Tell me what your microbiota looks like, and I’ll tell you how the Covid vaccine protects you. 

That’s the takeaway from a study ¹ published last September in the academic journal Signal Transduction and Targeted Therapy.

The researchers succeeded in demonstrating that the presence of certain bacteria and molecules in the gut prior to the first injection may reinforce the immunity conferred by the vaccine, thereby extending its duration of action. 

A promising avenue for the development of new adjuvants.

• 161 participants
• two Covid-19 vaccines
• six months follow-up

This finding was made thanks to the participation of 161 volunteers enrolled for six months. 

121 participants received two injections of Comirnaty, Pfizer-BioNTech’s mRNA vaccine, while the remaining 40 received CoronaVac, Chinese firm Sinovac Biotech’s inactivated virus vaccine. No volunteers were infected with Covid during the study. Immediately prior to vaccination, then one month and six months later, the researchers took the following samples from the participants:

• blood samples to measure antibody concentrations; 
• stool samples to identify the bacteria in their gut microbiota and measure the levels of substances produced by the subject and their bacteria (vitamin B3, GABA, fumaric acid, etc. – i.e., the renowned “metabolome”).

The researchers found, first of all, that Comirnaty achieves better immunity than CoronaVac. 

State of gut flora modulates vaccine-induced immune response

In the Comirnaty group, patients whose gut microbiota before the first injection was abundant in bacteria such as Bacterium adolescentis, Bifidobacterium (sidenote: Bifidobacterium A genus of Y-shaped bacteria, most species of which are beneficial to humans. They are found in the gut of humans, and in some yogurts.

They:
- Protect the gut barrier 
- Participate in the development of the immune system and help fight inflammation 
- Promote digestion and improve symptoms of gastrointestinal disorders Sung V, D'Amico F, Cabana MD, et al. Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis. Pediatrics. 2018 Jan;141(1):e20171811.  O'Callaghan A, van Sinderen D. Bifidobacteria and Their Role as Members of the Human Gut Microbiota. Front Microbiol. 2016 Jun 15;7:925. Ruiz L, Delgado S, Ruas-Madiedo P, et al. Bifidobacteria and Their Molecular Communication with the Immune System. Front Microbiol. 2017 Dec 4;8:2345. ) bifidum and Roseburia faecis had higher levels of SARS-CoV-2 antibodies in their blood six months later. The same type of stronger, longer-lasting immunity was found in those with a metabolome richer in vitamin B3 and GABA.

In the CoronaVac group, a low abundance of Faecalibacterium prausnitzii and a higher abundance of Phocaeicola dorei – a signature found in Covid-infected patients – was associated with better immunity at six months, as was a higher presence of fumaric acid in the metabolome, a compound known to hinder virus replication.

Another finding was that, for the Comirnaty group, a greater proportion of the bacterial strains in the microbiota altered by the vaccine had not recovered their pre-vaccination state when compared with the CoronaVac group. While it remains difficult to analyze the consequences, the researchers point out that some of the strains affected are the same as those found altered in people suffering from long Covid.

Immune responses to the Covid-19 vaccine depend on multiple factors, among them gut microbiota composition. At the same time, vaccination may in turn modulate gut flora. To better understand this bi-directional interaction, a prospective longitudinal study was carried out in Hong Kong. Blood and stool samples were collected (at baseline and then at one and six months post-vaccination) from subjects vaccinated with either BNT162b2 (sidenote: BNT162b2 Covid-19 vaccine comprising lipid nanoparticle-encapsulated mRNA, developed by Pfizer-BioNTech and marketed under the name “Comirnaty” in the EU. ) (121 subjects, mean age 42 years) or CoronaVac (sidenote: CoronaVac Covid-19 vaccine developed by Sinova comprising whole inactivated and adjuvanted (adjuvant: aluminum hydroxide) virus. Approved in many countries in Asia and South America. In Europe, it has been approved in Bosnia, Ukraine, and Turkey. Source: www.mesvaccins.net/ ) (40 subjects, mean age 55 years) who did not contract Covid during the study.

Effect of microbiota on vaccine response

The immunogenicity of BNT162b2 (mRNA vaccine) was stronger and longer lasting than that of CoronaVac, with subjects showing higher antibody levels at six months.

In subjects vaccinated with BNT162b2, a higher content of Bifidobacterium adolescentis, B. bifidum, and Roseburia faecis at the time of vaccination was associated with a better vaccine response. The abundance of three bacterial species (B. adolescentis, Lachnospira pectinoschiza, and Lactococcus lactis) at baseline even predicted vaccine response at six months. Twenty-eight metabolites, including nicotinic acid (Vitamin B) and γ-aminobutyric acid (GABA), were positively or negatively associated with vaccine response.

In those who received CoronaVac (inactivated virus), more antibodies at six months were associated with more short-chain fatty acid-producing bacteria such as Phocaeicola dorei, Blautia massiliensis, and Dorea formicigenerans and a lower abundance of Faecalibacterium prausnitzii at baseline. The abundance of three bacterial species (Clostridium fessum, Actinomyces sp. ICM47, and Enterocloster citroniae) at baseline predicted antibody titles at six months. Forty-two metabolites, including L-tryptophan, were found to be negatively associated with antibody titles at six months. Thus, each vaccine technology is associated with a particular immune response, depending on initial microbiota composition.

Effect of vaccine on microbiota

At the same time, both vaccines altered the gut microbiota: reduced diversity; increased content of Bacteroidota and Pseudomonadota, decreased content of Bacillota and Actinomycetota; depleted histidine biosynthesis pathways, increased methionine and arginine degradation pathways. Alterations to the gut microbiota associated with CoronaVac vaccination more closely resembled those induced by SARS-CoV-2 infection. The technology used in CoronaVac (inactivated whole virus) may explain this difference.

Lastly, the gut microbiota of the BNT162b2 group recovered its diversity more quickly, but a greater proportion (58.0%) of the species modified by vaccination had not returned to initial levels at six months post-vaccination compared with CoronaVac (21.6%).

Osteomicrobiology is a new research field aiming at exploring the mechanisms linking the gut microbiota and the skeleton, and looking into many hypotheses about the mechanisms involved. For example, the gut flora may stimulate certain white blood cells, thus inducing inflammation, which in turn leads to bone loss. Numerous other mechanisms have been put forward, some involving 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. ) produced by bacteria via fermentation of fibers in the colon, or dietary compounds such as vitamins K or D. However, large-scale studies are still lacking. Or rather, were lacking, since a study on more than 2,000 Americans has provided new evidence.

Bone health: two bacteria under the spotlight

The study included participants from two markedly different studies: 836 elderly men (average age 84.2) on the one hand, and 1,227 men and women in their fifties (average age 55.2), on the other. Despite this heterogeneity of profiles in terms of age and sex, two bacteria, Akkermansia and Clostridiales DTU089, seem to be systematically associated with poorer bone health, and therefore a higher risk of osteoporosis (sidenote: Osteoporosis A disease characterized by a reduction in bone mass and a breakdown in the structure of bone tissue. It makes bones more fragile and thus considerably increases the risk of fractures. Source: Inserm ) and fracture at the slightest trauma. These bacteria are more abundant in those with low levels of physical activity and very limited protein intake – two behaviors not recommended for maintaining bone health.

Conversely, gut flora rich in Lachnospiraceae and Faecalibacterium were associated with stronger shins. It thus seems that certain bacteria influence how our bones remodel themselves as the years go by. Although this hypothesis has yet to be confirmed.

Sun, exercise, and a balanced diet

This finding is merely preliminary. Further studies are required, in particular to better understand the mechanisms by which certain bacteria can influence the integrity of our skeleton. This holds out the major hope of one day being able to modulate our gut microbiota to better protect bone health.

In the meantime, time spent outdoors (the sun pushes the body to produce vitamin D, which in turn facilitates calcium absorption), regular exercise, and a balanced diet will all help preserve bone health as you get older.

A number of mechanisms have been put forward to explain a link between the digestive microbiota ¹, from mouth to rectum, and atherosclerosis such as interference with lipid metabolism, inflammation linked to bacterial translocation or bacterial metabolites... However, studies to date have been hindered by multiple limitations (interactions with patient treatments, lifestyle, etc.). These biases have been partly overcome by a Swedish multicenter study involving 8,973 members of the SCAPIS ² cohort aged 50 to 65 with no history of atherosclerosis. Oral and fecal microbiota samples were collected and analyzed, then coronary atherosclerosis was measured using a Coronary Artery Calcium Score (sidenote: Coronary Artery Calcium Score quantitative assessment of the extent of calcified atheromatous deposits on the walls of the coronary arteries, i.e. the arteries of the heart. Higher Coronary Artery Calcium Scores mean greater cardiovascular risk. Source : CHversailles   ) and an angiography. Although asymptomatic, 40.3% of participants had coronary calcification, and 5.4% at least one stenosis with an occlusion exceeding 50%.

64 gut and oral species involved

The composition and diversity of the digestive microbiota were found to be associated with subclinical atherosclerosis. 64 species were associated with the Coronary Artery Calcium Score: 51 were harmful (the strongest associations being observed for Streptococcus anginosus and Streptococcus oralis subsp oralis) while 13 were protective. 

Of the 64 species, 19 were associated with markers of inflammation (C-reactive protein), including streptococci and other oral cavity species, and 16 with markers of infection (neutrophil count). According to the authors, many of these bacterial species (S. anginosus, S. oralis subsp oralis, S. parasanguinis, S. gordonii) are capable of crossing the oral or gut barrier during dental care or due to lesions, and then infecting coronary valves and vessels (infective endocarditis).

From digestive dysbiosis to atherogenesis

The composition of the gut microbiota may also contribute to atherogenesis through the alteration of host metabolism. Gut microbial species common to the oral cavity (e.g. all Streptococcus spp associated with coronary calcification, Rothia mucilaginosa, Bifidobacterium dentium, and Ligilactobacillus salivarius) were associated with lower plasma levels of indole propionate (considered protective against atherosclerosis) and higher levels of microbiota-derived plasma metabolites such as secondary bile acids and imidazole propionate (pro-inflammatory). 

While further longitudinal and experimental studies remain necessary, this work provides evidence of an association between the composition of the digestive system’s microbiota (notably Streptococcus spp and other species also present in the oral cavity), coronary atherosclerosis, and markers of systemic inflammation.

New research ¹ reveals that the age-old adage “an apple a day, keeps the doctor away” also applies to nourishing our microscopic inhabitants - the gut microbiome. Scientists discovered that plant- associated bacteria migrate to and persist within the human digestive tract. This study represents the first evidence for the transmission of plant microbes to the gut via consumption.

Plant microbes hitchhike to colonize gut microbiota

The scientists from The Institute of Environmental Biotechnology ² in Austria performed a sophisticated computational genomic analysis, reconstructing 156 bacterial genomes from fruit and vegetable metagenomic datasets. These microbial DNA sequences served as a reference to detect fresh produce-derived bacteria within publicly available human stool metagenomes. The researchers also examined a longitudinal cohort tracking infant stool samples over three years to assess bacterial persistence.
Researchers were surprised to find common bacterial genera inhabiting both fresh produce and people's intestines. Core plant genera detected in subjects' guts included Enterobacterales, Burkholderiales and Lactobacillales.

Plants seed 2% of total gut bacteria  

On average, nearly 2% of an individual's unique gut bacteria originated from fruits and vegetables. This proportion increased in younger kids and with greater vegetable intake.

Even if this proportion remains low compared to the total bacterial community, these plant-derived bacteria provide essential health components such as short-chain fatty acids, vitamin B12 and vitamin K. Their minority abundance belies a major functional role– supplementing human genes and metabolism.

Finally, the study showed that eating over 10 different plants weekly, compared to less dietary diversity, was associated with heightened gut species richness. Regular vegetable consumption was also linked to a more heterogeneous bacterial community structure.

Soil seeding our microbiome future

As human activity shrinks natural ecosystems and depletes environmental bacteria, dwindling microbial input from fresh produce may have far-reaching public health consequences we have only begun to grasp.

This research spotlights produce's unsuspected significance as vital conduits seeding our gut ecosystem - and suggests plant and soil conservation may "sow" seeds for better global microbiome futures.

We can also argue that diminishing microbial input from intensively farmed, less microbiome-rich produce may have negative public health impacts. This spotlight on fruits and vegetables as vital but vulnerable conduits transmitting environmental bacteria to our guts carries urgent implications for agriculture, conservation, and medicine.

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We've all heard "an apple a day keeps the doctor away." But what if that crunchy fruit is also feeding an invisible world inside you? New research ¹ has uncovered that when we bite into apples, carrots, and other fresh produce, we may be delivering microbes that seed our gut ecosystems, comprising the vast community of bacteria residing in our intestines.

Scientists from The Institute of Environmental Biotechnology ² in Austria have discovered a surprising new link between the fruits and vegetables we eat and the bacteria residing in our intestines. This new research has found that many types of gut bacteria actually originate from fresh produce, migrating to our digestive systems when we eat fruits, veggies and other plant foods.

By examining bacterial DNA, the researchers identified dozens of genera of bacteria that live both on produce and inside human intestines. These microbes make up a small but significant proportion of our gut ecosystems – on average close to 2% of an individual's unique gut bacteria come from fruits and vegetables.

This figure is higher among younger children and people who eat more vegetables. Although relatively few in number, these produce-derived bacteria provide 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. ) , vitamin B12 and vitamin K. 

More Plant Diversity, More Gut Diversity

The study also showed links between produce consumption and gut health. Eating over 10 different types of fruits and vegetables weekly was associated with a greater diversity of gut bacteria compared to a less varied plant diet. People who ate more vegetables tended to have a greater variety of gut microbes.

This is one of the downsides of international travel: among other things, it encourages the spread of antibiotic resistance. As knowledge on the subject is still very patchy (studies on small cohorts, poorly characterized microorganisms, etc.) despite the threat posed by such resistance, a team has screened the microbiota of 267 Americans recruited in 3 clinics (Boston, New York and Salt Lake City) before and after a trip abroad.

Dysbiosis in travelers

The first finding of the study is that travel disrupts the intestinal microbiota, with a significant loss of microbial diversity in 61% of travelers, varying according to destination (from 42% of travelers to Central America to 76% of those who went to South America).

The abundance of Escherichia spp. and several other enterobacteria (Klebsiella, Enterobacter and Salmonella) increases with the acquisition of new strains, while the genus Alistipes virtually disappears. Travel to South Asia increases the risk of returning with an intestinal stowaway, while consumption of unfiltered tap water or prior vaccination against typhus seems to limit it.

When resistance travels

A third of the 267 travelers reported diarrhea and 18% of them were treated with antibiotics.

More significantly, on returning from their trip, 38% of the 267 travelers had acquired at least one of the 3 types of resistant bacteria targeted by this study: of these, 98% acquired extended-spectrum beta-lactamase-producing Enterobacteriaceae (sidenote: Extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae Enterobacteria that produce enzymes (extended-spectrum lactamases) with the ability to hydrolyze and cause resistance to various types of newer antibiotics. Klebsiella pneumoniae and Escherichia coli are the main ones. ESBL-producing Enterobacteriaceae, which make up the majority of multi-resistant bacteria, are responsible for potentially severe infections and prescriptions for broad-spectrum antibiotics. Sources :

Pitout JD, Laupland KB. Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis. 2008 Mar;8(3):159-66. doi: 10.1016/S1473-3099(08)70041-0. Et Vodovar D, Marcadé G, Raskine L et al. Entérobactéries productrices de bêta-lactamases à spectre élargi : épidémiologie, facteurs de risque et mesures de prévention [Enterobacteriaceae producing extended spectrum beta-lactamase: epidemiology, risk factors, and prevention]. La Revue de medecine interne, 34(11), 687–693. https://doi.org/10.1016/j.revmed.2012.10.365 ) (in 98% of cases, E. coli), 18% colistin-resistant Enterobacteriaceae, and 3% carbapenemase-producing Enterobacteriaceae.

And which risk factors encourage the acquisition of such resistance? Visits to friends and relatives, a trip to South Asia and eating raw vegetables. On the other hand, pre-departure intestinal diversity, the presence of a specific bacterial taxon, street food consumption and antibiotic use did not change the situation.

Limiting risks 

Among the types of resistance acquired during travel, fluoroquinolone resistance was particularly noteworthy: more than 1 in 2 travelers (56%) without resistance before the trip returned with at least one gene associated with resistance to an antibiotic in this class. In all, the group of 267 travelers returned to the United States with 72 new resistance genes, 15 of which are of public health concern!

These results call for warnings (especially for the riskiest destinations) and a reminder of good practices (cooked vegetables, hand-washing, etc.). Conversely, modulating intestinal microbiota before the trip (with probiotics, for example) would have no added value in this particular case.

A growing body of research is pointing to the existence of distinct microbiotic signatures for different food allergies. This field of research is helping to position the microbiota as a central player in the development of such allergies. A new longitudinal study published recently in the Journal of Allergy & Clinical Immunology has shed new light on possible links between the onset of a peanut allergy and microbiota.
 
As this allergy generally develops during infancy, the researchers studied the microbiota of children at risk of developing a peanut allergy at the age of 10 months (SD: 3.1), then at 9 years (SD: 0.6). Within this population, 35 (28.7%) of the children developed a peanut allergy before the age of 9.

A different gut microbiota signature from the very first months of life

These 35 children in the PA (Peanut Allergy) group had a less diverse microbiota at inclusion (p=0.014) than the NPA (Non-Peanut Allergy) group. Their microbiota diversified with age, while that of the NPA group remained stable.

At age 9, both groups showed a comparable microbiotic diversity.

At inclusion, the PA group had a higher proportion of Clostridium sensu stricto 1 sp, while Streptococcus sp was more prevalent in the NPA group. By the age of 9, the relative abundance of these two species was normal in both populations. Conversely, the abundance of the Bifidobacterium sp species dropped in the PA group and even became higher in the NPA population.

Allergy development is identified as being associated with altered levels of 139 metabolites in the metabolome (FDR ≤ 0.05). 

These metabolites are associated with a histidine metabolism pathway (FDR = 0.037, pathway impact = 0.28).
Six short-chain fatty acids were studied in particular. The butyrate and isovalerate levels dropped in the PA group, while the isovalerate level remained stable in the NPA group with an increase in butyrate.

Is there a pathophysiological mechanism of peanut allergy?

The authors speculate that the lower microbiota diversity in PA infants may suggest that they have less stable gut communities during this phase of rapid immune system development.

The reduced relative abundance of Bifidobacterium sp, known for its use as an anti-allergy probiotic and for inducing mast cell apoptosis in mice, could also play a role in the development of allergies. 

The authors also note that the micro-organisms present in the gut of children predisposed to developing this allergy species capable of producing metabolites originating from the histidine metabolism pathway, the precursor of histamine, the effector characteristic of allergic reactions.

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Travel is a great way to make memories...including some you'd rather not have! While it's no surprise that a third of the 267 Americans studied who traveled abroad reported diarrhea, it's more worrying that 61% of travelers left some of their protective gut microbial diversity behind. Worse still, many returned with intestinal stowaways (Escherichia and other enterobacteria such as Klebsiella, Enterobacter and Salmonella) and sacrificed their intestinal population of Alistipes on the altar of exoticism.

Bacteria and antibiotic resistance

Some would say it's just a few bacteria! Yes, but many of which are resistant to antibiotics. And therein lies the problem. On their return from abroad, 38% of the 267 travelers had acquired at least one of the 3 antimicrobial (sidenote: Antimicrobials Antimicrobials — such as antibiotics, antivirals, antifungals and antiparasitics — are drugs used to prevent and treat infections in humans, animals and plants. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance  ) -resistant organisms targeted by this study, and above all, 98% of them had acquired vicious enterobacteria (generally E. coli), capable of resisting the effects of many antibiotics and currently representing enemy No. 1 in the fight against antibiotic resistance.

In all, the group of 267 American travelers in this study returned from their 2-week peregrinations abroad with 72 new resistance genes, including 15 of public health concern!

Travel advice

If we don’t want to abandon all thought of travel, what can we do to reduce the risk of importing antibiotic resistance?

Known to be effective in the prevention of traveler's diarrhea ^2,3, probiotics would not have any added value here to prevent bringing home these multi-resistant germs, according to the authors. The study suggests that the composition of one’s microbiota prior to departure has no impact on the acquisition of these resistant bacteria. There's no need to deprive yourself of street food once you're there—it doesn't change anything.

On the other hand, eating raw vegetables seems very risky! Don't let your guard down when visiting family or friends abroad; eat only well-cooked vegetables, peel your fruit and, as at home, wash your hands regularly!

And be particularly vigilant when traveling to South Asia, a destination that goes hand in hand with an increased risk of returning with an intestinal stowaway!

For children, peanut allergy is a common but serious challenge. In Western countries, it affects almost 2% of children. ¹ Symptoms include breathing difficulties, swelling of the throat, diarrhea, nausea, skin rashes, and fainting. These symptoms vary in severity, but the most serious, anaphylaxis – an intense whole-body reaction – can prove fatal. ^2,3 Peanut allergy often manifests itself in early childhood, can be much more severe than other food allergies, and, unlike them, lasts into adulthood in 80% of cases. ¹

A link between the microbiota and food allergy?

What about the gut microbiota? For many years, it has been known that the microbial communities in the gut also play a key role in building the immune system. Recent research even suggests that the gut microbiota may be involved in the development of food allergies. Patients with food allergies present an unbalanced gut microbiota.

So, what happens in early childhood before allergies even appear? Researchers in the US set out to answer this question by analyzing the microbiota of 122 children from infancy to the onset of the allergy. Their aim was to better understand how the allergy develops, with the hope of one day being able to prevent it.

Tell me about your microbiota, and I’ll tell you your future allergy...

The researchers’ first finding was that patients who developed peanut allergy around the age of nine had a poorly diversified gut microbiota during their first months of life. Their microbial communities evolved more dynamically, with a less homogeneous distribution of species compared to the microbiota of children who did not develop the allergy, while their gut flora evolved more continuously and homogeneously over time.

Their second finding was that certain species of the Clostridium genus were more present in infants who did not have peanut allergy, while Streptococcus sp were more present in those who did. By the age of nine, Bifidobacterium, well-known beneficial bacteria, were more present in non-allergic patients.

In addition to the changes in abundance of certain bacteria being different between the two groups of children, the authors observed that the metabolites produced by the microbiota, i.e., the metabolome, were different in the children who developed an allergy. In particular, certain  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. ) , such as butyrate and isovalerate, decreased over time in the children who subsequently developed an allergy. Isovalerate is already known for its protective properties against allergy (asthma and atopy).

The development of peanut allergy was associated with changes in 139 metabolites, and particularly with a pathway for the metabolism of histidine, the precursor of histamine, a bioactive molecule released during allergic reactions.