How do you explain that only two sweeteners have an effect on blood sugar levels (saccharin and sucralose) while the four sweeteners tested had an impact on the composition and functions of the gut microbiota?

The use of sweeteners can be suggested in people with metabolic diseases to help them reduce their calorie intake, lose weight and improve their metabolic risk [4]. However, over time, concerns have emerged due to the fact that sweeteners do not have a neutral effect [5, 6]. In 2014, the authors of this publication had already shown that mice consuming high doses of aspartame, saccharin and sucralose developed glucose intolerance due to disturbances in the gut microbiota [7]. In this new research, they have gone one step further by carrying out a well-conducted clinical study in humans. In 120 healthy participants, the researchers assessed the effects on glucose tolerance of sucralose, saccharin, stevia and aspartame administered for 14 days (5 study arms, 20 participants per group and one control group). Sweeteners were used at levels lower than the recommended daily intake. The ingestion of sucrose and sucralose aggravated glucose tolerance, while aspartame and stevia had a neutral effect. These sweeteners had distinct effects on the composition of the oral and faecal microbiota and on key functions (such as purine and pyrimidine metabolism, glycolysis, and amino-acid metabolism). The most significant effect was observed with sucralose. Microbiota transfer studies (human to mouse) have established the causality of effects. Animals colonised with samples from sweetener-supplemented subjects showed varying degrees of altered glucose tolerance. The chemical composition of sweeteners appears to influence the microbiota; however, the precise mechanism by which they exert these variable effects on the host through changes in the faecal microbiota requires further detailed study. More specifically, sucralose, saccharin and stevia are partially metabolised in the upper digestive tract and only a tiny proportion reaches the colon.

Does this mean you recommend that your patients should not use non-nutritive sweeteners, since they may not be physiologically inert?

In my clinical practice, we do not systematically suggest patients use sweeteners, as there is no evidence that they are an effective weight-loss tool. Although, in patients who are unable to lose their sweet tooth, we prefer suggesting the use of natural sweeteners such as steviol glucoside, which can be used on a short-term and reasonable basis. However, the above discussed results highlight the need for a rigorous assessment of the short- and longterm impact of the available sweeteners on human health before deciding whether or not to recommend their continued use as an aid to reducing metabolic risks.

IDIOPATHIC URETHRITIS IN MEN: NEW INFECTIOUS ETIOLOGIES?

^{Plummer EL, Ratten LK, Vodstrcil LA, et al. The urethral microbiota of men with and without idiopathic urethritis. mBio 2022; 13: e0221322.}

Some Australian researchers sought to determine which infectious agents, apart from those already known, might contribute to non-gonococcal urethritis in men, taking into account their sexual practices and the biological sex of their partner. For this, they conducted a case study including 199 men, 96 of whom had symptoms of idiopathic urethritis and 103 of whom did not, who served as controls. The median age of participants was 31 years, 73 had had a sexual relationship with a man in the month prior to inclusion (classified as MSM), and the remainder were classified as MSW. For all of them, the researchers had samples of urinary and urethral microbiota available for sequencing analysis. Their results revealed that Haemophilus influenzae, which naturally colonizes nasopharyngeal microbiota, was more abundant in MSM participants with idiopathic urethritis. In addition, H. influenzae was clearly associated with clinical features such as urethral burning, dysuria and purulent discharge. The researchers believe having oral sex without a condom could be the main mode of contamination by this bacterium. They observed more of the genus Corynebacterium in affected MSW, which they found surprising since it is considered commensal in male genital microbiota. The scientists conclude that some specific species of Corynebacterium may become pathogenic when present in abundance. There were also more Ureaplasma, Staphylococcus haemolyticus, Streptococcus pyogenes, Escherichia and Streptococcus pneumoniae in the urinary and urethral microbiota of symptomatic subjects, so they may all promote urethritis. Possible infectious causes of non-gonococcal urethritis, previously described as idiopathic, have thus been discovered. If these results are confirmed by other studies, doctors may eventually be able to offer their patients more targeted treatments.

PREGNANCY AND COVID-19: IS VAGINAL DYSBIOSIS A SOURCE OF COMPLICATIONS?

^{Deng H, He L, Wang C, et al. Altered gut microbiota and its metabolites correlate with plasma cytokines in schizophrenia inpatients with aggression. BMC Psychiatry 2022; 22: 629.}

And what if the harmful effects of Covid-19 in pregnant women required the intervention of the vaginal microbiota? In order to check this hypothesis, researchers conducted a prospective case-control study including 28 non-infected pregnant women and 19 pregnant women suffering from Covid-19. A sample of the vaginal microbiota was obtained with a swab during the active phase of the disease in the month following recovery and evaluated by 16S rRNA gene sequencing. The Covid-19 group displayed significantly greater diversity than the control group. In addition, the Bacteroidetes had gained the upper hand over the Firmicutes, and, at bacterial genus level, the Lactobacillus sp. were significantly less abundant than in the control group. Well, previous studies showed that there was an increased risk of miscarriage or premature birth in pregnant women whose vaginal microbiota were depleted in Lactobacilli. These data corroborate this finding, since 3 women in the Covid-19 group gave birth prematurely (versus 0 in the control group). Despite the small size of the sample, the investigators observed other differences in the composition of the vaginal microbiota in the Covid-19 group. In particular, the women suffering from moderate to severe forms of Covid-19 displayed much higher levels of Ureaplasma spp.: 2.05% vs 0.1% in case of asymptomatic to mild forms. The genus Ureaplasma is involved in different gynecological infections (salpingitis, urethritis, and cervicitis), its over-representation in case of severe Covid-19 also argues in favor of an association of vaginal dysbiosis both with SARS-Cov-2 infection and risks of pregnancy complications. All the more as, in the 3 premature births that occurred in this study, 2 were in the moderate to severe Covid-19 subgroup (n=6). Thus, although this study does not allow the conclusion that a causal relationship exists, these results suggest that Covid-19 may trigger an unfavorable disruption of the vaginal microenvironment in pregnant women. This would be even more pronounced when the infection is severe, and could lead to an increased risk of complications, such as premature birth.

DIET-INDUCED MODIFICATIONS TO HUMAN MICROBIOME RESHAPE COLONIC HOMEOSTASIS IN IRRITABLE BOWEL SYNDROME

^{Bootz-Maoz H, Pearl A, Melzer E, et al. Diet-induced modifications to human microbiome reshape colonic homeostasis in irritable bowel syndrome. Cell Rep 2022; 41: 111657.}

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that can be classified to different subtypes: diarrheaor constipation-predominant IBS (IBS-D and IBS-C, respectively), IBS with mixed bowel habits, and unclassified IBS. Many IBS patients benefit from low-fermentable oligo-, di- and monosaccharides as well as polyols (FODMAP) diet. However, only about 60-70% of patients clinically respond to the diet. This study examined the effects of 6-weeks low-FODMAP diet on the gut microbiota in therapy-naive patients with IBS-D. The diet led to an increase in the abundance of Acutalibacter timonensis and Oscillibacter species, as well as a decrease in Bifidobacterium adolescentis, Eubacterium ventriosum, and Clostridium disporicum. Seventy percent of the patients showed improvements in disease manifestations. The authors then studied using ex vivo gut organ cultures how the fecal samples affected gene expression. The post-diet microbiota induced expression of genes implicated in enteric neuronal and muscle functions and suppressed the expression of many genes encoding pro-inflammatory proteins. Gene ontology analysis revealed that post-diet microbiota increased pathways related to extracellular matrix organization, cellular adhesion, and junction assembly. Because many pathways and genes associated with the abundance of B. adolescentis, the authors co-cultured colonic epithelial cells with B. adolescentis and administered mice with the bacterium to find a mechanistic link between the bacterium and gut health. Both in vitro and in vivo, B. adolescentis disrupted epithelial tight junction integrity and gut barrier functions. Ultimately, using in vitro cultures it was found that fructose avoidance under low-FODMAP diet explained the reduced B. adolescentis levels in patients’ postdiet microbiota. The study provides a mechanistic link between diet, microbiome and intestinal functions which will help, in the future, the development of personalized microbiome-based therapies for human diseases.

ALTERED FUNCTIONAL CONNECTIVITY STRENGTH IN CHRONIC INSOMNIA ASSOCIATED WITH GUT MICROBIOTA COMPOSITION AND SLEEP EFFICIENCY

^{Chen Z, Feng Y, Li S, et al. Altered functional connectivity strength in chronic insomnia associated with gut microbiota composition and sleep efficiency. Front Psychiatry 2022; 13: 1050403.}

Little is known about the link between the gut microbiota and resting-state brain activity in patients with chronic insomnia (CI). CI manifests with, for instance, difficulties in initiating or maintaining sleep, obtaining refreshing sleep, and a hyperarousal state. Moreover, CI can impair social, cognitive, and behavioral functioning of the patients. This study investigated associations between the brain functions, gut microbiota composition and neuropsychological performance in patients with CI. The gut microbiota composition strongly associated with neuropsychological performance in CI patients. Specifically, the abundance of Intestinibacter, Lachnospiraceae UCG-003 and Faecalicoccus correlated with the functional connectivity strength (FCS) in the left superior parietal gyrus. This part of the brain is involved in aspects of attention and visuospatial perception, including the representation and manipulation of objects. As expected, the FCS was lower in CI patients than in healthy controls. At the genus level, Alloprevotella, members of Lachnospiraceae family and Faecalicoccus associated with mood and sleep assessment scores. Because Alloprevotella and members of Lachnospiraceae are producers of short chain fatty acids (SCFA), the authors hypothesized that these genera could affect brain functions by modulating SCFA metabolism in CI patients. However, no mechanistic link was established in the study. While the findings of the study were interesting, longitudinal studies are needed to determine whether interventions could affect the gut microbiota of the CI patients and whether the gut microbiota could be targeted, e.g., with probiotic interventions to improve the brain functions in insomnia patients.

MODE OF DELIVERY MODULATES THE INTESTINAL MICROBIOTA AND IMPACTS THE RESPONSE TO VACCINATION

^{de Koff EM, van Baarle D, van Houten MA, et al. Mode of delivery modulates the intestinal microbiota and impacts the response to vaccination. Nat Commun 2022; 13: 6638.}

Various factors influence infant’s vaccine responses, such as genetics, birth weight, maternal antibodies, and feeding type. Less is known on the role of gut microbiota in immune responses to vaccination though the microbes importantly affect the development of the immune system early in life. This study determined whether the mode of delivery-induced differences in gut microbial colonization patterns in early life are associated with antigen-specific IgG responses to the pneumococcal 10-valent PCV (PCV-10) and the meningococcal MenC conjugate vaccine. Among many variables studied, the mode of delivery and feeding type were the only early life factors significantly associated with IgG responses against one or more serotypes. The diversity of the gut microbiota was not associated with the PSV or MenC IgG responses. The infants, whose gut microbiota was characterized by low abundances of Bifidobacterium and Escherichia coli had the lowest IgG concentrations against both vaccines. Contrarily, anti-MenC IgG concentrations in infants with high abundance of E. coli were ~2-fold higher, which was also associated with vaginal birth. However, at the age of one year, the gut microbiota did not associate with vaccine responses, confirming that early life microbiota is more related to vaccine responses than the microbiota close to the time of vaccination. Regarding the early life gut microbiota, higher abundances of E. coli and Bifidobacterium associated with high anti-pneumococcal responses, while Clostridium, Prevotella and Streptococcus pyogenes associated with low responses. In high anti-MenC responders, higher abundances of many low abundant OTUs belonging to the Lachnospiraceae family were observed. The study proves that understanding the microbial factors driving immune maturation and vaccine immunogenicity is key to improve vaccine performance in children.

Gut microbiota research is now developing complex clinical applications such as faecal microbiota transplantation (FMT), next-generation probiotics derived from the human microbiota, medicines developed from microbial products (postbiotics) and also diets based on our current knowledge of host/microbiota interactions. The challenges and issues raised by the arrival in clinical practice of these new forms of medicines today bring up a large number of regulatory, ethical and scientific questions which were developed throughout the congress. At the opening of the symposium, Professor Eugène B. Chang (Chicago, USA) introduced the challenges and new concepts involved in the development of this new type of medicine. Some of these include: the pressing need to establish a specific regulatory framework and design industrial standards capable of underpinning the development of new probiotics; and the need to understand treatments targeting the microbiota in an ecological and dynamic manner, i.e. evolving products that fit into an ecological niche which, in turn, they help to modify.

New pre- and probiotics to boost anti-tumour immune response

We have known about the important role played by gut microbiota in modulating anti-tumour immune response for around 10 years; however, the underlying mechanisms are still poorly understood. During the first session of the congress, Dr. Michael Scharl (Zurich, Switzerland) and Professor Harry Sokol (Paris, France) presented their latest findings regarding the identification of microbiological and metabolic candidates for combination therapies with conventional treatments to stimulate anti-tumour immunity. Thus, by studying differences in tumour development in murine models from different animal houses, Dr. Scharl’s team identified four bacterial strains which, when administered alone, reduced tumour development in mice (Eubacterium hallii, Faecalibacterium prausnitzii, Roseburia intestinalis, Anaerostipes caccae) [1].

Interestingly, administration of the supernatant of these strains was sufficient to obtain a stimulatory effect on the anti-tumour immune response.

The metabolism of 3-OH dodecanoic acid has been identified as one of the mechanisms potentially responsible for this effect, paving the way to the development of specific postbiotics.

In line with these findings and the bacterial consortium identified, Professor Sokol presented unpublished work confirming the beneficial impact of Faecalibacterium prausnitzii in the response to immunotherapy.

In addition to the plenary scientific sessions, several workshops were organised to foster lively exchanges with the experts. Thus, the session on “Engineered microorganisms as therapeutic agents” explored the current advances and perspectives in the development of new genetically engineered microbiological therapeutic agents. During this session, Dr. Nicholas Arpaia (New York, USA) presented an engineered strain of Escherichia coli developed with a lysis cycle coordinated between the different bacteria via a quorum sensing mechanism resulting in the release of a nano-antibody (anti-CD47 antibody fragment) inhibiting an immune tolerance signal in phagocytes [2]. In mice, injection of these bacteria at the tumour graft site resulted in the complete elimination of implanted tumours by the immune system via phagocytosis stimulation but also through adaptive immunity recruitment, thus suggesting the generation of a sustained immune and anti-tumour response. However, the ethical and regulatory framework required to allow the clinical evaluation of this type of treatment has yet to be defined, and this point was specifically discussed during the remainder of the workshop.

Faecal microbiota transplantation, gaining a better understanding of mechanisms underpinning its effectiveness

Among microbiota-based therapies, FMT is currently the most widely evaluated treatment in clinical practice across many indications. Despite a large number of studies, the factors determining the effectiveness of FMT and its mechanism of action are not yet fully understood. The work presented by Dr. Gianluca Ianiro on the combined analysis of 226 FMTs provided new insights into understanding this therapy by showing that the beneficial effect of FMT was correlated to the engraftment capacity of donor strains in the recipient and that this could be enhanced by the prior administration of antibiotics to open up the intestinal ecological niche, along with the combination of several methods when administering FMT [3].

Foods preserving intestinal barrier integrity

Several presentations also explored the importance of dietary factors in maintaining the intestinal barrier integrity and its consequences on health. Especially a fibre-rich diet has been shown to prevent the degradatation by Akkermansia muciniphila of the mucus layer that protect the colonic epithelium (presentation of Dr. Mahesh S. Desai, Luxembourg). Conversely, some food additives can boost the penetration of bacteria in the mucous layer in contact with the epithelium and predispose to the development of inflammatory colitis (presentation of Dr. Benoit Chassaing, Paris, France) [4].

This better understanding of the mechanisms underpinning the efficacy of microbiota- targeted therapies and the complexity of their use in clinical practices illustrates the need for clinical experts able to develop and use microbiota-based applications in the routine care. Dr. Ianiro, a world expert in FMT suggested that such qualifications should be grouped together under the concept of «microbiome clinician ».

At this 11th congress, the GMFH symposiums, by creating a rich and accessible space for exchange between clinicians and researchers, contribute to the emergence of this type of expertise.

What do we already know about this subject?

The prevalence of allergic diseases has increased dramatically. It has been shown that children living in the countryside are less prone to asthma than those living in cities. Indoors, dust is the main source of bacteria and fungi. Its composition reflects the outdoor environment and is influenced by external activities (e.g., agricultural), building materials and animals.

The establishment of gut microbiota during the first 1,000 days of life shapes the subsequent development of allergic diseases. Some well-known factors influence the composition of the gut microbiota of infants including antibiotics, delivery method and diet. Any resulting dysbiosis is thought to increase the subsequent likelihood of developing allergic diseases. In contrast, breastfeeding and vaginal delivery protect against the subsequent development of allergic diseases. The intestinal microbiota of these types of infants is characterised by a predominance of bifidobacteria, especially Bifidobacterium breve. Decreased contact with nature was seen to favour intestinal dysbiosis with a dysregulation of Th1/Th2 immune balance in favour of Th2, which is the adaptive immune response involved in allergic diseases (Cukrowska Nutrients).

The mechanisms by which gut dysbiosis in early life influences the development of allergies and asthma are little understood. Farm dust and bacterial lipopolysaccharide are known to induce endotoxin tolerance, thus reducing allergic asthma.

What are the main insights from this study?

The authors compared urban and rural environmental exposures in China in a human and mouse study. The EuroPrevall-INCO human cohort included 5,139 urban and 5,542 rural school-age children. The prevalence of food allergies and especially asthma, rhinitis, and eczema were higher in urban children (p < 0.001).

A case-control study included 225 children: 151 urban and 74 rural children. The gut microbiota of all children was analysed via 16S rRNA sequencing and metabolic pathways were assessed via shotgun sequencing. Clinical data and allergen sensitizations were collected. The Prevotella-to-Bacteroides ratio was significantly higher in rural children (p < 0.001). This difference was due to Prevotella_9 accounting for 25% of amplified variants in rural children and <5% in urban children (figure 1). However, no significant difference was observed in gut microbiota composition between cases and controls in both urban and rural participants. The analysis of metabolic pathways identified 14 different pathways between urban/rural participants and nine between controls/ cases. Among these, the L-lactate producing pathway was strongly associated with allergy and pathways involved in sugar degradation and lipopolysaccharide synthesis were abundant in the microbiota of control children.

To mimic the microbial exposure of children in urban and rural environments, mattress dusts were collected from ten urban and ten rural families and dusts from five henhouses from rural families (on the assumption that these may contribute to the microbial environment in rural families). Enterobacteriaceae and Rhizobiaceae were predominant only in urban house dusts (figure 2). A significantly higher a diversity and endotoxin content was observed in rural house dusts compared to urban house dusts and henhouse dusts. Finally, urban house dusts had a significantly higher proportion of potentially pathogenic bacteria. In addition, Aspergillaceae dominated in urban house dusts, whereas Trichocomaceae (genus Penicillium) was more abundant in rural house dusts (hence the higher diversity) and henhouse dusts (figure 2).

To test the impact that exposure to environmental dusts may have on allergic disease by altering the gut microbiota, the researchers exposed mice to dust by intranasal exposure (OVA-induced allergic model). Prior exposure to house dust in rural areas attenuated allergic inflammation (eosinophilic infiltration of airways, in bronchoalveolar lavage (BAL), increased sIgE). Mice exposed to rural dusts showed the lowest increase in the proportion of potentially pathogenic bacteria. The abundance in the gut of Bacteroidales increased and while Clostroidales (including species belonging to both Lachnospiraceae and Ruminococcaceae families) decreased in control mice exposed to PBS as well as those exposed to urban dusts. Finally, the relative abundance in the gut microbiota of Bacteroides and Ruminiclostridium was correlated to eosinophils in BAL (r = 0.59 and p = 0.001 and r = – 0.45 and p = 0.05 respectively).

What are the consequences in practice?

Early modulation of the gut microbiota, targeting the beneficial effect of rural house dusts could prevent the development of allergic diseases.

What do we already know about this subject?

Cancer is one of the leading causes of death worldwide. The tumorigenesis, progression and treatment-response of cancer are influenced by various interactions between the immune system of the host and bacteria in the microbiota. However, the role of fungi (mycobiota) in these processes remains largely unexplored. Fungi and bacteria co-colonise the gastrointestinal tract, skin epithelium, airways and reproductive organs of mammals, forming a complex ecosystem of microbe-microbe and host-microbe interactions with significant implications for human health. While fungal infections account for over 1.5 million deaths worldwide each year, they only account for 0.1% of microbial DNA in the gut, suggesting a disproportionate influence of species from this kingdom on the overall gut microbiome and host immunity. Whether referring to viruses, bacteria or fungi, an ever growing body of scientific evidence suggests a link between the human microbiome and cancer and its outcomes. Several cases showing the association between bacterial species and cancer development/progression have been observed in recent years. Helicobacter pylori is responsible for approximately 75% of the risk attributable to gastric cancer, while genotoxic Escherichia coli, Bacteroides fragilis, Streptococcus bovis/gallolyticus and Fusobacterium nucleatum have been implicated in colorectal carcinogenesis [2]. The common feature of these bacteria is their ability to trigger chronic inflammation, a feature considered to contribute to their tumorigenic capacity. Recent reports have also identified intracellular bacteria in many types of tumour [3].

The mycobiome plays a key role in the activation of innate immunity in the gut. Mycotoxins and bioactive amines have been associated with carcinogenesis. Recent experimental studies support fungal involvement in cancer in some contexts [4]. Sequencing data from tumour banks have revealed the presence of microbial sequences, although the fungal component has not yet been explored.

What are the main insights from this study?

By analysing several types of cancer using “The Cancer Genome Atlas” (TCGA), the authors extracted tumour-associated mycobiome profiles with a species-level resolution. After eliminating contamination and false-positive signals, the authors reported that fungal compositions varied according to the type of cancer, and that some fungi were tumour-type specific, in both gastrointestinal and non-gastrointestinal locations (figure 1A). Overall, up to one fungal cell per 104 human tumour cells were observed, a rate consistent with the finding that fungi make up 0.1-1% of the microbiome, while bacteria are estimated to make up less than 1% of tumour cells [2, 3]. Abundant numbers of several species of Candida, Saccharomyces cerevisiae and Cyberlindnera jadinii have been found in gastrointestinal tumours, while Blastomyces and Malassezia species are abundant in lung and breast tumours, respectively. The authors then showed that several Candida species are alive and transcriptionally active in the tumour. Finally, the abundance of some fungi within the tumour could predict host tumour gene expression, disease status and survival (figure 1B), although these findings still need to be confirmed. Overall, these results suggest an involvement of fungi, especially Candida, in the pathogenesis of gastrointestinal cancers but also highlight their potential as a therapeutic target and prognostic tool.

What are the consequences in practice?

Alongside bacteria, this study reported the presence of fungi in many gastrointestinal and non-gastrointestinal tumours, with some degree of specificity across tumour types and a potential for predicting severity. These results suggest that fungi play a role in the cancer process and its severity. They could also pave the way for the development of new biomarkers or new cancer treatments targeting the fungal component.

Mechanism

The morphology, warmth and moisture of the mouth affords the oral microbiota a highly diverse habitat for colonisation and growth. From birth, children acquire a simple oral microbiome, and with age, the eruption of teeth, and the additive role of external factors, this community becomes increasingly complex. Both host-derived and microbially-derived factors maintain the homeostatic equilibrium of the oral microbiome required for health.

Ecological shifts in a dysbiotic ecosystem favour the colonisation and proliferation of pathogenic oral bacteria (figure 1). When these species increase in quantity, the risk of oral disease significantly increases. Periodontal disease is a chronic, non-resolving, inflammatory process leading to tissue breakdown of the tooth-supporting apparatus, and can lead to tooth loss, if untreated. Routine activities including chewing, flossing, and toothbrushing can induce bacteraemia, which facilitate haematogenous dissemination of oral bacteria and inflammatory mediators, inducing systemic inflammation in some patients [2]. Patients with periodontal disease––the sixth most prevalent condition affecting humankind globally [3]––show micro-ulcerated sulcular epithelia and damaged periodontal tissues, and thus seem more susceptible to bacteraemia. Therefore, the inflammatory state from periodontal disease metastasises to other sites of the body, which can occur at clinically-relevant levels. Good oral hygiene is therefore essential for controlling the total bacterial load in the mouth, maintaining or re-establishing the oral symbiotic equilibrium, and preventing the dissemination of oral bacteria to other sites in the body.

Diabetes

Type II diabetes is a metabolic disorder characterised by an insufficiency of insulin production and the subsequent inability for the body to metabolise glucose, leading to elevated levels of blood glucose (chronic hyperglycaemia). Severe periodontitis strongly influences glycated haemoglobin (HbA1c) and fasting blood glucose levels in people with and without diabetes [4]. Periodontitis is thus recognised as the sixth major complication of diabetes, as the risk for periodontitis is raised by 2-3 times for people with the condition [5]. 

Untreated severe periodontitis is associated with an increase in the circulating levels of bacteria and bacterial antigens, pro-inflammatory mediators and cytokines, and increased levels of interleukin 6, tumour necrosis factor alpha, C-reactive protein, and oxygen free radicals. This combined effect fosters the conditions for systematic inflammation, impairing insulin signalling and resistance [6]. Clinically, this is recognised through increased HbA1C and the progression of diabetes, with greater risk of diabetic complications. Periodontal treatment reduces the oral bacterial load, and therefore lowers the circulating levels of inflammatory mediators, thereby reducing the degree of the systematic inflammatory state (figure 2). Hence, the dental management of periodontitis can lead to a clinically-relevant improvement in glycemic control, where patients with diabetes experience HbA1c reductions of 0.3–0.4% up to four months after treatment.

Atherosclerotic cardiovascular disease

Atherosclerosis describes the accumulation of fats, cholesterol, and blood cells that form hardened plaque deposits within the artery walls, occluding blood flow through the vessels, increasing the risk of cardiovascular complications.

Chronic periodontal disease can lead to endothelial dysfunction, through an elevated systematic inflammatory state, which can be shown through increased levels of IL-6, fibrinogens, and periodontopathic bacterial products, such as outer membrane vesicles and gingipains [8]. Much of the atherosclerotic pathology appears to be attributable to Porphyromonas gingivalis. However, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Tannerella forsythia and Fusobacterium nucleatum have each been studied in relation to this association. The primary microbial implications are endothelial dysfunction and the promotion of atherosclerosis in cardiovascular cells. P. gingivalis has the ability to attach to endothelial target cells, and external factors mediate its cellular entry, where it induces pro-coagulant effects. The results of a parallel-group, single-blind, randomised, controlled trial found that although intensive periodontal therapy led to systemic inflammation and endothelial dysfunction in the immediate term, 6 months after treatment, clinical and biochemical improvements in endothelial function were noted [9]. This study added to the theory that periodontal control may modulate atherosclerotic cardiovascular processes.

Rheumatoid arthritis

Rheumatoid arthritis is a chronic, autoimmune inflammatory condition affecting the synovial fluid of joints in a symmetrical pattern, and if untreated, other organs. Porphyromonas gingivalis is implicated in the pathophysiology of rheumatoid arthritis, where the bacteria produce enzymes with the capacity of citrullinating proteins, increasing the probability of reductions in the host immune tolerance and promoting the release of autoantibodies characteristic to the condition [10]. 

Several studies have shown that periodontitis caused by dysbiotic oral biofilms, can trigger rheumatoid arthritis with systemic inflammation and increased bone erosion. A bidirectional relationship has been postulated between the inflammatory conditions, but further evidence is needed to verify this [11]. Clinicians involved in the rheumatological care of arthritis patients should be aware of the role of periodontitis as a factor modulating the efficacy of biologic disease- modifying anti-rheumatic therapies, since the maintenance of systemic inflammation could affect treatment response.

In patients with dysbiotic oral biofilms, where the proportions of periodontopathic bacteria capable of citrullinating proteins are higher than in health, preventive and curative treatment to stabilise the oral microbiome and periodontal inflammation would be prudent to include as a core aspect of the rheumatological care plan.

Prevention

Scientific advances in the understanding of the oral microbiome demonstrate its contribution to both oral and general health and well-being. The ecological plaque hypothesis is the currently accepted theory desiring microbiological changes in the mouth, where shifts in the ecology of the oral microbiome result in disharmony, which foster key harmful pathogens to increase in number [13]. The dissemination of oral bacteria to systemic bodily sites is substantially reduced by enhancing control of the oral microbial load. Daily mechanical removal of plaque, through a systematic and comprehensive toothbrushing and interdental cleaning technique, reduces the volume of this load, and prevents the colonisation of pathogenic species. Good plaque control also prevents the risk of developing periodontal diseases, characterised by micro-ulceration of the gingival architecture, thereby producing channels for the leakage of bacteria and inflammatory mediators.

Supplemented with professional interventions by dental practitioners (commonly oral hygiene instruction, risk factor control, and mechanical plaque removal), periodontal disease processes can be stabilised and if mild, reversed.

Little is known about male urethral microbiota, since sampling is painful and often reserved for men with sexually transmitted infections (STIs). However, there is increasing evidence to suggest that microorganisms colonize this mucosa, even in healthy individuals. An American study including 110 men with no urethral symptoms, infections or inflammation has finally uncovered them.

A “core” microbiota...

Most of the individuals were heterosexual. A swab was inserted 2 cm into each man’s urethra to analyze the microbiota (shotgun sequencing). In total, 117 different species of bacteria were detected. Most of the samples contained lactic acid bacteria (e.g., Streptococcus mitis) and corynebacteria, which could represent the “core” microbiota responsible for the health of the urethra. But that’s not all. Scientists have also identified bacteria in some men that are associated with bacterial vaginosis in women, in particular Gardnerella vaginalis. As a consequence, the male genital tract could be colonized by bacteria that are potentially pathogenic for women, even though on the whole its microbiota differs greatly from that of the vagina.

And two types of urethral microbiota

Two types of urethral microbiota (or urethrotypes, UT) were identified: type 1 microbiota (UT1) which is less abundant and diversified, mainly dominated by S. mitis, and type 2 microbiota (UT2) which is more abundant and diversified, dominated by G. vaginalis and composed of nine bacteria associated with vaginal disorders (bacterial vaginosis, vaginitis, etc.) and capable of forming biofilms with G. vaginalis. Given the bacteria’s degree of affinity for oxygen, researchers believe that these two microbiomes are located in different niches: UT1 is located close to the urinary meatus and UT2 slightly deeper.

In addition, UT2 is associated with vaginal intercourse and certain bacteria related to bacterial vaginosis are still detectable 60 days after sexual intercourse and, to a lesser extent, after a year or even over a lifetime. Vaginal intercourse in the last two months alone explains 4.26% of the variance in the composition of male urethral microbiota. And sexual practices as a whole (oral, vaginal, anal) account for around 10% of this variance.

Finally, no other variable, whether anal or oral intercourse, age, ethnicity or history of STI, was associated with either urethrotype.

Is bacterial vaginosis an STI?

The male urogenital microbiota could therefore be linked to sexual behavior and the male urethra could, in some men, harbor a wide range of agents that are potentially pathogenic for the female vaginal flora. Could they represent a reservoir for sexually transmitted microorganisms and risk contaminating women during unprotected sex? If so, shouldn't bacterial vaginosis be considered an STI? Currently it is not considered as such but this hypothesis (which is not new) will be explored in further research involving couples this time.

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