In ancient times, the haruspex (sidenote: Haruspex Priest and seer responsible for predicting the future and interpreting the will of the gods by examining the entrails of certain animals. )  read the future in the entrails of sacrificed animals. In the near future, we may be able to predict the length of our life by reading our own entrails. So suggests a recent study of the gut microorganisms of more than 9,000 individuals aged between 18 and 101 years.

An increasingly unique gut microbiota

The first finding of this study is that from our forties the gut microbiota becomes increasingly unique to each individual. This uniqueness goes hand in hand with microbial markers recognized as beneficial in terms of immunity, inflammation, aging and longevity. Moreover, life expectancy is reduced by four years in people aged 80 and over who retain a high dominance of bacteria of the Bacteroides genus and/or who have low gut microbiome uniqueness. These results can be considered all the more solid since they were observed in three demographically distinct study groups.

Compounds that increase life expectancy?

The second finding of the study was a link between the gut signature of individuals that enjoy healthy aging and blood metabolites produced by the bacteria of the gut microbiota. For example, degradation products of amino acids tryptophan and phenylalanine were identified. Interestingly, some metabolites had already been observed in the blood of centenarians but not in that of healthy young individuals. Others, such as indole, had already been shown to have a role in extending life expectancy in numerous animal models. Therefore, aging could be characterized by a modification of the gut flora’s activity, which no longer produces exclusively specific molecules. It can’t be said enough: taking good care of your gut microbiota throughout life contributes to longevity and good health. Now you can’t say you didn’t know…

A “metabolic” injustice all too familiar... some lose excess weight with ease, while others, despite their efforts, see no change or even put on weight. How can such differences be explained? Better nutritional choices for some? More lengths in the pool for others? Better luck in the genetic lottery?

Nutrition, exercise, genetics...

The answer may instead lie in the gut microbiota. This is the hypothesis of researchers who followed 83 Chinese adults (72 of whom were overweight or obese) in a 6-month weight-loss program that involved recommended menus and daily exchanges with a dietician via smartphone. The aim was to reduce calories by 30% to 50%. Participants recorded their food intake several times a week, wore a sensor that calculated calories burned, and weighed themselves each Saturday. They also provided stool samples so that their microbiota and changes to it during the diet could be characterized. A saliva sample was also taken to determine their genetic predisposition to obesity.

...or the microbiota?

The results? Far more than diet, the level of physical activity or even genes, it was the initial gut microbiota that best predicted the weight curve during the study. The abundance of two bacteria, Blautia wexlerae and Bacteroides dorei, was found to be a particularly good predictor of future weight loss. Changes in weight during the diet were also accompanied by changes in the abundance of certain bacteria: Ruminococcus gnavus was significantly enriched in obese individuals and decreased in abundance during weight loss, whereas Akkermansia muciniphila and Alistipes obesi were significantly present in lean individuals and their abundance increased during dieting. The composition of our microbiota may thus predict our ability to lose weight, which could open the way to personalized nutritional programs that better target the microbiota. Could this be the end of metabolic inequalities?

Anti-PD-1 has been one of the major therapeutic advances of the past decade. It provides long-term clinical benefits to patients with advanced melanoma. In preclinical models and cancer patients, the efficacy of this therapy correlates with the composition of the gut microbiota. The aim of this Phase II clinical trial was to investigate whether resistance to anti–PD-1 can be overcome by modulating the gut microbiota.

Fecal microbiota and anti-PD-1: a winning combination?

The purpose of this clinical trial was to evaluate the safety and efficacy of FMT in combination with an anti-PD-1 agent (pembrolizumab) in metastatic melanoma patients previously refractory to this therapy. Fifteen patients received an anti-PD-1 (administered every 3 weeks until change) and a single FMT from seven donors who had previously shown a complete (4 patients) or partial (3 patients) response to immunotherapy. Radiographic assessments were performed every 12 weeks.

The gut microbiota of recipients and donors was analyzed via shotgun sequencing. For each recipient, one pre-FMT sample (collected 7 to 21 days beforehand) and all post-FMT samples (collected weekly for 12 weeks, then every 3 weeks) were sequenced. Patients’ progress was followed for 12 months on average.

FMT alters the gut microbiota

This combination was very well tolerated and provided significant clinical benefit in 6 patients, with regression or stabilization of the tumor for more than a year. In these patients, the median survival was 14 months.

The composition of the gut microbiota of the 15 FMT patients changed following FMT, regardless of whether the patient responded to immunotherapy. The gut microbiota composition of the 6 responders became more similar to that of the donors than did that of the non-responders. Their gut microbiota became richer in species of Firmicutes (Lachnospiraceae and Ruminococcaceae) and Actinobacteria (Bifidobacteriaceae and Coriobacteriaceae) and depleted in Bacteroidetes species.

FMT and immunotherapy reshape immune response

In the 6 responders, immunological changes in the blood and at tumor sites suggest increased activation of immune cells (increased CD8+ T cell activation, decreased frequency of IL-8). In addition, the responders had distinct proteomic and metabolomic signatures, with these changes apparently regulated by the gut microbiota. On the other hand, according to the researchers, non-responders may be refractory to immunotherapy for multiple reasons linked to the composition of their gut microbiota.

Although these findings require further investigation with broader clinical trials, the study suggests that a single FMT administered with a PD-1 inhibitor is enough to successfully change responders’ gut microbiota and reprogram the tumor microenvironment to overcome immunotherapy resistance. FMT changes the composition of the microbiota, improving the efficacy of anti-PD-1 therapy and inducing clinical responses in patients with immunotherapy-refractory melanoma.

Lung transplant is the only existing treatment for end stage lung disease but is associated to very poor survival rates compared to other organ transplants. The respiratory microbiota of lung transplant patients differs from that of healthy individuals. These differences include an increased bacterial load and a distinct bacterial community composition. The clinical significance of these differences for lung transplant outcomes remains, however, unclear, to this day.

Influence of lung microbiota on post-transplant survival

The researchers carried out a prospective study on 134 patients who had received lung allografts at the University of Michigan between October 2005 and August 2017. Their aim was to assess the clinical importance for subsequent CLAD-free survival of post-transplant changes in respiratory microbiota. They analyzed bronchoalveolar fluid samples collected from asymptomatic patients during bronchoscopy one year after lung transplant. Patients’ lung function was controlled at least every three months via spirometry to monitor for the development of CLAD.

Bacterial load in the lungs is a risk factor

Within the 500 days of follow-up, 18% of patients developed CLAD, 4% died before confirmed development of CLAD, and 78% remained CLAD-free. An increased bacterial load in the lungs was associated with a higher risk of developing CLAD or dying after lung transplant. Another finding was that this association between an increased bacterial DNA load and the risk of developing CLAD was not attributable to the presence or relative abundance of Pseudomonas spp., as previous studies had suggested.

Is bacterial community composition a predictive indicator for survival?

The study also found that the composition of the lung bacterial community differed significantly between patients who developed CLAD or died and patients who survived and remained CLAD-free. In contrast, no individual bacterial taxa were definitively associated with CLAD development or death. As an initial assessment, the researchers concluded that composition may not be as relevant as total bacterial load in predicting CLAD-free survival. Further studies are required to determine whether lung bacteria are modifiable via antibiotics or other interventions, and whether variations in the lung microbiota can explain variations in patient responses to therapy after lung transplant.

Atopic dermatitis (or eczema) is the most common chronic skin disease (sidenote: https://www.worldallergy.org/UserFiles/file/WAOAtopicDermatitisInfographic2018.pdf   ) . It is characterized by dry skin and eczematous lesions (redness, itching, etc.), which are non-contagious and develop in flare ups. This condition is the result of a complex interaction between environmental and genetic factors and can show an early onset, even in infants, but can persist or even appear for the first time in adolescents and adults. Among environmental factors, the role of the gut microbiota, but also of the skin and nasal microbiota, has been clearly demonstrated. Despite major research efforts in recent years, the number of people affected by the disease continues to grow worldwide. What explains this increase? Initial explanations point to environmental changes resulting from improved hygiene and urbanization. Surprisingly, rates of the disease in African countries seem quite low, whereas African Americans are more affected. This new study sought to understand why this is so. To this end it analyzed the links between dust microbiota in rural and urban homes and the development of the condition in South African children.

Urban dust and rural dust: what does the microbiota tell us?

The researchers scoured the homes (rural and urban) of 86 South African children aged 12 to 36 months with and without atopic dermatitis. Their goal? To collect dust samples in order to analyze the bacterial microbiota contained therein. Their first finding was that there was a significant difference between dust from urban and rural homes in terms of overall microbial composition. Dust from urban homes had significantly lower bacterial diversity than that of rural homes. There was also a lower abundance of specific bacteria (Clostridia, Lachnospiraceae, Ruminococcaceae and Bacteroidaceae).

Bacteria that protect against atopic dermatitis?

Another finding of the study was that the composition and diversity of the dust bacteria differed between the homes of affected and unaffected children. Dust in the homes of unaffected children living in the countryside had a higher relative abundance of bacteria from the Clostridia, Ruminococcaceae and Bacteroidaceae bacterial families. This suggests that these bacteria may have a protective role against atopic dermatitis. In contrast, in urban environments, no difference was observed in the abundance or diversity of dust bacteria between the homes of affected and unaffected children.

The bacterial composition of house dust may therefore be an important risk factor for the development of atopic dermatitis, and this association may be driven in part by the gut microbiome. Unknowingly, young children ingest and inhale house dust on a daily basis. According to the researchers, it is likely that some of the bacteria present in this dust reach the gut, potentially protecting children against eczema.

Loss of libido is a sexual disorder with multiple consequences, including reduced quality of life, low self-confidence and self-esteem, and a loss of connection with one’s partner. Doctors use the term “hypoactive sexual desire disorder” (HSDD) when a deficiency or absence of sexual desire causes marked distress or interpersonal difficulties. This combination of symptoms (low desire and associated distress) is present in up to 10% of American women, with similar prevalence rates seen across the globe.

The gut microbiota has already been implicated in certain mental and neurological conditions and recent studies suggest it may play a role in loss of libido and HSDD, which are partly regulated by the brain.

Bacteria, emotions, and sexuality

To find out more, researchers compared the stool of 24 women with HSDD to that of 22 women with normal libido. In the HSDD subjects, they observed a lower abundance of certain bacteria, while others, such as Lactobacillus and Bifidobacterium, increased in number. The greater the differences in abundance compared to the microbiota of the women with normal libido, the greater the drop in sexual desire. More research is required to understand the mechanisms at play, though gut bacteria are thought to secret small molecules into the body that may influence the brain. The stakes are high, since these still tentative results may one day lead to improved management of low libido in women.

Serenity or desire, do we have to choose?

The authors also point out that high levels of Lactobacillus and Bifidobacterium–which signal a loss of libido–have previously been associated with a reduction in aggressive thoughts and feelings of sadness. They believe everything may be linked: anger or stress could represent a prelude to sexuality, particularly since these emotional states generate arousal that can then turn into desire. In other words, we may have to choose between serenity and libido!

With life expectancy getting longer, scientific research is increasingly interested in health conditions linked to old age. Among them is sarcopenia, a geriatric syndrome characterized by a deterioration in muscle mass (sidenote: Martin FC, Ranhoff AH. Frailty and Sarcopenia. 2020 Aug 21. In: Falaschi P, Marsh D, editors. Orthogeriatrics: The Management of Older Patients with Fragility Fractures [Internet]. Cham (CH): Springer; 2021. Chapter 4 ) . Sarcopenia develops as a result of multiple pathophysiologic mechanisms, including inadequate nutrition and physical activity, inflammation, immunosenescence, anabolic resistance, and oxidative stress. The gut microbiota has a significant influence on these processes, particularly those related to inflammation and the immune system. A number of studies have described alterations in the gut microbiota in the elderly, but this is the first study of its kind to explore the role of the gut-muscle axis in sarcopenia.

Sarcopenia: reduced gut diversity...

The gut microbiota of three groups was analyzed via 16S rRNA gene sequencing: 60 healthy controls (average age 68.38 ± 5.79 years), 11 sarcopenic patients with impaired muscle function and reduced muscle mass (average age 76.45 ± 8.58 years), and 16 potentially sarcopenic patients suffering from impaired muscle function only (average age 74.00 ± 6.94 years). Alpha diversity (Chao1 and observed species diversity indices) was found to be significantly reduced in the sarcopenic and potentially sarcopenic subjects compared to the controls. These patients showed a reduction in certain butyrate-producing species (Lachnospira, Fusicantenibacter, Roseburia, Eubacterium and Lachnoclostridium). Butyrate is an essential compound through which the gut microbiota influences host physiology. It is known to reduce inflammation and some studies have shown that short-chain fatty acids (such as butyrate) contribute to the maintenance of skeletal muscle mass. In addition, the genus Lactobacillus was more abundant in the symptomatic individuals than in the controls, with the family Lactobacillaceae identified as a biomarker for the potentially sarcopenic group. At the same time, the family Porphyromonadaceae appears to be a biomarker for sarcopenia.

...and modified functional pathways

To study the functional impact of gut microbiota composition in the patients, the researchers identified a number of altered functional pathways. In the sarcopenic and potentially sarcopenic subjects, some were overrepresented (particularly lipopolysaccharide, or LPS, biosynthesis), while others were underrepresented (phenylalanine, tyrosine and tryptophan biosynthesis pathways, among others). These results suggest that key metabolic pathways related to cellular energy production, protein processing and nutrient transport are differentially regulated in the pathologic setting of sarcopenia. In addition, the enrichment of LPS biosynthesis suggests that sarcopenia is associated with a pro-inflammatory metagenome. These results confirm those of previous studies (sidenote: Volpi, E., Kobayashi, H., Sheffield-Moore, et al. Essential amino acids are primarily responsible for the amino acid stimulation of muscle protein anabolism in healthy elderly adults. Am. J. Clin. Nutr. 78, 250–258. https ://doi.org/10.1093/ajcn/78.2.250 (2003) )  showing the importance of phenylalanine, tyrosine and tryptophan biosynthesis pathways in stimulating muscle anabolism in the elderly.

These preliminary results indicate that structural and functional alterations in the gut microbiota may contribute to the loss of skeletal muscle mass and function in sarcopenic patients. However, future studies involving larger samples are needed to confirm this hypothesis.

What doesn’t kill you makes you stronger. The immune system applies this saying to the letter. Its adaptive responses to pathogens allow for a swifter and more robust defense against subsequent infections. What if the same were true of the gut microbiota? Could initial infections allow it to develop an optimal antimicrobial function, thus increasing resistance to host colonization? So suggest the researchers in this study.

Metaorganism memory

The experiments in question involved the bacterium Klebsiella pneumoniae (Kpn). In orally infected mice, the bacterium is detected transiently in the lumen of the colon and then disappears from the feces. The only exception is when the mice have received a broad-spectrum antibiotic (streptomycin) beforehand, in which case their fecal Kpn load remains high. Colonization of the host by this pathogen thus seems to be regulated by the microbiota. With this point confirmed, a long series of experiments allowed the researchers to progressively elucidate the mechanisms by which a transient infection leads to what they call a long-term “metaorganism memory”. The latter is based on the interdependent and combined functions of the host and its microbiota.

Bile acids involved

Following infection, the host’s liver sees increased production of bile acids. Microbial groups in the gut microbiota that are capable of using these acids (particularly taurine) via anaerobic respiration multiply as a result. They convert taurine into sulfide, an inhibitor of aerobic cell respiration. Many pathogens depend on aerobic respiration to survive. Without it, they die, limiting host colonization. On the other hand, sequestering sulfide favors invasion by pathogens. Interestingly, the intake of exogenous taurine has the same effects as an infection: multiplication of bacteria capable of metabolizing it, reinforcement of resistance to colonization, etc.

Resistance to colonization: questions and hopes

However, many questions remain. For example, what signals trigger increased bile acid synthesis following infection? Does the host immune system work alongside the microbiota to promote resistance to colonization following infection? In any case, with antibiotic resistance worryingly on the increase, using bacterial metabolites to fight infection–rather than bacteria themselves–provides a reassuring alternative. Moreover, this strategy has another clear advantage: therapies based on bacteria (such as fecal transplant) face the problem of inter-individual heterogeneity, whereas more “universal” microbial metabolites should respond to much broader targets.

Loss of smell (anosmia) and taste (ageusia): Covid-19 disturbs our senses. Almost half of symptomatic patients present such disorders¹, with strong variations according to ethnicity (e.g. the incidence in Caucasian populations is three times that of Asians)². Sensory changes are severe in those affected. In a multilingual survey of 4,039 Covid-19 cases worldwide, patients reported an average loss of 80% of their sense of smell and 70% of their sense of taste³.

Daily practice to recover sense of smell

Unfortunately, anosmia is not limited to the often transient cases related to Covid-19. Head trauma, nasal inflammation, allergies and even old age can lead to a loss of smell. The cause? A deterioration in the sensory cells that line the nasal cavities and are responsible for detecting odors. To counteract anosmia, Austrian researchers train their patients to smell and visualize various odors (lemon, rose, etc.) twice a day. The results are positive, with patients regaining their sense of smell after six months of training. Furthermore, MRI imaging shows that the brain areas dedicated to smell are partially restored.

Focus on the nasal microbiota

In addition to this training, the researchers also sought to determine the influence of the microorganisms living in the nasal cavity. They were on the right scent, since they observed a higher diversity of bacteria in the noses of patients with a reduced sense of smell. One bacterium in particular is suspected of altering olfactory performance. Encouraged by these results, the team is taking a close look at whether patient training also modifies the balance of the nasal microbiota. The results are not yet known, but the study raises significant hopes of finding key microbes that are capable of restoring patients’ sense of smell and directing them towards the most appropriate treatment for the disorder.

Long considered a source of infection, today microorganisms are often classified as either “good” or “bad”. Is this black or white view appropriate?

Microbes are neither “good” nor “bad”; nor are they our “friends” or “enemies”. We can’t apply this humanized classification to them. Even the most harmless microbe can cause death if the immune system is weakened. However, it is well known that many microorganisms can benefit their host under certain circumstances, whereas others are generally pathogenic.

For example, Staphylococci are very abundant on human skin. Staphylococcus aureus has quite a bad reputation: it is often associated with wound infections and several skin disorders, it carries many virulence genes, and its multidrug-resistant form (methicillin-resistant S. aureus, or MRSA) is a major cause for concern in hospital environments. At the same time, numerous recent studies have shown that Staphylococcus epidermidis can stimulate the immune system and the skin’s defenses and even destroy S. aureus biofilms. On the other hand, S. epidermidis is a major cause of implant-related infections and can also become resistant to multiple antibiotics, whereas many people are colonized by S. aureus without experiencing any problems. Therefore, it’s not always a good idea to try to improve skin health by simply lowering the ratio of S. aureus to S. epidermidis on the skin. A good balance between the two should be sought.

Which microorganisms are involved in atopic dermatitis?

While microorganisms are probably not the main cause of the disease, they make a significant contribution to its pathology. Affected skin areas can be characterized by a microbial dysbiosis: an increased abundance of S. aureus and a reduced presence of typical skin bacteria such as Cutibacterium and Corynebacterium. S. aureus may benefit from a weakening of the skin barrier, possibly the result of altered antimicrobial peptide production in the skin and/or mutations in filaggrin genes¹, leading to dryness and cracking of the skin. Inflamed skin is usually treated with antibiotics, which risks causing severe damage to the beneficial part of the skin’s microbiota, as well as antibiotic resistance. Probiotic strategies which aim to increase/restore the abundance of coagulase-negative staphylococci (CoNS) are considered optional and/or complementary.

Can topical and/or oral probiotics prevent or cure skin diseases? What part can they play in therapeutic strategies, now and in the future?

The addition of live microorganisms (probiotics) can certainly benefit the host’s health, for example, by reducing the abundance of pathogens or stimulating the host’s defenses and immune system. Due to the existence of a gut-skin axis, oral probiotics can also have a positive impact on the skin.

However, for most (if not all) major skin diseases,the role of the skin microbiota remains unclear. Although such diseases see marked changes in the structure (community composition) and function (physiological properties) of the skin microbiota, it’s not usually clear whether these changes are the cause or effect of the underlying disease. This is the classic chicken and egg conundrum.

Therefore, in my opinion, it’s a little too early to hope that a simple probiotic cream or capsule can make a significant therapeutic contribution to the prevention or cure of serious skin diseases. Furthermore, research in the gut has shown that, compared to conventional chemical therapies, the effects of probiotics are rather mild and influenced by so many factors that it’s difficult to extrapolate them from highly standardized animal models to humans. Only robust clinical trials could show the effectiveness of probiotics. However, although it’s too early to give a definite opinion for the most serious diseases, to me probiotics seem to be an additional therapeutic option for managing less serious skin disorders and a valuable strategy for improving skincare products. Since it now seems clear that a balanced and diversified microbiota is a characteristic of healthy skin, it makes full sense to preserve and protect such a state, including with probiotic approaches, for example in the case of blemished, sensitive or irritable skin, etc.

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