The disease is linked to aging and affects more than 200 million people worldwide. One of the main pieces of advice from specialists upon diagnosis is to supplement our diet with vitamin D. However, to be useful to our bones, vitamin D must be absorbed by our gut once consumed. After studying this crucial step, a team of Chinese researchers formulated a hypothesis: the gut microbiota plays a key role in this process.

Groundbreaking study on the link between osteoporosis, the gut microbiota, and vitamin D

It all started with a simple observation: patients with severe osteoporosis have low blood levels of vitamin D, which is associated with increased gastrointestinal disorders, suggesting the gut microbiota may be involved in severe osteoporosis. What’s more, previous studies have assessed the gut microbiota’s potential as a diagnostic tool. The team tested their hypothesis on 36 patients who were given the same diet for the duration of the study. Divided into two groups according to the stage of the disease (primary or severe), the patients’ gut microbiota and blood vitamin D levels were examined. This is the first time that the relationship between osteoporosis severity, the gut flora, and vitamin D status has been studied.

Microbiota varies according to severity…

The first finding was that patients with severe osteoporosis have a more diverse gut flora than those with a less advanced form. One key observation was the lower abundance of Bifidobacterium in patients with severe osteoporosis, with this bacterium already known to be involved in the intestinal absorption of certain fats and vitamins.

^{Sources (sidenote: Epidemiology of osteoporosis and fragility fractures_International Osteoporosis Foundation
Kanis, J.A. et al., A reference standard for the description of osteoporosis. Bone 2008. 42: p. 467-75 )}

… as do blood levels of vitamin D

The second finding was that patients with severe osteoporosis have significantly lower blood levels of vitamin D than patients in the primary stage. Since both patient groups received the same diet (and therefore the same amount of vitamin D) for the duration of the study, the difference may therefore lie in intestinal absorption.

Together, these two findings suggest the gut microbiota’s involvement in vitamin D absorption.

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Diarrhea can affect up to 80% of children taking antibiotic treatment.

Since the discovery of penicillin in 1928, antibiotics have been the main weapon in the fight against bacterial infections and have increased life expectancy by almost 20 years, in parallel with vaccinations.²

However, although antibiotics eradicate the pathogenic (sidenote: Pathogen 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. ) bacteria responsible for our infections, they can also destroy some beneficial bacteria in our microbiota causing an imbalance within this complex ecosystem, this is called dysbiosis (sidenote: Dysbiosis Generally defined as an alteration in the composition and function of the microbiota caused by a combination of environmental and individual-specific factors. Levy M, Kolodziejczyk AA, Thaiss CA, et al. Dysbiosis and the immune system. Nat Rev Immunol. 2017;17(4):219-232.   ) .³

This dysbiosis can have consequences for our health, such as bowel transit changes that can lead to antibiotic-associated diarrhea (AAD):⁴ this is moreover the most common side effect of antibiotics in the short term.

It is usually mild and stops by itself after 1–5 days. It can affect up to 35% of patients^4–6 on antibiotics but in children, this figure can reach 80%.⁵

Antibiotics could generate longer-term effects

Antibiotic-associated diarrhea is not the only side effect, the dysbiosis is supposedly responsible for longer-term effects when it occurs very early in life. During the perinatal period, that is the critical time window for the development and maturation of the microbiota and of the immune system,⁷ disruption of the gut microbiota associated with the taking of antibiotics is suspected to increase the risk of several chronic diseases (obesity, diabetes, asthma, chronic inflammatory bowel disease).⁸

In addition, poor compliance with antibiotic treatments (excessive or inappropriate use) is responsible for antibiotic resistance,⁹ meaning that antibiotic treatment is no longer effective against bacterial infection. This phenomenon leads to longer hospital stays, even sometimes deaths, and rising health care costs.

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Colic, allergies, obesity, altered immune development... gut dysbiosis in newborns is associated with a wide range of health problems that may persist throughout life. Despite this, broad-spectrum antibiotics continue to be prescribed at a high rate (up to 10% of all neonates) because of suspected early-onset neonatal sepsis (sEONS).

Randomized trial of three antibiotic combinations 

To better understand the effects of early-life antibiotics, a randomized trial was conducted in 147 infants treated with broad-spectrum antibiotics during their first week of life. The infants were randomized to receive one of three commonly prescribed intravenous antibiotic combinations, namely penicillin + gentamicin, co-amoxiclav + gentamicin or amoxicillin + cefotaxime. Eighty healthy infants (not treated with antibiotics) served as controls.

Diversity down, resistance up

Microbial diversity was similar in all infants before antibiotic treatment, but α-diversity in the treated infants fell dramatically immediately after treatment. Subsequently, their α-diversity slowly recovered, though it remained significantly lower during the first year of life. The composition of the gut microbiota was also impacted. Facultative anaerobic genera such as Escherichia and Staphylococcus were abundant in the first samples collected directly after birth, rapidly followed by Bifidobacterium. Subsequent abundances depended on whether the infant received antibiotics: in treated infants, Bifidobacterium spp., Escherichia, Staphylococcus spp., and Bacteroides were less abundant, while Klebsiella and Enterococcus spp. were more abundant. Lastly, the team observed more antimicrobial resistance genes in the treated children.

Not all antibiotics are the same

Significant differences were observed between the three antibiotic regimes, with the “amoxicillin + cefotaxime” combination having the greatest effect on gut microbiota composition and antimicrobial resistance, and “penicillin + gentamicin” having the least effect. As a result, the researchers suggest that treatment with the latter combination should be reconsidered in neonatal wards where it is not currently popular.

Also known as “the clap” or “drip”, gonorrhea is a sexually transmitted infection (STI) that poses a public health problem for both sexes. In women, it can remain silent (more than 50% of women are asymptomatic) or show symptoms such as purulent discharge, lower abdominal pain or burning urination. The reasons for this difference are not known.

^{Sources (sidenote: https://www.who.int/news-room/fact-sheets/detail/sexually-transmitted-infections-(stis) )}

Neisseria gonorrhoeae to blame

Gonorrhea is caused by Neisseria gonorrhoeae, a very discreet bacterium which, according to one recent study, represents only 0.24% of the bacteria present in the vagina and cervix of infected women (it is obviously absent in uninfected women). The presence of other bacteria in the vagina of infected women varies according to the symptoms.

Gonorrhea: a question of lactobacilli?

In asymptomatic infected women lactobacilli dominate. These rod-shaped bacteria, well known to yogurt lovers, represent more than 92% of the bacteria found in the cervix and vagina of these women. This results in the correct acidification of the vagina, which is thought to keep other microorganisms at bay.

On the other hand, in symptomatic infected women, lactobacilli are depleted, accounting for less than a quarter of the bacteria present (21.2%). Instead of being dominated by these “good” bacteria, the microbiota shows significant diversity and heterogeneity in terms of the microorganisms present. This composition is generally not a good sign for the vaginal microbiota. Unlike the body’s other microbiota (gut, skin, etc.), the vaginal microbiota is healthy when lactobacilli dominate. Furthermore, the bacteria found in the vagina of symptomatic women are not to be desired, since they are frequently associated with bacterial vaginosis.

^{Sources (sidenote: https://www.who.int/news-room/fact-sheets/detail/multi-drug-resistant-gonorrhoea )}

One in 5 pregnancies ends in an early miscarriage (before 12 weeks), and half are caused by chromosomal abnormalities (aneuploid miscarriages). Late euploid miscarriages can occur between 12 and 24 weeks, usually in connection with an infection (2 in 3 cases). Little is currently known about the mechanisms involved, but it is thought that the vaginal microbiota may play a role.

Miscarriages: a question of lactobacilli?

To answer this question, researchers monitored 167 pregnancies: 74 full-term pregnancies, 54 non-genetic miscarriages (euploid pregnancies) and 39 genetic miscarriages (aneuploid). Analysis of their microbiota (16S RNA) revealed the existence of 2 types of vaginal microbiota: the first is 94.2% dominated by Lactobacillus spp. (75% of samples); the second is characterized by a depletion of lactobacilli, with an average concentration of just 18.5% (25% of samples). 

At the same time, compared to aneuploid miscarriages, euploid miscarriages have been shown to be associated with a vaginal microbiota that is:

• richer in bacteria and diversity
• low in Lactobacillus spp. 
• rich in Streptococcus spp. (60% of cases) and Prevotella spp. (40%).

Vaginal microbiota and inflammation

In terms of inflammation, low levels of lactobacilli are associated with high concentrations of cytokines in the vaginal/cervical fluid, regardless of pregnancy outcome. Above all, subgroups dominated by Prevotella or Streptococcus spp. have significantly higher concentrations of TNF-α and of some proinflammatory interleukins (IL-6, IL-8, IL-1β). A depletion in Lactobacillus spp. may therefore be associated with a proinflammatory environment detrimental to the smooth progress of pregnancy. This would be consistent with the higher frequency of miscarriages observed in cases of low levels of vaginal microbiota lactobacilli.

In addition, a high concentration of streptococci is thought to be the most significant risk factor for euploid miscarriages, and the main factor responsible for the increase in proinflammatory mediators in such patients.

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Miscarriage: Every pregnant woman’s nightmare.1 in 5 pregnancies end before 12 weeks due to early miscarriage. Half of these are linked with chromosomal abnormalities (genetic errors). Late miscarriages can still occur between 12 and 24 weeks, and 2 in 3 cases are caused by an infection. However, vaginal microbiota bacteria could prove to be precious allies in preventing miscarriage.

Long live lactobacilli!

Let’s get one thing straight from the start: vaginal microbiota like to do things differently. Unlike other body flora, which benefit from diversity, the vagina is quite monomaniacal; good vaginal health is believed to be closely associated with a very low diversity and high proportion of lactobacilli. Very, very high in fact: in a recent study, these bacteria, recognized easily by their rod shape, accounted for 94.2% of the vaginal flora bacteria in ¾ of the 167 pregnant women monitored... But what about the other women? Their lactobacilli made up only a small percentage of their microbiota, i.e., 18.5% of their vaginal bacteria. Yet this decrease in lactobacillus dominance appears to have serious consequences on pregnancy outcome.

_{Sources (sidenote: Why we need to talk about losing a baby_WHO )}

From vaginal microbiota to miscarriage

Miscarriages that have no genetic explanation are more common in women who have a vaginal microbiota that is:

• richer in bacteria and diversity
• low in lactobacilli (as has already been shown in a previous Chinese study)
• rich in other bacteria, for example streptococci (60% of cases) or Prevotella (40% of cases).

Moreover, this decrease in lactobacillus dominance appears to be associated with more frequent vaginal inflammation. Therefore, it would appear that a lower concentration of lactobacilli goes hand in hand with inflammation of the female reproductive system. As a direct consequence, this creates an environment unfavorable for fetus implantation, and the pregnancy cannot progress normally. This would explain the higher frequency of miscarriages observed when lactobacilli have disappeared. Yet it also creates a glimmer of hope, as vaginal microbiota may be a target of choice for reducing the risk of miscarriage.

We know that B vitamins influence microbial function, host metabolism, and inflammation, and this is particularly so for biotin (B8) produced by gut bacteria. B vitamins are thus involved in the regulation of host metabolic health. Is this also the case in severely obese humans? This is an important question, since previous preclinical and clinical studies have shown altered serum and tissue biotin levels in obese subjects.

Fewer biotin-producing or transporting bacteria

To answer the question, researchers looked at data from 1,545 subjects participating in the multicenter European MetaCardis (sidenote: https://cordis.europa.eu/project/id/305312/fr ) study, comparing 608 severely obese patients (BMI>35) with 299 overweight or obese patients (25<BMI<35), and 638 normal BMI (BMI<25) control subjects. 

They found that severe obesity is associated with a deficiency in bacteria that produce and transport biotin. Since the abundance of these bacteria is correlated with inflammatory status and associated metabolic disorders, this has implications for obese patients. 

Moreover, the severely obese had suboptimal levels of circulating biotin and an altered expression of genes coding for this vitamin in their adipose tissue.

Gut bacteria to blame?

Human to mice microbiota transfer experiments confirm the gut microbiota’s contribution to the level of biotin in the blood. However, diet also plays a role, with the Western diet (sidenote: Western diet Diet rich in processed foods, refined sugar, salt, saturated fats (red meats) and trans fats (pastries) Zinöcker MK, Lindseth IA. The Western Diet-Microbiome-Host Interaction and Its Role in Metabolic Disease. Nutrients. 2018 Mar 17;10(3):365.  ) leading to a decrease in biotin-producing gut bacteria, as well as a reduction in circulating levels of biotin. Furthermore, gut inflammation observed in obese patients paradoxically limits the absorption of biotin from food.

Ultimately, a vicious circle may be at play in the case of severe obesity: the molecular signals of the dysbiotic microbiota could aggravate host inflammation and contribute to a biotin deficiency in tissue.

Therapeutic avenues?

How to break the vicious circle? Bariatric surgery, which improves metabolism and inflammation, promotes biotin-producing bacteria. This leads to an improvement in the host’s systemic biotin. Another avenue is prebiotic (fiber) and biotin supplementation. In mice fed a high-fat diet, these two pathways improved gut microbiota diversity and bacterial production of biotin and other B vitamins, while limiting weight gain and glycemic deterioration. Two avenues that may make a vicious circle virtuous.

World Parkinson’s Day (sidenote: https://parkinsonscare.org.uk/worldparkinsonsday/ ) (April 11) is an opportunity each year for patient associations and health professionals to see how research is progressing on this complex neurodegenerative disease for which there is no treatment to date. This year, discussions will no doubt focus on a new study by a team of Taiwanese researchers. The team wanted to determine whether SCFAs could discriminate between Parkinson’s patients and healthy individuals, and whether there was a correlation with disease severity. To do this, they analyzed plasma and fecal levels of several subtypes of SCFAs in addition to the gut microbiota of 181 participants (96 patients and 85 controls). They also studied the motor and cognitive effects of the disease. The study results were published in Neurology in early 2022.

Different fecal and plasma SCFA levels in Parkinson’s patients 

In Parkinson’s patients, the results showed reduced fecal SCFA levels compared to healthy individuals (butyric acid, valeric acid and propionic acid), whereas plasma levels were higher. 
Another takeaway: fecal quantities of the same SCFAs were lower in patients with advanced Parkinson’s disease compared to patients in the early stages of the disease.

Correlation between SCFA levels and symptom severity 

Fecal and plasma concentrations vary depending on the severity of motor and cognitive symptoms. 

More severe motor impairment is correlated with a low fecal concentration of most SCFAs, coupled with an increased plasma propionic acid concentration.

More serious cognitive symptoms are associated with lower fecal levels of butyric acid and higher plasma concentrations of butyric acid and valeric acid.

Link between the composition of patient microbiota and SCFAs

The study showed that microbial diversity in Parkinson’s patients differed from that in healthy patients. This study highlights the correlation between SCFA concentrations and the abundance of pro-inflammatory bacteria (Clostridiales and Ruminococcus), particularly in the case of propionic acid. This supports the hypothesis that gut inflammation is associated positively with disease aggravation.

This method was recently shown to be a simple and direct way to measure the gut transit time. It means how long the food takes to pass throughout our gastrointestinal tract, from eating to evacuation, and it is usually assessed to evaluate gut motility, which is a key component of gut health. In a recent study [1] by Asnicar and colleagues, published in Gut, authors evaluated the blue dye method as a marker of gut transit time, and its association with specific health markers (including stool consistency and frequency, gut microbiome composition and function, and cardiometabolic health) in 863 healthy individuals.

First, they found that harder stool consistency, measured with British Stool Chart, is associated with a longer gut transit time (>5 days median for type 1), while softer consistency corresponds to shorter gut transit time (1 day median for type 6).

Moreover, they also found that gut transit time is associated with several features of gut microbiome. Alpha diversity, which is a marker of microbial health, was positively correlated with gut transit time. Longer transit time was associated with specific microbial taxa, including Akkermansia muciniphila (a beneficial strain with favorable metabolic properties), Bacteroides spp. and Alistipes spp. Generally, gut transit time was associated with gut microbiome features more than stool consistency or stool frequency.

Finally, longer transit time was associated with visceral fat mass and postprandial lipid and glucose responses (both cardiovascular risk factors).

In conclusion, blue dye method appears to be a simple and inexpensive marker of gut transit time, which was found to be associated with markers of human health, including gut microbiome diversity and composition, and specific cardiovascular risk factors. It could be a reliable method to evaluate gut transit time when needed, i.e. in patients with constipation). The way this procedure is being diffused (viral expansion through social media) suggests that lots of patients will require this testing to physicians. As for all patient- driven examinations, I would first recommend a visit with a health professional with expertise in digestive disease to avoid the DYI approaches. Then, if the physicians confirm the need of a gut transit time test, then the blue dye method would be a reliable and cheap one.

Future evaluations, including comparisons with other methods of gut transit assessment, are needed to confirm these results and allow a large-scale positioning of this tool into the diagnostic armamentarium of GI and nutritional disorders.

PROFILING THE VAGINAL MICROBIOTA TO PREVENT PRETERM BIRTH

^{Pruski P, Correia GDS, Lewis HV, et al. Direct on-swab metabolic profiling of vaginal microbiome host interactions during pregnancy and preterm birth. Nat Commun. 2021 Oct;12(1):5967.}

Predicting the risk of preterm birth using a simple, rapid, and inexpensive method is a challenge for obstetricians, who still lack a reliable predictive method for this clinical complication, the leading cause of death in children under the age of five. The risk factors are well known: vaginal dysbiosis associated with local inflammation. A team of researchers had the idea of using their recently-described DESI-MS (Desorption Electrospray Ionization Mass Spectrometry) analysis method to identify – in less than 3 minutes and without the need for sample preparation – the metabolites present in the cervicovaginal mucosa. Their hypothesi,s? The metabolome thus characterized may make it possible to predict the composition of the vaginal microbiota and local immune and inflammatory responses, and to monitor their development towards states associated with the risk of preterm birth. DESI-MS was used to analyze more than 1,000 cervicovaginal samples from 365 pregnant women in two cohorts.

Among the metabolites detected, 113 made it possible to effectively distinguish between two types of microbiota: one depleted and the other dominated by lactobacilli, a marker of good vaginal health. The metabolic profile obtained using DESI- MS also predicted the levels of several immune markers (IL-1β, IL-8, C3b/iC3b, IgG3, IgG2, MBL – Mannose-Binding Lectine) measured in a subgroup of 391 women. Some of these (C3b, IL-1β, IgG2, IgG3) were found at high levels in Lactobacillus- depleted vaginal microbiomes, indicating activation of the local innate and adaptive immune response. In a final series of tests, the metabolic vaginal profile obtained using DESI-MS could not reliably predict the direct risk of preterm birth. However, the researchers foresee potential clinical applications. Monitoring vaginal metabolites using DESI- MS could help detect changes in the vaginal microbiota and local immune markers associated with preterm birth.