Our gut microbiota is dominated by two groups of bacteria, Bacteroidetes and Firmicutes, with a relatively stable ratio. A disruption in this balance (dysbiosis) opens the way to the development of a variety of disorders (inflammatory or infectious diseases) and even obesity. On the contrary, a balanced microbial composition is a key element of an individual’s wellness and good health. Among the main architects of our gut flora, food is by far the most active. But it seems that what we drink is just as important.

Key role of polyphenols

Besides water, tea is the most consumed beverage in the world. Its high content in polyphenols reduces the number of some pathogenic bacteria and prevents their growth. To accurately determine the full range of effects of tea on gut bacteria, two English researchers reviewed the scientific literature on this subject. According to the results, daily consumption of green tea (between 400 and 1000 ml) favorably modifies the composition of our microbial ecosystem, leading to changes that support the Bacteroidetes/Firmicutes balance. By preventing dysbiosis, tea could counteract the negative effects of obesity or high-fat diet, which could explain why, in several studies, its consumption is associated with weight loss. Although most studies focused on green tea, those dedicated to black tea or less well-known types of tea such as Fuzhuan, Pu-erh or Oolong, revealed similar benefits.

Further studies are required

It is now necessary to understand how the different teas impact the gut microbiota and what regular consumption levels are required in healthy adults with normal weight. The role of tea consumption to alleviate symptoms of some gastrointestinal disorders needs to be further analyzed, according to the researchers.

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How can we specifically target pathogenic bacteria without creating resistance or inducing collateral damages to other members of the microbial community, and with a simple yet effective tool. A team from London may have found a solution, based on CRISPR-Cas9, i.e. “molecular scissors” that can implement gene corrections: a guide RNA recognizes a DNA sequence (called CRISPR) to which Cas9 nuclease binds, and cuts the target sequence. And we know that any cut into circular bacterial DNA prevents its replication and induces cell’s death.

A plasmid vector

The idea behind this study is the following: instead of inserting Cas9 into the bacterial DNA, researchers inserted it into a plasmid, a small DNA component present in addition to the bacterial genome. What is the advantage? Bacteria spread these plasmids through a process called conjugation (sidenote: Conjugation The donor bacterium binds to the recipient, transfers it a strand of the plasmid DNA which will later be transformed again by the recipient into a double-stranded plasmid ) , even between different species. But until now, studies were restricted by the low frequency of these plasmid transfers. This deficiency was overcome by the development of a plasmid containing not only Cas9 nuclease but also any equipment necessary to the conjugation process. Thanks to the successive conjugations between bacteria (the recipient becoming the donor, and so on), this new plasmid spreads very quickly, from an E. coli (donor) population to a nearly 100% Salmonella enterica population, considering that the closer the contact between cells (for instance in a biofilm), the greater the conjugation frequency. It should be noted that this propagation is possible because the expression of Cas9 is controlled: arabinose is required for nuclease expression and thus for bacterial killing. In the absence of arabinose, the plasmid is only able to spread.

Target: non-essential genes

Plasmid efficacy to kill target bacteria still had to be assessed, by varying one parameter: the gene cut by nuclease. The researchers thus tested 65 fragments of guide RNA, each recognizing a different gene of the bacterial DNA of S. enterica–some essential and some non-essential. By using E. coli again as initial donor of the plasmid, the team found that S. enterica mortality rate varied from 1 to 100%, depending on the target gene. Although questions remain to explain these differences, targeting essential genes seems less efficient: this gives rise to the insertion of DNA fragments into the plasmid, which then loses its ability to kill bacteria. This does not happen with non-essential genes.

A solution to reach biofilms?

Even though the model is only based on 2 tested species, the plasmid could theoretically be transferred to a complex microbial community: the conjugation could therefore be no longer the limit. The researchers must now focus on the plasmid efficacy and parameters impacting its activity. This process could have a wide range of applications, including the penetration of biofilms which are difficult to reach through other vectors: a native bacterium of the biofilm could be the initial donor, thus allowing the plasmid to spread very quickly and destroy target bacteria, even the most resistant to antibiotics.

The feeding method will directly influence the composition of the gut microbiota of newborns. The gastrointestinal tract of breastfed newborns contains more bifidobacteria and lactobacilli than that of formula-fed babies. But how is the microbiota of breast milk modulated? Several studies indicate that the mother’s diet during pregnancy and lactation has an influence on its composition. And more recently, another hypothesis suggests that bacteria found in the mother’s gut microbiota migrate to the mammary gland.

Two dominant bacterial genera

To get a clearer picture, a team of Brazilian researchers analyzed the microbial composition of breast milk from 94 women who recently gave birth. Among the 85 identified bacterial genera, 3 were systematically present and 10 were found in the composition of at least 90% of milk samples analyzed. Two genera were largely dominant: streptococci and staphylococci, which are believed to trigger the colonization of the gastrointestinal tract of babies. Bifidobacteria and lactobacilli, which are abundant in the gut microbiota of breastfed babies, were also present but in lower amounts.

Effect of vitamin C and polyunsaturated fatty acids

The researchers then examined the effects on the microbiota of diet during pregnancy and during the first month of breastfeeding. Their two main findings were:

- Only the consumption of vitamin C during pregnancy was associated to a specific bacterial profile, dominated by staphylococci, suggesting that is has an impact on the microbiota of breast milk.

- The consumption of polyunsaturated fatty acids (Salmon, tuna...) during the lactation period slightly modulated the abundance of bifidobacteria.

A different influence before and after delivery

A woman’s diet seems to have an effect on the microbial diversity of her milk. But this influence appears to be stronger during pregnancy than during the lactation period.

The discovery of bacterial DNA in the fetal environment has put an end to the long-term belief that it is sterile. However, a question remains: does the identified DNA come from viable and metabolically active bacteria, originating from the mother? An American team provided an answer by combining studies in humans and mice. First step: Characterizing bacterial populations of mother-child pairs (5 premature babies and 5 born at full term) based on samples extracted post C-section delivery, under optimal sterility conditions. The analysis has made it possible to specify the origin of bacteria found in the child’s mouth and meconium, based on mother’s vaginal, rectal, uterine, placental and amniotic microbiotas. As a result, the existence of a fetal microbiota as soon as 24 weeks of gestation was confirmed. It comes from the uterine environment and is mainly composed of Escherichia and Acinetobacter.

Living bacteria in the fetus...around mid-pregnancy

Second step: in mice, researchers visualized the fetus’ gut flora and observed its viability as well as the frequent changes it undergoes during pregnancy. Their data suggest that in the middle of the gestation period, the fetus is exposed to viable and culturable bacteria of variable maternal origin. On the contrary, at the end of the gestation period, and despite the presence of bacterial DNA mainly of placental and amniotic origin, the samples turned out to be non-culturable. The suggested hypothesis is that the (late) maturation of the immune system leads to the progressive elimination of microorganisms that crossed into the fetal environment.

A viable transmission was confirmed

The team validated its observations on the bacterial transmission during gestation by colonizing the gut of pregnant mice with labeled E. coli, before recovering these viable bacteria in their offspring. All these results make the case for the existence of a fetal microbiota of maternal origin, that changes during pregnancy and is likely to have an impact on the development of the immune system and the constitution of the newborn microbiotas after birth.

The vaginal microbiota is a changing and well characterized microbial ecosystem. It is divided into five large groups based on composition: four are dominated by a single Lactobacillus species (L. crispatus, L. gasseri, L. iners or L. jensenii) and the fifth is heterogeneous with a larger number of anaerobic strains, such as Gardnerella vaginalis, Atopobium vaginae and Prevotella spp. The latter is a sign of bacterial vaginosis and is associated to an increased risk of infertility and sexually transmitted infections.

Considering the impact of the vaginal microbiota of women's intimate health and its consequences on reproduction, an American team focused on the link between bacterial profile and colonization by the Candida yeast. Candida is a commensal member of the vaginal microbiota, but it is responsible for vulvovaginal candidiasis characterized by an aggressive response of the host to the excessive proliferation of the opportunistic fungus. Vaginal swabs were taken from 255 women aged between 14 and 45 years, of Caucasian (53%) or African (47%) descent, and were used to identify dominant lactobacilli and to assess and quantify colonization by Candida.

Ethnic variations of the microbiota...

Test results: 16% of women had candidiasis (90% of C. albicans and about 10% of C. glabrata), with a higher percentage in microbiotas with a predominance of L. iners versus L. crispatus (respectively 39% and 20%). This gap is reflected at ethnic level, since the group with a predominance of L. iners is more frequently associated to women of African descent than to women of Caucasian origin (46.7% vs. 31.9%). This study findings confirm data from the literature.

...and lactic acid regulation

The researchers believe that the correlation between Lactobacillus species and the risk of developing candidiasis is based on the lower or higher ability of each strain to acidify the vaginal environment. In vitro tests have shown that L. crispatus produces larger quantities of lactic acid, leading to a decrease in the local pH (near 4.0) versus a pH of 4.6 with L. iners, which is enough to inhibit C. albicans growth.

Differentiating vaginal bacterial communities could thus allow us to identify predisposition to candidiasis. This is a first step towards tailored preventive and curative strategies based on microbiota modulation.

Bacterial vaginosis is a frequent, difficult-to-treat female disorder caused by an imbalance in the vaginal microbiota and characterized by a decrease in lactobacilli and an increase in potentially harmful bacteria, especially Gardnerella vaginalis. Despite antibiotic treatment, around 60% of affected women will relapse within the following year.

Change of method

Since a link between blood levels of some nutrients and the risk of bacterial vaginosis is suspected, many studies have been conducted but their results have been inconsistent. The authors of a new study published in Reproductive Health believe it is due to the methods used in these studies which are based on vaginal swabs or clinical endpoints and mainly focused on vitamin D. To examine the association between the use of dietary supplements and bacterial vaginosis, they analyzed the composition of the vaginal microbiota of 104 young women, including 25% with bacterial vaginosis. They also analyzed their daily intake on micro- and macronutrients based on their answers to a benchmark questionnaire. The researchers also reviewed the scientific literature on this topic.

Higher betaine intake?

They managed to profile women with vaginosis: such women use more frequently vaginal douches, have a high body mass index, and less often use a hormonal method of contraception, compared to women with a balanced vaginal microbiota. Overall, those with lower nutrient intakes have a lower risk of vaginosis. However, betaine is the one exception since a limited intake increases the risk. In vitro, this substance seems to stimulate the survival of lactobacilli and the production of lactic acid, and to prevent colonization by pathogens. According to the authors, it acts directly on the vaginal microbiota by promoting bacterial balance or indirectly through the gut microbiota. This discovery opens up new perspectives to limit the risk of vaginosis, such as increasing betaine intake by changing diet or using dietary supplements.

The study of gut microbiota evolution led many researchers to compare humans and primates. Their works, conducted on a limited number of species, indicated that bacteria found in our gut microbiota descend from bacteria that colonized the gastrointestinal tract of our common ancestors and that they co-evolved. However, although humans are genetically close to large primates (bonobos, chimpanzees), their digestive system is closer to that of Old World monkeys (baboons, macaques) whose environment and dietary habits are quite similar to humans’.

A microbiota closer to that of Old World monkeys

To support the hypothesis stating that these two parameters have a much larger impact on the gut microbiota composition than commonly believed, an American team compared the bacterial flora and its different functions between human populations living in industrialized or non-industrialized countries and 18 wild primate species. While the gut microbiota of populations living in industrialized countries was very different from that of other primates, the gut microbiota of populations living in non-industrialized countries was, on the contrary, very similar to that of primates. There are, however, differences: when compared to the microbiota of other primates, that of humans has unique microbial characteristics (it contains some species, but others are lacking), specific functional pathways and a greater inter-individual variability. The latter could reflect the greater adaptability of humans to new environments. More surprisingly, the gut flora of humans had more similarities with that of baboons than with that of their monkey ancestors.

The influence of environment is underestimated

These results emphasize the influence of environment, diet and physiological adaptations on the gut microbiota composition, especially on their functional capabilities, and belie the idea that it is almost exclusively the result of the co-evolution of bacteria and their host. The authors believe that these discoveries provide a new perspective on the role of the gut microbiota in the evolution of mankind.

Several studies have documented the pivotal role of the gut microbiota in immunity, although clinical evidence remains limited. Better understanding the underlying mechanisms is crucial in terms of public health, especially to develop therapies targeting the microbiota in cases of immune disorders. In this context and based on the observation that vaccine efficacy varies as much as the gut microbiota of individuals on the different parts of the world, researchers focused on the impact of antibiotics on the immune response to vaccination.

Effect of antibiotics on vaccination

To this end, the scientists studied two populations with different levels of anti-flu antibodies at baseline. In the first population, 22 healthy adults were vaccinated against seasonal influenza (vaccine containing 3 strains of attenuated viruses); and 3 days before vaccination, half of them started an antibiotic treatment lasting 5 days. As expected, antibiotics deeply and durably impacted the composition of the gut microbiota. But contrary to the researchers’ hypothesis, the production of antibodies in response to vaccination was not affected by the use of antibiotics. An effect was only observed in the second cohort composed by 11 subjects with no significant pre-existing immunity against influenza (no recent flu or vaccination (sidenote: As proven by low levels of antibodies (1st cohort: serum levels < 320 for at least 2 out of the 3 strains included in the vaccine; 2nd cohort: serum levels ≤ 320 for the 3 strains contained in the vaccine) ) ): antibiotics produced a decrease in the production of IgG1 and IgA antibodies against the H1N1 virus strain. Broad-spectrum antibiotics thus could, in some cases, disrupt the immune response to vaccination.

Bile acids: inflammation messengers

Researchers also observed that changes induced by vaccination at the blood metabolites level were different between the group who received antibiotics and the control group, especially for substances derived from the metabolism of bile acids. It should be reminded that the microbiota transforms primary bile acids secreted by the gallbladder and supplied to the intestines, into secondary bile acids. They are then partly reabsorbed. But in subjects who received an antibiotic therapy, an increase in blood levels of primary bile acids and a major decrease in secondary bile acids were observed. Antibiotic therapy could even reduce by a factor of 1,000 the most important of them, i.e. lithocholic acid. This decrease in secondary bile acids was strongly correlated to the increase of pro-inflammatory molecules. This suggests that a change in the ratio of bile acids induced by antibiotic therapy could be one of the mechanisms regulating the inflammatory response.

Two different response pathways

Is there a link between the pathway modulating the production of antibodies and that involving bile acids and inflammation? According to the researchers there is no such link: they mapped all the different signaling pathways, from the microbiota disruption following the administration of antibiotics, to the changes in blood metabolites; and they concluded that the two pathways are independent. In conclusion, the profound disruption of the microbiota induced by the use of antibiotics could modulate the immune function through two distinct mechanisms: by directly interacting with immune cells, or in a systemic way, by modulating the production of some key metabolites.

Fecal microbiota transplant: a miracle cure?

The frenzy surrounding fecal microbiota transplant (FMT) is real and it needs to be slowed down a bit: some patients have unrealistic expectations regarding the benefits of FMT in their particular case. Every week I receive dozens of letters about anything and everything. However, FMT is a not a magical cure! For now, it is indicated to treat a single disease: recurrent C. difficile infection. For all other indications, it is just a potential therapeutic avenue which cannot replace current treatments. Moreover, the future most likely lies in treatments combining stool transplant (or other therapies that target the microbiota) and more standard treatments that target the immune system, for instance.

Why does C. difficile respond that well to fecal microbiota transplant?

This infection is almost exclusively related to a disruption in the gut microbiota, while in other diseases, the role of the gut microbiota–although presumed– is only one of several contributing factors and its importance probably varies significantly from one disease to another. For instance, in the case of ulcerative colitis, for which we have the strongest data: clinical trials indicate a 20 to 30% rate of remission within a 8-12 week period; which is good, but very far from the results obtained in C. difficile infections (near 90%). This clearly shows that other factors (immune, genetic...) also play a role.

Are there obstacles to the development of clinical research focused on FMT?

Research on FMT is still at a very early stage since it started less than 10 years ago; which is why we must take the time needed to assess it properly. In France, the handling of feces is subjected to major regulations and the selection of donors is strictly regulated. As a result, clinical trials are expensive and require complex logistics. In addition, since hospitals do not automatically assign a budget to FMT, the mobilization of health professionals varies from one facility to another, thus depriving researchers from a specific structure to rely on. It is time for public authorities to better understand this issue and to invest in order to provide hospitals with the means to develop this line of research. In Assistance Publique-Hôpitaux de Paris (Paris public hospital system), we hope to quickly see the emergence of a structured approach to FMT in the healthcare system.

In animals, the physical trait “obese” or “thin” can be transferred through fecal microbiota transplant with a clearly established causal link. In humans, the situation is a little more complex but the presence of dysbiosis associated to metabolic disorders in obese or hypertensive subjects led scientists to conclude that FMT could be a promising avenue. Works are ongoing to assess the impact of the change in gut microbiota experienced by patients with metabolic syndrome^17,14.

Mixed benefits

Several clinical studies were conducted on obese patients with a metabolic syndrome. The first one was carried out on a small group of individuals and showed that stool transplant from thin donors improved the metabolic profile of recipients. The second included a larger number of patients and produced more mixed results. Only a few participants had an improved metabolic profile after the FMT, namely those who initially had a gut microbiota that was not very diversified. The response to transplant thus seems to be dependent on the patient’s initial gut microbiota. However, the benefits did not withstand the test of time...nor did the transformation of the gut microbiota, which quickly returned to its initial composition.

Complex relationships

Overall, these results highlight the complexity of the link between the gut microbiota and metabolic functions. According to some scientists¹³, metabolic and microbial responses to FMT could be based on interactions between the donor’s microbiota and the recipient’s. Several trials are ongoing to assess this technique’s ability to reduce metabolic disorders as well as several obesity-related parameters. These eagerly awaited results should open the way to new strategic approaches in the treatment of metabolic syndrome.