dysbiosis promotes known mechanisms for the disease 

Several mechanisms characteristic of Parkinson’s disease were thus identified. Among the 55 species enriched in the gut microbiota of Parkinson’s patients, 11 are opportunistic pathogens (Porphyromonas asaccharolytica, Escherichia coli, Klebsiella) that have lipopolysaccharides on their surface. Lipopolysaccharides cause an immune reaction by releasing pro-inflammatory cytokines into the body.

On the other hand, there was a reduction in species, genes, and pathways that degrade polysaccharides and produce SCFAs.  In the gut, inadequate levels of SCFAs were linked to constipation, a weakening of the gut barrier, and inflammation, all characteristic symptoms of the disease.

They also found a dysregulation in the synthesis and metabolism of neuroactive molecules dopamine, glutamate, GABA, and serotonin; preponderance of molecules that induce alpha-synuclein pathology and over-production of toxicants; and a reduction in anti-inflammatory and neuroprotective factors, such as nicotinamide or trehalose.

Our diet remains the easiest way to modulate the gut microbiota, since the bacteria that colonize the gut feed on undigested food compounds, such as fibers and polyphenols. Such compounds are found in abundance in vegetables. Other polyphenol-rich foods that benefit our gut microbiota are herbs and spices. How exactly do they effect the bacterial composition of the gut?

A randomized (sidenote: Randomized trial Study in which the products tested are distributed randomly, between the participants. ) , controlled (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. ) , double-blind trial (sidenote: Double-blind trial both the participants and the researchers are unaware who has received the test product (capsule containing the active compound) and who has received a placebo (control capsule not containing the active compound). ) conducted on 54 American adults at risk of cardiovascular disease provided the answers. During three successive four-week periods (separated by washout periods of at least two weeks), the participants were fed a classic American diet enriched with a mixture of herbs and spices in various concentrations.

Boosting Ruminococcaceae

The result: this simple mixture modified the participants’ gut flora. Bacterial diversity increased with the dose (higher diversity with 3.3 g/d than with 0.5 g/d) and compared to the initial diversity. However, the latter result should be viewed with caution, since it may be due as much to the change in diet among the participants (who were provided with standardized meals) as to the herb and spice capsules.

The second finding of the study is that meals rich in herbs and spices seem to go hand in hand with a higher presence of beneficial bacteria, primarily from the Ruminococcaceae family. According to a previous study, these bacteria are associated with lower long-term weight gain. The consumption of spices also enriched the Agathobacter genus and the bacterium Faecalibacterium, which produce 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. ) , such as butyrate and propionic acid, whose benefits include their anti-inflammatory effects.

Do spices naturally boost a gut microbiota beneficial to our health? This avenue needs to be explored further. In the meantime, add some herbs and spices to your menu...

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