Immune checkpoint inhibitors (ICI) represent a major breakthrough in the treatment of certain cancers, offering patients an overall survival superior to that expected with chemotherapy, notably in non-small-cell lung cancer (NSCLC) and melanoma. However, some patients do not respond to this treatment as hoped. This difference may be linked in part to the gut microbiota, which is thought to influence the effectiveness of ICIs.

Akk in lung cancer: neither too little nor too much

A first retrospective multicenter study analyzed the microbiota of 338 French patients with advanced NSCLC. The aim was to predict a positive clinical response to anti-PD-1, a type of ICI treatment. More specifically, the investigators sought to confirm previous results obtained in smaller cohorts suggesting that the composition of the gut microbiota, and more specifically the presence of the bacterium Akkermansia muciniphila (Akk), could serve as a biomarker of response and survival at twelve months.

The results? The relative abundance of Akk was clearly associated with clinical benefit (better response rate, better survival). Moreover, the presence of Akk in the gut was an indicator of the richness of the intestinal ecosystem. It was associated with a specific bacterial community linked to health or immunogenic status, represented by Ruminococcacae and Lachnospiraceae, as well as B. adolescentis and I. butyriciproducens. 

However, good survival rates require the right abundance of Akk, neither too little nor too much. Indeed, antibiotic use (20% of cases) favored an overabundance of Akk and of the genus Clostridium, both of which are associated with resistance to ICI and an unfavorable outcome (reduced survival). Thus, it appears that antibiotic-induced dysbiosis reduces beneficial bacteria associated with survival (such as Ruminococcus), in favor of harmful bacteria associated with immunoregulatory or pro-inflammatory pathways (such as Escherichia coli and Clostridium bolteae). Therefore, the relative abundance of Akk represents a potential biomarker (favorable or unfavorable) to refine the stratification of NSCLC patients receiving anti-PD-1 immunotherapy. It may even provide a way of improving responses to treatment via Akk supplementation.

Relationships more complex than expected

A second study based on five previously published cohorts (n = 147) and five new cohorts (n = 165) confirmed that the gut microbiome is associated with response to ICIs and survival in advanced melanoma. However, this association was found to be cohort dependent. In other words, each cohort had its own signature. Consequently, no single species could be regarded as a fully consistent biomarker across studies. Instead, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp., and Akk., may serve as such.

Thus, this second study confirms what the first study suggested: the role of the human gut microbiota in responses to ICI is more complex than previously thought. Neither the presence or absence of any single bacterial species, nor the abundance thereof, as with Akk., is sufficient to define responders or non-responders to ICI treatment.

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Vaginal dryness, itching, frequent urination, pain during intercourse... The period following menopause (postmenopause) is not always easy.
Genitourinary syndrome of menopause (GSM)¹ is a condition whose symptoms can mostly be attributed to the estrogen deficiency typical of menopause. Displaying various degrees of severity, the condition can be treated via hormonal treatments such as estradiol vaginal tablets, or non-hormonal treatments such as vaginal moisturizers.
The question is, what impact do these treatments have on vaginal pH, the vaginal microbiota, and metabolites produced by the microorganisms contained in it?

Importance of vaginal microbiota for health

We know that the bacteria in the vaginal microbiota contribute to maintaining a healthy vaginal environment. Unlike the gut microbiota, the vaginal microbiota is balanced when it is not very diverse and is composed mainly of lactobacilli. Some of these bacteria produce lactic acid, which maintains the vagina’s acidic pH (pH ≤ 4.5), thus preventing the growth of pathogens. At menopause, estrogen levels decrease significantly. As a result, vaginal pH increases and the vaginal flora undergoes a change (fewer lactobacilli and greater bacterial diversity).²

Treatments have different impact on vaginal microbiota

This new clinical study³ involved 144 postmenopausal women (mean age 64) experiencing moderate to severe vulvovaginal discomfort. The researchers compared the impact on the microbiota of an estradiol vaginal tablet, a moisturizing gel, and a double placebo (tablet and gel with no active compound).

At 12 weeks, 80% of women in the estradiol group had vaginal bacterial communities dominated by Lactobacillus and Bifidobacterium, compared to only 36% in the moisturizer group and 26% in the placebo group. Moreover, in the women treated with estradiol, more than half of the metabolites in the vaginal fluid changed, with an increase in lactate production almost certainly contributing to the marked decrease in pH in this group.

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Belgium

Finland

France

Mexico

Portugal

Russia

United States

What has the national grant allowed to discover in your microbiota research area?

The Foundation Portuguese grant allowed us, in a first step, to understand the impact of maternal obesity on the acquisition and maturation of the child’s gut microbiota throughout the first year of life. In early life, the establishment, development, and maturation of the microbiota are shaped by microbial and host interactions, in which the mother plays a key role as she represents the most important source of microorganisms. The transfer of obesogenic microbiota between mother and child has been suggested as a possible pathway for the intergenerational transmission of obesity. Since the early-life represents a critical window for immune stimulation, gut dysbiosis can compromise the development of a balanced immune phenotype. Therefore, our second step will unravel the impact of a dysbiotic and obesogenic maternally acquired gut microbiota on the immune system priming.

What are the consequences for the patient?

With Biocodex Microbiota Foundation support, we anticipate understanding the impact of maternal obesity on the child's gut microbiota and unraveling the impact of early life dysbiotic microbiota on the immune system stimulation and regulation up to one year after delivery. The understanding of how dysbiotic maternally acquired gut microbiota impacts immune system priming may reveal new strategies for disease prevention through early-life gut microbiota manipulation, opening new paths for the development of innovative and personalized diagnostic and therapeutic tools.

BMI 22.15

What has the national grant allowed to discover in your microbiota research area? 

"This grant allowed us to better understand the pathogenesis of cirrhosis and the possibility of the impact of probiotics on some links in it."^1,2

What are the consequences for the patient?  

"The results of our study may show the benefit of using probiotics for the treatment of cirrhosis, which may improve the quality of life and prognosis of these patients."

BMI 22.14

Immunotherapy is now a common treatment for non-small-cell lung cancer (NSCLC). However, only 35% of patients experience long-term benefits from this treatment. Identifying biomarkers of response to immunotherapy may thus improve patients’ chances of survival.

Akkermansia muciniphila under the spotlight

Researchers at the Gustave Roussy Cancer Institute in France had already shown that the presence of Akkermansia in the gut microbiota was associated with clinical benefits in patients treated with immunotherapy.

The work of Lisa Derosa’s team, the results of which were published in prestigious medical journal Nature Medicine in 2022, goes one step further. The team investigated Akkermansia’s potential as a predictive marker of survival and response to immunotherapy among NSCLC patients.

They monitored 338 patients undergoing immunotherapy for four years :

• 131 had Akkermansia in their gut flora (Akk+)
• and 207 did not (Akk-). Their conclusions are very promising.

Better patient survival 

The first finding was that patients with Akkermansia in their microbiota responded better to treatment: the Akk+ group had an overall survival of 18.8 months, compared to 15.4 months for the Akk- group. 

Another finding was that, unlike the Akk- group, the Akk+ patients had greater microbial diversity in their microbiota, which included bacteria with recognized beneficial effects on health and immune status, such as bifidobacteria, Faecalibacterium prausnitzii and Eubacterium hallii. 

Unsurprisingly, antibiotic use had an adverse effect on overall survival for both the Akk+ and Akk- groups, confirming the link between the use of antibiotics and a poor clinical outcome.

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The link between osteoporosis and vitamin D is well established and the link between the gut microbiota and osteoporosis is receiving increasing attention. What about the relationship between the microbiota and vitamin D?

First study on potential link between microbiota, vitamin D, and severe osteoporosis

It all started with a simple clinical observation: patients with severe osteoporosis (SOP) have low plasma concentrations of 25(OH)D₃, which in turn is associated with increased gastrointestinal disorders.

A Chinese team thus hypothesized that the composition of the gut microbiota could affect intestinal absorption of vitamin D. To test this hypothesis, 18 patients with primary osteoporosis (OP) and 18 with severe osteoporosis (SOP) were given identical diets.  

Measurements of the patients’ plasma concentrations of cholecalciferol (vitamin D3) and 25(OH)D₃, together with an analysis of their gut microbiota composition, produced promising results.

More diverse microbiota in SOP patients

A diverse microbiota is usually a sign of good health. However, this is not the case for osteoporosis and vitamin D metabolism. Indeed, it has already been shown that a diverse microbiota is associated with reduced bone mass (sidenote: Xu Z, Xie Z, Sun J, et al. Gut Microbiome Reveals Specific Dysbiosis in Primary Osteoporosis. Front Cell Infect Microbiol. 2020 Apr 21;10:160.Wang J, Wang Y, Gao W, Wang B, Zhao H, Zeng Y, Ji Y, Hao D
Wang J, Wang Y, Gao W, et al. Diversity analysis of gut microbiota in osteoporosis and osteopenia patients. PeerJ. 2017 Jun 15;5:e3450.  ) . This study has shown that SOP patients have a more diverse microbiota than OP patients and reduced levels of Bifidobacterium, bacteria involved in the intestinal absorption of certain fats and fat-soluble vitamins. On the other hand, Firmicutes were more abundant in the SOP patients than in the OP patients. A high Firmicutes/Bacteroidetes ratio is a potential indicator of dysbiosis. This may explain in part why the SOP patients suffered from more severe gastrointestinal symptoms.

Microbiota involved in intestinal absorption of vitamin D

Concentrations of cholecalciferol and 25(OH)D₃ in the blood were positively correlated, with plasma levels of both substances lower in the SOP patients. Since the meals provided to both groups were identical, circulating concentrations of 25(OH)D₃ therefore depended on the amount of cholecalciferol absorbed by the gut, which may be influenced by the gut microbiota. 

The differences in gut microbiota composition associated with low blood concentrations of 25(OH)D₃ in SOP patients suggest that certain gut bacteria are involved in the intestinal absorption of vitamin D, which may in turn influence the deterioration of OP to SOP.

There is many research in the gut microbiota field.
In your point of view, what is the biggest breakthrough these last years?

Deanna Gibson: Just over a decade ago, scientists came to appreciate how widespread and vast the effects that the microbiota has on human health. Still, while much excitement grew over the years of finding the microbiome as a major factor associated with many disease conditions, a healthy dose of skepticism was also present to try and explain how a  major piece of the puzzle had been missed to explain major diseases like: 

• obesity,
• diabetes,
• inflammatory bowel disease,
• etc...

Breakthroughs, ~ a decade ago, came from the use of germ-free mice (sidenote: Germ-free mice mice that have no microbes at all, raised in sterile conditions. ) often transplanted with human feces from various disease conditions, which guided our view that the microbiome was central to many mammalian physiological processes. Early evidence demonstrated that the human gut was a perfect environment for many microbes, which helped propel the beneficial relationship between us and our microbes. The microorganisms (sidenote: Microorganisms Living organisms that are too small to be seen with the naked eye. They include bacteria, viruses, fungi, archaea and protozoa, and are commonly referred to as “microbes”. What is microbiology? Microbiology Society. ) themselves are vital for balanced and effective immune responses since pieces of them act like a key in our guts, unlocking responses that keep us protected and healthy.

Obesity studies revealing relationships between the gut microbiome and energy metabolism using fecal transplants from humans into germ-free mice,² transformed how we understood the gut microorganisms' role in causing and regulating obesity. These observations captivated us since a few clever experiments uncovered that western diet (sidenote: Western diet Diet rich in processed foods, refined sugar, salt, saturated fats (red meats) and trans fats (pastries) Zinöcker MK, Lindseth IA. The Western Diet-Microbiome-Host Interaction and Its Role in Metabolic Disease. Nutrients. 2018 Mar 17;10(3):365.  ) intake resulted in the extinction of microbes and this was compounded over several generations.³

Effectively, the western gut, starved of fiber, had been replaced with microbes that chew away at our protective mucus (sidenote: Mucus Protective substance that’s excreted from multiple areas of the body (mouth, throat, lungs, intestines, stomach ... Mucus itself consists of multiple constituents, but its major component is a substance called mucin. The mucins in mucus can work as a selective barrier, lubricant, or viscous material depending on their structure. Recent studies have shown that the maturation and function of the mucus layer are strongly influenced by the gut microbiota.   Brandtzaeg P. (2017) Role of the Intestinal Immune System in Health. In: Baumgart D. (eds) Crohn's Disease and Ulcerative Colitis. Springer, Cham. Schroeder BO. Fight them or feed them: how the intestinal mucus layer manages the gut microbiota. Gastroenterol Rep (Oxf). 2019 Feb;7(1):3-12. ) in the gut potentiating colonic erosion and an unhealthy gut.⁴ These compelling studies shaped the way we viewed the microbiome and the undeniable evidence that indeed the microbiome was a key factor in many chronic diseases.

Obesity studies revealing relationships between the gut microbiota and energy metabolism using fecal transplants from humans into germ-free mice:

Many scientists posit that a bridge between the gut and the brain promotes brain morphology, neurogenesis, and complex behaviors. There is considerable evidence that molecules or metabolites (sidenote: Metabolites Small molecules produced during cellular or bacterial metabolism. For example, short-chain fatty acids are metabolites produced by intestinal microbiota during fermentation of non-digestible complex carbohydrates (fibers, etc.). 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.  Lamichhane S, Sen P, Dickens AM, et al An overview of metabolomics data analysis: current tools and future perspectives. Comprehensive analytical chemistry. 2018 ; 82: 387-413 ) influenced by the microorganisms, perhaps even produced by microbes, can signal through the central nervous system influencing behaviors including psychosis, anxiety, even personality, and certainly neuroinflammatory conditions.⁵

Still scientists must affirm a causal role of the microbiota on brain processes. A recent study uncovered the role the gut microbiota has on social behaviors through neuronal circuits that mediate stress responses in the brain. It seems that specific bacteria in our gut flora may limit the activation of specific brain neuronal axis.⁶ This breakthrough in the colliding fields of the gut microbiota and neurology gives us hope that by changing the microorganisms we harbor in our bodies, we can have better control over our moods, choices, and cognitive function.

Human gut microbiota is considered as our second brain.
What can we claim today with certainty regarding the implication of gut microbiota in human health or diseases? 

D.G.: Many people have indeed acknowledged that the gut microbiota is considered our second brain. The evidence supports that the microbiota is implicit in controlling physiological processes that influence human health and disease. While a healthy degree of skepticism is needed when evaluating microbiome data, specific key evidence would be hard to refute, including the role of the gut microbiota in energy metabolism with consequences to metabolic health. Additionally, it is clear that the gut microbiota also influences cardiovascular health since studies using mice that have no microbes at all have less vascular development.

Other critical physiological effects of the gut microbiota include immune cell development, immune tolerance (sidenote: Immune tolerance State of unresponsiveness of the immune system to substances or tissues that have the potential to induce an immune response. Immune tolerance_Nature portfolio   ) , brain development, liver function, and even infectious disease susceptibility. Finally, the evidence that the gut microbiota promotes cancer therapies is compelling. Datum show that the types of microbes present in the gut can predict cancer therapy success, revealing the microbes themselves are active players in host drug metabolism.

Innovative therapies that focus on changing the microbiome, including those for inflammatory bowel disease, obesity, diabetes, autism, and fecal transplantations for the treatment of Clostridioides difficile infections, may be more successful than current therapies, including antibiotics treatment. The latter reveal at least something in the feces of healthy people, whether a microbe, consortium of microbes, or metabolites, can cure C. difficile infection. Studying single and or several combined microorganisms as drugs for specific diseases will be vital in confirming the microbiota's place in modern medicine.

What we still have to discover?
Can we imagine in 10 years target the gut microbiota to diagnose or to treat associated diseases?

D.G.: While we have learned over the past decade that we must pay attention to the large plethora of microbes living inside (and outside) our bodies, we have only scratched the surface of the microbiome field. In the next decade, we aspire to ascribe specific mechanistic roles to specific types of microbes in the microbiome, which will further help identify new and effective probiotics.

Now that we can appreciate how an unbalanced microbiota (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.   ) ) is associated with several diseases, we must learn how to reset this dysfunctional microbiome with the hope that this will also reset the inflammatory and metabolic processes the microbiome influences.

Given that recent evidence supports that drug metabolism is altered by microbiota, the future of medicine will have to be personalized. Every individual has their own set of microbes that make up their microbiome, meaning a more personalized approach to solving medical problems will be unavoidable.

This surely will include microbiome-based therapeutics or even personalized dietary guidelines as adjunctive therapies alongside drugs since diet is one of the most significant predictors of the gut microbiome.

The role of the gut microbiota in human health:

^{Adapted from Leah D. D’Aloisio}

_{Several factors such as lifestyle, age, dietary patterns, antibiotic use, genetics & exercise can influence the gut microbiota. In the past decade, research has shown that bi-directional communication between the gut-brain-axis occurs, which can impact brain function and influence mental illnesses such as anxiety, depression & schizophrenia. While essential for the development of our immune system, the gut microbiota is also involved with various diseases including inflammatory bowel disease, vascular disease, obesity, diabetes, liver disease, and allergies.}

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Can the gut microbiota slow cognitive decline?

Memory loss, difficulties with spatial orientation, anxiety disorders... Aging is often associated with psychological and cognitive decline.

Is it inevitable? No, thanks to the gut microbiota which could slow this decline. In fact, one preclinical study² suggests that the gut-brain axis plays a key role in aging.

The authors believe that these results encourage therapeutic approaches that aim to modulate the gut microbiota to improve cognitive function in the elderly and, consequently, their quality of life. This avenue is being very seriously investigated by scientists who hope to prevent the development of age-associated memory disorders.

A Mediterranean diet: the recipe for long life?

Aging is accompanied by general inflammation and the deterioration of many bodily functions, which contribute to the frailty syndrome found in the elderly. Does diet play a part? Very probably.

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. ) is no longer presented*as: THE benchmark for diets that promote health and well-being. It must be said that it contains a certain number of foods and culinary practices that are particularly beneficial for our bodies and propitious to healthy aging.

In fact, according to a study conducted among the elderly,³ the Mediterranean diet allows the microbiota to remain diversified (a sign of good health) and increases the number of “good” bacteria. These bacteria are associated with improved brain function (especially memory) and decreased inflammation and frailty.

Other beneficial changes obtained by this diet: increased walking speed and better manual strength. Would you like a bit more salad?

Microbiota and allergic rhinitis: what is the link?

The symptoms of rhinitis are caused by an overreaction of the immune system to allergens. Allergic rhinitis is described as seasonal (the notorious “hay fever”) when it is linked to the pollen of grasses, trees or herbaceous plants. It is described as perennial when it is caused by allergens present throughout the year (dust mites, animal hairs, molds).²

This disease is associated with an imbalance of the ENT microbiota (ear-nose-throat) and of the gut microbiota, also 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.   ) ”.

Some studies report disparities in the composition of the gut microbiota between people suffering from acute episodes of seasonal allergic rhinitis and non-allergic individuals.³ One study in children⁴ reveals that the diversity of the nasal microbiota is reduced when they are suffering from rhinitis, with a specific bacterial signature that reflects the respiratory disease and its severity level.

Protective factors against allergic rhinitis?

It would seem that exposure to microorganisms (sidenote: Microorganisms Living organisms that are too small to be seen with the naked eye. They include bacteria, viruses, fungi, archaea and protozoa, and are commonly referred to as “microbes”. What is microbiology? Microbiology Society. ) in early childhood is beneficial for the prevention of allergies. Contrary to received ideas, living in an aseptic environment does not necessarily offer protection.

In fact, some studies report that house dust might protect against allergies.⁵ Living in the countryside is also thought to be beneficial, thanks to the farming environment that suppposedly shapes the development of the gut microbiota.⁶ Finally, living with others also has its benefits and may prevent the occurrence of the allergy: researchers have thus observed that in children without siblings attending a kindergarten, there is a significantly reduced risk of allergic rhinitis, compared to children without siblings who are kept at home.⁷ Faced with allergic rhinitis, hurrah for large families!

The importance of the first 1000 days of life

This period from conception to 2 years of age is critical for infant growth and development.⁸ In fact, it is during this time window that colonization of the gut microbiota begins and that the immune system starts to develop and mature.

Antibiotics, delivery method, diet... all these factors that impact and destabilize the gut microbiota can have long-term effects on susceptibility to disease (allergic rhinitis among many others).⁹