Imbalances in the microbiota (dysbiosis) have been associated with numerous diseases, including diabetes mellitus, obesity, neuropsychiatric or neurodegenerative disorders, and even cancer. Metabolites produced by the gut bacteria enter the bloodstream early. With this in mind, a new study has sought to establish the profile of serum metabolites linked to the gut microbiota. The goal? To find a serum metabolite signature associated with the gut microbiota in people with colorectal cancer (CRC) or adenomas. This non-invasive, accurate, and rapid detection method would allow the early diagnosis of these conditions.

Metabolomic alterations at all levels

The analysis of serum samples from a discovery cohort (31 healthy individuals, 12 patients with adenoma and 49 with CRC) identified 885 serum metabolites whose relative abundance differed between adenoma or CRC patients and healthy individuals.
We know gut microbiota alterations in patients with colorectal anomalies can reprogram the fecal metabolome; but can they reprogram the serum metabolome? To determine the potential of these markers to predict colorectal anomalies, the researchers performed an analysis of serum and fecal metagenomic metabolites of the gut microbiota in 11 healthy individuals and 33 abnormal colorectal patients. 322 metabolites were found to be associated with the gut microbiota, including species known to be associated with CRC onset and progression (Fusobacterium nucleatum, Parvimonas micra, etc.). An algorithm was then used to accurately identify 8 serum metabolites that distinguished the healthy individuals in the cohort from those with adenomas and CRC (area under the curve 0.96). These metabolites were selected as a predictive panel for colorectal disease: gut microbiome-associated serum metabolites (GMSM).

Towards a predictive model?

This model was tested on a modeling cohort (72 healthy individuals and 120 with colorectal disease) and an independent validation cohort (53 healthy individuals and 103 abnormal colorectal patients) and reliably distinguished adenoma and CRC patients from healthy individuals (area under the curve 0.98 and 0.92, respectively). Lastly, this model was compared to other commonly used detection methods, the carcinoembryonic antigen (CEA) test and fecal occult blood test (FOBT). The GMSM panel was superior to the CEA in discriminating patients from healthy individuals in the validation cohort (area under the curve of 0.92 vs 0.72), and also beat the FOBT in discriminating between the two groups (sensitivity 83.5% vs 65.2%). 

Many studies have been conducted throughout the world recently to identify the special characteristics of disturbances in the gut microbiota of people suffering from mental illnesses. Is their intestinal flora less rich than that of people in good health? Less diversified? Are some species of micro-organisms very well represented? Or conversely are they missing? The stakes are high because if specific characteristics associated with one or more mental illnesses are found in different studies, they could serve as useful markers for the diagnosis of patients, the treatment strategy or the assessment of the response to treatments. However, up to now, these studies provide results that are still contradictory.

Imbalances common to several psychiatric illnesses 

A publication in JAMA (sidenote: JAMA Journal of the American Medical Association   )  Psychiatry is gaining ground by reviewing nearly 60 studies performed on this subject. The objective of its authors is to confirm that mental illnesses are indeed associated with disturbances of the gut microbiota and to determine if these are specific to each illness:

• depression,
• bipolar disorders,
• OCD,
• schizophrenia,
• psychosis,
• anorexia,
• anxiety,
• etc.

Scientists have observed a significant reduction in the richness of the gut microbiota of patients with mental disorders, but little difference in the diversity of species in comparison with the microbiota of participants in good health. Instead of demonstrating specific characteristics for each illness, these studies rather show similar imbalances of the intestinal flora shared by several mental disorders. In particular, these disturbances result in the increase in certain species promoting inflammation and the reduction of other species with an anti-inflammatory action in bipolar disorders, schizophrenia and anxiety.

Confusion factors to be taken into consideration

Finally, the review has made it possible to determine the factors responsible for the variations of results between the studies. On the one hand, the geographical area: diet, so the microbiota and the imbalances in the microbiota are not the same in China as they are in Western countries. On the other hand, the taking of medicines: psychotropic drugs seem to favour dysbioses. Researchers must, therefore, keep these parameters in mind to be able to unveil all the mysteries of the link between the gut microbiota and mental illnesses, for the benefit of patients. 

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Microbiota and obesity: dysbiosis in the hot seat

The gut microbiota, a real ecosystem lodged in our gut is essential for our health. As far as obesity is concerned. it is now known that a lack of diversity in the gut microbiota and the over-representation of some species of bacteria increases the risk of adiposity, insulin resistance and inflammation. So obese patients would have flora that is less rich than that of thin people even though the results are not yet unanimous.

Microbiota and obesity: risk factors

Apart from genetic factors, there are other factors that contribute to the development of obesity in children: The mother's diet during pregnancy, the method of giving birth, nutrition of the newborn (breast or bottle feeding), antibiotic treatment during childhood, etc. The biological mechanisms by which these possible risk factors will influence the development of obesity have not yet been clearly determined. However, the microbiota is suspected and a special interest is taken in it.

Microbiota and obesity: scientifically proven

It is obvious that obesity is a multi-factorial disease. It is therefore too early to raise an exclusive cause and effect link between the microbiota and obesity in humans. However, this link has been proved in animals where studies have shown that the “obese” characteristic can be transmitted from an “obese” donor mouse to a “thin” receiver mouse by faecal microbiota transplantation and vice versa. 

A single study has attempted to transplant the microbiota of thin people into overweight people. No reduction in the Body Mass Index (BMI) (sidenote: Body Mass Index (BMI) Body Mass Index (BMI) assesses the corpulence of an individual by estimating the body fat mass calculated by a ratio between weight ((kg) and height squared (m2). https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmicalc.htm https://www.euro.who.int/en/health-topics/disease-prevention/nutrition/a-healthy-lifestyle/body-mass-index-bmi ) has yet been observed.

Microbiota and obesity: when bacteria control our plate and our weight

Appetite/obesity, how does it work? The relationship between microbiota nutrition and obesity is complex. The modus operandi is as follows: food is digested and then the nutrients are metabolised by the bacteria. The molecules produced such as bile acids (sidenote: Bile acids Bile acids facilitate digestion and absorption of lipids in the intestine. They also exercise hormonal functions and are involved in various metabolic processes. The gut microbiota will modify the bile acids. In return the various bile acids will have an impact on its composition. Staels B, Fonseca VA. Bile acids and metabolic regulation: mechanisms and clinical responses to bile acid sequestration. Diabetes Care. 2009;32 Suppl 2(Suppl 2):S237-S245.  Li R, Andreu-Sánchez S, Kuipers F, Fu J. Gut microbiome and bile acids in obesity-related diseases. Best Pract Res Clin Endocrinol Metab. 2021;35(3):101493.  ) , short chain fatty acids (sidenote: Short chain fatty acids (SCFA) Short chain fatty acids (SCFA) are a source of energy (fuel) for an individual’s cells. They interact with the immune system and are involved in communication between the intestine and the brain. Silva YP, Bernardi A, Frozza RL. The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication. Front Endocrinol (Lausanne). 2020;11:25. ) or other molecules will in turn initiate certain mechanisms which will have an effect on obesity. For example, an altered microbiota will affect the control of fat storage and excessively increase energy recovery. The intestine and the brain will no longer be able to exchange correctly, with a disturbance in appetite and the feeling of satiety.

Microbiota and obesity: personalise our diet for better prevention

It is obvious that our diet has an influence on the composition of our microbiota. The child's microbiota will develop during the first years of life. It reflects his/her living environment and diet. For researchers, this period of life is important for carrying out dietary interventions. How? Via prebiotics which are naturally present in food and which the bacteria adore, and also due to probiotics, which are micro-organisms that we can ingest directly.

Adapting diet depending on the specific nature of one's microbiota. This new approach would provide better prevention of the risks of obesity from childhood onwards. And should this personalised diet become an ally of weight in the fight against obesity, a worldwide scourge which has almost doubled in the space of half a century¹? The range of possibilities - and hope - remains open...

^{1 https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight}

The gut microbiota has been linked to disease progression in several cancers. However, there is limited research detailing its influence in breast cancer. At the same time, antibiotics have an impact on the bacterial population of the gut microbiota. Antibiotic use is common among cancer patients, despite controversy surrounding the benefits. Accordingly, a study evaluating the effect of antibiotics on the gut microbiota and their impact on the clinical course of breast cancer was overdue. A recent study in a mouse model published in iSciences has filled the gap.

Accelerated tumor growth and microbiota depletion in mice receiving antibiotic treatment

Both before and after injection with breast cancer-specific tumor cells, mice were given a cocktail of antibiotics: vancomycin, neomycin, metronidazole, amphotericin, and ampicillin (VNMAA). Compared to the control group, these animals rapidly exhibited significantly accelerated tumor growth and strong depletion of the gut microbiota.

The researchers then focused on the effects of an antibiotic widely used in breast cancer patients: cephalexin. Although cephalexin had a smaller impact on the microbiota than the VNMAA cocktail, it caused a similar increase in tumor growth.

Anti-tumor role of certain gut bacteria

In the mice undergoing antibiotic treatment, metagenomics revealed a dysbiosis which, while not favorable to pathogenic bacteria, adversely affected protective bacteria. Animals treated with VNMAA and cephalexin had a lower relative abundance of bacteria thought to play an anti-tumor role: Lactobacillus reuteri, Lachnospiraceae bacterium, and Faecalibculum rodentium. By simply reintroducing the latter bacteria, the previous level of tumor growth was restored.

Mast cells, drivers of tumor growth in dysbiosis

Antibiotic-induced microbiota disturbances do not have a significant impact on the tumor immune microenvironment. However, they do increase the number of mast cells in the tumor stroma.

The researchers treated both control and VNMAA-treated mice with cromolyn, a mast cell stabilizer. While cromolyn inhibited tumor growth in the antibiotic-treated mice, it had no effect on the controls. These data suggest a potential role for mast cells in breast cancer progression in individuals with antibiotic-induced dysbiosis.

Chemotherapy has significantly improved the overall survival rate of people with cancer. At the same time, the adverse events (sidenote: More than 87% of chemotherapy patients report at least one adverse event. ) related to treatment still have a major impact on patients’ physical (vomiting, diarrhea, constipation, fatigue, hot flushes, etc.) and psychological (depression, insomnia, cognitive disorders, etc.) well-being. Moreover, chemotherapy also suppresses immune responses and increases the incidence of infection and subsequent morbidity and mortality. The gut microbiota is suspected of being associated with both the efficacy and adverse effects of chemotherapy, although few data are available. Hence this literature review, which examined 17 studies (involving 742 patients with different forms of cancer (sidenote: 5 studies on colorectal cancer, 3 on acute myeloid leukemia, 2 on non-Hodgkin lymphoma, 1 on breast cancer, 1 on lung cancer, 1 on ovarian cancer, 1 on liver cancer, and the remaining 3 on various other types of cancer. ) ) on the relationship between the gut microbiota, chemotherapy and chemotherapy’s side effects.

Microbiota, efficacy and toxicity of chemotherapy

Of the 17 studies reviewed, 7 were observational. Of these, 3 assessed the relationship between the gut microbiota, chemotherapy efficacy, and chemotherapy adverse events using fecal samples collected before treatment. Four other studies assessed the relationship between the gut microbiota, chemotherapy, and adverse events using fecal samples collected post-treatment. The results? The gut microbiota is associated with both the effectiveness of chemotherapy and the occurrence of adverse events.

The ten other studies were prospective (allowing causal links to be examined) and analyzed the impact of chemotherapy on the gut microbiota (risk of infection, diarrhea, etc.) using multiple stool samples taken before, during and/or after treatment. The conclusions? Chemotherapy modulates the gut microbiota of cancer patients. This modulatory effect is associated with an increased risk of infection and impacts the effectiveness of the treatment. In addition, the dysbiosis induced by chemotherapy appears to be related to the adverse events.

Biomarker and modulator

These results have significant implications: the gut microbiota may serve as a biomarker to predict the outcome and adverse effects of chemotherapy, while modulating the gut microbiota during treatment may reduce adverse effects and improve treatment efficacy. These hypotheses are supported by previous studies involving lifestyle interventions such as prebiotics and exercise.

This review of the complex relationships between the gut microbiota and chemotherapy highlights the potential for future research to improve patient care. Further results will require international multicenter trials that control for the various confounding factors (age, ethnicity, gender, co-morbidities, drug use, geography, diet, physical activities, etc.).
 

Cervical cancer, the third most frequent female cancer in the world (or even the 2nd in women aged between 15 and 44), is caused by the persistence of the famous papillomavirus (HPV), a public enemy actively tracked down during smear tests. Generally a long precancerous phase, with progressive lesions, precedes the appearance of cancer. Researchers have put forward the hypothesis that the vaginal microbiota might play a part in the risk of contamination with HPV, its persistence and the development of lesions.

Fewer lactobacilli

By studying the microbiota of the cervical mucus of 94 women aged from 18 to 52, researchers have demonstrated that it differs depending on the stage of the disease. The more advanced the lesions, the more the bacterial diversity within the cervical flora for each woman increases and the more the domination of the lactobacilli (rod-shaped bacteria) wanes progressively to the advantage of other bacteria. Unlike the intestinal microbiota, the vaginal microbiota is in equilibrium when it shows low diversity and when the lactobacilli are largely predominant (> 70% of the bacterial community in healthy women). So it is completely the opposite in women with cervical cancer: the diversity is at its maximum and the lactobacilli have lost their impact.

Markers for advanced lesions or cancer

Second observation from the team: the vaginal microbiota of women with high grade lesions or even cancer differs more and more from that of healthy women in terms of the range of bacteria present. New bacterial species (Porphyromonas, Fusobacterium, Prevotella and Campylobacter) seem to go hand in hand with the presence of cervical cancer whilst other bacteria (Sneathia) indicate the presence of high grade lesions. Is it the lesions which destabilise the flora or the imbalance of the flora which participates in the development of the lesions? The causality relationship must still be studied in greater depth.

IS THE VAGINAL MICROBIOTA TO BLAME FOR DYSMENORRHEA?

^{Chen CX, Carpenter JS, Gao X, et al. Associations Between Dysmenorrhea Symptom Based Phenotypes and Vaginal Microbiome: A Pilot Study. Nurs Res 2021 [Epub ahead of print].}

In a pilot study - the first to focus on the link between the composition of the vaginal microbiota during menstruation and the intensity of period pain - 20 women were classified into three groups according to the pain they experienced during their period: “mild localized pain”, “severe localized pain”, or “severe multiple pain and gastrointestinal symptoms”. The vaginal microbiota was analyzed both during menstruation and outside of menstruation. The results showed that the vaginal microbiota composition significantly varied between women as well as over the course of the menstrual cycle, but the composition during menstruation varied even more depending on intensity of pain. In particular, during menstruation, women with more severe dysmenorrhea had a lower abundance of lactobacilli and a higher abundance of potentially pro-inflammatory bacteria.

Although limited in terms of size, age groups studied and ethnic diversity, this pilot study is a first step towards larger studies on associations between the intensity of pain during menstruation and the composition of the vaginal microbiota. The researchers hypothesize that during menstruation endometrial tissue is broken down, releasing compounds (prostaglandins) that may cause uterine muscle contractions and increased sensitivity, thus contributing to menstrual pain. Certain bacteria in the vaginal microbiota may promote the release of these compounds and of pro-inflammatory cytokines that exacerbate the symptoms of dysmenorrhea. If these hypotheses are confirmed, the pilot study would underline the importance of taking into account inter-individual differences and the dynamics of the vaginal microbiota during the menstrual cycle.

CERVICOVAGINAL MICROBIOTA: A MARKER FOR PERSISTENT PAPILLOMAVIRUS INFECTION?

^{Qingqing B, Jie Z, Songben Q, et al. Cervicovaginal microbiota dysbiosis correlates with HPV persistent infection. Microb Pathog 2020; 152: 104617.}

In this new study, the cervicovaginal microbiota of 15 women was analyzed via 16S rRNA gene sequencing, and HPV genotyping was performed. Six of the women showed persistent infection (infection with the same HPV type for more than 12 months), four showed transient infection (infection cleared in less than 12 months) and five were HPV-negative. The three groups showed significant differences in the composition of the cervicovaginal microbiota. In the healthy women and those with transient infection, the Lactobacillus genus predominated, whereas women with persistent infection had a more diverse cervicovaginal microbiota. A statistical analysis revealed 36 bacteria to be associated with transient or persistent infection status, with these bacteria having the potential to serve as biomarkers. Among them, and in line with previous studies, the genera Acinetobacter, Prevotella and Pseudomonas were correlated with persistent infection. On the other hand, Lactobacillus iners was correlated with transient infection. The women with persistent HPV infection had significantly higher concentrations of IL-6 and TNF-α in their cervical secretions and a higher number of regulatory T cells and myeloid-derived suppressor cells in their peripheral blood. The results of this study suggest that changes in the cervicovaginal microbiota may be linked to persistent HPV infection. However, it is not known whether dysbiosis induces persistence of the infection or vice versa. Despite this, the identification of a microbial signature for persistent HPV infection may allow earlier diagnosis, ultimately leading to earlier intervention to eradicate the infection and reduce the likelihood of developing malignant cervical lesions.

FECAL MICROBIOTA TRANSPLANTATION AND FIBER SUPPLEMENTATION TO CONTROL METABOLIC SYNDROME IN OBESE PERSONS

^{Mocanu V, Zhang Z, Deehan EC, et al. Fecal microbial transplantation patients with severe obesity and metabolic syndrome: a randomized double-blind, placebo-controlled phase 2 trial. Nat Med 2021; 27: 1272 -9}

Obesity and metabolic syndrome (MS) comprise one of the greatest health epidemics of the 21st century. MS is associated with increased risk of cardiovascular diseases and all-cause mortality. To establish FMT as a pragmatic therapy for obesity and metabolic syndrome, novel strategies using non-invasive delivery methods in patients suffering metabolic dysfunction are needed. The authors tested oral FMT and dietary fibres supplementation to improve insulin sensitivity. In this double-blind randomized phase II trial, 70 severely obese patients with MS were randomized in four groups. The 1st and 2nd groups received single-dose oral encapsulated FMT followed by high-fermentable (HF) or low-fermentable fiber (LF) supplement for 6 weeks, respectively. The 3rd and 4th group received placebo and HF or LF supplementation. The primary outcome was the evaluation of changes in insulin sensitivity between baseline and after 6 weeks of treatment using the homeostatic model assessment (HOMA2-IR/IS). No serious adverse effects were reported during the intervention. After 6 weeks, insulin sensitivity improved only in the FMTLF group insulin levels also improved, but fasting glycemia, glycated haemoglobin and anthropometric values did not change. FMT resulted increased gut microbial richness, the change was greatest in the FMT-LF group. Phascolarcobacterium, Bacteroides stercoris and B. caccae were associated with HOMA2-IR and insulin sensitivity and may be used for future treatment.

GUT MICROBIOTA, EPITHELIAL DEFENCE AND NEONATAL BACTERIAL MENINGITIS

^{Travier L, Alonso M, Andronico A, et al. Neonatal susceptibility to meningitis results from the immaturity of epithelial barriers and gut microbiota. Cell Rep 2021; 35(13): 109319.}

Group B streptococcus (GBS) is a leading cause of meningitis, pneumonia and sepsis in infants, and 68% of GBS neonatal meningitis are late-onset infections (developing from 7 days to 3 months after birth). This infection may result from intestinal GBS colonization transmitted from mother to child during pre- or post-delivery. The authors examined in mice the reasons of neonatal susceptibility to GBS and showed that it was associated with gut microbiota dependent/independent factors as well as age. Mature gut microbiota resists GBS colonization, strengthens gut barrier function limiting GBS invasion and plays a central role in the maturation of immune system. In neonatal gut, age-dependent Wnt pathway activity in intestinal and choroid plexus epithelia favors GBS translocation due to lower cell-cell junctions polarization. Moreover, gut microbiota immaturity is associated with decreased resistance to GBS colonization and increased vascular-gut barrier permeability, which favors bacteremia. The authors suggest that maturing neonatal microbiota with probiotics and/or prebiotics may help in preventing neonatal bacterial meningitis. In conclusion, fluoroquinolone prophylaxis gives short-term protection against infections but does not increase the risk of cross-resistance to other antibiotics.

MICROBIOTA, STRESS AND SOCIAL BEHAVIOUR

^{Wu WL, Adame MD, Liou CW, et al. Microbiota regulate social behavior via stress response neurons in the brain. Nature 2021; 595(7867): 409-14.}

The microbiota-gut-brain axis (MGBA) is a two-way communication system linking the gut microbiota and brain. MGBA modulates behavior such as sociability and anxiety in mice, however underlying mechanisms remains unknown. In this article, antibiotic-treated mice and germ-free mice showed decreased social activity associated with increased corticosterone level. This stress hormone is produced by the activation of the hypothalamus–pituitary–adrenal axis (HPA). Gut bacteria transplantation from SPF (Specific Pathogen-Free) mice donors corrected social activity and lowered corticosterone level. Glucocorticoid receptors in the hypothalamus were negative regulators of the HPA axis These receptors regulated corticosterone levels and social behaviors, both of these functions were regulated by gut microbiota. In antibiotic-treated mice, genetic ablation of glucocorticoid receptors or chemogenetic inactivation of neurons producing the corticotrophin-releasing hormone (CRH) induce social behaviour reversal. Activation of CRH and glucocorticoid receptor-expressing neurons induced social behavior alterations in mice having normal microbiota, indicating neural pathway regulating social behavior. Finally, neomycin-sensitive bacteria, e. g. Enterococcus faecalis, mediates social behavior. The present results suggest that specific bacteria prevent overactive stress reaction by attenuating corticosterone production mediated by HPA-axis. The detection of neural pathway mediating signals from the gut to the brain may enable procedures that modulate social behavioral disorders.

GUT MICROBIOTA AND BRAIN INFARCT

^{Zhu W, Romano KA, Li L, et al. Gut microbes impact stroke severity via trimethylamine N-oxide pathway. Cell Host Microbe 2021; 29(7): 1199-1208.e5.}

Clinical studies reported that circulating gut-microbiota derived metabolite trimethylamine- N-oxide (TMAO) are associated with stroke. However, the direct involvement of gut microbiota in cerebral vascular diseases (including stroke) is not known with certainty. Circulating TMAO is generated by microbial metabolism of TMA-containing precursors, including choline, which is commonly enriched in a Western diet. By using rodent models of stroke, the authors investigated whether gut microbiota in general or either TMAO or a functioning gut microbial cutC gene (choline utilisation [cut] c gene catalyzes choline-TMA transformation) can impact stroke severity. Germ-free mice were colonized with human gut microbiota from subjects with high or low serum TMAO levels followed by experimental stroke injury. The authors showed that stroke severity was transmissible, and TMAO levels correlated with stroke severity. Specific gut bacterial taxa positively correlate with high TMAO levels, brain infarct size through dietary choline. Gut microbial cutC gene increases host TMAO levels, cerebral infarct size, and functional deficits. In summary, gut microbiota with choline- TMAO pathway increases stroke severity and worsens functional outcome. Western diet (and diet rich in red meat) contains TMA precursors and have been associated with stroke risk. Dietary interventions in patients with high stroke risk merit further investigation. CutC activity is the key factor for stroke severity and TMAO pathway could be a potential target for the prevention or treatment of stroke.