Cardiovascular disease (CVD) is the world’s number one cause of death. By 2030, CVD-related deaths are expected to peak at 23.6 million. Its diagnosis currently involves a series of time-consuming and costly examinations (clinical tests, ECG, chest X-rays, echocardiogram). An alteration (dysbiosis) of the gut microbiota has been linked to several types of CVD, including hypertension, heart failure and atherosclerosis. So why not use artificial intelligence to design a diagnostic test for CVD based on gut microbiota composition?

CVD “signatures” present in the stool

Machine learning is a branch of artificial intelligence that involves inputting data into a computer so that it can learn how to solve a problem. In healthcare, it has been successfully used to diagnose and predict various diseases, such as cancer, diabetes mellitus and inflammatory bowel disease. To test its usefulness for diagnosing CVD, a team of researchers compared different analytic algorithms and sought to identify characteristic “signatures” for the disease in stool samples obtained from 478 patients with CVD and 473 healthy subjects. They found significant differences between the two groups in the relative intestinal abundance of 39 bacteria.

Strong diagnostic capacity

The researchers identified a specific algorithm which, by targeting 25 bacterial families within the gut microbiota, could discriminate between the two groups with 70% accuracy. This level of accuracy is only slightly below that of the conventional approach, which is able to diagnose 76% of CVD patients, but requires an array of clinical data (age, gender, smoking status, blood pressure, cholesterol levels, etc.). According to the authors, the use of machine learning to identify intestinal dysbiosis characteristic of cardiovascular disease has very promising diagnostic potential in the context of routine check-ups.

The equilibrium between “good” and “bad” microbiota bacteria can be disrupted by many different phenomena. This imbalance, known as dysbiosis (sidenote: Dysbiosis Generally defined as an alteration in the composition and function of the microbiota caused by a combination of environmental and individual-specific factors. Levy M, Kolodziejczyk AA, Thaiss CA, et al. Dysbiosis and the immune system. Nat Rev Immunol. 2017;17(4):219-232.   ) , can cause many diseases of varying severity. Fecal transplant (also called fecal bacteriotherapy) is a possible therapeutic solution.

Fecal transplant: a centuries-old solution

Fecal transplant is a very old treatment, since it was already being carried out in China in the 4th century! Its effectiveness was only recognized by European learned societies in 2013. To date, it has only been indicated in recurring C. difficile pathogenic bacteria infections, which it cures in 90% of cases. 
However, the involvement of microbiota in numerous other diseases (Inflammatory Bowel Diseases, diabetes, obesity, neuropsychiatric disorders, etc.) suggests that indications for fecal transplant could soon be expanded.

The procedure

Once selected, the donor prepares by taking laxatives. Their stool is then diluted in a sterile solution and filtered to be administered to the recipient. The recipient ingests a preparation similar to that used for colonoscopies in order to eliminate the disrupted microbiota.
There are several administration routes for the stool: the introduction of a probe through the nose to the stomach or duodenum, colonoscopy, enema, or, more rarely, ingestion of gastro-resistant capsules. It is up to the patient to decide with their doctor which route best suits their situation.

The Biocodex Microbiota Institute is dedicated to education about human Microbiota for General Public and Healthcare Professionals, it doesn't give any medical advice.

We recommend you to consult a healthcare professional to answer your questions and demands.

Bear this in mind before embarking on a trip to Mars: space missions aren’t all fun. Microgravity can atrophy idle muscles and subject bones to early osteoporosis; gastrointestinal transit slows down; altered day-night cycles disrupt sleep; and isolation affects mental health. If that’s not enough, the gut microbiota becomes unbalanced and the skin, nose and tongue microbiota start to mimic those of other crew members. Is this all connected? Might the microbiota alterations contribute to other imbalances? A recent review focusing on astronauts’ health suggests so.

Microbiota: the central factor?

We know the microbiota produces short-chain fatty acids (SCFAs¹), small molecules that affect appetite and satiety. Turned upside down by life in space and subjected to a fiber-depleted diet, the gut flora may accordingly inhibit astronauts’ appetite by synthesizing appetite-suppressant compounds. In addition, an alteration of the gut microbiota may reduce absorption of vitamins and minerals and play a role in the deterioration of the musculoskeletal system. Psychomotor functions and neurocognitive performance also deteriorate with time in space and these too may be under the influence of the gut microbiota, which acts on mood, stress, cognition, behavior, among others. Even the decline in astronauts’ immune functions may be partly explained by changes in the microbiota.

Helping out the microbiota

Therefore, space travel significantly modifies astronauts’ microbiota, particularly their gut microbiota. This may have an impact on their bone and muscle health, their metabolism and their immune system, and may even affect their nerves. Should we help nourish their microbiota using prebiotics or introduce beneficial bacteria via probiotics? The question is worth asking and future clinical trials may provide the answer.

^{1. Short Chain Fatty Acids}

Standard therapies designed to deprive the body of androgens, which are responsible for the growth of prostate cancer, are not always effective. In such cases, abiraterone acetate (AA) is used, and unlike other treatments, it is taken orally. Since AA is poorly absorbed, a significant portion of it is excreted in the stool and interacts with the gut microbiota. Several studies have highlighted the role of the gut microbiota in the development and progression of certain cancers, and in the effectiveness of treatments. However, there are still few data on the gut microbiota’s role in prostate cancer. The researchers therefore sought to show how AA (highly effective in hormone-refractory prostate cancer) affects the gut microbiota, and to assess whether the latter can influence responses to treatment.

Androgen deprivation remodels the gut microbiota

To this end, they used 16S rRNA sequencing to examine the gut microbiota composition of 68 prostate cancer patients divided in three groups:

- treatment-naive patients (n=33) ;

- patients receiving standard therapy (n=21) ;

- patients receiving standard therapy + AA (n=14)

Compared with the control group, standard therapy alone or standard therapy combined with AA led to a significant reduction in Corynebacterium, pro-inflammatory bacteria that metabolize androgens such as testosterone. AA intake led to a significant enrichment of Akkermansia muciniphila and increased production of vitamin K2, known for its anti-tumor properties.

A. muciniphila plays a key role in response to treatment

These results were confirmed in a simulated gut model, which excluded the possibility of immune involvement. Further investigations revealed that AA is metabolized by gut bacteria. Compounds derived from this degradation selectively impact the gut microbiota, characterized by the growth of A. muciniphila. This bacterial species known for its health benefits and anti-inflammatory properties is thought by the authors to play a key role in treatment response. Previous work had brought to light its beneficial role in responses to certain immunotherapies. This study highlights the gut microbiota’s key role in responses to an oral anti-cancer treatment, via mechanisms yet to be elucidated. Exploring drug-microbiota interactions could improve treatment outcomes for numerous diseases.

Rigorous monitoring of food intake is often required to avoid the infamous post-diet yo-yo effect. But is there another solution? As it happens, transplanting to yourself your own gut microbiota acquired following the diet may do the trick. The idea certainly seems a little off-putting since it involves ingesting the microbiota present in the feces via capsules. It has shown promise, nonetheless.

A two-step “slimming program”

Let’s start from the beginning. Obese patients were subjected to an exercise program and one of the following three diets: the classic guidelines; the Mediterranean diet plus a handful of nuts (rich in polyphenols); or a “green” Mediterranean diet (less meat, more fish, and lots of vegetable products with a high polyphenol content, e.g. Mankai duckweed and green tea). Six months later, 90 participants had lost an average of 8.3 kilos. The researchers then prepared capsules containing the microbiota in their stool. Over the next eight months, 44 of the patients took capsules containing their own fecal microbiota, while the remaining 46 were given a placebo.

A controlled yo-yo effect

The results? Patients who followed a green Mediterranean diet and then took capsules containing their own microbiota regained only 1.6 kg in the eight months post-diet, whereas those who followed the same diet but received a placebo regained 3.6 kg. Members of the first group also maintained their waist size and insulin level (hormone that controls blood sugar level), an effect not observed for the other two diets.

Effect of green Mediterranean diet on microbiota

Ultimately, the green Mediterranean diet had the most significant effect on the gut microbiota and bodily functions. When followed by the regular ingestion of the microbiota present in the gut on its completion, this diet has the potential to profoundly modify the gut microbiota and limit the yo-yo effect. Specific bacteria and changes in sugar transport may be the cause.

Obviously, this experiment should not be tried at home!

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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