What do we already know about this subject?

Covid-19 has wreaked havoc on a global scale, resulting in millions of confirmed cases and fatalities as of March 2023. Long-term complications of Covid-19 are pervasive, affecting even individuals with mild or asymptomatic cases. Among pathophysiological responses triggered by Sars-CoV-2 infection, several studies have linked gastrointestinal symptoms and altered gut microbiota in Covid-19 during and after the infection. On SARS-CoV-2 infection, growing evidence supports the role of gut microbiota in influencing Covid-19 severity and post-Covid effects [2]. Dysbiosis, an imbalance in the gut microbiota composition, is a critical factor in the development of various diseases. Severe Covid-19 cases have been associated with alteration of the intestinal microbiota that may persist for up to a year following the initial infection [3, 4]. However, until now, it was known that Covid-19 can alter the composition of the intestinal microbiota, but we were unaware of the causal effects that the post-Covid microbiota can have on the host’s physiology.

What are the main insights from this study?

Microbiota analysis of 72 individuals with a history of Covid-19 (post-Covid group) and 59 healthy controls showed no significant differences in gut microbiota diversity (α and β diversity) between the groups, while post-Covid subjects exhibited a higher prevalence of Enterobacteriaceae strains with drug-resistant phenotypes. A higher proportion of post-Covid individuals reported antibiotic use, likely due to Covid-19 treatment. Importantly, Klebsiella strains, associated with antimicrobial resistance (AMR), were notably increased in post-Covid gut microbiota (figure 1).

To understand the direct contribution of post-Covid microbiota to the host, fecal microbiota transplantation (FMT) was performed in germ-free mice using samples from post-Covid and control donors. Post-Covid mice exhibited lung inflammation (figure 2A).

They were also more susceptible to infection with multidrug-resistant Klebsiella pneumonia displaying a more severe lung pathology and inflammatory cell infiltration but were less efficient at clearing the bacteria. Increased Enterobacteriaceae levels in the blood of post-Covid mice suggested systemic translocation. In addition, reduced serum acetate levels were observed in post-Covid Klebsiella pneumonia-infected mice (figure 2A).

Post-Covid mice exhibited memory impairment in cognitive behavioral tests, along with increased TNF expression and decreased neuroprotective factors in the hippocampus (figure 2B). Administration of a strain probiotic to mice infected with a murine coronavirus prevented memory impairment, reduced weight loss and lung tissue inflammation.

What are the consequences in practice?

This study warns about the relationship between Covid-19 and the global burden of antimicrobial resistance. Furthermore, it highlights for the first time the causal effect of post-Covid microbiota on lung and nervous system alterations.

What do we already know about this subject?

Anorexia nervosa (AN) is a very common psychiatric condition in adolescence, with a high mortality rate. AN is characterised by dysmorphia, reduced calorie intake and malnutrition. Although the pathophysiology of AN is poorly understood, the gut microbiome (GM) is thought to play an important role. GM is actually involved in the gut-brain axis, in malnutrition and also in excess weight, and is altered by diet. The aim of the study was to analyse GM alterations over time in AN patients. It was a one-year study conducted on inpatients until they were discharged from hospital, with an assessment of the clinical parameters associated with the GM in AN.

What are the main insights from this study?

This is the first longitudinal study on gut microbiome (GM) alterations in AN patients, conducted over such a lengthy time frame (one year). The study included 56 patients aged between 12-20 years and 34 controls. Stools were collected at admission and discharge (T0-T7) then one year after admission (T8). Eight patients were re-admitted during the study; patients were separated into those who had recovered their weight (BMI≥15th p [percentile]) and those who still had a low weight (BMI<15th p).

GM composition differed significantly at admission during the acute malnutrition phase, with no difference in terms of alpha-diversity (figure 1). GM differences observed in AN patients compared to controls, even when non-significant, persisted throughout the study. In adolescents with a BMI<15th p at one year, alpha-diversity (Chao1 index) was significantly reduced during hospitalisation compared to admission, discharge and at the 1-year follow-up. A similar trend was observed in AN patients who recovered a BMI≥15 compared to the controls. At admission, the PERMANOVA analysis showed a significant reduction in the genera Legionella, Dialister, Ruminococcaceae UCG-003 and Limnobacter compared to the controls. During in-hospital treatment, the differences between AN patients and controls were reduced, and only remained in the amplicon sequences variants (ASVs). At one year, significant differences were still observed between AN patients with a BMI<15th p and controls in terms of the phyla, classes and orders (p = 0.001 to <0.001), whereas smaller differences were observed between AN patients with a BMI≥15th p and controls (p = 0.063 in terms of ASVs) (figure 2).

Between admission and the 1-year follow-up, AN patients with a BMI<15th p had a significant abundance of the genera Anaerostipes, Clostridium sensu stricto 1 and Romboustia (p = 0.02) while surprisingly, the GM of AN patients who recovered a BMI≥15th p was more similar during the follow-up. The same was true for changes in GM between hospital discharge and the 1-year follow-up: with a four fold greater abundance of the genus Escherichia-Shigella (p = 0.04) and two fold greater abundance of Alistipes (p = 0.03) in AN patients with a BMI<15th p. GM analysis at admission revealed a significant association between illness duration (phylum-family level, p = 0.011 to 0.022) and amount of weight loss (class-genera level, p = 0.030 to 0.047). A longitudinal PERMANOVA analysis, with correction for the use of laxatives, showed a significant association between GM and the amount of ingested calories (p = 0.003, R2 = 0.009), the BMI-SDS (p = 0.006, R2 = 0.008) and leptin concentration at admission, discharge, and 1-year follow-up (p = 0.02, R2 = 0.02). The genera Ruminiclostridium 5 (p=0.006) and Intestinibacter (p= 0.03) were associated with the risk of hospital readmission. A linear model analysis, with correction for laxative use, illness duration, weight loss and BMI-SMS at admission, identified that at admission four genera were associated with BMI-SDS at the 1-year follow-up: Sutterella, Parasutturella, Lachnospiraceae FCS020 group and Clostridium stricto sensu (p = 0.008 to 0.04) (figure 3).

What are the consequences in practice?

Dysbiosis is observed in acute-phase AN patients and improves partly with treatment. GM composition at admission can help predict the risk of relapse in the first year and improvement in BMI at one year. Thus, a GM analysis at admission could identify the genera and taxa Parasutturella, Lachnospiraceae FCS020 group, Clostridium stricto sensu and uncultured Alistipes as indicative of a poorer prognosis. As a higher abundance of Sutterella is indicative of a positive outcome, it could be used as a probiotic target.

What do we already know about this subject?

Almost half of patients with advanced melanoma receiving anti-PD-1 monotherapy develop primary resistance, highlighting the need to develop new therapeutic strategies to improve the response to immune checkpoint inhibitors (ICIs). Although the combination of anti-PD-1 and anti-CTLA4 (cytotoxic T lymphocyte-associated antigen-4) increases the response rate, this therapy is limited by the high number of immune-related adverse events (IR-AEs). The gut microbiome has emerged as an essential regulator of local and systemic immune responses. Several studies in cancer patients treated with ICIs have shown that specific gut bacteria are associated with both immune system response and adverse events [1]. More specifically, the presence of certain commensal genera, such as Ruminococcus, Faecalibacterium and Eubacterium, has been associated with positive outcomes in melanoma patients [2]. The therapeutic potential of the gut microbiome was first demonstrated in mouse models combining ICIs with FMT using faeces from non-responder (NR) patients who were associated with ICI resistance [1]. Two studies showed that FMT in patients with a long-term response to ICI therapy circumvented anti-PD-1 resistance in almost 30% of patients with ICI–refractory melanoma [3, 4]. In these studies, the microbiota of patients changed after FMT, and an increase in Ruminococcaceae and Bifidobacteriaceae was observed in responder (R) patients plus a reprogramming of the tumour microenvironment with increased CD8+ T-cell infiltration and interferon-γ signalling. These clinical findings confirm the potential of microbiome-based interventions to overcome ICI resistance in melanoma.

What are the main insights from this study?

In this article, the authors reported the clinical and translational findings from a Phase I trial (NCT03772899) combining FMT from healthy donors with the PD-1 inhibitors nivolumab or pembrolizumab in treatment-naive patients with advanced melanoma (figure 1). The toxicity observed (85% IR-AEs, of which 25% grade 3 toxicity and zero grade 4 or 5 toxicity) was similar to that reported in the Phase III trials for anti-PD-1. The observed clinical efficacy (objective response 65%) was higher to that of nivolumab and pembrolizumab monotherapy in Phase III trials (objective response 42-45%) and in real-world data (objective response 17.2-51.6%). However, the absence of a control arm and the small size of the study hindered the interpretation of the results.

Unlike the previous studies [3, 4], it included patients receiving first-line treatment, a single FMT was performed by oral capsule, donors were healthy subjects (and not ICI responders) and, finally, only PEG (without the use of antibiotics) was used for the preparation. By studying the microbiota of donors and recipients, the authors observed that the microbiota of responders was enriched in Ruminococcus SGB15234 and SGB15229, Alistipes communis, Eubacterium ramuleus and Faecalibacterium SGB15346, while the abundance of Enterocloster aldensis and Enterocloster clostridioformis decreased. In previous studies, the increase in Faecalibacterium was also associated with the response to ICI [3, 4].

The authors then experimented on mice colonised with human microbiota and observed a similar efficacy of the faecal transplantation from healthy subjects in this context, with an effect associated with an increase in the infiltration of CD8+ T memory lymphocytes in the tumour microenvironment.

What are the consequences in practice?

Despite its limitations, this study suggested that microbiota modulation via FMT could increase ICI efficacy when administered in a first-line setting for metastatic melanoma. Although the wide-scale use of FMT seems difficult in current practice, modulating the microbiota, in particular with new-generation probiotics, in combination with ICI could become a standard treatment.

The relationship between the microbiota and diarrhea

Diarrhea can involve various mechanisms (table 1), and the majority of them are related to the role of microbiota:

• Protection of the microbial balance, this state, known as eubiosis, is fundamental for the health of the human body because it prevents and slows down the expansion of pathogens. Disturbance of the balance between the main microbial strains, known as dysbiosis, can increase susceptibility to infections and contribute to diarrhea. The literature generally indicates that diarrhea represents a major dysbiosis and that the degree of dysbiosis is related to the etiology and the stage of diarrhea [6]. Following acute diarrhea, the taxonomy of the microbiota changes a lot. In early stages of diarrhea, facultative fastgrowing anaerobes such as Proteobacteria (mostly Enterobacteriaceae/Escherichia coli) and Streptococcus (mainly Streptococcus salivarius and Streptococcus gallolyticus) dominate and favor the drastic disappearance of obligate anaerobic gut commensals (Blautia, Prevotella, Faecalibacterium, Lachnospiraceae, Ruminococcaceae, etc.) [2, 3]. The consequence is that short-chain fatty acid (SCFA) also decreases, and the integrity of the intestinal barrier starts to be under threat, possibly leading to gut permeability. In the recovery phase after diarrhea, a proposed model shows that in the midstage, there is an abundance of Bacteroides (the 7th day since disease onset). At the same time, in the late-stage Prevotella and SCFA-producing Firmicutes dominate [4, 5].
   
• Protection against pathogenic invaders. The microbial community of the gut microbiota competes for resources, produces antimicrobial substances, and acts as a barrier against enteropathogens. Beneficial bacteria in the gut, such as certain strains of Bifidobacteria and Lactobacilli, have been demonstrated to have beneficial effects on infectious diarrhea caused by rotavirus in young children. However, there are no clinical trials to demonstrate it [6]
   
• Regulating the immune system. The gut microbiota helps educate and modulate immune responses, promoting tolerance to harmless substances and defending against pathogens. Dysregulation of the immune response due to microbiota imbalances can contribute to inflammation and diarrhea. After antibiotics for Clostridioides difficile-induced diarrhea, such as vancomycin, a reduced relative abundance of Bacteroidetes and Firmicutes is observed, while Proteobacteria and Fusobacteria increase and leading to a decrease in SCFA propionate, creating premises for inflammation [7]
   
• Maintenance of gut function and metabolism. Beneficial bacteria ferment dietary fibers to produce short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate. SCFAs contribute to maintaining a healthy intestinal lining, promote water absorption, and provide an energy source for colonocytes. Imbalances between bacterial strains may impact these functions, leading to functional diarrhea due to decreased SCFA production. Increasing its production enhances colonic fluid absorption. [8]

Diarrheal illnesses and microbiota management

Infectious diarrhea

Bacterial, viral or parasitic gut infections cause acute diarrhea and are frequently spread through contaminated water. Most cases of diarrhea are improved in a few days, but severe diarrhea can lead to serious dehydration and can become lethal [9].

Rotaviruses remains the primary cause of diarrhea-associated deaths in children [11], and management of this viral disease generally involves oral or intravenous hydration, tailored to the severity of dehydration [12]. Furthermore, based on the latest conclusions from the ESPGHAN committee (2023) [13], healthcare providers might suggest certain probiotic strains for acute gastroenteric episodes in children, acknowledging their potential (certainty of evidence: low; grade of recommendation: weak) to decrease the duration of diarrhea, and/or hospital stay, and/or volume of fecal discharge. However, a randomized, double-blind, controlled trial of Bolivian children with acute rotavirus diarrhea demonstrated a decreased duration of diarrhea by using an oral rehydration solution plus a mixture of probiotics by comparison with simple rehydration solution [11].

Travelers diarrhea

More than 60% of the adults from developed countries who travel to developing countries experience acute diarrhea, also known as traveler’s diarrhea (TD). The most frequently identified pathogens implicated in traveler’s diarrhea episodes are Escherichia coli, Campylobacter jejuni, Salmonella species and Shigella species. Thus, the recommended treatment strategies include antibiotic therapy with azithromycin or fluoroquinolones for moderate to severe cases [14]. However, antibiotics are not recommended to prevent TD, due to insufficient evidence of their prophylactic efficacy and partially due to the risk of antibiotic resistance [15].

There is conflicting data regarding the efficacy of probiotics in preventing traveler’s diarrhea [16]. One systematic review and meta-analysis compared the efficacy of rifaximin and probiotics in preventing TD. [15].

Antibiotic-associated diarrhea

Antibiotics are one of the most prescribed medications and represent an effective treatment for several infectious pathologies [17]. One of the complications associated with antibiotic therapy is antibiotic-associated diarrhea (AAD), which occurs in 5%-35% of the patients who receive antibiotherapy [18]. AAD can be defined as three or more watery or loose stools per day for at least two consecutive days, which is strictly related to antibiotics administration and no other cause [14]. The highest risk is attributed to aminopenicillins, cephalosporins and clindamycin, which primarily target anaerobes [19]. 

The lack of an infectious agent identified in AAD may be explained by the direct toxic effect of the antibiotics on the intestinal mucosa, which may cause diarrhea. Due to their beneficent properties, probiotics are now being researched and used for both treatment and prophylaxis of AAD [16, 18].

Clostridium difficile associated diarrhea

Clostridioides difficile (CD) infection is the most common cause of nosocomial antibiotic-associated diarrhea in adults. Risk factors include age over 65 years, long hospitalization in intensive care, and administering antibiotics (fluoroquinolones, clindamycin, cephalosporins, and betalactams in particular) or proton pump inhibitors. During antibiotherapy, anaerobes that produce SCFAs may disappear due to antibiotic-induced alterations in the gut microbiota, which may also disturb the metabolism of carbohydrates and bile and cause an osmotic imbalance. Following antibiotic intake, all three intestinal barriers are affected: the epithelial intestinal cells, the mucus and antimicrobial peptides layer, and the immunoprotective layer composed of different immune cells and various biomolecules (figure 1). This event can interfere with the production of mucin, cytokines, and antimicrobial peptides, dysregulating intestinal function and leading to other infections or even causing recurrent episodes of infections. The American Gastroenterological Association (AGA) conditionally recommends specific probiotics for preventing CD infection in individuals on antibiotics, noting that the quality of evidence is low [20].

Emerging discoveries and the future of diarrhea management

Recent breakthroughs in microbiota research, including metagenomic analysis and microbial transplantation, are revolutionizing our approach to diarrhea treatment (figure 2).

There is limited data regarding the prebiotics and fibers in treating diarrhea (table 2). Apparently, prebiotics are more prone to prevent and treat the recurrence of diarrhea. At the same time, fibers, mainly the viscous ones, are more indicated during acute episodes due to their water-retaining capacity. Other therapeutic options involve, in some cases, the probiotic administration and (table 3), in severe cases, the use of fecal microbiota transplantation (FMT).

The fascinating journey of FMT discovery has roots in ancient China, where Ge Hong treated patients with severe diarrhea using a “yellow soup” consisting of feces suspension. In modern times, Dr. Ben Eiseman used fecal enemas from healthy individuals to treat pseudomembranous enterocolitis back in 1958. Nowadays, there is growing interest in fecal microbiota transplantation (FMT) as a treatment for recurrent Clostridioides difficile infection (CDI), which points out its utility [22]. Research is ongoing regarding its efficacy towards inflammatory bowel disease, diabetes, cancer, liver cirrhosis, and brain diseases such as Parkinson’s [23]. The benefits of using FMT in patients with diarrhea are based on the idea that the healthy microbial flora introduced via FMT has the ability to outcompete pathogens and restore the composition of a healthy gut microbiome (figure 3).

One of the features of the vaginal microbiota is that it is balanced when it is largely dominated by Lactobacillus crispatus. On the other hand, colonization by anaerobic bacteria such as Gardnerella vaginalis and Mobiluncus mulieris is associated with an increased risk of STIs, bacterial vaginosis and preterm birth. However, the mechanisms involved remain unclear, although the literature suggests that the production of extracellular vesicles by certain bacteria is involved. Could this mechanism be at work in the reproductive system? This is the hypothesis ¹ put forward and validated by the team led by Dr. Michal A. Elovitz of the Icahn School of Medicine at Mount Sinai ² in New York, who studied, in vitro, the extracellular vesicles produced by the beneficial L. crispatus and the detrimental G. vaginalis and M. mulieris. 

Vesicles rich in proteins of interest

After using electron microscopy to observe the actual presence of vesicles ranging from 90 to 420 nm in diameter in cell culture media, the team analyzed their contents. The vesicles produced by G. vaginalis, M. mulieris and L. crispatus contained 491, 336 and 247 bacterial proteins, respectively. Several of these were of functional interest: the G. vaginalis cargo was rich in vaginolysin, a toxin capable of inducing cell lysis (breakdown of the cell wall) in cervicovaginal epithelial cells and common in bacterial vaginosis; that of M. mulieris contained proteins capable of stimulating an immune response, while several proteins in L. crispatus vesicles protect the epithelial barrier.

An immune response with overproduction of cytokines

Exposure of cervical and vaginal epithelial cells to the contents of G. vaginalis and M. mulieris bacterial vesicles induced a dose-dependent immune response. The response of endocervical cells was more pronounced than that of ectocervical cells. In contrast, L. crispatus did not induce any significant cytokine overexpression.  

Thus, cervical and vaginal epithelial cells respond with overproduction of cytokines when exposed to G. vaginalis and M. mulieris vesicles, but not to L. crispatus. This immune response is mediated by signaling pathways activated by the TLR2 receptor (sidenote: TLR2 receptor Toll-like receptor (molecular pattern recognition) located in the cell membrane, encoded by the TLR2 gene and involved in the recognition of various pathogens, including bacteria, viruses, fungi and parasites. Source: Oliveira-Nascimento L, Massari P, Wetzler LM. The Role of TLR2 in Infection and Immunity. Front Immunol. 2012 Apr 18;3:79.  ) .

This could be the umpteenth "Spring Special" issue of a women's magazine extolling the virtues of the latest fad diet...But no, these are the results of a particularly rigorous study published in the journal Nature Metabolism ¹ that is generating interest and presenting the potential weight-loss benefits of resistant starch. By modulating the structure of our gut microbiota, this dietary fiber—found in legumes, whole grains and green bananas—could well help us shed unwanted pounds and improve our health. Let’s take a closer look at the results.

Zero dieting and several pounds lost

The researchers recruited 22 overweight men and 15 overweight women (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 ) > 24) with a normal (non-hypocaloric) balanced diet, and supplemented them with either resistant starch or "normal" placebo starch (see box). They measured changes in BMI, gut microbiota and various metabolic parameters.

The results first indicate that taking 40 g of starch daily for 2 months is associated with an average weight loss of 6.17 lbs, with in particular:

• a reduction in visceral fat, the riskiest in terms of cardiovascular risk;
• improved insulin sensitivity and glucose tolerance, factors that protect against diabetes.

None of these effects were observed with the placebo starch.

It's all in the gut microbiota!

Analyses indicate that resistant starch led to a veritable remodeling of the structure of the volunteers' gut microbiota, with an increase in several bacterial strains, particularly Bifidobacterium adolescentis. The researchers' calculations show that the abundance of this bacteria is strongly correlated with the reduction in BMI and visceral fat.

When they transplanted the fecal microbiota of volunteers who had consumed resistant starch into mice (FMT) (sidenote: Fecal Microbiota Transplantation (FMT) A therapeutic procedure to restore the gut microbiota by transferring fecal bacteria from a healthy donor to a recipient. Explore https://www.science.org/doi/10.1126/scitranslmed.abo2750 ) , the researchers found the same type of effects on weight and insulin sensitivity. And the same effects were obtained by supplementing mice with the beneficial bacteria identified as B. adolescentis. 

This reinforces the hypothesis that the changes in the gut microbiota induced by resistant starch are responsible for its beneficial effects.
 

Several metabolic pathways involved

The changes in the gut microbiota, among other things:

• influenced bile acid metabolism: this increased the production of certain so-called "secondary" bile acids capable of acting on cellular receptors involved in glucose and lipid regulation;
• reduced inflammation by restoring the intestinal barrier (low-grade inflammation is known to be involved in obesity and insulin resistance);
• inhibited the absorption of dietary lipids.

These results need to be confirmed by a larger-scale study. But they suggest that increasing the resistant starch content of one's diet is both a simple and powerful strategy for losing weight...or keeping it off after dieting!
 

Functional dyspepsia: a strange-sounding name for a condition you’re surely familiar with, since it affects almost 1 in 10 people, particularly women, smokers, and patients taking non-steroidal anti-inflammatory drugs (ibuprofen, ketoprofen). Functional dyspepsia is a common digestive disorder characterized by chronic pain or discomfort centered on the stomach.

Common symptoms are an unpleasant feeling of being too full after a normal-sized meal, of feeling full when you’ve just started eating, or of pain and/or burning at the bottom of the stomach. All this can last for weeks on end.

From dysbiosis to dyspepsia

While the many causes and mechanisms of functional dyspepsia are still poorly understood, the gut microbiota has been singled out for blame. For example, the Helicobacter pylori bacterium that sometimes makes itself at home in the stomach appears to be a major contributor to the development and progression of the disease, probably via inflammation of the gastrointestinal mucosa and disruption of gut motility.

In more general terms, the gut microbiota as a whole may be involved. This may be both directly (an imbalance in composition and abundance may lead to gut dysfunction) and via the bacterial metabolites it produces, which can have a protective (e.g. short-chain fatty acids (sidenote: Short chain fatty acids (SCFA) Short chain fatty acids (SCFA) are a source of energy (fuel) for an individual’s cells. They interact with the immune system and are involved in communication between the intestine and the brain. 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. )  produced by Firmicutes) or harmful (pro-inflammatory sphingolipids produced by Bacteroidetes and Prevotellaceae) effect on the host.

Treatment via the microbiota

One direct consequence of the gastrointestinal microbiota’s involvement in functional dyspepsia is the search for solutions to restore this microbiota, and thus host’s (patient’s) health. Several trials ¹ on patients appear to show that probiotics can significantly improve symptoms by restoring the balance of the gut flora.

Another, slightly more aggressive, approach is the use of broad-spectrum antibiotics which eliminate undesirable bacteria. This nuclear option is highly effective, particularly in women, but causes considerable collateral damage to good bacteria. Hence the need for further research to better understand the mechanisms involved and propose targeted, effective diagnostic methods and treatments.

A heavy feeling in the stomach after eating, feeling full too early in a meal, epigastric burning – just some of the disabling symptoms of functional dyspepsia (FD), a common disorder of the gastrointestinal tract that gives rise to numerous medical complaints. The prevalence of FD is high, estimated at 7.2% worldwide, with women, smokers, and patients taking non-steroidal anti-inflammatory drugs at particular risk. The gut microbiota may be involved.

From dysbiosis to dyspepsia

The gastrointestinal tract hosts a microbiota that increases in abundance from the stomach (non-sterile) to the colon: Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes account for over 98% of the gut microbiota in healthy individuals. This microbial community is widely implicated in digestive health, from preserving the integrity of the gut barrier to modulating the mucosal immune system. 

At times, the balance of this community is upset, leading to dysbiosis: the presence of Helicobacter pylori in the stomach seems to contribute to the development and progression of FD, while a dysbiosis in the duodenum (an increase in Streptococcus, Firmicutes, Bacteroides, and Proteobacteria, together with a decrease in Prevotella, Veillonella, Leptotrichia, Actinomyces, Neisseria, and Porphyromonas) appears to correlate with FD.

The gut microbiota may be involved both directly (an imbalance in composition and abundance may lead to gut dysfunction) and via the bacterial metabolites it produces, which can have a beneficial (e.g. short-chain fatty acids produced by Firmicutes) or harmful (pro-inflammatory sphingolipids produced by Bacteroidetes and Prevotellaceae) effect on the host.

Treatment via the gut microbiota

Modulation of the gut microbiota thus has widely recognized potential as a therapeutic approach. A number of clinical trials have underlined this potential: a combination of probiotic Bacillus strains (Bacillus coagulans, Bacillus clausii, and Bacillus subtilis) improves certain symptoms (belching, reflux, bloating), as does a probiotic combining Bacillus coagulans MY01 and Bacillus subtilis. A probiotic-enriched yogurt (Lactobacillus gasseri) did not alter patients’ symptoms but did reduce their frequency (17.3% vs. 35.2% in the placebo group).

Imagine opening a book that tells the story of a hidden city within your own home that you never knew existed. That's what scientists from Stanford University have done with the discovery of "Obelisks" (sidenote: Obelisks Newly discovered virus-like entities found within the bacteria of the human mouth and gut. Characterized by their unique RNA structures, these entities challenge traditional understandings of microbial and viral life forms. ) , a newly identified type of virus-like particles living inside the bacteria of our mouths and guts.

Like uncovering an ancient relic, the researchers used advanced genetic tools to map out the DNA landscapes of these bacteria, revealing that "Obelisks" dwell in about 7% of gut bacteria and an astonishing 50% of oral bacteria. This breakthrough not only shifts our view of the tiny life forms residing within us but also hints at rewriting the rules on how we understand viruses and the intricate ecosystems of our body's microbiome.

How were "Obelisks" discovered?

The research team employed a cutting-edge technique known as whole metagenome sequencing to analyze the genetic material from mouth and gut bacteria samples. This method allows scientists to read and compare the DNA sequences present, providing a comprehensive overview of the microbial landscape. By leveraging sophisticated bioinformatics tools, researchers identified these "Obelisks", which are characterized by their circular RNA genomes and unique rod-like structures.

One intriguing aspect of "Obelisks" is their RNA-based genome. RNA, or ribonucleic acid, is a molecule similar to DNA and is crucial for various biological roles, including acting as a messenger carrying instructions from DNA for controlling the synthesis of proteins. Unlike most organisms that store genetic information in DNA, these entities use RNA, which adds another layer of complexity to their nature.

What can we do with this?

The presence of "Obelisks" in such significant proportions within the human microbiome hints at their potential role in influencing our health, possibly affecting everything from digestion to immune responses. The study found that these entities could persist in individuals for over 300 days, suggesting they may have long-term effects on their hosts – Us!

In recent years, research has highlighted the health potential of the microbiome, leading to a burgeoning market for DTC tests that promise consumers the best of everything. Researchers and clinicians in the US are questioning these claims, and in an article published in Science, they have thoroughly examined the online services and promises of 31 companies, 17 of them based in the United States. These services mainly relate to the gut microbiota and to a lesser extent to the vaginal and skin microbiota.

Similar to DNA testing

In practical terms, these tests resemble DNA tests: you order a kit, take a sample and return it to the laboratory where it is sequenced to determine the taxonomic composition of the microbiome. The customer receives a report, often in graphic format, and a verdict (healthy microbiome or dysbiosis) obtained via comparison with databases with questionable representativeness. If a dysbiosis is detected, the customer is given recommendations, as well as the offer of dietary supplements sold by 45% of the companies marketing these tests. Predictably, they are also recommended regular tests to monitor improvements.

Tests with no validity or usefulness

For the authors of the article, the three requirements guaranteeing the accuracy and usefulness of a test have not been met:

• analytical validity (false-positive and false-negative rates) cannot be guaranteed: the bacterial microbiome has not yet been fully deciphered, the test does not analyze all bacteria, results vary from one laboratory to another or even within the same laboratory (non-standardized methods, variable databases, etc.);
• clinical validity (healthy or dysbiotic microbiome?) is doubtful, given the lack of a standard for “healthy” microbiota;
• clinical usefulness is questionable, since the information obtained does not allow for recommendations or treatment.

To be sure, many companies are careful to point out that their tests have no “diagnostic” value. However, their marketing suggests otherwise, especially since the results give the impression of being scientific.