What has the national grant allowed to discover in your microbiota research area? 

Using an animal model of early life stress in “dirty” animals that provide a more translationally relevant approach to the study of the microbiota-gut-brain axis, we were able to determine that fecal transplantation in adult animals reverses the behavioral, metabolic and neuroendocrine consequences of stress during childhood. 

What are the consequences for the patient?   

This is the first study, to our knowledge, that aims to provide microbiota- focused therapies for adults that already present mental, metabolic and neuroendocrine diseases as a consequence of suffering stress during childhood. Although, the importance of prevention treatments, such as probiotic treatment in children, is undeniable; these interventions are not relevant for developing countries that are already struggling with the devastating effects of early life suffered by individuals many decades ago. Recent evidence from our lab, showed that in Mexico, 90% of the population from 35 to 65 years of age that seek medical care in public institutions reported adverse childhood experiences. These, are related to the high prevalence of depression and metabolic diseases observed in our clinical settings. Hence, by evaluating the efficacy of fecal transplantation in clinically relevant animal models, such as “dirty” animals, we will be able to identify and refine strategies with translational potential for the treatment of depression and metabolic diseases in adults.   

BMI 22.24 

It is a diet that is now unanimously recommended by the international learned societies of cardiology and diabetology. ^2,3,4 Epidemiological studies show that the Mediterranean diet is associated with better general health and a significant reduction in cardiometabolic risks.  Recent studies go further and suggest an additional benefit on morbi-mortality of the reduction of animal proteins and fats in favor of their vegetable equivalents (nuts, seeds, olive oil, etc.) in the Mediterranean diet.

Green-Med, a diet based on plants and their polyphenols

Researchers have conducted a study corroborating these results while providing a better understanding of the role of the microbiota in these effects. They randomized 294 participants from the DIRECT-PLUS⁵ cohort over 30 years of age (88% men) with abdominal obesity and/or dyslipidemia into three groups: standard healthy diet recommendations, Mediterranean diet and "Green-Med", an "optimized" Mediterranean diet. The Green-Med incorporates Mankai duckweed (100 g per day), an Asian plant rich in fiber and plant protein that reduces the amount of meat, and green tea (3 to 4 cups per day). The authors highlighted the high content of polyphenols in these foods, which are capable of modifying the taxonomic structure of the intestinal microbiota and intervening in fat metabolism. ⁶ Both diets were supplemented with nuts (28g per day) and were isocaloric and restrictive (1500-1800 kcal for men and 1200-1400 kcal for women). All three groups combined the diet with moderate physical activity.

Changes in the structure and enzymatic activity of the microbiota

Fecal samples from the participants were collected and analyzed by sequencing at baseline and at 6 months. All subjects showed changes in the structure of their gut microbiota. Green-Med led to even more substantial changes, mainly in its rare (<50%), person-specific, and diet-influenced species. Specifically, it led to an increase in Prevotella, signaling adherence to a "vegetarian" diet, and a decrease in Bifidobacteria, known to improve dietary glycemic index and facilitate weight loss. The researchers also found a reduction in the biosynthesis of branched-chain amino acids, metabolites involved in obesity and insulin resistance. 

Superior results on weight and cardiometabolic markers

The Green-Med was more effective in terms of weight loss (-6.5% vs -5.4% for the Mediterranean diet and -1.58% for the standard diet). In addition, improvements following a similar trend were observed on markers of cardiovascular risk, with a decrease in Framingham score, waist circumference, mean blood pressure, insulin resistance and plasma leptin levels.

 According to the researchers' modelling, these benefits are partly related to the impact of changes in the microbiota caused by Green-Med, contributing for example to 12% of the weight loss and 18% in the reduction of the Framingham score.

In your point of view, what is the biggest breakthrough related to microbiota these last years? 

In my opinion, the most important breakthrough in microbiota research in the last years is the recognition of the role of our intestinal microbiota in very different aspects of our health, including mental health. The realization that the balance or disbalance in the microbiota defines health or disease systemically and not only at the human intestine is a major discovery of modern science.
 

Do you think there is a growing interest on microbiota recently? 

Most definitely. Human microbiota and microbiota research are themes that are gaining great inertia both among general publics and among the scientific community. 
 

Do you have a tip for taking care of our microbiota? 

A tip that I want to share is to maintain the microbiota balance and diversity is to regularly consume portions of fermented foods in your diet: i.e., yogurt, wine, beer, kombucha, pickles, among others.   

BMI 22.23 

What has the national grant allowed to discover in your microbiota research area?

Biocodex Foundation grant (2020) allow us to initiate a multidisciplinary study aiming to understand the interaction between the gut microbiota and women´s cognitive dysfunction. 

Scientific evidence indicates that Alzheimer´s patients develop a more severe gut dysbiosis as disease progresses. Preliminary data from our laboratory show that female transgenic mice for Alzheimer´s disease lack specific gut bacteria related to estrogen metabolism. Estrogen is a sex hormone that associates with enhanced cognitive function. After menopause, the abrupt decline in estrogen levels correlates with cognitive dysfunction and dementia. Thus, we elaborate the hypothesis that gut dysbiosis might increase the risk to develop dementia in women due to lack of estrogen-related bacteria.  

We designed a transversal clinical study with Alzheimer´s women and healthy controls in collaboration with the National Neurosurgery and Neurology Institute (INNN). As a translational approach we are running a preclinical study in CINVESTAV with female transgenic mice and wildtype littermates to determine the reproducibility of the human data. We are currently at the final stage to complete the experiments.  

What are the consequences for the patient?  

Being women is a risk factor to develop Alzheimer´s disease, as two thirds of cases worldwide are women. It has been proposed that the lack of estrogen after the menopause leads to cognitive dysfunctions and dementia. However, estrogen replacement therapies have not shown consistent results due to estrogen optimal levels and a narrow therapeutic window.  

Nowadays, more than 50 million persons are diagnosed with Alzheimer´s disease, more than 33 million are women. If our hypothesis of work is approved, we can design therapeutic interventions to increase the abundance of estrogen-related bacterial to prevent cognitive alterations and dementia after menopause in women. This approach will impact significantly the quality of life of women for decades following the menopause. 

BMI 22.22

Seeing yourself as fat when you are thin (body dysmorphia), and panicking at the idea of gaining just an ounce in weight: these are the main characteristics of anorexia nervosa. But what if the gut microbiota were involved? 

Roseburia: bacteria that are never there...

Several studies have tried to assess the involvement of the gut microbiota in this condition, with differing results. In order to clarify the matter, one team carefully scrutinized data from three earlier studies comparing the composition of the gut microbiota in anorexic patients vs. healthy controls. The results? Only bacterial species belonging to the Roseburia genus were in short supply in the anorexic patients. And nothing seemed to be able to change this state of affairs. Not even hospital treatment leading to an improvement in patient condition, not even weight gain - these bacteria remained less abundant and less diversified in anorexic patients. Something that suggests that these gut bacteria may play a role in the initiation of the disease..... dispelling the hypothesis that their reduction could have been a consequence of the disease.

...with health capital 

Well, Roseburia are allies for our health in our gut microbiota: by breaking down the fibers that our digestive system has not digested, they 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. ) . These small fatty acids are known to regulate inflammation and to maintain the equilibrium of our gut functions: thanks to them, our epithelial barrier is strengthened and our colonic transit is correctly regulated. And that’s not all: the beneficial effect of Roseburia is thought to extend beyond just our digestive health, since its presence seems to go hand in hand with an improvement in several health markers of our bodies, such as the concentration of triglycerides, prealbumin, and iron in our blood, for example. And as the cherry on the cake, although this point has yet to be confirmed: Roseburia could also help us to have a positive outlook on life, since its depletion is associated with the depressive symptoms often observed among anorexics.

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Immune checkpoint inhibitors (ICI) represent a major breakthrough in the treatment of certain cancers, offering patients an overall survival superior to that expected with chemotherapy, notably in non-small-cell lung cancer (NSCLC) and melanoma. However, some patients do not respond to this treatment as hoped. This difference may be linked in part to the gut microbiota, which is thought to influence the effectiveness of ICIs.

Akk in lung cancer: neither too little nor too much

A first retrospective multicenter study analyzed the microbiota of 338 French patients with advanced NSCLC. The aim was to predict a positive clinical response to anti-PD-1, a type of ICI treatment. More specifically, the investigators sought to confirm previous results obtained in smaller cohorts suggesting that the composition of the gut microbiota, and more specifically the presence of the bacterium Akkermansia muciniphila (Akk), could serve as a biomarker of response and survival at twelve months.

The results? The relative abundance of Akk was clearly associated with clinical benefit (better response rate, better survival). Moreover, the presence of Akk in the gut was an indicator of the richness of the intestinal ecosystem. It was associated with a specific bacterial community linked to health or immunogenic status, represented by Ruminococcacae and Lachnospiraceae, as well as B. adolescentis and I. butyriciproducens. 

However, good survival rates require the right abundance of Akk, neither too little nor too much. Indeed, antibiotic use (20% of cases) favored an overabundance of Akk and of the genus Clostridium, both of which are associated with resistance to ICI and an unfavorable outcome (reduced survival). Thus, it appears that antibiotic-induced dysbiosis reduces beneficial bacteria associated with survival (such as Ruminococcus), in favor of harmful bacteria associated with immunoregulatory or pro-inflammatory pathways (such as Escherichia coli and Clostridium bolteae). Therefore, the relative abundance of Akk represents a potential biomarker (favorable or unfavorable) to refine the stratification of NSCLC patients receiving anti-PD-1 immunotherapy. It may even provide a way of improving responses to treatment via Akk supplementation.

Relationships more complex than expected

A second study based on five previously published cohorts (n = 147) and five new cohorts (n = 165) confirmed that the gut microbiome is associated with response to ICIs and survival in advanced melanoma. However, this association was found to be cohort dependent. In other words, each cohort had its own signature. Consequently, no single species could be regarded as a fully consistent biomarker across studies. Instead, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp., and Akk., may serve as such.

Thus, this second study confirms what the first study suggested: the role of the human gut microbiota in responses to ICI is more complex than previously thought. Neither the presence or absence of any single bacterial species, nor the abundance thereof, as with Akk., is sufficient to define responders or non-responders to ICI treatment.

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Vaginal dryness, itching, frequent urination, pain during intercourse... The period following menopause (postmenopause) is not always easy.
Genitourinary syndrome of menopause (GSM)¹ is a condition whose symptoms can mostly be attributed to the estrogen deficiency typical of menopause. Displaying various degrees of severity, the condition can be treated via hormonal treatments such as estradiol vaginal tablets, or non-hormonal treatments such as vaginal moisturizers.
The question is, what impact do these treatments have on vaginal pH, the vaginal microbiota, and metabolites produced by the microorganisms contained in it?

Importance of vaginal microbiota for health

We know that the bacteria in the vaginal microbiota contribute to maintaining a healthy vaginal environment. Unlike the gut microbiota, the vaginal microbiota is balanced when it is not very diverse and is composed mainly of lactobacilli. Some of these bacteria produce lactic acid, which maintains the vagina’s acidic pH (pH ≤ 4.5), thus preventing the growth of pathogens. At menopause, estrogen levels decrease significantly. As a result, vaginal pH increases and the vaginal flora undergoes a change (fewer lactobacilli and greater bacterial diversity).²

Treatments have different impact on vaginal microbiota

This new clinical study³ involved 144 postmenopausal women (mean age 64) experiencing moderate to severe vulvovaginal discomfort. The researchers compared the impact on the microbiota of an estradiol vaginal tablet, a moisturizing gel, and a double placebo (tablet and gel with no active compound).

At 12 weeks, 80% of women in the estradiol group had vaginal bacterial communities dominated by Lactobacillus and Bifidobacterium, compared to only 36% in the moisturizer group and 26% in the placebo group. Moreover, in the women treated with estradiol, more than half of the metabolites in the vaginal fluid changed, with an increase in lactate production almost certainly contributing to the marked decrease in pH in this group.

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Belgium

Finland

France

Mexico

Portugal

Russia

United States

What has the national grant allowed to discover in your microbiota research area?

The Foundation Portuguese grant allowed us, in a first step, to understand the impact of maternal obesity on the acquisition and maturation of the child’s gut microbiota throughout the first year of life. In early life, the establishment, development, and maturation of the microbiota are shaped by microbial and host interactions, in which the mother plays a key role as she represents the most important source of microorganisms. The transfer of obesogenic microbiota between mother and child has been suggested as a possible pathway for the intergenerational transmission of obesity. Since the early-life represents a critical window for immune stimulation, gut dysbiosis can compromise the development of a balanced immune phenotype. Therefore, our second step will unravel the impact of a dysbiotic and obesogenic maternally acquired gut microbiota on the immune system priming.

What are the consequences for the patient?

With Biocodex Microbiota Foundation support, we anticipate understanding the impact of maternal obesity on the child's gut microbiota and unraveling the impact of early life dysbiotic microbiota on the immune system stimulation and regulation up to one year after delivery. The understanding of how dysbiotic maternally acquired gut microbiota impacts immune system priming may reveal new strategies for disease prevention through early-life gut microbiota manipulation, opening new paths for the development of innovative and personalized diagnostic and therapeutic tools.

BMI 22.15