GUT MICROBIOTA MODULATES RESPONSE TO PROSTATE CANCER TREATMENT

^{Pernigoni N, Zagato E, Calcinotto A, et al. Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis. Science 2021 Oct 8;374(6564):216-224.}

Prostate cancer (PC) is one of the most common cancers in males. Because tumors growth and progression depend on androgen levels, androgen deprivation therapy (ADT), surgical or chemical castration is used to treat patients with PC. However, some of them develop a castration- resistant prostate cancer (CRPC) which result in tumor progression and new treatment strategy are under investigation. Since recent studies have highlighted the role of microbiota in both cancer development and therapy success, the authors used PC mouse models and patient data to examine the role of gut microbiota in PC carcinogenesis. Enrichment of Ruminococcus spp. and Bacteroides acidifaciens was detected after development of CRPC but gut microbiota ablation slowed tumor growth in CRPC mice. Castration resistant (CR) fecal microbiota transplantation (FMT) from castration-resistant (CR) mice and R. gnavus administration led to increased circulating androgen levels and increased PC growth and CRPC development. PC growth was controlled by FMT from hormone sensitive PC individuals and Prevotella stercorea administration. CRPC patients had enrichment of Ruminococcus and Bacteroides genera associatied with poor outcome while hormone- sensitive PC patients had higher abundance of Prevotella genus linked with more favorable outcome.

Commensal gut microbiota in androgen- deprived patients and mice produce androgens that promote PC growth and the development of CRPC via systemic circulation. Modulation of gut microbiota could theoretically be used as additional therapy for PC.

THE ASSOCIATION BETWEEN GUT DYSBIOSIS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE

^{Li N, Dai Z, Wang Z, et al. Gut microbiota dysbiosis contributes to the development of chronic obstructive pulmonary disease. Respir Res 2021 Oct 25;22(1):274.}

Chronic obstructive pulmonary disease (COPD) refers to lung diseases (emphysema, bronchitis and asthma) characterized by progressive respiratory distress. Recent studies have revealed changes in the gut microbiota linked to disease development in the lungs. While primarily considered a respiratory disease, COPD commonly co-occurs with chronic gastrointestinal tract diseases. In the present study, the authors took an interest in the the gut-lung axis linked to COPD. Stool analyses have revealed that patients with severe COPD had lower abundance of Bacteroidetes but higher abundance of Firmicutes. Of bacterial families, Prevotellaceae abundance was higher in mild COPD, whereas Bacteroidaceae and Fusobacteriaceae abundancies were lower in severe COPD compared to healthy controls. Short chain fatty acid (SCFA) levels were significantly lower in severe COPD. Fecal microbiota transfer (FMT) to mice from COPD patients caused a significant weight reduction and airway mucus hypersecretion in mice. Acceleration of lung function decline was detected in FMT mice during biomass smoke exposure. This study revealed that COPD patients have gut microbiota dysbiosis with reduced SCFA levels. These changes are possibly linked to airway inflammation and COPD progression.

THE IMPACT OF COMEDICATION ON THE TREATMENT EFFICACY OF IMMUNE CHECKPOINT INHIBITORS

^{Kostine M, Mauric E, Tison A, et al. Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse effects. Eur J Cancer 2021 Nov;157:474-484.}

Immune checkpoint inhibitors (ICI) have dramatically improved the prognosis of several advanced cancers. Evidence have shown that gut microbiota may modulate the treatment response for ICI, and may also be involved in the pathogenesis of immune-related adverse events (IRAE). While antibiotics are known to deteriorate the prognosis of ICI treated cancer patients, little is known about the effect on the microbiota of various co-medications when given at ICI initiation. In the present study, the authors examined the effect of co-medications given 1 month before or after administration of ICI therapy on the treatment results and the occurrence of IRAE.

The use of antibiotics, glucocorticoids (daily dose > 10 mg), proton pump inhibitors, psychotropic drugs, morphine and insulin were associated with significantly shortened survival and decreased tumor response. Combination therapy with these drugs decreased survival more than monotherapy. These medications were also associated with decreased incidence of IRAE. Co-administration of statins, angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers, non-steroidal anti-inflammatory drugs, aspirin and oral antidiabetic drugs did not impact patient survival. The present study showed that co-medication influences both to the response and IRAE of ICI treatment. The impact of co-medication may be mediated via microbiota or other immunomodulatory mechanisms. In clinical practice, baseline co-medications should be carefully assessed when ICI therapy is planned. Drugs with negative impact on ICI therapy should be avoided when possible.

In 2020 the theme of World Digestive Health Day, sponsored by WGO, was “Global Issues in the Microbiome”. Eamonn MM Quigley, on behalf of the many colleagues who contributed to this program, presented its proceedings which encapsulated an overview of the gut microbiome. The factors that influence the microbiome and shape its development through that critical and vulnerable period from birth through early childhood were delineated and the role of diet, throughout the lifespan of the individual, stressed. While a role for the microbiome in many disease states has been proposed, many studies describe association, not causation.

One disorder where a role for the microbiome has generated much excitement is irritable bowel syndrome (IBS). Mirjana Rajilic-Stojanovic explored this in detail and delineated the factors that compound the interpretation of microbiome studies in IBS (e.g. small study population size, heterogeneity of phenotype, variable study design) which, no doubt, contribute to the absence of a consistent microbial signature for IBS. She did alert us to two organisms that may be of particular interest: Methanobrevibacter smithii and Faecalibacterium prausnitzii; the former through its production of methane and the latter through its role in signaling to enterochromaffin cells leading to increased biosynthesis of serotonin – a critical enteric nervous system neurotransmitter and target of much IBS pharmacology.

FECAL MICROBIOTA TRANSPLANTATION

The microbiome offers tremendous therapeutic potential. Francisco Guarner updated the WGO probiotic guideline and the fascinating topic of Fecal Microbiota Transplantation (FMT) was tackled by Pavel Drastich. He contrasted the efficacy of FMT in Clostridioides difficile related disease to the much more mixed data from other disease states. Among the latter, ulcerative colitis provides the best data (though still rated as of only moderate quality). Here, the interpretation of results is bedeviled by the same factors that confound so many FMT studies: variability in population selection, study endpoints and study protocol. The latter includes such vexing variables as use of fresh vs. frozen stool, route of delivery (naso- jejunal, vs. enema, vs. colonoscopic vs. swallowed capsule), number of treatments (single vs. multiple) and source of material (single donor vs. pooled material from multiple donors). Most fascinating was the glimpse he provided into the future of FMT, predicting an evolution from FMT as we currently know it (i.e. whole stool samples) through the development of specific combinations or consortia of microbes (an area of frantic scientific and commercial activity) to the elaboration of biologically and therapeutically active compounds from microbes. Both the promise and the limitations of FMT in IBS were further developed by Mirjana Rajilic-Stojanovic. Here confounders are vividly displayed: a highly heterogenous phenotype with a variable range and severity of symptoms which fluctuate over time, an incomplete understanding of the role of the microbiome and an, at best, speculative concept of how FMT might act. No wonder that results, to date, are so variable.

CURRENT SITUATION OF MICROBIOTA RESEARCH

Francisco Guarner led off one of the opening sessions of the entire program on a topic that I have retained to the end of this piece – the current situation of microbiota research. This was a typically thoughtful and insightful lecture and most timely given the impact of the Covid-19 epidemic and the global antibiotic resistance crisis; do we need any further reminders of the importance of the microbes that co-habit this planet with us? He returned to the global theme by illustrating the primacy of poor diet in global risk mortality but deftly pointed out that these very diets impoverish not just humans but their microbes and butyrate producers in particular. Low levels of gut microbial diversity have been linked to several disease states with one of the most compelling examples being childhood asthma. Looking to the future, he stressed the inadequacies of a taxonomic approach to the study of the microbiome in disease states and illustrated this point by showing that in normal individuals the composition of the gut microbiome is highly dynamic; up to 90% of strains appear and disappear over time! He called, therefore, for a new approach to the definition of normal vs. abnormal microbiomes (or eubiosis vs. dysbiosis, as some prefer) which emphasized functional competence and ecological stability (incorporating such concepts as resistance to community structural change over time and resilience, an ability to rapidly return to baseline when disrupted, such as by an antibiotic). These are key concepts and reflect the current move away from simple enumeration of microbial numbers, species and strains to the description of functional potential using metagenomics and assays of metabolic products through metabolomics and metatranscriptomics.

GUT MICROBIOTA SIGNATURES IN COVID-19 PATIENTS

As gut microbiota has been considered a hot topic in the scientific community with a pivotal role on host immune and inflammatory functions, we investigated if changes in gut microbiota composition are associated with an increased clinical severity of Covid-19 [4]. A national multicenter cross-sectional study was conducted in 115 Covid-19 patients categorized by: 1) location of recovery from Covid-19: ambulatory (household isolation), ward or intensive care unit; and 2) Covid-19 severity scale: asymptomatic/mild-to-moderate or severe. Severely ill patients exhibited profound changes in gut microbiota composition compared with mild-to-moderate patients in ambulatory or admitted to the hospital ward (Figure 1). These changes included: 1) lower overall gut microbial diversity; 2) lower abundance of beneficial butyrate-producing bacteria such as Roseburia and Lachnospira; 3) lower Firmicutes/ Bacteroidetes ratio; 4) higher abundance of Proteobacteria. In addition, we detected the virus in fecal samples, which must be considered in public health recommendations [5, 6] Publications from other colleagues have shown that low diversity could be a clinical biomarker predicting greater risk of severity [7-9].

RESPIRATORY MICROBIOTA IN COVID-19 CRITICALLY ILL PATIENTS

The conventional wisdom was that the healthy lungs were sterile. In the last decade, the application of techniques of microbiota research clearly showed that was not the case. The lungs are colonized by a very low bacterial load compared with the gut [10]. The different parts of the respiratory tract (oropharynx, airway, lungs) present different diversity and compositions related to the colonization sources, colonization rates, extinction rates and distances between each other according to the adapted island model, being the “mainland” the oral cavity [11]. Recent studies in severe Covid-19 patients showed dysbiosis of the airway microbiota (analyzed in BALF samples) similar to the dysbiosis observed during lower respiratory tract infections, pneumonia for example [12, 13]. In addition, Acinetobacter – a common gram-negative non-fermenting bacilli pathogen of ventilator-associated pneumonia that is the most severe ICU-acquired infection in patients undergoing invasive mechanical ventilation – was a common bacterial genus found in lung tissues in deceased patients [14]. The presence of some pathogens in the lung of deceased patients and in the oral cavity is related to the adapted island model migration [15]. As a result of the Covid- 19 associated immune dysregulation, several epidemiologic studies showed an increased risk of hospital acquired infections, namely ventilator associated pneumonia as our group showed. In our study we found that Covid-19 patients presented twice the risk of ventilator associated pneumonia in comparison to non-Covid-19 patients [16].

WHAT DO WE ALREADY KNOW ABOUT THIS SUBJECT?

Antibiotic-resistant bacteria are the cause of many neonatal deaths. The emergence of resistant bacteria is favoured by the use of antibiotics, which is associated with a higher number of antibiotic-resistance genes (ARGs) carried by these resistant or multi-resistant bacterial strains. Mobile genetic elements (MGEs) transmit ARGs between bacteria. It is also known that the type of diet modifies the intestinal microbiota, as well as the quantity of ARGs. The magnitude of the impact of infant diet on resistance has not been adequately described in the literature.

WHAT ARE THE MAIN INSIGHTS FROM THIS STUDY?

The authors included 46 infants born prematurely between 26 and 37 weeks of gestation of which 21 were fed with formula, 20 with fortified breast milk and 5 with breast milk. Stools were collected within 36 days to analyse the composition of gut microbiota and presence of ARGs. Thirty infants received an antibiotic treatment: stools were collected approximately two weeks after the end of treatment to limit confounding effects.

To compare the results with literature data, a meta-analysis of five studies including 696 neonates with similar data was analysed in parallel.

The results showed that infants fed with formula had significantly higher amounts of ARGs than infants fed with fortified breast milk (x 3.6; 95% CI, 1.61-8.9) or breast milk (x 4.3; 95% CI, 1.61-11.56) (p < 0.01) (Figure 1). The abundance of MGEs was similarly increased (p < 0.05).

The abundance of Enterobacteriaceae, whose genome is known to contain more mobile ARGs, was higher in formula-fed infants (p < 0.05) (Figure 2) and tended to be inversely correlated to gestational age (p < 0.1). It was noted that the longer the gestation the lower the abundance of these ARGs (x 0.72; 95% CI, 0.57-0.89) (p < 0.001). Several ARGs were significantly more abundant in formula-fed infants including genes encoding the extended-spectrum beta-lactamase present in Klebsiella (p < 0.05). Similar results were observed in the meta-analysis with a 70% relative increase in ARGs in formula-fed neonates (p = 0.013). The median ARG load was higher in the formula-fed infants in all cohorts (Figure 3). Finally, an analysis of gut microbiota revealed that bacteria belonging to Bifidobacteriaceae, Veillonellaceae, Clostridiaceae, Lachnospiraceae, and Porphyromonadaceae families (including strict anaerobe bacteria) were depleted in neonates fed with infant formula; conversely, facultative anaerobe bacteria belonging to the Enterobacteriaceae, Staphyloccoccaceae, and Enterococcaceae families were increased (p < 0.05).

Similarly, several potentially pathogenic species including facultative anaerobe species such as S. aureus, S. epidermidis, K. pneumoniae, K. oxytoca, and a strict anaerobe species Clostridioides difficile, were enriched in formula-fed neonates (p < 0.001). Thus, the use of infant formulas enhances the proliferation of pathogenic bacteria with ARGs.

WHAT ARE THE CONSEQUENCES IN PRACTICE?

These results support the benefit of breastfeeding. Feeding premature neonates with infant formula is associated with a 70% increase in ARGs compared to those fed exclusively with breast milk. Enriched breast milk results in a smaller increase in these ARGs.

WHAT DO WE ALREADY KNOW ABOUT THIS SUBJECT?

Gut microbiota plays a major role in the development of the immune system and maintenance of immune homoeostasis. Gut microbiota influence the immune system both on a local and systemic level, maintaining a balanced immune response. In common with a wide range of diseases such as obesity, chronic inflammatory bowel disease, neuropsychiatric disorders, and colorectal cancer (CRC), disruption to the microbial balance (dysbiosis) is implicated.

CRC, as one of the most frequently diagnosed malignant diseases, remains the leading cause of cancer deaths worldwide related to lifestyle (diet, tobacco, alcohol) or obesity risk factors, which are all closely related to changes in the composition of healthy gut microbiota.

Gut microbiota is altered in CRC patients, with an increase in taxa such as Bacteroides or Fusobacterium [2] and a decrease in bacterial Clostridiales taxa compared to healthy individuals [3]. A majority of colorectal tumours have low immunogenicity and therefore do not respond to current T-cell activation immunotherapies. Anti-PD-1, anti-PD-L1 and/or anti-CTLA4 monoclonal antibodies are only effective in 4-5% of CRC tumours with a mismatch repair defect or high microsatellite instability [4]. Recent studies have shown how some members of the gut microbiota are able to modulate the efficacy of anti-cancer treatments [5, 6]. In this study, the authors evaluated whether a cocktail of four bacterial strains, specifically associated with a low tumour burden in an experimental CRC model, could trigger an effective anti-tumour immune response.

WHAT ARE THE MAIN INSIGHTS FROM THIS STUDY?

Based on animal models, the authors observed that mice with a microbiota low in Clostridiales bacteria (Ruminococcaceae and Lachnospiraceae families) had increased susceptibility to CRC. Based on these analyses, the authors selected a combination of four Clostridiales species (CC4), i.e. Roseburia intestinalis, Eubacterium hallii (Anaerobutyricum hallii), Faecalibacterium prausnitzii and Anaerostipes caccae, whose abundance is decreased in CRC patients, to conduct additional studies on mouse models. CC4 administration had an effect on the mice microbiota, with an increase in species belonging to the Ruminococcaceae and Lachnospiraceae families.

In several solid cancer models, including for CRC, lung and breast cancer, CC4 administration slowed down tumour growth. This benefit was primarily lymphocyte-mediated as it disappeared in mice without mature lymphocytes (Rag2 KO mice). The main candidates are interferon-gamma producing cytotoxic CD8+ T cells, which massively infiltrate the tumour in animals receiving CC4. The protective effect was also observed individually with each of the bacterial strains tested in a CRC model, but with varying degrees of efficacy (Figure 1). The therapeutic effect was unrelated to butyrate producing-bacteria.

Finally, in the CRC model (MC-38), the CC4 cocktail had a superior effect to anti- PD-1 immunotherapy. Moreover, no additive effect was observed among mice having received immunotherapy and the four bacteria.

CONSEQUENCES IN PRACTICE?

This study has shown that in addition to having an adjuvant role in the immunotherapy treatment of cancer, some microbiota bacteria exert their own anti-cancer effect in solid tumour mouse models. These results pave the way to the development of cancer treatments in man based on gut microbiota. These therapies could be used alone or in combination with other “conventional” anti-cancer treatments. However, the patient groups that would benefit most from this type of therapeutic approach are yet to be determined.

Gut microbiota, central nervous system and neurodevelopment

The human gut microbiota (GM) consists of approximately 1013 microorganisms, mainly bacteria, fungi and viruses. GM plays a central role in human health, ensuring intestinal barrier function, modulation of the immune response and metabolic synthesis, but also a direct protection against infections. Dysbiosis characterized by an unbalanced GM has been associated with several diseases such as inflammatory bowel diseases, cancers, diabetes or obesity [4]. Consistent findings also suggest robust interactions between GM and the central nervous system (CNS) [5] (Figure 1).

A reciprocal crosstalk between brain and GM is mediated by microbial metabolites (mainly short chain fatty acids) and immune modulators directly by crossing both the blood-gut and the blood-brain barriers and indirectly via the stimulation of the vagus nerve [6]. Evidence supports the involvement of GM in the regulation of both human behaviors and cognitions - specifically socio-communication skills – even if its exact mechanisms are still unknown [5].

ASD are neurodevelopmental disorders characterized by impairments in social communication, social interactions, and repetitive/stereotyped behaviors, of childhood onset affecting approximately 1% of the general population. The determinism of ASD is mainly driven by genetic factors, with a heritability estimated reaching 0.8- 0.9, but pre- and post-natal environmental events may act as precipitating factors or modulators of the symptom severity. The trajectory of brain development at an early stage of life overlaps with those of the GM. This latter begins to develop early after birth and its composition stabilizes into an adultlike profile around the age of 3 years old. GM early composition is deeply influenced by environmental factors such as the place of birth, delivery mode, breastfeeding and xenobiotics (e.g. antibiotics use).

Germ-free mice are a model lacking all microorganisms e.g are microbiologically axenic (no living organisms can be cultured from germ-free mouse specimens). Germfree mouse models are valuable to decipher the mechanisms underlying the roles of GM in neurodevelopment, but also the relationship between microbiome and disease. Studies showed that germ-free mice exhibit i) default in brain-blood barrier permeability; ii) higher brain volume; iii) more immature microglia gene expression and less microglial immune responsiveness; iv) increased myelination ; and v) decreased Brain-Derived Neurotrophic Factor expression and in a subunit of N-Methyl-D-Aspartate receptors [5, 7]. All these data stress the role of GM in blood-brain barrier formation and integrity, neurogenesis, microglia homeostasis, myelination and brain growth/ function.

Gut microbiota, gastrointestinal symptoms and autism spectrum disorders

Germ-free mice displayed autistic-like behaviors such as social avoidance, repetitive/ stereotyped behaviors, lack of interest in social novelty. Some of these behaviors disappeared after colonization by a GM from wild type mice whereas colonization by GM from ASD mouse models increased these behaviors. GM seems indeed crucial for the programming and presentation of social skills and adaptive behaviors [8].

A growing number of evidence shows that GI symptoms are overrepresented in ASD children. GI symptoms such as abdominal pain, constipation, diarrhea are reported in nearly 30-50% of patients with ASD and profoundly impact the quality of life of children [1]. GI symptom severity was correlated with the severity of autistic symptoms and gut dysbiosis is well documented even if there is still no specific signature related to autistic symptoms. Studies exploring GM reported differences in microbiota diversity, and abnormal metabolite patterns when compared to healthy controls. Two recent meta-analyses exploring GM composition in ASD patients reported a decrease in Bifidobacterium and increase in Faecalibacterium and Clostridium genera in ASD patients [9, 10] compared to controls. The exploration of the fecal metabolome also displayed an increase in p-cresol, a bacterial metabolite derived from tyrosine, in individuals with ASD. All together, these data may indicate the potential association between GM abnormalities and GI symptoms in ASD patients.

However, most studies have heterogeneous results and methodological limitations. Merely confounding factors such as different countries with different lifestyles and dietary habits are major drawbacks of these studies. Indeed, a recent study in a large cohort of 247 subjects with ASD did not report direct links between ASD diagnosis or autistic symptoms, and GM dysbiosis. Dysbiosis was associated with a less-diversified diet which is common in patients with ASD [8].

Modulation of the gut microbiota in autism spectrum disorders

A growing number of studies explored the potential impact of microbiota-based therapeutic strategies to improve GI symptoms and core symptoms in individuals with ASD.

Probiotics, live microorganisms, have been used in ASD and could have a beneficial effect on patients with ASD. Some preclinical studies showed increased social interactions with probiotics supplementation (Bacteroides fragilis, Lactobacillus reuteri) in mouse models of ASD. The improvement of social communication was linked with an increased oxytocin expression in CNS. In humans, several studies reported positive effects of probiotic treatments on GM composition and GI symptoms in ASD [11]. However, few of them reported an improvement of core autistic symptoms. Most clinical trials providing probiotics in autistic individuals showed inconsistency in terms of probiotics, dosage administration per day or in total, and duration of the whole treatment. Even if some studies suggest that probiotics could be interesting to prevent GI symptoms in ASD patients, the results request replication to guarantee the positive effect of such strategy.

Similarly, the efficacy of prebiotics, such as galacto-oligosaccharide (GOS) or fructo-oligosaccharide have been explored in ASD [12]. Chronically stressed mice showed alteration in GM and a decrease in social interest. Using this mouse model, the administration of prebiotics was associated with increased social interactions in these mice. In humans, the use of GOS associated with a casein-free and gluten-free diet showed improvement in GI symptoms and social interactions together with an increase in GM Bifidobacterium abundance. Appropriate double-blind randomized clinical studies are needed to confirm preliminary evidence.

Fecal microbiota transplantation (FMT) has also been studied in ASD. FMT involves transplanting GM from a donor to modify the GM of the receiver. Its efficacy on Clostridioides difficile infection is now well demonstrated, even in children. A recent exploratory unblinded and non-randomized clinical trial involving 18 children diagnosed with ASD and GI evaluated the effect of microbiota transfer therapy (MTT) - a modified FMT protocol [13]. MTT consisted in a two-week antibiotic treatment, a bowel cleansing, before receiving the MTT treatment which consisted of a high dose through oral or rectal administration followed by an oral maintenance dose for 7-8 weeks. Adverse events at the initiation of vancomycin treatment were observed (disruptive behaviors, hyperkinesia) but disappeared spontaneously after 3 days of treatment. The MTT protocol led to a significant improvement in GI symptoms after the following survey of 8 weeks. More surprisingly, an improvement on core autistic symptoms (stereotyped and repetitive behaviors, social communication skills) had also been observed 8 weeks after MTT. Interestingly, improvement on GI symptoms and autistic symptoms persisted 2 years after treatment and was correlated with GM increased diversity [14]. Two years after MTT, the average reduction of the Gastrointestinal Symptom Rating Scale (GSRS) total score was still over 50%. Changes in autistic symptoms measured with the Childhood Autism Rating Scale - CARS, the Social Responsiveness Scale - SRS, or the Autistic Behavior Checklist - ABC were all positively correlated with percent changes in GSRS scores. These results are not yet confirmed by placebo-controlled doubleblind randomized studies.

Recently, a pilot open label clinical trial in ASD has explored the effect of an oral GI-restricted adsorbent (AB-2004) modulating several GM metabolites. The authors reported a decrease in anxiety-like behaviors in mice, driven by a gut microbial metabolite decrease [15]. The study also presented preliminary results from a clinical trial in which an AB-2004 weight-adjusted dose was administered, for 8 weeks, to 30 adolescents with ASD. At week 8, reduced levels of GM metabolites in plasma and urine were observed. More interestingly, after treatment, less subjects displayed GI symptoms but also ASD-associated behaviors, anxiety, and irritability. There was also a remnant effect with a persistence of the efficacy at 4 weeks after treatment discontinuation [15]. The factors linking clinical improvements and administration of AB-2004 remain to be determined, some indirect factors have not been studied such as the effect of AB-2004 on nutrition changes, immune status or GI function. Larger, double-blind placebo- controlled studies trials are warranted to further dissect the role of AB-2004 in social communication in humans.

In the context of the lack of specific treatment for GI symptoms and autistic symptoms in ASD patients, new well tolerated therapeutic strategies targeting GM or microbial metabolites such as FMT/MTT need to be more performed specifically in early and critical stages of brain development during childhood.

Although we need only very small quantities, vitamins are no less essential to our health—if we do not get enough vitamin C, for example, we can develop scurvy, a disease from which many sailors died when a lemon would have been enough to save them. To a lesser extent, cognitive disorders, numbness or a persistent state of fatigue can also be signs of a vitamin B deficiency. Moreover, the etymology of the word reveals something of its “vital function”: “vitamin” comes from the Latin “vita,” meaning life.

The B7 engine

Among the many vitamins essential for our body to function properly are the B vitamins, including the famous vitamin B7, also called biotin (sidenote: Biotin Called vitamin B7, or B8 in certain countries. This vitamin plays a key role in the metabolism of carbohydrates, lipids and amino acids. It is also involved in the biosynthesis of other vitamins (B9 and B12). Many foods are good sources of biotin (whole grains, eggs, milk, nuts, etc.). This vitamin is also synthesized by the bacteria in gut flora. Biotin_NIH National Cancer Institut ) . One of our main sources of biotin is food, but that’s not all! The bacteria in gut microbiota also produce it... or not, as the case may be. And this has consequences for our health, especially in the case of obesity.

The vicious circle of obesity

A team of researchers has just shown that the gut bacteria that produce and transport biotin are absent in severely obese patients (BMI (sidenote: Body Mass Index (BMI) Body Mass Index (BMI) assesses the corpulence of an individual by estimating the body fat mass calculated by a ratio between weight ((kg) and height squared (m2). https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmicalc.htm https://www.euro.who.int/en/health-topics/disease-prevention/nutrition/a-healthy-lifestyle/body-mass-index-bmi ) > 35). Their obese host is thus deprived of this additional non-dietary source, despite actually needing more than the average person (vitamin B being necessary for well-balanced adipose tissue). Experiments in animals show that the 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.  ) , well known for promoting obesity, reduces both the quantity of biotin-producing gut bacteria and the circulating levels of this vitamin in serum. Also, paradoxically, the gut inflammation observed in obese patients limits the absorption of biotin supplied by the diet.

In cases of severe obesity, a vicious circle is thus set in motion, since gut dysbiosis is believed to aggravate inflammation (and obesity) as well as tissue biotin deficiency.

Boosting biotin production

How can we break this vicious circle? Weight-loss surgery (bariatric surgery), which improves metabolism and inflammation, stimulates growth of biotin-producing bacteria, resulting in an increase—at least during the first year—in the level of biotin circulating in the body. Another approach involves supplementing with prebiotics (fructo-oligosaccharide type fibers) and biotin. This has been tested in mice fed a high-fat diet, and was found to improve the diversity of gut microbiota and boost bacterial production of biotin and other B vitamins, while limiting weight gain and deterioration of blood sugar levels.

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Recently, research has revealed the involvement of gut microbiota (GM) in the pathogenesis of MS, yet little is still known about its mechanisms.

A novel multiomic approach

For the first time, a research team has investigated interactions between diet, immune system, metabolism and gut microbiota in the development and progression of MS. For this, the researchers adopted a multiomic methodology.

An altered relationship between gut microbiota and the immune system in MS patients

The results were similar to those of previous studies: on the whole, both groups share a similar bacterial community structure. However, MS patients had a lower abundance of bacteria with immunomodulatory properties. Moreover, the microbiota of patients differed depending on the extent of their disability, suggesting a possible link between certain species and disease severity. 

The results of the multiomic analyses also suggest dysfunctional homeostasis of microbiome–immune system interactions, because a disrupted immune cell–microbiome relationship and modification of the blood metabolic profile were observed in the group of MS patients.

Meat consumption: a possible explanation? 

Study of the participants’ food diaries played a key role in this research.

The researchers found that MS patients consumed more meat. This consumption was correlated with an increase in the quantity of Th17 cells, involved in the autoimmune process, and of S-adenosyl-L-methionine (SAM), a metabolite produced from methionine (an amino acid enriched in meat) and involved in the activation of Th17 cells. Conversely, MS patients had reduced proportions of B. thetaiotaomicron bacteria, known for being highly capable of digesting polysaccharides.

A new therapeutic approach? 

This data points to pathways of interaction between diet, gut microbiota, immune response and blood metabolome through B. thetaiotaomicron, Th17 and SAM. For the authors, these results suggest that decreasing dietary consumption of meat or methionine could reduce the number of circulating pro-inflammatory Th17 cells in MS patients.

Microplastics (MPs) are now everywhere, including in what we eat and the air we breathe. Does this increased human exposure present a health risk? Although the answer to this question is still largely unknown, researchers suspect a link, in the digestive system, with an increased risk of inflammation, oxidative stress, increased intestinal permeability and microbiota dysbiosis. This is an already long list, to which we may have to add IBDs, such as Crohn’s disease and ulcerative colitis, if we are to believe the results of a study comparing the characteristics of fecal MPs in 52 IBD patients and 50 healthy subjects from 10 Chinese provinces.

Microplastics in stools: Significant differences

First observation: the researchers detected MPs in all stool samples. Most were much smaller than 300 µm and shaped in the form of sheets (1 MP in 2) or fibers (1 MP in 3). 

In contrast, MP concentrations differed according to the person’s state of health. The stools of IBD patients contained:

• 50% more MPs (41.8 pieces/gram of dry fecal matter, vs 28.0 in healthy subjects);
• more very small MPs (<50 μm), whereas those of healthy participants contained MPs measuring 50 to 300 μm;
• a different relative abundance of each type of MP in terms of its chemical nature, among the fifteen or so types found. In the stools of healthy participants, the researchers found mainly PET, a plastic typical of water bottles (22.3%), and to a lesser extent polyamides from textiles (8.9%) and polypropylene typical of food packaging (8.7%).

In IBD participants, PET (34.0%) and polyamides (12.4%) were more abundant, followed closely by the type of PVC found in pipes, PVC floors, etc. (10.3%), and ahead of polypropylene (9.5%).

Bottled water and fast food are suspected

So where do these MPs come from? Based on the answers to their questionnaire, the team showed that the concentration of MPs in stools increased twofold when drinking bottled water (vs boiled tap water). This is because bottled water contains 22 times more MPs, in particular PET, than tap water.

Other factors that went hand in hand with a near twofold increase in fecal MP concentration were consumption of fast food (vs homemade food) and exposure to dust at work or in daily life.