While various species of the gut microbiota are linked to colorectal cancer (CRC), a direct role of bacteria in the onset of carcinogenic mutations has not been demonstrated yet. For example, certain bacteria, including genotoxic strains of E. coli, are more commonly found in the feces of CRC patients than in those of healthy subjects (60% vs 20%). These bacteria carry a DNA unit called pks (polyketide-nonribosomal peptide synthase operon) that encodes enzymes for synthesis of colibactin, a toxin capable of damaging DNA.

An ex vivo signature...

Through repeated luminal injections over five months, a group of researchers exposed human intestinal organoids (sidenote: Organoids Organoids are new ex vivo models of organs, halfway between in vivo models and in vitro cell cultures. The stem cells or partially differentiated cells from which they are obtained spontaneously self-organize into functional tissue in an adapted three-dimensional environment )  to genotoxic E. coli (pks+ E. coli). Sequencing of the organoid genome before and after this exposure showed that colibactin induces a mutation (recombination between the two DNA strands) at a very specific location in the genome. This mutation was then “corrected” (i.e. resolution) by the cells of the organoid via single base substitution (SBS) or insertion/deletion (ID), based on recognizable patterns. These two types of resolution, called SBS-pks and ID-pks, are not observed in organoids exposed either to non-genotoxic E. coli strains or to a simple dye. Therefore, they represent the signature of an exposure to pks+ E. coli.

...confirmed in humans

It remained to be seen whether SBS-pks and ID-pks signatures were present in human tumors. Based on data from more than 5,000 tumors covering dozens of different types of cancer, both signatures are much more commonly found in CRC-derived metastases than in any other cancer type. Moreover, an analysis of seven cohorts of CRC patients showed that 2.4% of the mutations that most frequently lead to CRC were colibactin-induced. Many of these mutations affected the APC gene, which prevents uncontrolled cell proliferation.

A way to prevent CRC?

Another team had previously found these signatures in the colonic crypts of healthy individuals. This suggests that mutagenesis takes place in the healthy colon of individuals who harbor genotoxic strains of pks+ E. coli, increasing the risk of CRC. This cohort also included a few cases of urogenital cancer and head and neck cancer displaying pks signature, which suggests that pks+ E. coli may also act outside the colon. Accordingly, the detection and suppression of pks+ E. coli, as well as the reevaluation of pks-carrying probiotic strains, may reduce the risk of cancer in a large number of individuals.

Ageing is associated with the deterioration of numerous body functions and generalized inflammation, which contribute to frailty syndrome (sidenote: Frailty syndrome Frailty syndrome is diagnosed based on three of the following five criteria: sedentary lifestyle; recent weight loss; exhaustion or fatigue; decreased muscle strength; and slow walking pace. It involves a risk of functional decline, institutionalization, and death, French National Academy of Medicine, 2013.  )  among the elderly. It seems highly likely that diet plays a role in this process, since lack of variety leads to alterations in the gut microbiota thought to increase the risk of frailty. Conversely, it is possible that a balanced diet contributes towards maintaining or restoring the bacterial flora and helps fight frailty. A group of researchers sought to find out whether this is the case, focusing specifically on the Mediterranean diet (sidenote: Mediterranean diet Rich in fruit, vegetables, cereals, oilseeds (nuts) and fish, and low in red meat, saturated fats and dairy products. Lăcătușu CM, Grigorescu ED, Floria M, et al. The Mediterranean Diet: From an Environment-Driven Food Culture to an Emerging Medical Prescription. Int J Environ Res Public Health. 2019 Mar 15;16(6):942. ) .

“Good” bacteria associated with “good” ageing

The Mediterranean diet is the “ultimate” healthy diet, and offers many benefits, including reduced inflammation, lower risk of disease and lower mortality. According to numerous studies, it is also associated with changes in the gut microbiota. The researchers therefore analyzed the gut microbiota of approximately 600 individuals aged between 65 and 79 years who showed few or no signs of frailty. This was done before and after the subjects had followed a normal diet or a Mediterranean diet for one year. With the Mediterranean diet, the gut microbiota remained diverse (associated with good health) and the number of “good” bacteria (associated with decreased frailty, improved brain function and reduced inflammation) increased. The researchers also observed improved memory, increased walking speed and increased strength in participants’ hands.

Bacteria to protect against frailty?

These results confirm the benefits of Mediterranean diet for the elderly, and reveal that part of these benefits is directly linked to changes in the gut microbiota. The results therefore open up new avenues for the prevention of frailty among people at risk, based on direct administration of the “good” bacteria identified in the study.

Recommended by our community

Whether it is the coronavirus or not, any microbe (bacterium, virus or fungus) that enters our body is potentially dangerous. When this occurs, defense mechanisms carefully orchestrated by immune cells and the intestinal flora are put into action to eliminate it. This protective barrier, erected by the intestine, prevents foreign bodies from entering the bloodstream.

Intestinal barrier

The purpose of this immune system-gut alliance is to promote and maintain intestinal balance throughout our lifetime. The gut microbiota forms a microbial lining which prevents bad bacteria from colonizing the gut and multiplying. A balance between intestinal cells and flora creates an environment conducive to the development of good bacteria. On the contrary, any change in this ecosystem alters the interactions involved: a vicious circle sets in whereby inflammation promotes colonization by harmful microorganisms, which in turn exacerbate inflammation. Intestinal cells, for their part, form a natural physical barrier lined with thick mucus which ensures that bacteria, viruses and fungi are confined to the center of the gastrointestinal tract.

Intestinal defense cells

Some immune cells, such as macrophages (sidenote: Macrophages and lymphocytes Macrophages and lymphocytes are white blood cells that act as immune cells. They defend the body by eliminating intruders ) , promote innate immunity, which is quick-acting but non-specific (sidenote: Non-specific action is general and not targeted against a particular molecule or microbe. ) : “I see you, I catch you, I kill you”. The rest, including lymphocytes (sidenote: Macrophages and lymphocytes Macrophages and lymphocytes are white blood cells that act as immune cells. They defend the body by eliminating intruders ) , are part of the adaptive immune system, which mobilizes more slowly, is specific (sidenote:  Specific action is targeted against a particular molecule or microbe. )  and remembers previous infections: “I recognize you, I catch you, I kill you”. Among other functions, cells of the adaptive immune system produce antibodies. Precise control of the immune system prevents excessive inflammation in response to good bacteria and avoids food allergies by allowing tolerance of nutrients. (sidenote: Nutrients Nutrients are small molecules released during the digestion of food. )

Highly synchronized cooperation

Bacteria are in constant dialogue with the intestine, either directly or through the transmission of signals. The messages received enable the immune cells to be on constant alert and to strengthen the intestinal barrier where necessary. They also facilitate activation of the innate and adaptive immune responses. According to studies carried out on animals, these exchanges have an impact on other organs too: a diet rich in fiber enables the microbiota to produce small molecules that have a beneficial effect on pulmonary allergic responses. Indeed, the microbiota can slow excessive inflammation even at a distance from the intestine (infection, stress, seasonal allergy or food intolerance (sidenote: Food intolerance occurs when the immune system incorrectly identifies food molecules as harmful substances. ) ).

Boosting our microbiome

Even if these mechanisms are still to be confirmed in humans, and although studies on a possible link between COVID-19, microbiota and the immune system are incomplete, a healthy lifestyle which takes care of the microbiota (with a balanced diet for example) seems to be the best way of maintaining our intestinal barrier.

Fever, cough and respiratory distress are three symptoms of COVID-19, but they are not the only ones. A first study^a has reported that half of patients testing positive for coronavirus also complain of digestive symptoms such as loss of appetite, diarrhea and, to a lesser extent, vomiting or abdominal pain.

Digestive symptoms

Excluding loss of appetite, which is not specific to intestinal disorders, about one in five patients involved this study had strictly digestive symptoms which worsened with the aggravation of COVID 19.^a The incidence of diarrhea varied widely between studies (2%-34%)^a,b but the genetic material of the virus –or even active virus (i.e. able to spread)– was found in patients’ feces^c-e, suggesting that it may multiply in our digestive system. Another study showed an imbalance of the intestinal flora (dysbiosis) in two patients aged 65 and 78 years who subsequently died from COVID 19^f; however, the link between intestinal dysbiosis and COVID-19 seems of little relevance here since it is well known that elderly people typically display gut flora imbalances.^g Lastly, a debate^h has recently kicked off about the potential role played by Prevotella bacteria in the infection, but to date no scientific evidence has confirmed any such role.

At-risk patients

Admittedly, these initial findings are open to criticism, since the studies were carried out in a limited number of patients^f, and some of them were not subject to peer review prior to publication.^f Despite this, the findings warrant caution. For example, on March 16, 2020, the ANSM (sidenote: ANSM French Agency for the Safety of Medicines and Health Products )  enhanced precautionary measures in the case of fecal microbiota transplants in order to prevent intestinal infections due to the transmission of other pathogens through Clostridium difficile treatment. Enhanced precautions will also apply to patients suffering from inflammatory bowel disease, particularly to those treated with immunosuppressants, who are more susceptible to viral infections, even if specific data^b are still lacking. While they are not advised to discontinue immunosuppressive treatment (the risk of flare-up far exceeds other), they must carefully comply with prevention measures.^b

Fever, cough and respiratory distress are three symptoms of COVID-19, but they are not the only ones. A first study¹ has reported that half of patients testing positive for coronavirus also complain of digestive symptoms such as loss of appetite, diarrhea and, to a lesser extent, vomiting or abdominal pain.

Digestive symptoms

Excluding loss of appetite, which is not specific to intestinal disorders, about one in five patients involved this study had strictly digestive symptoms which worsened with the aggravation of COVID 19¹. The incidence of diarrhea varied widely between studies (2%-34%)^1,2 but the genetic material of the virus –or even active virus (i.e. able to spread)– was found in patients’ feces^3,4, suggesting that it may multiply in our digestive system. Another study showed an imbalance of the intestinal flora (dysbiosis) in two patients aged 65 and 78 years who subsequently died from COVID 19⁵; however, the link between intestinal dysbiosis and COVID-19 seems of little relevance here since it is well known that elderly people typically display gut flora imbalances⁶. Lastly, a debate⁷ has recently kicked off about the potential role played by Prevotella bacteria in the infection, but to date no scientific evidence has confirmed any such role.

At-risk patients

Admittedly, these initial findings are open to criticism, since the studies were carried out in a limited number of patients⁶, and some of them were not subject to peer review prior to publication⁶. Despite this, the findings warrant caution. For example, on March 16, 2020, the ANSM (French Agency for the Safety of Medecines and Health Products) enhanced precautionary measures in the case of fecal microbiota transplants in order to prevent intestinal infections due to the transmission of other pathogens through Clostridium difficile treatment. Enhanced precautions will also apply to patients suffering from inflammatory bowel disease, particularly to those treated with immunosuppressants, who are more susceptible to viral infections, even if specific data² are still lacking. While they are not advised to discontinue immunosuppressive treatment (the risk of flare-up far exceeds other), they must carefully comply with prevention measures²

E-cigarettes are extremely popular among young Americans since they are used by more than 20% of high- school students and almost 5% of junior high students in the United States. Portrayed until now as a healthy alternative to tobacco, they no longer seem so harmless. The latest generation of e cigarettes have nicotine and toxicity levels comparable to those of tobacco and are thought to be responsible for a cascade of inflammatory reactions through their effect on the oral microbiota. However, a study published in 2018 had cleared e-cigarettes of having any adverse effects on the gut, mouth or saliva microbiotas.

Oral microbiota imbalance among vapers

To measure the impact of vaping on the oral microbiota, a team divided around a hundred volunteers into three groups: smokers (half a pack per day on average), vapers (half an e-cigarette per day) and non-smokers. Their first finding was that the severity index of tooth, gum and mouth diseases among vapers (42.5%) was significantly lower than among smokers (72.5%), but markedly higher than among non-smokers (28.2%). The second finding was that vapers showed an imbalance (dysbiosis) of the oral microbiota comparable to that of smokers. Their saliva was generally richer in bacteria than that of non-smokers, and displayed proliferation of various species harmful to oral health. In addition, human cells exposed to e-cigarette aerosols show increased sensitivity to bacterial infections compared to cells exposed to air.

Understanding long-term effects

According to the authors, the results of this study–carried out both on human subjects (in vivo) and on cells (in vitro)–confirm that vaping leads to an imbalance of the oral microbiota and increases susceptibility to infections (cavities, periodontitis (sidenote: periodontitis Inflammation of the membrane surrounding the teeth ) ). However, this link remains to be proven, and more in-depth studies on the overall effects of vaping on oral, respiratory and cardiovascular health, particularly over the long term, seem necessary.

An intestine-lung axis

Researchers recently rediscovered the critical role the intestinal microbiota plays in our defense mechanisms against infections. Changes in the composition of the intestinal microbiota (called dysbiosis) can affect our immune response and, as a result, can be involved in the onset of certain respiratory diseases like asthma, chronic obstructive pulmonary disease (COPD), and respiratory infections. Australian researchers have shed light on the connection between the microbiota and the “gut-lung” axis.

Focus on asthma and COPD

In the case of asthma, beyond revealing intestinal dysbiosis, a reduction of certain bacterial components in the stool (lipopolysaccharides) seems to be associated with a risk of developing symptoms. In COPD, it appears to be difficult to specify whether changes in the intestinal microbiota or the respiratory microbiota are the cause or the consequence of the disease. Nevertheless an undeniable "intestine-lung" link exists.

The protective effect of the intestinal microbiota

Lastly, for respiratory infections, the intestinal microbiota’s protective effect has largely been recognized: several studies have shown a link between imbalance in the microbiota, disruptions in immune defense mechanisms, and the development of bacterial or viral respiratory infections. Certain probiotic strains (particularly certain lactobacilli and certain bifidobacteria) have shown clinical usefulness in these circumstances. According to the authors, although additional studies are necessary to further understand the relationship between the intestinal microbiota and respiratory diseases, this result indicates the potential for the emergence of new therapeutic options.

To know more about Intestinal microbiota

By 2003, the complete human genome had been decoded. In 2008, genome decoding was launched for human microbial populations (MetaHIT and HMP (sidenote: Human Microbiome Project ) projects), followed by an analysis of their health roles (IHMC (sidenote: International Human Microbiome Consortium ) ). While these databases are essential for understanding the structure and function of microbial communities and their role in diseases, they mainly focus on the gut microbiota. This situation changed in early 2020 with the publication of VIRGO (sidenote: Vaginal integrated non-redundant gene catalog ) , a gene catalog for the vaginal microbiota.

VIRGO: the most complete vaginal gene catalog

VIRGO was built using metagenomic data (n = 264) and data from complete genomes (n = 308) gathered through urogenital samples and isolates. For the moment, the database mainly relates to bacteria, containing only a few viral and fungal gene sequences. It catalogs almost a million non-redundant (sidenote: That do not create duplicate code for the same protein )  bacterial genes, classifying them both by taxonomic rank and function. VIRGO covers more than 95% of human vaginal microbiota and can be used for various ethnic groups (sidenote: North America, Africa and Asia ) , making it possible to characterize genes and analyze their abundance and expression in the vaginal microenvironment. It has already shown that there is much more intra-species diversity within the vagina than previously thought, to the point of calling into question the idea that a major strain of Lactobacillus is dominant.

VOG: protein families grouped by function

The genes identified in VIRGO were then translated and grouped by protein family and function in a second catalog, VOG (Vaginal Orthologous Groups). The team used this catalog to search for new protein variants. The result was the identification of a previously unknown alanine-to-valine substitution in the protein sequence of a toxin excreted by Gardnerella vaginalis. The catalog will therefore make it possible to identify different variants of the same protein, suggest a biological significance for these variants and put forward new hypotheses.

A fast and accurate tool

VIRGO is a fast, accurate and multi-faceted tool for characterizing vaginal microbiota: it provides a global view of vaginal bacteria groups and has a gene-centric design that allows characterization by function and taxonomy; it also has high scalability, high sensitivity–making it possible to characterize low-abundant bacteria–, and is a simple tool for assessing genetic richness and intra-species diversity. It will be particularly valuable for users with limited computer skills, a large volume of data to sequence, and/or a limited computer infrastructure.

The bladder is not a sterile environment and the recent discovery of the urinary microbiota has opened up a whole new field of research. In this light, a cross-sectional study was carried out on 224 continent adult female patients at a large medical center in the United States, who were aged 48 years on average and were mostly Caucasian (66%) and overweight (average BMI (sidenote: Body Mass Index.  Ratio of weight in kg to square of height in sq.m ) of 29.96 kg/m2). The subjects underwent a physical examination for a potential prolapse and were asked to fill in a questionnaire (overactive bladder, quality of life, weight, age, etc.). A urine sample taken by catheter was used to characterize their urinary microbiota.

Two methods of choice

Three methods of analysis were compared: the standard method, the expanded quantitative urine culture, or EQUC protocol (larger volume of urine, incubation under various conditions, extended incubation period) and RNA sequencing. With the standard method, bacteria were detected in 13 samples (6%), with the EQUC protocol in 115 (51%), and with RNA sequencing in 141 (63%), of which 89 were shared with the EQUC method. Therefore, the EQUC protocol and/or RNA sequencing appear to be the methods of choice, whereas the standard method is not recommended due to the high percentage of false negatives it produces.

Different urotypes

The results show that the microbiota in the bladder is variable, permitting the definition of urotypes based on the predominance (> 50%) of a taxon. The most common urotype was that dominated by Lactobacillus (19%), with no differences due to age, menopausal status, parity, sexual relations or even ethnicity (although the vaginal microbiota of black women is known to be more frequently dominated by lactobacilli). This was followed by the Streptococcus, mixed (no single taxon dominating), Gardnerella and Escherichia urotypes. The Gardnerella urotype was more common in younger women (average age of 36) and Escherichia in older women (average age of 60). The mixed urotype was frequently found in African American women (46%).

Causes and consequences?

Hormones may explain these differences in urotype, especially since they are known to have a beneficial effect on the growth of Lactobacillus in the vagina and lower urinary tract. However, the biological consequences remain a mystery. The different urotypes may provide protection from or result in a predisposition to various urinary disorders, including incontinence, overactivity or infections. In any case, the experts insist that medical treatment should preserve or restore the native urinary microbiota, particularly lactobacilli, as the disruption of this microbial community may increase susceptibility to infection.