Trastuzumab is the first therapeutic option for women with HER2-positive breast cancer and works by blocking the HER2 receptor. Recent studies have shown that it also has immunomodulatory properties. Although effective against HER2-positive breast cancer, a large number of patients present or develop resistance to this treatment. To try to understand this, the authors of the study focused on the gut microbiota, which has been implicated in the efficacy of both chemotherapy and immunotherapy in other types of cancer via the modulation of host immunity. The study involved experimental models and 24 women with HER2-positive breast cancer.

Efficacy mediated by the microbiota...

First the researchers demonstrated in murine models that the efficacy of the treatment was influenced by the gut microbiota. Mice exposed to antibiotics–either directly or via a fecal microbiota transplant from mice that had received antibiotic treatment–saw the complete suppression of trastuzumab’s tumor growth inhibition effect. At the same time, antibiotic exposure not only led to changes in the tumor immune microenvironment, but also altered the gut microbiota. More precisely, the study showed that the modification of the gut microbiota affected intestinal mucosal immunity and systemic cytokine circulation (impaired recruitment of CD4+ T cells and GZMB+ cells in tumors). For the authors, all of this ties in: alterations to the gut microbiota modify the tumor immune microenvironment, which in turn reduces the efficacy of treatment.

...with confirmation in patients with HER2-positive breast cancer

The study subsequently focused on 24 patients with HER2-positive breast cancer treated with trastuzumab. An analysis of their gut microbiota revealed a lower α-diversity and a lower abundance of certain bacteria in nonresponsive patients (NR) compared to responsive patients (R), similar to antibiotic-treated mice. In addition, the transplant of fecal microbiota from R and NR patients into mice resulted in the same response to trastuzumab observed in the patients. Lastly, fecal microbiota β-diversity distinguished patients according to their response to treatment, independently of tumor intrinsic subtype. For the authors, the direct involvement of the gut microbiota offers promising therapeutic strategies involving the manipulation of gut bacteria to improve the efficacy of anti-HER2 therapy. Furthermore, it presents a potential biomarker for treatment response.

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.