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.

GONORRHEA IN WOMEN: A LINK BETWEEN VAGINAL MICROBIOTA AND SYMPTOMS?

^{Lovett A, Seña AC, Macintyre AN, et al. Cervicovaginal Microbiota Predicts Neisseria gonorrhoeae Clinical Presentation. Front Microbiol 2022; 12: 790531.}

Each year, nearly 90 million cases of gonorrhea are reported worldwide. In women, infection of the lower genital tract by Neisseria gonorrhoeae has highly variable consequences, from no symptoms at all to cervicitis. Although the factors behind this variability are not known, the cervico-vaginal microbiota may be involved. In fact, a team has recently shown that the cervico- vaginal microbiota predicts the clinical presentation of gonorrhea in women.
These are the results of a pilot study in the US on 19 patients infected with N. gonorrhoeae, 10 of whom were symptomatic and 9 asymptomatic. Most of these patients were African American, a population whose microbiota is more frequently low in lactobacilli than that of Caucasian women. Neisseria spp. accounted for only 0.24% of the bacteria present in all 19 patients, whether symptomatic or asymptomatic. Half of the patients in each group also had co-infections with Chlamydia trachomatis and/or Trichomonas vaginalis.
The cervico-vaginal microbiota of the asymptomatic patients with no co-infection more frequently contained microbial communities dominated by lactobacilli (92.2% of bacteria on average) than that of the symptomatic patients with no co-infection (21.6%).
In contrast, the symptomatic women had microbial communities characterized by more diverse and heterogenous bacterial taxa. They were composed of a mixture of anaerobic bacteria associated with bacterial vaginosis (BV): Prevotella, Sneathia, Mycoplasma hominis and Bacterial Vaginosis- Associated Bacterium-1 (BVAB1) / Candidatus Lachnocurva vaginae.
These results are merely those of a pilot study based on a small sample. This is a crucial first step, but further studies are needed to evaluate the potentially protective effect against N. gonorrhoeae infection of a Lactobacillus-dominated vaginal microbiota.

CROSS-COHORT GUT MICROBIOME ASSOCIATIONS WITH IMMUNE CHECKPOINT INHIBITOR RESPONSE IN ADVANCED MELANOMA 

^{Lee KA, Thomas AM, Bolte LA, et al. Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Nat Med 2022; 28: 535-44.}

Immune checkpoint inhibitors (ICIs) have significantly improved the treatment of advanced melanoma. However, not all patients respond to the treatment, which has been thought to be linked to the gut microbiota. Lee et al. performed metagenome shotgun sequencing of fecal samples from five European ICI-naïve cohorts, with a total of 165 advanced cutaneous melanoma patients. Due to clinical and mutational differences between the cohorts, they were analyzed separately and not pooled. The authors found a significant difference in the gut microbiota composition between responders and non-responders in the PRIMM-UK cohort, but not in the PRIMM-Netherland (NL) cohort. Further, by analyzing publicly available databases (n = 147 metagenomic samples), it became evident that there was limited reproducibility of response predictions across cohorts. No single bacterium was an entirely constant biomarker of response to ICIs across all datasets. However, a panel of microbial species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, was identified in the study associated with responders. Regarding the functional genes of the microbiota, e.g., DNA adenine methylases were increased in the responders. In conclusion, though a potential panel of microbial biomarkers showing the responsiveness to ICI treatment was identified, future studies in larger cohorts are needed. In addition, several clinical factors should be considered as confounding when evaluating the biomarkers that may be useful in diagnostics

INTESTINAL AKKERMANSIA MUCINIPHILA PREDICTS CLINICAL RESPONSE TO PD-1 BLOCKADE IN PATIENTS WITH ADVANCED NON-SMALL-CELL LUNG CANCER

^{Derosa L, Routy B, Thomas Am et al. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer. Nat Med 2022; 28: 315-24.}

Many patients with non-small-cell lung cancer (NSCLC) do not respond to the treatment with immune checkpoint inhibitors (ICIs), such as anti-PD-1. Recent evidence shows that certain members of the gut microbiota, especially Akkermansia muciniphila, can influence the efficacy of ICIs in patients with NSCLC. In addition, the treatment resistance has been associated with lower inflammatory tumor microenvironment. Derosa et al. prospective, multicentric study included 338 patients with advanced NSCLC treated with ICIs to determine whether the gut microbiota metagenome profiles could explain the treatment response. They show that higher Akkermansia abundance in the baseline feces was associated with higher response rate to the ICI treatment, associated with clinical benefit (increase in survival). In addition, the presence of Akkermansia associated with other potentially prognosis- relevant shifts in the gut microbiota. Several differentially expressed tumor genes were linked to the response to PD-1 blockade suggesting that Akkermansia could promote migration of T helper cells to the tumor microenvironment. To ultimately show that Akkermansia could rescue the ICI resistance, the authors inoculated two different strains of A. muciniphila to mice that were previously transplanted with feces of a patient with resistance to PD-1 blockade. Compared to the control mice, the two strains rescued the treatment response. By far, this study is the largest metagenomics prospective analysis that has validated Akkermansia as a potential prognostic factor for ICI-treated NSCLC patients and showed the mechanistic potential of Akkermansia.

FAECAL MICROBIOTA TRANSPLANTATION FOR BIPOLAR DISORDER: A DETAILED CASE STUDY

^{Parker G, Spoelma MJ, Rhodes N. Faecal microbiota transplantation for bipolar disorder: A detailed case study. Bipolar Disord 2022 (ahead of print).}

The only validated indication for FMT is recurrent Clostridioides difficile infection, However, the involvement of gut microbiota in numerous other diseases (Parkinson disease for example) suggests that indications for FMT could soon be expanded.Gut microbiota can also modify numerous depression-associated processes, such as hypothalamic- pituitary-adrenal gland axis. So far, there are no published trials using FMT to treat patients with bipolar conditions. The longitudinal study by Parker et al. presents the case of a 28-year-old male with bipolar disorder. At the age of 10, he developed depressive episodes. Symptoms included a severely depressed mood, suicidal thoughts, anergia, impaired concentration, psychomotor retardation, and insomnia. The symptoms were commonly associated with irritability and anxiety. At the age of 15, he developed his first hypomanic episode. For years, he was successfully treated with drugs, but then mood problems occurred again. He voluntarily started taking probiotics (strains of Lactobacillus and Saccharomyces. After the probiotics, he self-reported a huge relief of symptoms. Encouraged by the improvements, the patient read on microbiome research and elected to trial FMT. This procedure was performed via colonoscopy by a gastroenterologist. After the FMT, he charted his mood states for 470 consecutive days. He self-reported that mood episodes decreased in frequency and severity over the months. He was also able to reduce the drug treatment significantly. Twelve months after FMT, he stated having distinct highs, virtually no bipolar symptoms, and attention deficit hyperactivity disorder symptoms had improved. Though this is only a case study, FMT was able to reduce the bipolar symptoms, thus warranting the need for FMT studies in larger bipolar cohorts.

WHAT DO WE ALREADY KNOW ABOUT THIS SUBJECT?

Neurodevelopment disorders are frequent in young children, affecting up to 8.4% of individuals under 5 years of age worldwide. Head circumference growth (HCG) is a marker correlated with early neurodevelopment.

It is important to seek environmental factors which could be modified to reduce neurodevelopment disorders. Interventional nutrition studies have failed to show significant results on neurodevelopment (e.g.: the benefit of breast feeding). The authors investigated the gut microbiome (GM) because its acquisition during the first months of life and the use of antibiotics during the first year are associated with various pathologies including neurodevelopment disorders later in childhood, in particular attention deficit hyperactivity disorder and autism spectrum disorder. The study objective was to determine whether there is a relationship between the characteristics of the early GM and a suboptimal trajectory of the HCG (SHCGT).

WHAT ARE THE MAIN INSIGHTS FROM THIS STUDY?

Infants of < 37 weeks postmenstrual age (Chicago neonatal care unit) were included between January 2010 and December 2018. HCG trajectory was the difference between head circumference z-scores measured at birth and at 36 weeks postmenstrual age (PMA); 0.5 z-score interval losses were used to define the groups having an appropriate HCG trajectory (AHCGT) or a suboptimal trajectory (mildly, moderately and severely impaired, SHCGT).

The β diversity of the GM differed significantly between SHCGT and AHCGT infants, as did the change in abundance of the taxa in the stool samples at 30 PMA. The loss in HCG z- score > 0.5 occurred between 31 and 36 weeks PMA in the SHCGT groups. This suggests that an «immature» GM precedes the SHCGT.

SHCGT infants had a significantly decreased abundance of Bacteroidota (p = 0.0009) (Figure 1) and Lachnospiraceae (p = 0.009), between 31 and 36 weeks PMA, which may result in a reduced carbohydrate utilisation capacity of these taxa. The prevalence of the Ruminococcaceae family (p = 0.007) was attributed to the species Faecalibacterium prausnitzii (p = 0.004), 48% in the AHCGT vs 8% in the SHCGT infants. It is to be noted that there was an increase in Firmicutes in the SHCGT groups from 24 to 30 weeks PMA (p = 0.009) but without any difference in the sub-taxa.

Analysis of the clinical parameters showed that changes in HCG were not due to caloric restrictions. There were more morbidities in the children of the SHCGT groups than in those with AHCGT: necrotising enterocolitis (p = 0.0006), severe neurological injury (p = 0.01), sepsis (p = 0.03). However, the analytical methods used, such as the random decision forest with permutations, showed that the most important factors associated with HCG trajectories were the characteristics of the GM rather than the comorbidities, whether from 24 to 30 PMA or from 31 to 36 PMA (Figure 2). In infants free from severe morbidities, the differences in Bacteroidota and Lachnospiraceae were still present but the abundance of Actinobacteriota was significantly greater in the AHCGT and in the mildly SHCGT than in the moderately and severely SHCGT groups.

Delivery mode had more effect on HCG trajectories than factors influencing GM such as enteral nutrition and antibiotic treatments. This is linked to the transmission of the GM at delivery because the abundance of Bacteroidota was greater in vaginally delivered infants than in those delivered by caesarean section. Moreover, among the vaginally delivered infants, those with a SHCGT had a fall in the abundance of the taxa described above as related to HCG trajectories, compared with the AHCGT. Moreover, the birth term is an important factor because all the vaginally delivered SHCGT infants were born < 27 weeks postmenstrual age, whereas only 17% of the vaginally delivered AHCGT infants were born < 27 weeks postmenstrual age.

WHAT ARE THE CONSEQUENCES IN PRACTICE?

It is suggested therefore that SHCGT starts with a reduction in the abundance of Bacteroidota and Lachnospiraceae, and then is exacerbated with the reduction in Actinobacteriota.

Vaginal birth enables the vertical transmission of Bacteroidota.

One must however be vigilant concerning infants born before 27 weeks PMA because even those delivered vaginally appear to be at a higher risk of SHCGT.

Studies designed to optimise GM from the first days of life in very premature infants may confirm and refine these results.

WHAT DO WE ALREADY KNOW ABOUT THIS SUBJECT?

Studies based on deep sequencing of the gut mycobiota in several cohorts of patients supply coherent evidence that «fungal dysbiosis» is a characteristic of chronic inflammatory bowel disease (IBD) [2], the most widespread forms of which are Crohn’s disease (CD) and ulcerative colitis (UC), which affect millions of individuals worldwide. Anti-Saccharomyces cerevisiae antibodies (ASCA), directed against the mannans presented by the cell wall of fungi, define sub-types of IBD, because their presence in the serum is associated with CD but not with UC, which establishes an additional link between fungi and IBD. Candida is the most widespread fungal genus, and its presence is systematically increased in several cohorts of patients with IBD analysed by sequencing of the faecal microbiota [2].

In particular, C. albicans in the gut induces a set of antifungal antibodies and acts as an immunogen for ASCA. Candida species associated with the gut mucosa are detected by the macrophages present in the gut and have been shown experimentally to have the potential to induce protective immunity or to trigger inflammation, depending on the context [3]. Despite this evidence, it is currently unknown whether the fungi detected by sequencing technologies in the human gut have an essential role in the orientation of mucosal immunity or in the evolution of inflammatory disease in each individual patient. A lack of correlation has been repeatedly observed between changes in the composition of the mycobiota and the seriousness of the disease in IBD patient cohorts, despite a constant increase in Candida species. The authors have therefore emitted the hypothesis that the functional diversity of Candida strains determines the host-fungal relationship in human gut mucosa with an effect on intestinal inflammation.

WHAT ARE THE MAIN INSIGHTS FROM THIS STUDY?

In agreement with numerous other studies, the authors first observed that the mycobiota of patients with UC were rich in Candida albicans and, in contrast, poor in Saccharomyces. In the situation of impaired immune response induced by corticosteroid therapy, C. albicans exacerbates the severity of colitis in mice. The authors then isolated several strains of C. albicans from the mycobiota of healthy subjects and from patients with UC and observed a wide heterogeneity in terms of pro-inflammatory capacity. In particular, the capacity of causing cell damage to the macrophages, which are a key defence against fungi, varies from one strain to another. The strains able to inflict cell damage to the macrophages have a greater tendency to filament and have pro-inflammatory effects in vivo by inducing a Th17 response (Figure 1). The authors then showed that a large part of the pro-inflammatory effects were mediated by the secretion of a toxin, candidalysin, and the induction of IL-1β production. Subsequent analyses revealed a strong correlation between the pro-inflammatory capacity of strains isolated from patients with UC and the inflammatory activity of the disease. On the other hand, there was no correlation between the magnitude of intestinal inflammation and the overall abundance of Candida albicans in the patients. These results explain why the composition of the mycobiota is poorly correlated to the characteristics of human pathologies and suggest that the functional capacities (pro-inflammatory in this case) may provide a better explanation of the role of the mycobiota in these pathologies.

WHAT ARE THE CONSEQUENCES IN PRACTICE?

This study shows that, in addition to analyses of the composition of the mycobiota, in particular by sequencing, a functional analysis is necessary to understand its contribution to the disease and in particular in IBD. If pro-inflammatory strains of C. albicans, candidalysin and IL-1β are confirmed to have a role in UC, we can imagine a therapeutic option which targets one of these elements, especially as several molecules which antagonise the IL-1β pathway are already available.

STRESS-RELATED DISORDERS

Psychiatric disorders are chronic, debilitating disorders that significantly impair daily functioning, and are among the top ten leading causes of burden of disease worldwide [1]. Exposure to environmental stressors and trauma is associated with increased incidence of post-traumatic stress disorder (PTSD), major depressive disorder (MDD) and anxiety disorders [2, 3]. These stress-related disorders are associated with increased mortality, reduced life expectancy, are highly comorbid, and exhibit variable response to first line pharmacotherapy. There are no clinically actionable biomarkers for these disorders, further complicating their diagnosis and treatment. To facilitate the development of novel therapeutic strategies and potential interventions, it is imperative that we gain deeper insight into the biological mechanisms underlying these disorders.

THE MICROBIOME-GUT-BRAIN (MGB) AXIS

“Microbiota” is the term referring to the trillions of microorganisms that live in and on us. The complete catalogue of these microbes and their genes constitutes the human microbiome. The gut microbiome, crucial in maintaining numerous aspects of our physiological functioning, is a dynamic system, the composition of which is affected by numerous factors including host genetics, age, diet and ethnicity [4-6]. The microbiome-gut-brain (MGB) axis is a complex, bidirectional system of communication between the gut microbiome, the gut, and the central nervous system (CNS), facilitated by direct and indirect communication pathways (Figure 1).

The vagus nerve, the major parasympathetic nerve of the autonomic nervous system, represents a direct link between the gut and the brain, with vagal afferents and efferents facilitating reciprocal interaction between the enteric nervous system and the brain. Indirect communication within the MGB axis takes on many forms. Microbiota produce several microbial-derived molecules, including neurotransmitters and metabolites, which act at multiple locations in the body. Many of these molecules, including serotonin (5-HT) have been found to regulate behaviour, brain function and health. As much as 95% of the 5-HT in the body is produced in the enterochromaffin cells lining the intestine, and 5-HT levels in the gut are influenced by microbial metabolites including indole, bile acids and short-chain fatty acids (SCFAs). 5-HT produced in the gut cannot bypass the blood-brain barrier (BBB), and therefore cannot affect 5-HT levels in the brain. However, animal studies provide evidence to suggest that levels of the 5-HT precursor, tryptophan, modulated by certain gut bacteria, are associated the regulation of 5-HT neurotransmission in the brain [7].

Alterations in SCFAs, a product of bacterial fermentation of host-undigestible polysaccharides, have been found to be associated with exposure to chronic stress and depressive-like behaviour in animal studies. SCFAs are involved in a number of regulatory functions, including modulation of gut activity and intestinal integrity, and activation of microglia (innate immune cells in the brain, which play an important role in regulating neuronal survival and responses). SCFAs are capable of crossing the BBB, and in doing so, may affect brain function.

It is well established that the gut microbiome plays an important role in the development of both the peripheral and central immune systems, and accumulating evidence suggests that increased inflammation is associated with stress-related disorders. An imbalance in gut microbial composition can compromise the integrity of the intestinal epithelium [8], increasing intestinal permeability and facilitating translocation of bacteria, or bacterial components, across the epithelial barrier into systemic circulation. This promotes low-grade inflammation, which stimulates increased expression of pro-inflammatory cytokines. Proinflammatory cytokines can stimulate the hypothalamic-pituitary adrenal (HPA) axis to secrete cortisol, which may further increase intestinal permeability. Indeed, evidence of gut and brain barrier dysfunction has been reported in stress-related disorders.

INVESTIGATING THE GUT MICROBIOME IN STRESS-RELATED DISORDERS: PRECLINICAL AND CLINICAL FINDINGS

Several preclinical investigations support the idea that the gut microbiome composition is associated with stress-related disorders. Investigations using germ-free (GF, microbiologically sterile) animals have played a crucial role in our understanding of the MGB axis. In their seminal investigation, Sudo and colleagues [9] observed an exaggerated stress response, evidenced by increased levels of corticosterone, in GF mice compared to controls, following acute restraint stress. This exaggerated HPA axis response to stress was normalised upon mono-colonisation of the GF mice with Bifidobacterium infantum. Studies have also shown that it is possible to transfer anxiety- like behavioural phenotypes between two mouse strains, by means of fecal microbiota transplant (FMT) [10]. Similarly, several studies have reported on the development of depressive- and anxiety-like behaviour, and altered neuroendocrine-immune pathways, in microbiota-depleted rodents following FMT from humans diagnosed with MDD, suggesting a causal role for gut microbiota in depressive-like behaviour [11-13]. Animal studies have also shown that exposure to stress can cause long-lasting alterations in the gut microbiome – two recent studies reported on decreased relative abundance of Akkermansia muciniphila in the gut microbiome of stressed animals over time, compared to control animals [14, 15]. A. muciniphila and the outer membrane coat of the bacteria (Amuc_1100) have been found to ameliorate depressive-like behaviour, and increase circulatory levels of 5-HT.

Comparatively few clinical studies have been conducted to determine the association between the gut microbiome and stress-related disorders. Thus far, the only published data on the gut microbiome in PTSD emanates from our research group [16], where a consortium of four bacterial genera was found to predict PTSD status with 66.4% accuracy. In addition, MDD diagnosis in the sample was found to be associated with increased relative abundance of the phylum Bacteroidetes. Other studies indicate that bacterial taxa associated with both depression and anxiety disorders are characterised by a higher relative abundance of taxa that induce a proinflammatory environment and a reduced abundance of SCFA-producing bacteria [17].

This field of research is, however, still in its infancy, currently limited by the lack of standardisation in gut microbiome analysis, from sample collection to the analytical pipeline. In many cases, factors that may confound results, including diet, medication use, ethnicity and host genetics, were not accounted for in the studies reviewed above. Moreover, most of the studies conducted have been cross-sectional in design, limiting our ability to disentangle cause from consequence, and very few have investigated potential mechanisms underlying the associations.

MODULATION OF THE MGB AXIS: PROBIOTICS

The gut microbiome is tractable and has the potential to be modulated, making the search for gut microbiome markers associated with stress-related disorders particularly attractive. Probiotics are defined as living microorganisms which, when administered in adequate amounts, confer a health benefit on the host; psychobiotics refer to probiotics which confer a benefit on mental health, cognition and behaviour. Recent publications have indicated moderate beneficial effects of psychobiotics in alleviating depressive and anxiety symptoms in both healthy and clinically-defined cohorts [18]. It is, however, important to remain cautious when interpreting results from current studies, as they are variable with regards to probiotic formulation and dosage, sample characteristics (clinical phenotype and severity of depression/anxiety), and follow-up time. In addition, the benefit of psychobiotics over, and interactions with, antidepressant medication has not yet been extensively investigated, although some intriguing results from preclinical studies suggest that certain probiotics, when administered in multi-strain format, possess antidepressant effects similar to, and sometimes with larger effect than, current first-line antidepressants [19]. Such psychobiotics, when used in conjunction with antidepressants, may have particular use in individuals with treatment-resistant depression.

From birth, the formation of an infant’s microbiota depends on its closest microbial sources, above all the mother, but also the rest of the family, particularly brothers and sisters. However, there have been few studies on the influence of siblings in this regard. To fill the gap, Danish researchers sequenced fecal (taken at 1 week, 1 month, 3 months, 1 year, 4 years, and 6 years) and pharyngeal samples (taken at 1 week, 1 month, and 3 months) from 686 children in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC₂₀₁₀) cohort. Data on younger and older siblings were collected or updated at each visit. In addition, fifteen covariates were identified, including birth weight, antibiotic use, diet, and the presence of pets. The researchers then assessed the relationship between the gut microbiota signature of having siblings and the presence of asthma, allergic rhinitis, and allergic sensitization at six years of age.

Differences in diversity and abundance in young children with older siblings 

The researchers found siblings to be one of the most important factors in the development of a child’s gut and pharyngeal microbiota. Significant differences in composition, both in terms of diversity and quantity of bacterial genera, were found. The impact of siblings was particularly evident in the first year of life, and a smaller age difference with respect to the older sibling had a greater impact than the number of older siblings.

The pharyngeal microbiota of children with older siblings had a reduced alpha diversity at three months compared with that of only children. Moraxella and Neisseria were more abundant, whereas Staphylococcus was less abundant. No other factor, including even major factors such as breastfeeding or antibiotic use, had a greater impact on the composition of the pharyngeal microbiota than siblings.

As for the gut microbiota, children with older siblings showed a higher alpha diversity and a significant difference in beta diversity up to four years of age. At one year, siblings were the most important determinant of beta diversity after mode of birth. Children with older siblings had a significantly lower abundance of Escherichia/Shigella, other Enterobacteriaceae, and Veillonella, but a significantly higher abundance of Prevotella. Notably, the increased abundance of Prevotella was even more pronounced at four years and persisted at six years. Lastly, a gut microbiota with the sibling signature at one year of age was associated with a reduced risk of asthma at age six.

Better integration of siblings into studies on microbiota development

The researchers therefore believe that the development of an infant’s microbiota is significantly influenced by siblings, with consequences for the child’s health. They suggest that studies on the development of the microbiota in children should take into account the presence of siblings, especially older siblings.

Our bodies change throughout our lives. This includes our gut microbiota, to the extent that the species that make it up can pinpoint our age. We know that the gut microbiota changes with age, losing diversity, and ultimately becoming unbalanced (dysbiosis), which may in turn contribute to the aging process. Conversely, maintaining a balanced microbiota may preserve the proper functioning of the body’s metabolism and immune system, but also contribute to the fight against inflammation and the decline of cognitive and bone health.

Detour to the “blue zone” of longevity

Since the gut microbiota is implicated in aging, can we learn something from the microbiota of those who live very long and healthy lives? To answer this question, Italian researchers¹ traveled to the south of Sardinia, a region famous for its centenarians. As in other “blue zones” around the world, the researchers encountered men who had above-average longevity (and women with a longer life expectancy) while remaining in good physical shape.² They hoped to discover the unique features of a gut microbiota associated with exceptional longevity, but also to evaluate the extent to which the microbiota can be inherited by descendants, and the impact of environmental factors such as diet.

Gut flora of centenarians in the prime of life 

The researchers analyzed the gut microbiota of a group of 46 dashing centenarians and nonagenarians, and compared it to a control group of 46 healthy younger adults (40-60 years old). They also compared the gut microbiota of seven centenarians with that of their children. 

They found that the gut microbiota of the centenarians had a strong presence of bacteria from the Verrucomicrobiota phylum, particularly the species Akkermansia muciniphila. Among other things, this bacterium is known to contribute to immunity, metabolic health, and maintaining the integrity of the intestinal barrier. While the gut microbiota of the youngest participants was dominated by the Bacteroidetes phylum and in particular, the genus Bacteroides, that of the nonagenarians was associated with Actinobacteria, particularly Bifidobacteria. Moreover, the gut microbiota of the centenarians was closer to that of the youngest participants than that of the nonagenarians.

According to the researchers, the gut microbiota of the centenarians was a carefully balanced microbial community. It included species associated with intestinal health that oppose the action of pathogens and have an anti-inflammatory effect that benefits the entire body. In addition, its richness and complexity allow it to adapt to environmental disturbances.

Genetics and lifestyle acting together

The study showed the gut microbiota of the centenarians to be relatively similar to that of their children. The latter may therefore inherit characteristics of the microbiota, but also family lifestyle habits, particularly dietary habits, which predispose them to longevity. Moreover, a correlation was found between the species of the gut microbiota linked to longevity and adherence to a Mediterranean diet: further evidence of the benefits of this fiber- and anti-oxidant rich diet!

Recommended by our community