Recognized by the World Health Organization, fibromyalgia is characterized by generalized chronic pain, fatigue and sleep disorders. This pathology, which mainly affects women, is often difficult to manage due to a lack of diagnosis or appropriate treatment. A recent cross-sectional study might nevertheless give some hope: it looked at the role of the gut microbiota of fibromyalgia patients, and more specifically at certain bacteria producing secondary bile acids (SBAs).

A dysbiotic gut microbiota

The researchers thus closely examined the gut microbiota (stool samples) and circulating SBAs (blood samples) of 42 Canadian women suffering from fibromyalgia and 42 controls. They observed alterations in the relative abundance of several bacterial species involved in SBA metabolism in these patients: reduced presence of Bacteroides uniformis and B. thetaiotaomicron, known to synthesize an SBA called α-muricholic acid; depletion also of Prevotella copri, a bacterium that affects SBA synthesis and the expression of FXR, a hepatic nociceptor; increased abundance of Escherichia bolteae and Clostridium scindens capable of affecting the metabolism of other SBAs.

SBA alterations

This gut dysbiosis was accompanied by significant alterations in the serum SBA concentration, in particular α-muricholic acid, with levels on average 5 times lower in fibromyalgia patients. Furthermore, this depletion was correlated with pain intensity and fatigue. Thus the decrease in serum SBA levels, and in particular that of α-muricholic acid, could disrupt the normal pain inhibition mechanisms. The authors suggest a mode of action: the decrease in circulating levels of α-muricholic acid (inhibitor of the FXR receptor) and the possible increase in excitatory SBAs could lead to the activation of the FXR receptor, leading to hypersensitivity to pain.

^Sources

An objectified diagnosis in the pipeline?

A direct consequence of these observations is the possibility of detecting people with fibromyalgia on the sole basis of the concentration of these serum SBAs. This is a major step forward since diagnosis is currently based solely on subjective measurements. The model developed by the authors shows an accuracy of 91.7%, with a specificity of 90.5% and a sensitivity of 92.9%. Enough to fuel the hope of a future diagnostic tool.

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A recent article may put an end to misdiagnosis for thousands of women suffering from fibromyalgia, a disease characterized by chronic diffuse pain combined with intense fatigue and various issues, including sleep and mood disorders. There are no “markers” for making a diagnosis, such as a lesion in the body (unlike a fracture of the tibia, confirmed via a simple X-ray) or a laboratory parameter (unlike blood sugar levels, which indicate diabetes). This directly affects the quality of life of fibromyalgia patients.

Fibromyalgia: focus on 5 bacteria

New research may mark a turning point. Starting point: studying the differences between the gut microbiota compositions of 42 fibromyalgia patients and 42 other healthy women. Result: of the 16 various bacterial families present in the women with fibromyalgia, three were low while two others seemed quite high. Now, these 5 bacterial species have one thing in common: they transform molecules called primary bile acids (sidenote: Bile acids Bile acids facilitate digestion and absorption of lipids in the intestine. They also exercise hormonal functions and are involved in various metabolic processes. The gut microbiota will modify the bile acids. In return the various bile acids will have an impact on its composition. Staels B, Fonseca VA. Bile acids and metabolic regulation: mechanisms and clinical responses to bile acid sequestration. Diabetes Care. 2009;32 Suppl 2(Suppl 2):S237-S245.  Li R, Andreu-Sánchez S, Kuipers F, Fu J. Gut microbiome and bile acids in obesity-related diseases. Best Pract Res Clin Endocrinol Metab. 2021;35(3):101493.  ) into secondary bile acids (SBA).

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Furthermore, the authors observed differences in the concentrations of certain SBAs in the blood of patients suffering from fibromyalgia – e.g., α-muricholic acid levels were on average 5 times lower in women with this condition! In addition, the lower the α-muricholic acid levels, the greater the pain, fatigue and symptom severity scores. In short, there is a link between an intestinal imbalance and the blood levels of a specific bile acid, which are in turn associated with symptom severity in patients with fibromyalgia.

So can we expect a diagnostic test in the near future?

As a direct consequence of these observations, it may be possible to simply measure the concentration of these small acids, by means of a blood test, to accurately detect people suffering from fibromyalgia. This would enable us to objectify diagnosis of this disease. The model developed by the authors seems promising, showing accuracy of 91.7%. This is enough to raise hopes of a reliable diagnosis becoming available in the future, putting an end to the ordeal for thousands of women.

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Atopic dermatitis (AD) is a complex and multifactorial inflammatory skin disease in which genetics (abnormalities affecting the gene coding for filaggrin, a protein involved in the skin barrier), the immune system, and microbes play a role. For example, the skin of AD patients generally has an increased abundance of Staphylococcus aureus. But what about fungal communities? A recent study¹ has shed some light on this little-known area.

Less Malassezia in severe atopic dermatitis cases

Skin swabs were taken from 16 AD patients (9 cases of mild-to-moderate AD, 7 cases of severe AD) and 16 healthy individuals at four skin sites (antecubital crease, dorsal neck, glabella, and vertex). To observe the course of the disease, the AD patients were sampled at three time points (weeks 0, 2, and 4) and the controls at two time points (weeks 0 and 4).

An analysis of the 320 swabs showed that the Malassezia fungus (particularly the species M. restricta and M. globosa) predominated in all subjects, whether healthy or ill. However, in patients suffering from severe AD, this dominance was reduced in favor of fungi such as Candida or Debaryomyces, resulting in greater fungal diversity.

As for bacteria, AD was characterized by lower levels of Cutibacterium and a greater relative abundance of Staphylococcus, particularly S. aureus and S. epidermidis. A higher presence of S. aureus may favor the proliferation of Candida, a synergistic activity between the two microorganisms having previously been shown. 

Lastly, no changes in the fungal or bacterial microbiota were observed over the four weeks, regardless of the skin site.

Linked to AD severity

The study also showed a link between skin dysbiosis and the severity of AD: the bacterial and fungal communities of patients with severe AD differed significantly from those of controls and patients with mild-to-moderate forms of the disease. The skin communities of the latter two groups (mild-to-moderate AD and controls) were similar overall, with some distinctions in the bacterial communities (more staphylococci and less cutibacteria in mild-to-moderate AD versus no AD). Thus, a pronounced dysbiosis of the microbiota is characteristic of severe forms of AD, but not of less severe forms.

Dry and itchy skin, red plaques (especially in the folds) that appear in flares: atopic dermatitis (AD) is an inflammatory skin disease that affects nearly one in five infants. Although AD tends to improve with age, it is estimated that one in ten adults suffers from the disease in developed countries.

Why my child and why me? Many factors are involved, with both heredity (children of adults affected by AD are more likely to suffer from the disease) and the immune system playing important roles. Another key factor is the skin microbiota, the complex community of microorganisms (sidenote: Microorganisms Living organisms that are too small to be seen with the naked eye. They include bacteria, viruses, fungi, archaea and protozoa, and are commonly referred to as “microbes”. What is microbiology? Microbiology Society. ) (bacteria, fungi, parasites, and viruses) residing on our skin.

Malassezia depleted

In AD patients, some bacteria, such as Staphylococcus aureus, tend to be overrepresented, while others, such as Cutibacterium, are depleted. And what about microscopic fungi? There was no clear answer to this question until a recent study showed that the skin’s fungal flora differs in cases of severe dermatitis. Thus, while the Malassezia fungus predominates on healthy skin, it loses its prime position in AD patients. In its place, other fungi such as Candida or Debaryomyces make themselves at home. In other words, in cases of severe dermatitis, where Malassezia no longer dominates the skin fungi, there is greater fungal diversity.

Moreover, changes in the bacterial and fungal populations may be linked. For example, an increased abundance of S. aureus may favor the proliferation of Candida, as these two microorganisms have been shown to exhibit a synergistic activity.

Linked to AD severity

This skin microbiota imbalance (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.   ) appears to be linked to the severity of AD. With a few exceptions, the skin microbiota of patients suffering from non-severe AD is similar overall to that of individuals with healthy skin. On the other hand, the researchers found a strong divide between patients suffering from severe AD and those with healthy skin or mild-to-moderate AD. One important reason for this is lower levels of Malassezia.

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On the occasion of the World AMR Awareness Week organized each year by the WHO, the Biocodex Microbiota Institute makes a full review.

Antibiotics: how do they impact our microbiota?

Antibiotics: what are the long-term effects on our health?

Antibiotics: why is antibiotic-associated diarrhea under the spotlight?

Antibiotics: what is "antibiotic resistance"?

Antibiotics: can we protect our microbiota?

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Today, we speak of the "intestine-liver axis". Originating from the same germ layer, the liver and intestines are indeed connected at the anatomical and functional level, in particular through biliary secretion and the hepatic portal system. Furthermore, there is mounting evidence of an association between hepatitis B and alterations in the composition of the gut microbiota. However, no study had explored these changes as the disease progresses from chronic to cirrhosis to hepatocellular carcinoma.

A team therefore conducted a systematic meta-analysis of 16S sequencing results (from public databases) from fecal samples collected from HBV-infected patients at all stages of liver disease. Signatures of eventually identified microbiota were then validated in independent cohorts (23 chronic hepatitis B patients, 20 cirrhotic patients, 22 patients with hepatocellular carcinoma and 15 controls).

^{Sources (sidenote: Hepatitis B WHO (2017) )}

Microbiota signatures as a function of progression 

The researchers identified 13 bacterial genera that differed at each stage of liver disease, consistent between public data sets and validation cohorts. While the genera Monoglobus and Colidextribacter were more present in healthy controls, species belonging to the family Lachnospiraceae were specifically increased in chronic hepatitis B while Bilophia were reduced. The genera Prevotella and Oscillibacter were decreased in cirrhosis, Coprococcus and Faecalibacterium in hepatocellular carcinoma. According to the authors, these results indicate a decrease in key taxa of the gut microbiota at each stage of the disease, and an increasingly pronounced dysbiosis as the disease worsens. 

Their analyses corroborate the results of previous studies: Monoglobus, Colidextribacter and Bilophila were associated with protection against inflammation and/or liver damage and Prevotella and Oscillibacter were found to be decreased in severe alcoholic hepatitis. In addition, Coprococcus and Faecalibacterium produce butyrate, the depletion of which is thought to alter intestinal permeability and increase translocation of cancer-promoting bacteria.

New non-invasive biomarkers?

The use of these 13 bacterial genera reveals a diagnostic power to distinguish all stages of the disease, with varying degrees of accuracy (confirmed on data from databases and independent cohorts). These microbial signatures could serve as biomarkers for non-invasive monitoring of hepatitis B, according to the researchers, but also contribute to the development of therapies based on the gut microbiota.

What is your opinion regarding the hypotheses of researchers, suggesting that microplastic exposure may be related to IBD process or that IBD exacerbates the retention of MPs?

Up to 71% of patients with inflammatory bowel disease (IBD) believe diet affects symptomatology and 81% follow elimination diets while in remission. However, current dietary recommendations are confusing and contradictory. In this study by Dr Yan et al. [1], authors raised the provocative hypothesis that microplastics (MP) may contribute to the development of IBD. MP are small plastic particles (<5 mm diameter) and considered a major environmental problem due to the overuse of plastics nowadays. MP are widely distributed, easily ingested with our diet, or even inhaled, and may accumulate in various organs due to their small sizes and low rate of degradation. Although preclinical studies have suggested the adverse events of MP on metabolic disorders and inflammation, their impact on human health hasn’t been fully investigated yet. Here, authors collected feces of healthy and IBD patients and analysed the concentration of MP. Authors showed a higher concentration of fecal MP in IBD than healthy. Intriguingly, the concentration of MP positively correlated with the disease severity, suggesting MP as potential triggers of clinical activation in IBD while providing a potential link between diet and inflammation. Indeed, authors reported that patients with a higher abundance of fecal MP consumed more plastic-packaged products. Although it has been suggested that MP could pass through the intestinal barrier into the circulatory system and potentially impact health, the results are very preliminary and more information is needed before taking premature conclusions affecting patients. Independently of the impact on gastroenterology, this study highlights the global concerns regarding the large use of plastics nowadays, the implications it may have for human health through the food chain but also through commodities and agricultural products, and the pressing need of reducing plastic use.

What would be your advice to patients suffering IBD regarding the microplastic exposure?

Results need to be taken with caution and more research is required to understand the reported increase of faecal MP in IBD and the implications for clinical severity. Although dietary consumption seems to be the most plausible hypothesis, multiple demographic, methodological or clinical factors could be explaining this increase. It would be of interest to see whether these observations apply to countries other than China, where IBD is on the raise. IBD patients also present with an altered gut microbiome, absorption, permeability and motility, as well as different stool consistency, all factors that can influence MP excretion. Indeed, the gut microbiome is a complex and diverse ecosystem presenting microbes with the capacity to digest different components including MP, and IBD patients present an impaired microbiome. In addition, patients frequently consume different drugs or bioproducts (vitamins, probiotic, etc) to manage their symptoms and this could also indirectly affect faecal MP.
Finally, diet affects symptomatology in IBD and there is the wrong impression that ultraclean foods which are frequently plastic-packaged or bottled (e.g. the increase use of bottled water in the last decades), are beneficial. Thus, dietary choices by patients could potentially include more plastic-packaged food. My advice to patients is adhering to traditional and well-tolerated diets, preferring home-prepared and natural foods, and avoiding both ultra-processed and plastic- packaged foods. Reduction of plastic is also good for taking care of our planet!

THE VIROME

Pr. Dennis Sandris Nielsen introduced us to the virome, a collection of viruses that we carry, which is an emergent research field that appears to play an important role in human health and disease. Faecal sample analysis shows that approximately 6% of the found DNA is not of bacterial, but of viral origin. For every bacteria in the human body, a virus matches it. Like the microbiome, the virome is influenced by pre-, peri- and postnatal factors (diet, environment, siblings, medication, etc.). Those viruses are thus omnipresent in the gut and play a key role in the regulation of the gut microbiome. Bacteriophages are a type of viruses that attack bacteria in a host specific matter. Two different types of interactions are described: “kill-the-winner dynamics” and “piggyback-the-winner dynamics”. In the first, the bacteriophages attack the bacteria, inject its DNA and use the bacteria as a host to create new phage particles after the cell is lysed. The speaker makes an analogy with lions and gazelles in the Savannah, meaning constant-diversity dynamics, destruction of niche competitors, phage shunt and bacterial turnover and pressure on host for diversification of the phage receptor. In the latter, the virus rides with the winner, by integrating its DNA in the genome of the bacteria, altering the host cell and making it more efficient, thus making the winner a winner. A study on faecal samples of a healthy infant population in Denmark identified more than a 10.000 viral species, belonging to 248 viral families. Remarkably, 232 of those families were not previously described, supporting the hypothesis that only the tip of the iceberg has yet been discovered [1]. The questions that are raised is what implication it has on human health, and if it plays a role in immune system maturation. Gut virome imbalance might play a role in disease development (i.e. VEO-IBD, NEC, etc.).

C-SECTION AND MICROBIOME

The mode of delivery at birth plays a key-role in the early shaping of the gut microbiome. Babies that are born vaginally are exposed to different bacterial strains compared to those delivered by C-section, with different colonization as a consequence. In addition, the reason for a C-section is more than often due to a foetal emergency. Those babies are more likely to have a low pH on cord blood, which causes a reduction in tight junction permeability promoting dysbiosis.

Breastfeeding seems to counteract the deleterious effect of C-section on the microbiota and remains the golden standard in infant nutrition. However, women who deliver by C-section are less likely to breastfeed, or delay breastfeed initiation, and infants are then formula fed. For this reason, researchers are constantly looking for the perfect cocktail of pre-, pro-, syn- or postbiotics to mimic the gut microbiome of a breastfed infant.

Dr Eduardo López-Huertas discussed a strain of Lactobacillus fermentum and showed promising results in infants delivered by C-section. In a randomized controlled trial (RCT), they analysed the stool samples of infants fed with a symbiotic formula containing L. fermentum and GOS and found major resemblances to the samples of breastfed infants (higher bifidobacteria, lower faecal pH) [2]. Furthermore, it is shown in a recent meta-analysis (3 trials) that L. fermentum reduces the incidence of gastrointestinal infections with 73% in C-section born infants. More research is needed to investigate possible advantages in potential disease prevention, i.e., gastrointestinal tract or respiratory tract infections, especially in C-section born babies, that have a disadvantageous gut microbiome [3].

HMOS IN INFANT FORMULA AND THE MICROBIOME

Dr. Giles Major provided us with his insights in the link between glycans and the gut microbiome. Glycans or human milk oligosaccharides (HMOs) affect the overall gut microbiome composition. Mother milk consists of many different HMOs that vary in concentration in breastmilk depending on the ethnicity of the mother and during the infant’s growth. When the gut microbiome at an early age is investigated, we notice a predominance of bifidobacteria in breastfed compared to formula fed infants. These bifidobacteria are important as they take up carbon and produce short-chain fatty acids that modulate the gut barrier permeability. Their carbon-source are HMOs, and the microbiome plays a role in the digestion of those HMOs trough the presence of CAZymes. Thus, the CAZymes you have, will determine which glycans you can digest and the type of glycans a child is fed will steer the microbiome maturation trough early-life.

A RCT is conducted where a control group of formula fed infants was compared to test groups who received a 5-HMO-Blend formula. The trial is still ongoing, but preliminary results show that the overall gut microbial diversity was significantly different in the control group compared to the test group, where in the test group the composition became more similar to the breastfed infants. The speaker suggests this could be the consequence of promotion of bifidobacteria, although this was just a speculation.

A HISTORY OF VICIOUS PARTNERSHIP

Viral infections are known to precipitate bacterial co-infections. The majority of deaths in the 1918 influenza pandemic were directly attributable to secondary bacterial pneumonia [1]. Furthermore, severe clinical outcomes during the 2009 H1N1 influenza pandemic were associated with bacterial co-infections [2]. The challenge of viral-bacterial copathogenesis during infectious disease outbreaks can significantly complicate the global response, retard recovery, and accelerate antimicrobial resistance. Fortunately, findings from a multicentre cohort study of nearly 50,000 patients revealed that few bacterial infections were reported in patients hospitalised with Covid-19 [3]. However, it should be noted that diagnosing co-infections is complex, as the organisms might present prior to the viral infection; as part of an underlying chronic infection; or may be contracted nosocomially [4].

THE ORAL MICROBIOTA: FROM EUBIOSIS TO DYSBIOSIS

The oral cavity and upper respiratory tract harbour a high and richly diverse bacterial load. In health, the oral microbiome maintains a finely-tuned, harmonious relationship but small changes in routine behaviours can cause substantial ecological shifts in this symbiosis. Poor oral hygiene can render the environment pathogenic, transitioning the microbiome into a state of dysbiosis, where the conditions for disease processes are enhanced [5, 6].

Periodontal disease – chronic inflammation of the gingiva (gums) – is primarily mediated by the inflammatory components within the biofilm and alters the architecture of the gingival tissues to present micro-ulcers. These form a communication between the oral cavity and the blood, which leads to routine activities (e.g. chewing, flossing, and tooth brushing) inducing bacteraemia. Oral bacteria and inflammatory mediators are then disseminated widely via the blood, reaching vital organ systems. Evidence shows that exposure to bacteraemia can be significantly damaging and contributes to a low-grade systemic inflammation precipitating inflammatory conditions [5]. Moreover, periodontitis is known to be an aggravating factor in the incidence of type II diabetes and oral microbiota dysbiosis is involved in both periodontal and metabolic disorders (cardiovascular diseases, dyslipidaemia…) [7].

ORAL DYSBIOSIS AND COVID-19 SEVERITY, IS THERE A LINK?

Research on this association is limited, but the few studies that do exist point towards intriguing connections. A double-blinded cross-sectional study of 303 PCR-confirmed Covid-19 patients in Egypt investigated the interplay between three factors: 1) oral hygiene; 2) the severity of Covid-19; and 3) the C-reactive protein (CRP) values. CRP is a marker of hyper-inflammation, hence patients with high levels of CRP were hypothesised to have a poorer prognosis with COVID-19 [8]. The researchers found that poor oral health was correlated to increased values of CRP and delayed recovery period.

A (unmatched) case-control study of 568 patients in Qatar found that periodontitis was associated with severe COVID- 19 complications, including a 3.5 times increase in the need for a ventilator; a 4.5 times increase in the risk of intensive care admission; and an 8.8 times increase in the risk of death [9]. Although these results do not suggest causality and other factors may be implicated, the associations are stark and warrant further questions around the true role of oral dysbiosis on Covid-19 outcomes.

This largely hypothesised relationship is based on a number of factors that have shared relevance in the pathophysiology of SARS-CoV-2 infection and periodontitis. For instance, pulmonary radiological evidence of primary vascular pathological processes suggests an oral-vascular- pulmonary axis forming a direct route of infection, in addition to direct vascular delivery to the pulmonary vessels (Figure 1) [10]. Secondly, metagenomic analyses have determined that the upper respiratory tract – a key initial anatomical site of infection – is high in bacterial species implicated in oral diseases, and the role of the oral cavity as a natural viral reservoir. Thirdly, adequate viral survival within the sub-gingival biofilm and the ability for viral translocation from saliva to the periodontal pocket – both contributing towards an evasion of the host immune response. Fourthly, the abundance of angiotensin-converting enzyme 2 receptors on key components of the oral-vascular-pulmonary axis.

GOOD ORAL HYGIENE

Regardless of the precise nature of oral microorganisms implicated in the pathophysiology of Covid-19, good oral hygiene should be encouraged for the known benefits to oral and general health. Scrupulous toothbrushing twice daily, interdental cleaning and use of an adjunctive mouthwash are relatively simple measures that will disturb the biofilm, maintain a symbiotic flora and decrease the salivary viral concentration.