Was Pythagoras right? The father of vegetarianism (and veganism, free of any animal product) did not yet know that a healthy gut microbiota is the result of the balance between two large groups of bacteria: Bacteroidetes and Firmicutes. A balanced flora is typically associated to a diet rich in fruits, vegetables and cereals, and poor in sugars, fat and animal proteins. Western diet, which includes opposite dietary intakes, could be detrimental to the microbiota and promote obesity.

Beware of popular beliefs!

Reality is not that simple: extensive work on Bacteroidetes and Firmicutes showed that if some species from this bacterial group are truly more abundant in case of vegetarian and vegan diets (Prevotella and Ruminococcus), others (such as Bacteroides) are more abundant in people who frequently eat animal proteins and fats. This is why several studies have shown that an imbalance between Bacteroidetes and Firmicutes impacts the body mass index and corpulence... but with contradictory results!

Beneficial fibers

Fibers are favorable to “good” bacteria in the gut microbiota. They also promote the growth of species that degrade fibers into short-chain fatty acids, i.e., molecules with anti-inflammatory properties. Polyphenols, antioxidants very abundant in plants such as apples and grapes, also promote the growth of some bacterial species with protective effects (Bifidobacterium and Lactobacillus). Conclusion: the gut microbiota of vegetarians and vegans, more abundant and more diversified, could prevent inflammatory and cardiovascular diseases and obesity.

These interactions should be further explored

Long-term vegetarian and vegan diets seem to be the most effective way to promote diversity and abundance in the gut microbiota, which are a prerequisite for good health. However, the authors concluded that because of inter-individual differences (ethnicity...) and because it is a complex subject, additional studies should be carried out in order to characterize interactions between diet and gut microbiota and better measure the impact on health.

Hepatic encephalopathy (HE) is a complication of liver failure and symptoms include more or less severe, sometimes irreversible, cognitive disorders. This disorder is related to a dysregulation of the gut-liver-brain axis as gut dysbiosis is observed in cases of HE and promotes systemic inflammation. Current treatments, which combine prebiotics (lactulose) and antibiotics (rifaximin) have proven to be inefficient in some patients. That is why, an American team is trying to develop alternative strategies.

Enema vs. oral administration

In 2017, the same team had tested fecal microbiota transplant performed by enema and concluded that it had beneficial effects: decrease in the number of HE episodes, associated to an improvement in cognitive functions and gut microbiota composition. In a new Phase-1 clinical trial, the team evaluated the tolerability and effects of FMT given through a less invasive and eagerly awaited administration route, i.e. capsules. In a blind trial, 20 patients with cirrhosis and history of HE (at least 2 episodes in the previous year) were randomized between the case group and the control group and were given 15 FMT capsules (from the same donor) or placebo. Afterwards, they were monitored for a period of 5 months.

Well tolerated treatment

What were the results? FMT capsules proved to be well tolerated by patients, with no adverse events. The number of HE episodes, as well as the number of infections occurred during the study were the same in both groups. However, an improvement in the score obtained in one cognitive test (out of two performed tests) was observed in patients from the FMT group.

Microbiota: towards a return to balance

An increase in microbiota diversity in the duodenal mucosa was also brought to light in the FMT group, as well as an increase in Ruminococcaceae and Bifidobacteriaceae populations and a decrease in Streptococcaceae and Veillonellaceae populations. The two latter families are associated to cirrhosis while the former two are rather beneficial. Moreover, this improvement of the microbiota is correlated to an increased expression of proteins involved in the function of the gut barrier and of AMO (antimicrobial peptide), as well as a decrease in two inflammation markers: IL-6 expression in the duodenum and LBP (Lipopolysaccharide Binding Protein) blood levels. This potential therapeutic avenue still needs to be confirmed.

Between 1 and 2% of women suffer from recurrent miscarriage (at least three successive interrupted pregnancies prior to 12 weeks’ gestation). In the overwhelming majority of cases, the cause is unknown but a vaginal microbiota imbalance (called “dysbiosis”) is suspected to play a role and has already been recognized as a risk factor for premature delivery and low birth weight. On the contrary, a healthy vaginal flora, dominated by lactobacilli, prevents urogenital tract infections (bacterial vaginosis, mycosis, urinary tract infections or sexually transmitted infections) which can potentially cause miscarriages.

Lower abundance of lactobacilli

To test this hypothesis, researchers studied two groups of 10 individuals, one with women suffering from recurrent miscarriage, the other with healthy volunteers. They collected and analyzed vaginal samples, and the results show a significant difference in the microbiota composition: compared to “control” women, the microbiota of patients had a higher content of three bacterial genera. The authors also observed differences in the expression of some cell functional pathways (vitamin metabolism, cell motility...). Although they were not significant, they still raise questions and should be further explored.

Vaginal dysbiosis: cause or consequence?

Further analysis showed that a miscarriage could lead to a significant alteration of the vaginal microbiota composition; and that imbalances within this ecosystem could, in turn, promote the risk of miscarriage. Although they were not able to determine whether the vaginal dysbiosis was a cause or a consequence of miscarriage, Chinese researchers still suggest that bacterial balance of at-risk women should be restored through better health practices or the use of probiotics.

Gut dysbiosis and gastrointestinal disorders are frequently observed in children with autism spectrum disorders (ASD). That is why, American researchers had previously tested a treatment protocol based on fecal microbiota transplant (FMT) in 18 autistic children aged 7 to 17 years. In a new study, they reported changes in the participants’ symptoms two years after that first study.

Intensive protocol, durable results

The protocol, called “Microbial Transfer Therapy” (MTT), included a 2-week vancomycin treatment course, an enema, two days of FMT, followed by 7 to 8 weeks of FMT combined with gastric acid suppression with omeprazole. After this initial 18-week trial, gastrointestinal symptoms improved by 80% and autistic symptoms slightly decreased (communication difficulties, repetitive behaviors...). These positive results were maintained two years later: gastrointestinal disorders were 58% lower compared to the beginning of the study. Disease severity was measured by a professional and it sharply decreased: 83% of the children were considered as “severely autistic” at the beginning of the study, while two years later, 17% were rated as severe, 39% were in the mild to moderate range, and 44% of participants were below the ASD diagnostic cut-off scores.

Implantation of a healthier microbiota

Stool analysis of 16 out of the 18 participants also showed that, in most children, bacterial diversity was higher after two years than at the end of the 18 weeks of the initial trial, thus showing that the protocol had created a healthier microbial environment, favorable to the improvement of gastrointestinal and behavioral symptoms. More precisely, relative abundances of Bifidobacteria and Prevotella were multiplied by 5 and 84, respectively. This was a significant finding, since Prevotella (frequently depleted in autistic patients) is a bacterial genus that produces butyrate, a short-chain fatty acid favorable to gut mucosa. However, a cautious approach should be adopted here: the researchers indicated that during the two-year follow-up period, 12 out of the 18 children underwent changes in medication, diet or dietary supplements and that the omeprazole effect might explain by itself the improvement of symptoms related to gastric acidity. A randomized double-blind trial with a larger cohort is necessary to validate the hopes resting on this new protocol.

Celiac disease is an autoimmune digestive disease caused by the ingestion of gluten, a protein found in some grains. Although a genetic predisposition is necessary to the development of this autoimmune disorder (related to an overactive immune system), which is different from gluten intolerance, other factors are involved. Because they cause an imbalance in the gut microbiota (involved in the maturation of the immune system), antibiotics are often held responsible.

Massive analysis

A Scandinavian team analyzed data from Denmark (1995-2012) and Norway (2004-2012) birth registries, as well as antibiotic prescriptions in children under 2. In total, over 1.7 million children, including 3,346 with celiac disease, were included in the study. Researchers have also examined various maternal parameters (age at pregnancy, duration of breastfeeding, maternal smoking, body mass index before pregnancy...). Finally, they asked the mothers which disease had affected their children when they were under 18-month old, and searched hospital records for infections in babies under one year old.

More antibiotics = increased risk!

Analyses show that there is a positive correlation between exposure to antibiotics during the first year of life and the risk of developing celiac disease in both groups. The risk is increased in proportion to the amount of antibiotics ingested. But no correlation was found with the type of antibiotics used or the age of the baby during treatment. Results also exclude any link with other diseases–whether they are autoimmune or not–and with breastfeeding. The authors concluded that it remains to be determined whether it is an independent effect or an interaction with other risk factors such as infections, and urge others to pursue their work.

Ankylosing spondylitis (AS) and gut dysbiosis seem to be related: over 70% of patients with AS suffer from subclinical gut inflammation and between 5 and 10% of them have a severe form that can progress to a chronic inflammatory bowel disease (IBD). Although the bacterial gut microbiota of these patients has already been analyzed, until now no study had focused on their fungal microbiota (or mycobiota). It has now been done: a Chinese study characterized bacterial and fungal gut microbiota of 22 patients with AS and 16 control subjects.

Double dysbiosis: microbiota and mycobiota

The results show a 3-fold higher abundance of Proteobacteria and a significant decrease of Bacteroidetes in patients with AS. In addition to the bacterial dysbiosis in patients with AS, this study reveals an even stronger dysbiosis of the mycobiota, characterized by a significant decrease of fungal diversity: the Ascomycota phylum, and especially the Dothideomycetes class, becomes even more predominant, while the abundance of Basidiomycota phylum largely decreases, mainly because of the disappearance of Agaricales.

Impact of treatments

The authors also indicated that immunosuppressive therapy seems to exacerbate the mycobiota imbalance: fungal diversity decreased more in the 8 patients treated with etanercept (TNFα inhibitors) than in the 5 patients with AS who were not under treatment. However, NSAID therapy did not lead to significant changes in the 9 patients with AS who received this treatment. Finally, a strong positive correlation was found between C-reactive protein (CRP) levels, a biomarker of inflammatory flares, and the fungal microbiota. A change in fungal (but not bacterial) microbiota of patients with AS was also associated to the degree of disease activity and the intensity of X-ray damage, thus suggesting the mycobiome plays a role in the development of AS. Patients with AS, and especially those without treatment, presented a change in the number and intensity of interactions between fungi and bacteria, which could involve the inflammatory process. These interactions were incidentally affected by treatments with NSAIDs and immunosuppressants.

Environmental factors such as diet, contact with maternal microorganisms (from the vagina and skin) during labor or in the first moments of life, play a key role in the development of the gut microbiota from birth, and later in its composition throughout life. And some of them can very surprising!

In Japan, families take baths together!

One of these factors is the sharing of bacteria within the household: each home hosts its own bacterial ecosystem, mainly forged by the members of the family. This is even more so in Japan, where sharing baths is a common practice which is not exclusively related to hygiene: it is above all a relaxation ritual that helps strengthen family ties across generations. According to tradition, parents and children have to clean themselves with soap and rinse before taking a bath, either together, or one after the other. They thus enter the bathtub clean, and the water, which is free of bacteria at the start, is used by all participants. It successively gathers part of their gut bacteria–especially bifidobacteria which are found in higher proportion in Japanese people.

Exchange of bacteria

Some bacteria do not resist to the heat of the water or prolonged immersion (during one or more hours). But the analyses conducted in 5 Japanese households–21 persons in total–concluded that about 10% of microorganisms identified in the bath water and in the participants’ gut microbiota were the same. As an additional finding, the composition of gut microbiota is more similar between family members who take baths together. Researchers concluded that, just like mother-to-child transmission of bacteria, shared bath water is a two-way environmental driver of gut flora colonization.

Thanks to recent improvements in medical imaging, lesions caused by pancreatic cystic neoplasms are detected more and more often. Among them, intraductal papillary mucinous neoplasms (IPNMs) of the pancreas, which can progress to pancreatic cancer, are the most common. The pancreatic microbiota could be involved in many ways in the development of these lesions: 1) cancerous pancreatic tissue is richer in bacteria; 2) bacteria from the Fusobacterium species are associated with a poor prognostic; 3) intracystic bacteria could metabolize gemcitabine, thus reducing therapeutic effects of this anticancer drug.

Characterizing the cystic microbiome

A retrospective study has previously tried to characterize the microbiome found in different cysts, but showed no significant results, maybe because the methodology used could have induced contamination (samples were collected through the mouth and esophagus). To resolve the uncertainty, a prospective study was recently carried out, based on samples of cystic liquid and plasma collected during pancreatic resection in 105 patients at the Karolinska hospital in Sweden: 21 non-IPMN cysts, 57 IPMN cysts and 27 malignant IPMN cysts were diagnosed post hoc.

More bacteria and inflammation

Results show that patients diagnosed as carriers of an IPMN (whether it is malignant or not) have higher amounts of bacterial DNA and an increased level of IL-1β (pro-inflammatory interleukin) in the cystic liquid, compared to non-carriers. This correlation is not found in plasma, thus suggesting a local process limited to the cyst. Despite a strong individual variability of the intracystic microbiota composition, the study underlines that cysts occur simultaneously and show increased levels of some oral bacteria, such as Fusobacterium nucleatum and Granulicatella adiacens. Finally, clinical history indicates a strong presence of intracystic bacterial DNA associated, among others, to previous endoscopic lesions related to invasive procedures. However, this increase was independent from the use of proton pump inhibitors (PPI) and antibiotics.

Therapeutic outlooks

Although these results still require additional work, they suggest that some oral bacteria play a role in the development of cysts that are precursors to pancreatic cancer. Although it is too early to imagine a predictive test for pancreatic cancer based on intracystic bacterial DNA, the authors underline that the pancreatic microbiome could be eventually used to treat patients. The interest of the use of antibiotics and the impact of invasive procedures are among the avenues to explore.

C-section, infant formula and antibiotics are regularly associated with increased risks of obesity, allergy or even diabetes mellitus. What do they have in common? They all seem to disrupt the bacterial colonization of the gastrointestinal tract that started at birth. But we still do not know the individual effects of each of these parameters, as well as its combined impact, on the structure and composition of the gut microbiota. To try and find an answer, researchers analyzed the bacterial flora of 120 six-week old babies, divided into groups based on the type of delivery, type of breastfeeding (exclusive or mixed feeding) and exposure to antibiotics since birth.

Low content of bifidobacteria

Compared to children born vaginally, the gut microbiota of newborns born through c-section had significantly less bifidobacteria (which promote good intestinal and immune health) and an increased content of two types of potentially harmful bacteria. The gut microbiota of breastfed children was, however, approximately the same as that of babies who alternated between breast milk and formula. But when combining these two variables, the researchers observed that only children born through C-section were impacted by the type of breastfeeding. What if the microbiota of these babies was altered by maternal milk? When testing this hypothesis, the researchers observed that the microbiota of babies born through C-section and exclusively breastfed was very close to that of babies born vaginally. Exposure to antibiotics, however, had no impact on the gut flora. The authors believe this was probably because treatments were administered for a short period of time and at low doses.

C-section + maternal milk = healthy microbiota

This study provides new insights into a controversial issue, since only the mode of delivery seems to have an impact on the structure and composition of newborns’ gut microbiota. It also shows that in case of c-section, the flora can partly be restored by exclusive breastfeeding, thus unveiling new benefits of this practice which is strongly recommended by the World’s Health Organization.

Despite the positive results obtained with fecal microbiota transplants (FMT) as a first-line treatment for recurrent Clostridium difficile infections (rCDI), 8 to 50% of patients relapse. Recent works have shown the potential influence of bacteriophages–a virus that infects bacteria within the gut microbiota–on the success rate of fecal transplants. A Canadian team thus studied the impact of bacteriophage populations in donors and patients with rCDI treated with FMT via colonoscopy.

Impact of FMT on bacteriophages

Unsurprisingly, all 19 recipients from this trial had a less diversified gut microbiota than the 7 donors. The diversity of their bacteriophages was greater than that of donors and of the 96 control subjects. This was potentially due the administration of vancomycin in the 24 hours before the transplant, which could trigger the induction of phages. The FMT, which was effective from the first administration in 12 patients, led to a reduction of this increased diversity. For the 7 patients who received a second FMT, bacteriophage diversity was only reduced on the second attempt.

Importance of donors’ profile

On the bacterial front, recipients’ profile became more similar to the donors’ after a successful transplant: increased levels of Bacteroidetes and Firmicutes, decreased levels of Proteobacteria, which were prevalent until then (mainly species from the Klebsiella and Escherichia genera). Nevertheless, no difference was observed between patients who had a positive response after the first transplant and those who did not. On the contrary, donors’ bacteriophages seem to be correlated to the successful or failed outcome of the transplant: greater diversity as well as decreased relative abundance were associated to a successful FMT. But before using donors’ bacteriophage composition as a prognostic factor for FMT in the treatment of rCDI, the researchers call for revised research methods into this facet of the gut flora which is still largely unknown. They believe these results are probably only the “tip of the iceberg”.

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