New study has identified a specific clade of the bacterium Fusobacterium nucleatum (sidenote: Fusobacterium nucleatum Fusobacterium nucleatum is a Gram-negative, anaerobic bacterium commonly found in the human oral cavity. It plays a role in periodontal diseases and has been associated with various infections and inflammatory conditions. Fusobacterium nucleatum is notable for its ability to adhere to and invade host tissues, facilitating interactions with other microorganisms and host cells. ) (Fn) that dominates the colorectal cancer (sidenote: Colorectal cancer Colorectal cancer is a type of cancer that begins in the colon (large intestine) or the rectum. It typically starts as small, benign clumps of cells called polyps that form on the inner lining of the colon or rectum. Over time, some of these polyps can become cancerous. ) (CRC) niche, revealing significant insights into the bacterium's role in cancer progression. ¹ This groundbreaking study, led by Fred Hutchinson Cancer Center researchers, uncovers genetic and functional distinctions in Fn strains associated with CRC, highlighting potential targets for therapeutic interventions.

Identifying the culprit

The research team collected and sequenced genomes from 135 Fn strains, including 80 from healthy oral cavities and 55 from CRC tumors. Using advanced genomic techniques, they performed a pangenomic analysis, which identified 483 genetic factors enriched in CRC-associated strains. The findings revealed that the Fn subspecies animalis (Fna), previously considered a single subspecies, is actually composed of two distinct clades: Fna C1 and Fna C2. Among these, only Fna C2 was found to dominate the CRC tumor niche, suggesting a unique role in cancer development.

Genetic and functional Insights

Further analysis showed that Fna C2 possesses 195 genetic factors associated with increased metabolic potential and gastrointestinal colonization, distinguishing it from Fna C1. This clade-specific genetic repertoire includes genes that enhance the bacterium's ability to invade host tissues and evade immune responses. The study also demonstrated that Fna C2-treated mice developed significantly more intestinal adenomas compared to those treated with Fna C1 or control groups. This suggests that Fna C2 not only colonizes CRC tumors but also actively promotes tumor growth.

Implications for treatment

These findings have profound implications for understanding the microbiome's role in CRC and developing targeted treatments. The study highlights the potential of focusing on Fna C2 for therapeutic interventions. For instance, identifying and targeting the specific metabolic pathways and virulence factors unique to Fna C2 could lead to new strategies for preventing or treating CRC. Additionally, the research underscores the importance of considering bacterial clades rather than species alone in microbiome studies, as significant differences can exist within subspecies.

Is there an axis of communication between the gut and germ cells? Yes, according to a new study published in Nature. ¹

Dysbiosis, harmful to the reproductive system and future children

Researchers at the European Molecular Biology Laboratory in Heidelberg and Rome induced gut dysbiosis in male mice by administering either non-absorbable antibiotics (which do not cross the gastrointestinal epithelium) or osmotic laxatives. They then mated them with healthy females and analyzed their offspring. 

Result: the pups suffered not only from lower birth weight and severe growth restriction, but also an early mortality rate 3.5 times higher than that of litters from healthy males.

Leptin, a key signaling factor?

Even more interestingly, in male mice mutant for the leptin gene (mimicking the effect of dysbiosis on leptin gene activity), the researchers noted characteristics similar to dysbiotic males (lower testicular weight and abnormal seminiferous tubules). Their sperm also showed changes in the abundance of certain "microRNAs" known to play a role in placental development during gestation.

By crossing these mutants with normal females, the researchers noted that the embryos showed a significant number of genes differentially expressed compared with embryos from healthy males. For the researchers, this demonstrates that leptin may well be an important signaling molecule in the gut-germline axis.
 

Severely disrupted placental development

Analysis of fetuses from mating with antibiotic-treated males and their placentas showed down-regulation of several important factors in placental development.

Among the main genes differentially expressed in placentas from crosses with antibiotic-treated males versus placentas from crosses with healthy males, the researchers found several clinical markers of placental insufficiency, such as those for pre-eclampsia.

Also present were:

• reduction of certain areas of the placenta (labyrinthine zone)
• altered placental vascularization
• a decrease in the placental growth factor

In a nutshell

For the first time, this study demonstrated that the environment can, via modulation of the gut microbiota, lead to sperm defects that can alter placental function and, therefore, the health of future children. It now remains to be seen whether a gut-germline axis also exists in humans... More to follow!

Should a man wishing to have children postpone conception if he has been prescribed antibiotics, which are likely to cause gut dysbiosis?

It is quite possible, according to a new study ¹ that, for once, highlights men's responsibility for the future health of their offspring. Conducted on mice, this study shows that males suffering from dysbiosis at the time of mating father unhealthy offspring. Fortunately, when the microbiota is rebalanced, this transmission no longer occurs.

Transgenerational effects of gut dysbiosis

To reach this discovery, researchers at the European Molecular Biology Laboratory ² in Heidelberg and Rome exposed male mice to 6 weeks of antibiotics. The aim was to induce 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.   ) in the mice. They then mated them with healthy females, and the litters were analyzed after 3 weeks.

The result: compared to the offspring of fathers without dysbiosis (controls), mouse pups conceived by "dysbiotic" fathers:

• had a lower birth weight (a risk factor for diseases such as diabetes), 
• suffered more from stunted growth,
• had a higher mortality rate in the first 2 months.

To explain these surprising results, the scientists analyzed the reproductive systems of the antibiotic-treated males.

A direct impact on placental development

They noted that their testes had reduced size and sperm count and showed significant hormonal and metabolic changes. The sperm showed differences in certain molecules involved in the development of the placenta.

These data prove that the microbiota and germlines (the cells that transform into sperm) communicate with each other, and that there is therefore a "gut-sperm axis." 

• When analyzing the placentas of females mated with dysbiotic males during gestation, the researchers noted:
• poor placental vascularization, which could explain certain abnormalities in the offspring;
• the presence of markers similar to those of pre-eclampsia, a disease linked to abnormal placental development, responsible for intra-uterine growth restriction.

Towards a better pregnancy?

This is the first time that this kind of effect of the microbiota on the male reproductive system has been demonstrated in mammals. 

Is there also a gut-sperm axis in humans? As yet, this has not been confirmed, and further studies will have to be carried out. 

Considering that our lifestyles are likely to cause dysbiosis (poor diet, pollution, medications, etc.), proof of the existence of such an axis could pave the way for innovative approaches to ensure better reproductive health and more optimal pregnancies.

Although immunotherapy has revolutionized cancer treatment, its effectiveness varies greatly from one patient to the next. The gut microbiota seems to be involved in outcomes, with gut microbiota composition thought to modulate immune responses to tumors. Various manipulations of the gut flora have been explored in recent years, among them fecal microbiota transplantation (FMT). A counter-intuitive Chinese study ¹ has shown that the microbiota of elderly donors may be particularly beneficial when it comes to immunotherapy responses.

Better results in elderly patients

To reach this conclusion, the researchers first carried out a meta-analysis of 25 studies involving 2,985 patients. They found that elderly cancer patients respond better to immunotherapy and have a longer life expectancy after treatment. A regression analysis even showed a quasi-linear relationship between age and progression-free survival. The pivotal age is sixty: before this age, the younger you are, the poorer the results; whereas after this age, the older you get, the more the results exceed those observed on average. 

The immunity avenue

To understand the underlying mechanisms, the researchers turned their attention to the immune system, the target of immunotherapy. They showed that aging is accompanied by increased immune dysfunction and what they describe as a depletion of T cells over time. These age-associated T cell alterations could be mediated by the gut microbiota: an FMT of gut microbiota from elderly donors improves responses to immunotherapy, regardless of the recipient’s age.

Which bacteria?

Which gut bacteria promise the best response to treatment? Those present in an enterotype (sidenote: Enterotype A specific gut bacterial composition type in humans, similar to blood groups. Three distinct types have been identified in humans, characterized by a dominance of either Bacteroides, Prevotella, or Ruminococcus. ) that tends to become richer with age, characterized by Bacteroides, Clostridiales, Bilophila, and Faecalicatena. 

A series of experiments on a mouse model confirms the potential of these bacteria: fecal transplantation of this specific enterotype, whether from an elderly donor or a young donor (young people also possess this enterotype, but in less abundance), modifies the gut microbiota of recipient mice and improves their response to immunotherapy (the tumor grows less in weight and volume). How? By boosting T cell cytotoxicity.

The microbiota, made up of trillions of micro-organisms (bacteria, viruses, fungi, etc.), lives in our intestines, on our skin, and in our mouths, noses, and lungs. These organisms play a crucial role in our well-being by facilitating digestion, stimulating our immune system, and protecting us against infectious diseases. Beyond these functions, however, the microbiota also influences our mood, our metabolism, and even our longevity. Alteration of this delicate balance, often due to factors such as diet, lifestyle or medication, can lead to major health problems, ranging from gastrointestinal disease to cardiovascular disorders and depression. Therefore, maintaining a healthy microbiota in all these areas of the body is essential for our overall health and well-being.

About the Biocodex Microbiota Institute

The Biocodex Microbiota Institute is an international knowledge hub dedicated to human microbiotas. Available in 7 languages, the Institute is aimed at both healthcare professionals and the general public, to raise awareness of the vital role that this part of the body plays in our health. The primary mission of the Biocodex Microbiota Institute is educational: to promote the importance of the microbiota for everyone.

Medication, lifestyle, and hormonal changes during pregnancy are just some of the factors that can disrupt the temperature, humidity, pH, and protective barrier of the vaginal environment. These changes can facilitate the development of pathogenic bacteria and threaten the healthy dominance of Lactobacillus in the vaginal microbiota. This can lead to genital and urological diseases, since the anatomical proximity of the urethra and vagina facilitates close relations between their respective microbiomes.

Incontinence often accompanied by dysbiosis

Is stress urinary incontinence (SUI) part of the growing list of such pathologies? Yes, according to the results of a study ¹ of 32 post-partum patients in a hospital in Hunan province, China, 13 of whom suffered from SUI and 19 of whom did not. While 42.1% of the non-SUI group presented a vaginal dysbiosis, an imbalance in the vagina’s microbial flora, this figure rose to 84.6% for patients with SUI. In other words, vaginal dysbiosis was twice as common – indeed, almost systematic – in the mothers suffering from SUI. Their flora showed an increased relative abundance of Gardnerella, Streptococcus, Prevotella, Dialister, and Veillonella.

An over-connected microbiota?

To unravel the relationships between the various vaginal microorganisms potentially involved in SUI, the researchers carried out what is known as a network co-occurrence analysis of the patients’ microbiota. In other words, they mapped the potential links between various bacteria. They found that the vaginal microbiota of the SUI patients was much more interconnected and complex: when the links between the bacteria were mapped, the network of the non-SUI group displayed 96 nodes and 133 edges, compared with 200 nodes and 409 edges for that of the SUI patients. In general, microbial communities with a high degree of interconnectedness are considered less stable and therefore more susceptible to imbalance.

Stimulating and remobilizing the immune system to recognize and eliminate cancer cells: this is the principle behind immunotherapy, which has been revolutionizing cancer treatment since the 2010s. There is, however, one limitation: in some patients, it is not very effective.

Studies suggest that the gut microbiota may influence the outcome of this treatment, with certain bacteria living in our digestive tract secreting molecules capable of boosting our immune system in its fight against the proliferation of cancer cells. Some researchers have attempted to modify their patients’ gut flora prior to immunotherapy so as to stimulate the treatment. One way of doing this is via fecal microbiota transplantation.

Microbiota of seniors is preferable

If you were to receive a fecal microbiota transplantation (now a recognized therapeutic solution, or under study as such, for many diseases), you would tend to choose a young, healthy donor. So would researchers. However, they may have to revise this position and instead opt for stools from healthy eighty-year-old donors.

A recent study ¹ has shown that people over sixty respond better to immunotherapy, and that the older they are, the more their survival defies prognosis. But why?

Since with age, their gut microbiota seems to evolve towards a set of bacteria more favorable to the outcome of immunotherapy. In fact, by transplanting these bacteria typical of senior citizens into cancer-stricken mice prior to immunotherapy, tumor growth was reduced to a greater extent than without fecal transplantation.

What explains these results? At first glance, because these “elderly” bacteria give a “youthful” boost to an immune system that tends to become depleted with age. In this respect, it seems that the value of healthy microbiota increases with age.

Often considered taboo, urinary stress incontinence affects somewhere between 1 in 5 or 1 in 3 women, depending on the study. Motherhood and age increase the risk of these uncontrolled leaks, which can occur when lifting a full shopping bag, coughing, jumping, sneezing, or even laughing. Two mechanisms have traditionally been implicated: a weakening of the perineum (the muscular “hammock” which holds back the urogenital organs), particularly during pregnancy, and a weak urinary sphincter, the ring-shaped muscle that opens or closes the urethra, through which the bladder empties. According to a Chinese study ¹ published in 2024, the vaginal microbiota may also play a role.

Incontinence linked to vaginal dysbiosis

The study shows that 84.5% of young mothers suffering from urinary incontinence present a vaginal microbiota imbalance, compared with 42.1% of mothers not suffering from urinary incontinence. Instead of a healthy vaginal flora where Lactobacillus dominates, the vast majority of young mothers suffering from incontinence present a vaginal flora in which Gardnerella, Streptococcus, Prevotella, Dialister, and Veillonella hold more ground.

Careful readers will ask what connects the vaginal flora to urinary leakage (i.e. to the urinary flora). The answer is simple: the anatomical proximity between the urethral and vaginal orifices. These two regions are separated by just a few millimeters, facilitating close relations between their microbiomes. In fact, previous studies have repeatedly shown the existence of links between vaginal bacteria and urogenital diseases, i.e. diseases of the urinary and/or vaginal system.

An overly interconnected vaginal microbiota?

Now back to the subject of bacteria in women suffering from post-partum urinary incontinence. Another characteristic of these women’s flora is a hyper-interconnectedness between the microorganisms inhabiting their vagina. In other words, a highly developed network of relationships between the various microorganisms. This is not a good sign: in general, microbiota with a high degree of interconnectedness are considered less stable and therefore more susceptible to imbalance and dysbiosis.

Could you talk about the claims made on the video from a clinical perspective?

This drug increases GLP-1, which is a hormone primarily produced by the endocrine cells (also called enteroendocrine cells) in the gut. It boosts the secretion of insulin (incretin effect), slows down gastric emptying and stimulates the sensation of being full, making you feel less hungry.

What about fibre and taking a probiotic?

It is well known that dietary fibre, especially soluble fibre, can slow down gastric emptying, making you feel full and help control your appetite. Fibre can also help stabilise blood sugar levels by slowing down the absorption of carbohydrates, which can be beneficial in diabetic patients. What’s more, fibre-rich food often has a lower energy density, which can help reduce the overall calorie intake and potentially help patients to lose weight when eaten as part of a balanced diet. In terms of the gut microbiota, I agree with Dr. DeDecker about the fact that most fibre has a prebiotic effect and will nourish certain gut bacteria, which are then able to produce short-chain fatty acids (SCFAs) through fermentation, and these SCFAs can increase GLP-1 levels.

I would, however, qualify the statements about the bacterium she mentions, Akkermansia muciniphila, which she credits with tremendous benefits in terms of regulating energy metabolism and insulin sensitivity, as some studies have suggested it plays an indirect role in regulating the secretion of intestinal peptides such as GLP-1. However, this is preclinical data, and the link could be a fairly indirect one. Thus, there is no evidence to claim that supplementation with this bacterium could increase GLP-1 secretion and lead to weight loss.

Why do you think that this video has attracted so much attention? 

In my opinion, it was very easy for this video to create a buzz because it deals with weight loss, and in the West with our high rates of overweight and obese people (50-60% of the population), there are many who dream of being able to lose weight without changing their lifestyle, particularly their diet. So if you suggest that a natural method exists to lose 20% of your bodyweight without taking a drug, you can easily see why it appealed to so many people.

Would you give this information to your patients?

What could be the risks and/or pitfalls? That’s my personal opinion and I think that Dr. DeDecker’s comments are somewhat misleading, because neither taking any kind of probiotic nor increasing dietary fibre has shown any benefit in terms of weight loss, let alone a 20% one. However, despite these misgivings, I do think what she has to say is interesting as it could have the positive effect of reducing the misuse of anti-diabetic medication, as well as raising public awareness of the impact of the gut microbiota on our health. And, more importantly, she is encouraging people to eat more fibre. The current consumption of fibre in Western countries (less than 20 g/day) is well below the World Health Organisation’s recommendations (25-30 g/day), and only 5% of Americans eat enough fibre.