Memory loss, spatial orientation difficulties, anxiety disorders, etc.: ageing is often associated with psychological and cognitive decline. At the same time, the gut microbiota plays a major role in the development of brain areas dedicated to learning and memory, notably the hippocampus. This has led some scientists to suggest that microbiota ageing results in cognitive decline via the gut-brain axis.

Young mice… behaving like elderly mice

To evaluate this hypothesis, a team of researchers analyzed the gut microbiota of adult mice who had been transplanted bacteria from the digestive tracts of mice of the same age or of older mice. Bacterial composition was essentially the same following the fecal microbiota transplant (FMT), with the exception of four bacterial genera whose abundance was significantly lower in the mice that had received the aged microbiota. In the hippocampus of these mice, the expression of numerous proteins involved in important brain functions, such as learning and cognition, was altered.

Mice with memory loss

The mice were then subjected to two tests, the first assessing their ability to learn and remember a path through a maze, the second measuring their ability to recognize an object. In both cases, the mice given the microbiota of older mice performed less well than the other group. On the contrary, stool transplant from older mice had no effect on other aspects of ageing, such as locomotor activity or anxiety.

Restore the microbiota to slow down cognitive decline?

Therefore, cognitive decline due to fecal microbiota transplant from an aged donor resembles physiological decline observed during ageing, suggesting the gut-brain axis plays an important role in the ageing process. According to the authors, these results support therapeutic approaches that aim to improve cognitive functions and quality of life in the elderly by restoring their microbiota.

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In recent years, the incidence of IBD has increased alarmingly worldwide. Risk factors thought to be involved in the development of IBD include genetic predisposition, environmental factors (hygiene, antibiotics, etc.) and gut microbiota disorders. Antibiotic use in the first years of life has been linked to a risk of IBD in children, but data are scarcer and remain controversial for adults. In a large prospective case-control study, a team examined the relationship between antibiotic therapy and the risk of IBD.

Swedish population scrutinized

To select their patients, the authors used the information generated by the ESPRESSO (sidenote: ESPRESSO Epidemiology Strengthened by histoPathology Reports in Sweden ) study gathering all reports of gastrointestinal diseases in Sweden from 1965 to 2016 and cross-checked them with the Swedish Patient Register and Prescribed Drug Register. The authors then identified in the general population up to five control subjects per patient, matched by age, gender, place of residence and calendar year. Lastly, unaffected siblings were also included in the study as a secondary control group sharing genetic or environmental risk factors with the patients. In total, 23,982 patients with IBD aged 16 to 65, 117,827 control subjects and 28,732 siblings were included.

Twice the risk of developing IBD

According to the study, antibiotic use was associated with a 1.88-times increase in the risk of developing IBD. For ulcerative colitis (UC) and Crohn’s disease the risk increased by 1.74 and 2.27 times, respectively. The risk also increased with the number of antibiotic prescriptions and when the antibiotics used had broad-spectrum activity. For the authors, this result supports the hypothesis that a gut microbiota dysbiosis caused by antibiotic treatment may lead to dysfunction of the intestinal barrier and local inflammatory response, resulting in an increased risk of developing IBD.

Exposure to antibiotics: an independent risk?

Although tenuous, a link between antibiotic treatment and IBD risk was also observed among individuals who shared a genetic predisposition and exposure factors during childhood, i.e. when patients were compared to their siblings as a control population. Further research is required to investigate the mechanisms by which antibiotics modify the gut microbiota, leading to the development of IBD. Nevertheless, according to the authors, this is one more argument in favor of a cautious and targeted use of antibiotics.

Connections between gut and brain control gut’s tissue and its microbial and dietary content, by regulating physiological intestinal functions such as nutrient absorption and motility, as well as dietary behavior. It is therefore plausible to assume that circuits exist to detect gut bacteria and relay this information to areas of the central nervous system which, in turn, regulate gut physiology. Hence this study, which investigated the influence of the microbiota on enteric-associated neurons by combining gnotobiotic mouse models (sidenote: Gnotobiotic mice refers to laboratory animals in which only certain known strains of microorganisms are present )  with transcriptomics (sidenote: Transcriptomics Measures gene expression by quantifying all transcripts present in a cell at a given time and under given conditions ) , circuit-tracing methods (anterograde tracing (sidenote: Anterograde tracing Method for tracing axonal projections from their source to their point of termination ) , translational profiling (sidenote: Translational profiling Detection, quantification, and monitoring of compounds produced by the microbiota ) ) and functional manipulations (chemogenomics (sidenote: Chemogenomics Transgenesis techniques able to modify the response of a population of neurons to a chemical compound ) ).

Mapping the sympathetic nervous system of the gut

The authors traced the involvement of the cell bodies of the gut-extrinsic sympathetic nervous system (eEAN (sidenote: extrinsic Enteric-Associated Neurons )  system) zone by zone (ileum, jejunum, etc.) and divided them into two groups:

- afferent cell bodies (from the gut to the nervous system), which send information back to the dorsal root ganglion (DRG) and the nodose ganglion (NG, inferior ganglion of the vagus nerve);

- efferent cell bodies (from the nervous system to the gut), which stimulate the sympathetic coeliac-superior mesenteric ganglia (CG-SMG). The latter supply other organs (spleen, pancreas, liver) in addition to the intestine, and may have a much broader role (immunity, metabolism) than simply reducing intestinal motility.

This work has made it possible to pinpoint the flow of information entering and leaving the gut, based on the eEAN system

Microbiota modulates gut-brain axis

Lastly, in germ-free mice, the authors observed a higher activity in the NG and CG-SMG neurons connected to the gut (but not in the DRG), suggesting that an absence of bacteria activates these eEAN cell bodies. Conversely, in gnotobiotic mice colonized by a short-chain fatty acid-producing microbiota or germ-free mice consuming SCFAs via their drinking water, the CG-SMG neurons were not activated, suggesting SCFAs inhibit the efferent eEAN neurons. Therefore, eEAN detection of bacteria or their metabolites acts as a sensory system in which an intestinal dysbiosis is sufficient to activate neurons. According to the authors, the discovery of this circuit whereby the microbiota and/or its metabolites modulate the eEAN system may lead to new therapeutic strategies for regulating gut motility, visceral pain, enteric immunity and metabolic disorders, provided that the bacterial signals at work are better characterized.

Bacterial vaginosis (BV) is a highly common infection. Often displaying few symptoms, the disease can have serious consequences, increasing the risk of sexually transmitted infections (including HIV) and complications during pregnancy (preterm delivery, preterm labor, and late miscarriage). Treatment with long-term efficacy is lacking and BV recurs in up to 50% of women at 6–12 months following treatment.

Bacteria nesting under the foreskin

Do some men play a role, via their penile microbiota, in the development of BV in their partner? Numerous studies support this hypothesis, including those showing a lower frequency of BV (-40%) in women who have sex with circumcised men (sidenote: Gray, R. H., Kigozi, G., Serwadda, et al. The effects of male circumcision on female partners’ genital tract symptoms and vaginal infections in a randomized trial in Rakai, Uganda. Am J Obstet Gynecol. 2009 Jan;200(1):42.e1-7. ) . As the skin covered by the foreskin is particularly rich in bacteria associated with bacterial vaginosis, certain scientists believe circumcision to be a prevention factor.

The same species are found in penile and vaginal microbiota

A team of researchers followed 168 heterosexual couples, where the female partner was free of infection at the outset of the study. After one year of follow-up, nearly one in three women had developed bacterial vaginosis. According to the analyses, BV occurrence seemed to be directly related to the composition of the penile microbiota. The authors identified seven bacterial species whose presence accurately predicted the occurrence of bacterial vaginosis. Several of these species were also found in the vaginal microbiota of infected women.

Treat men to protect women?

These results led the researchers to put forward two hypotheses: either bacteria from the penile microbiota are transmitted directly during sexual intercourse, or they disrupt the vaginal flora and cause infection over the long term. In either scenario, the researchers advocate the inclusion of male partners when treating infected women and suggest evaluating a treatment that, by modifying the microbiota of the penis, would prevent the occurrence or recurrence of bacterial vaginosis.

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From the antibiotic era to the microbiota era

As an expert on microbiota, the Biocodex Microbiota Institute will participate in this event by dedicating a special edition to the impact of antibiotics on the body’s microbiota:

- Gut microbiota: up to 35% of patients using antibiotics suffer from diarrhea^2,3,4 

- Urogenital microbiota: 10% to 30% of women develop vulvovaginal candidiasis following treatment with antibiotics⁵ 

- Skin microbiota: 60% of patients treated for acne show macrolide-resistant strains of Cutibacterium acnes 

- ENT microbiota: antibiotics administered to treat upper respiratory tract infections increase the incidence of acute otitis media by a factor 2.6 

- Lung microbiota: broad-spectrum antibiotics used to treat pulmonary infections play a central role in the emergence of antibiotic resistance

Special thematic paper

This 12-page issue presents the key points based on scientific data, expert opinions, and clinical cases.

Changes to the intestinal microbiota have been linked to the severity of non-alcoholic steatohepatitis (NASH). However, the studies in question were limited to bacterial dysbioses, with patients’ viral microbiota having received little attention. Hence this prospective, cross-sectional and observational study on the links between the characteristics of the intestinal virome and the different histological stages of the disease. To this end, the researchers sequenced the metagenome of stool viruses in 73 NASH patients at various stages of the disease and of those in 22 control subjects. Patients with a high NAS score and advanced fibrosis are at increased risk of disease progression, carcinoma, and death.

Severity associated with viral diversity

Compared to the 29 NASH patients with a low histological score (NAS 0-4) or the control subjects, the 44 patients with a high NAS score (5-8) or cirrhosis showed:

- a significant loss of intestinal viral diversity

- a significant reduction in the proportion of bacteriophages (sidenote: Bacteriophage Virus that specifically targets and infects bacteria Scitable by Nature education_2014. Bacteriophage definition )  compared to other types of intestinal viruses, which was even more pronounced in patients using PPIs (proton-pump inhibitors).

In addition, the severity of fibrosis increased with viral dysbiosis.

Cause or consequence?

Therefore, two NASH severity markers (NAS score and fibrosis) were associated with significant decreases in viral diversity and bacteriophage abundance. However, these links were merely correlative, with further studies required to determine whether viral dysbiosis is a cause or consequence of NASH and to understand the mechanisms involved. The virome may directly affect the host by triggering an immune response and/or influence the bacterial microbiota, with an increase in certain Lactococcal phages (common in the most severe cases) and Bacteroides spp. associated with a decrease in these bacteria.

A predictive model?

The second step consisted of building a model that included a viral diversity index and simple clinical variables (age, platelet level, etc.), which was able to identify:

- patients with severe forms, with a reliability of 0.95

- F2-F4 stage fibroses, with a reliability of 0.88

The addition of viral diversity data significantly improved the models, compared to those based solely on clinical parameters or bacterial diversity–two criteria on which another team recently based their diagnosis of liver cirrhosis and distinguished it from fibrosis. Therefore, instead of carrying out highly invasive biopsies, it may be possible to identify patients at risk of NASH (as well as therapeutic targets) by analyzing fecal viromes.

The presence of bacteria in human tumors is no new discovery: we have known about it for over a century. Despite this, due to its low biomass, little is really known about the tumor microbiota. Using a combination of multiple technologies, a team of researchers has studied 1,010 tumor samples and 516 samples of healthy adjacent tissue, with a total of seven tumor types screened: breast, lung, ovarian, pancreatic, melanoma, bone, and brain.

Bacteria in tumors and macrophages

First finding: the frequency of bacterial DNA detection depends on the type of tumor, from 14.3% for melanoma to over 60% for breast, pancreatic and bone cancers. A study of more than 400 additional tumors has confirmed bacterial components (16S rRNA and lipopolysaccharides (sidenote: Lipopolysaccharides Molecules found in the outer membrane of bacteria ) ) to be frequently present in both cancer cells and adjacent immune cells. On the other hand, the detection of spherical or rod-like bacteria was rare, suggesting a possible alteration of the envelope of intra-tumoral bacteria.

A specific microbiota for each cancer

Second finding: breast cancer has a particularly rich and diverse microbiota, with an average of 16.4 bacterial species detected per tumor, compared to less than 9 for other types of cancer. The culture of fresh tumor samples appears to confirm that these bacteria thrive. More importantly, each type of tumor has a distinct bacterial composition. For example, species belonging to the Firmicutes and Bacteroidetes phyla are the most frequent in colorectal tumors, whereas Proteobacteria predominate in pancreatic cancer.

A niche effect

Lastly, metabolic activities of intra-tumoral microbiota are highly dependent on the type of tumor. For example, in lung cancer, there is an increase in the number of bacteria capable of breaking down the chemicals present in cigarette smoke (toluene, acrylonitrile, etc.). According to the researchers, high concentrations of these metabolites may create a niche favorable to bacteria capable of metabolizing them.

Manipulating the tumoral microbiota?

At this stage, the study does not tell us whether bacteria play a causal role in the development of a tumor, or whether the tumor itself is responsible for their presence (the tumor may disorganize the vascular system, allowing bacteria to penetrate its cells). However, just as other studies have shown the gut microbiota to influence response to ICIs (sidenote: Immune checkpoints are used by tumors to protect themselves from immune system attacks and may be blocked by ICI therapy in order to restore the immune system function. ) , the researchers hope that by manipulating the tumoral microbiota it may be possible to alter the tumor’s defenses and, therefore, its response to immunotherapy. Indeed, the microbiota of melanoma varies between patients who respond well or poorly to immunotherapy. This creates hope for new diagnostic tools or even treatment methods.

Nearly a quarter of the world’s population could be affected by intestinal parasites. However, parasites–as well as their interactions with the microbiota–are among the least known microorganisms colonizing the intestinal ecosystem. This is why a team tried to assess the links between presence of parasites and composition of the gut microbiota, its metagenome, and the host’s immune response, by studying 575 Cameroonian adults. The composition of the microbiota was analyzed through 16 S rRNA sequencing and amplification, as well as shotgun metagenomics.

Microbiota, an indicator of parasitism

Besides subsistence strategy (pastoralist, agropastoralist, or hunter-gatherer lifestyles), the presence of parasites–especially strong in hunter-gatherers–was the factor most strongly associated with microbiota composition. A larger number of gut parasites, and especially the (co-)presence of four soil-transmitted helminths–Ascaris lumbricoides, Necator americanus, Trichuris trichiura, and Strongyloides stercoralis (called “ANTS” parasites)–was correlated to an increased alpha diversity. The composition of the microbiota could predict the presence of helminths in the gut with an accuracy reaching about 80%, and up to 84% for ANTS parasites. Gut colonization with ANTS is associated with higher levels of circulating cytokines (including some proinflammatory), indicating that ANTS could modulate immune mechanisms. The microbiota could be involved in this process: its composition could predict circulating levels of interleukin 5, largely involved in the immune response to helminth infection.

Functional interactions between parasites and microbiota

To explore potential metabolic interactions between microbiota and parasites, the researchers have established a connection between the presence of parasites and different functions in the bacterial metagenome. In ANTS-positive individuals, they observed a larger presence of bacterial genes involved in the metabolism of purine and pyrimidine, two nitrogenous molecules used in the composition of DNA nucleotides that some parasites are not able to synthetize and are forced to extract from their surroundings. The size of the cohort also made it possible to analyze the links between subsistence strategy and gut microbiota. For instance, in the microbiota of some pastoralist ethnic groups, they observed an increased amount of several species that are able to metabolize galactose and dairy lipids, which are different from bifidobacteria found in Europeans. According to the researchers, deepening the knowledge on the interactions between host, parasites, and microbiota, could help develop microbiota-targeting strategies to treat or prevent helminthiasis.

Alcoholism is a major cause of death and has serious consequences for the proper functioning of organs. Collateral damage from alcoholism includes major alterations to the intestinal microbiota, leading to a dysfunction in the dialogue between gut and brain. The intestinal microbiota is thought to play a role in behavioral disorders and addictions, and with this in mind, a team of researchers investigated whether alcohol dependence can be reduced by transferring the gut microbiota of healthy individuals to alcohol-dependent patients. To this end, twenty men aged between 60 and 70 and suffering from chronic alcoholism were divided into two groups, one of which received a fecal microbiota transplant (FMT) from a healthy donor and the other a placebo enema.

Alcohol craving and consumption reduced by FMT

Fifteen days after the FMT, the researchers observed:

– a reduction in craving for alcohol among 90% of the FMT patients, compared with 30% of the placebo patients

– a decrease in the marker molecules for alcohol consumption in the urine of the FMT patients, a sign of reduced consumption

– an improvement in the FMT patients’ cognitive performance and psychosocial wellbeing

Six months after the transplant, the FMT patients continued to report fewer serious alcohol-related problems (hospitalization, admission to emergency rooms).

Gut-brain communication involved?

The beneficial effects of FMT to treat alcohol dependence were accompanied by an increase in both microbial diversity and the abundance of short-chain fatty acids (SCFAs) in the stool and blood. High SCFA levels were associated with the presence of certain bacteria and lower addiction scores. According to the authors, the improvement in patients’ behavior in relation to alcohol may result from the increase in SCFAs following FMT, with SCFAs potentially acting as messengers that enable improved communication between gut and brain. Although preliminary, these results anticipate the introduction of therapies that alleviate alcohol addiction disorders via modulation of the microbiota.