As Gram-negative (sidenote: Gram-negative bacteria A group of bacteria characterized by their unique cell wall structure, which makes them resistant to many antibiotics and often more challenging to treat. ) bacterial infections rise, our gut microbiome—home to trillions of beneficial bacteria—is under siege from broad-spectrum antibiotics. These drugs, though effective against infections, often wipe out our gut’s beneficial bacteria, leading to secondary infections. It's like using a sledgehammer to crack a nut. There’s an urgent need for antibiotics that zero in on the bad guys without harming the good ones.

This is where lolamicin comes in. Researchers have been working to design an antibiotic that specifically targets Gram-negative bacteria ¹.

The secret weapon? The Lol lipoprotein transport system, a critical mechanism exclusive to these harmful bacteria. By disrupting this system, lolamicin can take out the pathogens while leaving our beneficial bacteria unscathed.
 

Precision medicine: the art of crafting lolamicin

Developing lolamicin (sidenote: Lolamicin A newly developed Gram-negative-selective antibiotic that targets the Lol lipoprotein transport system, effectively killing pathogenic bacteria without disrupting the gut microbiome. ) was no small feat. Imagine trying to craft a key that perfectly fits a lock without disturbing the surrounding structure. Researchers began with whole-cell screens, identifying compounds that could inhibit the Lol system in a group of specific bacteria. Through a series of tweaks and modifications, they engineered a hybrid scaffold that led to the creation of lolamicin.
 

This new antibiotic was put through rigorous tests and delivered impressive results. Lolamicin showed potent activity against over 130 different strains of multidrug-resistant bacteria (sidenote: Multidrug-resistant Describes bacteria that have developed resistance to multiple classes of antibiotics, making infections caused by these bacteria particularly difficult to treat. ) , including notorious troublemakers like E. coli and Klebsiella pneumoniae. In mouse models of severe infections, lolamicin significantly reduced bacterial loads and improved survival rates, outperforming existing antibiotics.

Targeting the villains, sparing the heroes

But the real game-changer is lolamicin’s ability to preserve the gut microbiome. Unlike broad-spectrum antibiotics that ravage the gut's bacterial community, lolamicin treatment resulted in minimal changes. This was confirmed through advanced DNA sequencing techniques, which showed that the diversity and richness of the gut microbiome were maintained. Remarkably, lolamicin-treated mice could fend off secondary infections from Clostridioides difficile, a common complication of antibiotic use.
 

Although further validation in human trials is needed, lolamicin represents a revolutionary step forward. It's not just about fighting infections—it's about doing so with precision, ensuring our beneficial bacteria remain unharmed. This advancement heralds a new era in medicine, where antibiotics are tailored to target pathogens precisely, safeguarding our overall health.

Little known to the general public, functional dyspepsia (FD) is a very common gastrointestinal disorder that is under-diagnosed and still poorly understood today. FD accounts for 3% to 5% of GP visits in North America ¹ !

Functional dyspepsia’s varied symptoms are always associated with a feeling of poor digestion ²:

• feeling full long before you’ve finished your meal 
• the feeling of having eaten too much (stomach feels heavy and bloated), despite having eaten a perfectly reasonable-sized meal
• pain or burning in the upper stomach
• loss of appetite
• belching or hiccups
• nausea or even vomiting

Did you know?

The disorder is called functional dyspepsia since it is not accompanied by any structural abnormality in the digestive organs and tissues. Symptoms cannot be explained by the presence of a lesion in the stomach (no ulcers) or any other organic or structural abnormality: all tests (gastroenteroscopy, ultrasound, CT scan, etc.) come out negative.

How common is the disease? Who is most at risk?

Studies suggest that 10% to 30% of adults and 3% to 27% of children worldwide are affected by functional dyspepsia ². Women, smokers, and users of non-steroidal anti-inflammatory drugs (ibuprofen, ketoprofen) are at greater risk ³.

The consequences for patients are far from negligible: two-thirds of those affected by functional dyspepsia suffer from persistent and irregular symptoms that can affect their quality of life and well-being ¹.

Diet

Increasingly clear is the role played by diet in triggering functional dyspepsia symptoms. The culprits? Above all, fatty foods. But they’re not alone. Carbohydrate-containing foods, milk and dairy products, citrus fruits, spicy foods, coffee, and alcohol, have also been implicated ⁵. However, the results of these studies remain uncertain.

The mind may also play a role, with the memory of a bad experience leading patients to anticipate symptoms and over-experience them when exposed again. Experience has shown that distracting a patient with a cognitive task is enough to make them forget about their symptoms. Conversely, stating that the fat content of a yogurt is higher than it actually is increases the nausea felt by patients

Stress and anxiety

functional dyspepsia patients are often stressed and anxious: one large study showed that anxiety was clearly linked to the disease, and more specifically to postprandial distress; another study of 18,000 Japanese showed that patients with functional dyspepsia symptoms felt more stressed on a daily basis, more often mentioned not getting enough sleep, and complained more of difficulties in falling asleep ⁵.

Lack of physical activity

Functional dyspepsia patients generally report lower levels of physical activity. This is unfortunate since it appears that sport can actually reduce symptoms, and improve transit and gas evacuation in people suffering from bloating ⁵.

Tobacco

A study of 2,560 Swedes shows that smokers are at greater risk of postprandial distress syndrome: smoking 10 to 19 cigarettes a day increases the risk by 42%, while smoking more than a pack a day more than doubles the risk ⁷.

Obesity

Obesity is associated with many gastrointestinal symptoms, including functional dyspepsia. Several hypotheses have been put forward: for example, in obese people, the oral and gut receptors responsible for alerting the body to the presence of fats may be altered, amplifying the gastrointestinal effects in these patients, making them more sensitive to dietary fats ⁵.

Some specialists also point to a reciprocal link between functional dyspepsia and metabolic syndrome (sidenote: Metabolic syndrome Metabolic syndrome, also known as syndrome X, is characterized by the accumulation of several metabolic disorders in the same individual, including a large waist circumference (due to excess abdominal adipose tissue), hypertension, abnormal fasting blood sugar levels or insulin resistance, and dyslipidemia.  ) , with each promoting the other, creating a vicious circle ¹.

Helicobacter pylori bacteria

Since the 1980s, it has been known that the stomach, although highly acidic, is not sterile. It even harbors a community of microorganisms, including the bacterium H. pylori. However, infection by H. pylori appears to lead to the onset and progression of functional dyspepsia: patients with a history of H. pylori infection have a higher risk of developing functional dyspepsia ².

Dysbiosis throughout the digestive system

The digestive tract is home to almost 100 billion microorganisms from over 1,000 different species, which together are known as the gastrointestinal microbiota.

Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes dominate this community, making up more than 98% of the gut microbiota, with Firmicutes predominating, followed by Actinobacteria and Bacteroidetes ². At least in healthy patients. In those suffering from illnesses such as functional dyspepsia, this balance is not found; instead, dysbiosis is observed throughout the digestive system, from mouth to anus ².

In functional dyspepsia patients, studies have found, for example:

• a higher abundance of Firmicutes, streptococcus (associated with symptoms in the upper stomach), Bifidobacterium and Clostridium
• a lower abundance of Prevotella (accompanied by more symptoms of discomfort after eating)

The role of microbial metabolites

The microbiota’s role in functional dyspepsia is far from limited to the bacteria present, since each of these bacteria secretes various active molecules, both beneficial and harmful, that are closely linked to host health and to the onset and progression of numerous diseases ^2,3. For example: 

• some bacterial metabolites have a beneficial effect (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) 
• while others are harmful to the host (e.g. pro-inflammatory sphingolipids produced by Bacteroidetes and Prevotellacae) ³

While many gray areas remain, researchers believe that the mechanisms behind functional dyspepsia are likely to be multifactorial and vary from patient to patient ⁸. Thus, a range of mechanisms are involved in functional dyspepsia:

Disruption of the gut barrier

In normal circumstances, food passing through our digestive system remains isolated from our body by a barrier, the intestinal mucosa. This barrier is semi-permeable: it allows nutrients to be absorbed but bars passage to the various harmful substances and pathogens ingested along with our meal ². 

In functional dyspepsia patients, the integrity of this mucosa is compromised, so much so that it performs its filtering role less effectively

Disruption of gut immunity

In functional dyspepsia patients, there appears to be an excessive immune response: 40% of patients present inflammatory cells infiltrated into the duodenum, while a proliferation of bacteria (particularly oral bacteria) ⁹ is frequently observed in the small intestine, which may activate this immune response. Indeed, some researchers believe that a greater focus on the microbiota of the small intestine (sidenote: Small intestine Section of the digestive system between the stomach and the large intestine (i.e. the colon) essential for the digestion and absorption of nutrients. Measuring 21 to 23 feet, it is the longest portion of the digestive tract, comprising the duodenum, then the jejunum, and finally the ileum.  ) is required in order to better understand the pathogenesis of functional dyspepsia ⁹.

Deregulation of the gut-brain axis

There are complex interactions between the gut microbiota, the digestive system, and the central nervous system. This microbiota-gut-brain axis explains why stress can cause stomach ache, or why changes in the gut flora can alter intestinal motility and “inform” the brain, which in turn can regulate the gut. However, functional dyspepsia has been shown to be closely linked to gastrointestinal motility disorders (which are under cerebral control) and to gastrointestinal hypersensitivity, all of which are linked to the gastrointestinal microbiota ². From here to suggesting that everything is linked is only a short step...

An abnormal response to food ingestion

The presence of nutrients in the interior of the digestive tract produces signals that alter digestion. For example, a high-fat meal emains in the stomach longer, since gastric emptying is delayed. In functional dyspepsia patients, food ingestion may be associated with exaggerated signals from the gastrointestinal tract. This results in a whole series of symptoms which bear no relation to reality, such as feeling full when a meal has only just begun, hypersensitivity to gastric distension, and so on. ⁵

Diet

Logically, since diet is thought to play a role in functional dyspepsia, adapting it may improve symptoms. However, there is a dearth of studies highlighting the effects of specific diets. Nevertheless, experts believe that a large proportion of patients would benefit from a lower-fat diet and smaller meals eaten more often. In fact, functional dyspepsia patients are already doing so in practice: they have a slightly reduced dietary fat intake and tend to eat smaller meals more frequently ⁵.

Other patients would benefit more from avoiding spicy or acidic foods (tomatoes, citrus fruits, etc.) or foods rich in fiber or FODMAPs, which cause bloating. However, these restrictions should be managed with care so as to avoid an unbalanced diet ².

Proton pump inhibitors

Proton pump inhibitors (PPIs) are drugs used to reduce gastric acid secretion. They are prescribed by doctors to treat gastroesophageal reflux disease (GERD) and peptic ulcers.

In the short term, proton pump inhibitors (PPIs) may improve functional dyspepsia symptoms. However, their long-term use seems to go hand in hand with an increase in Streptococcus and, thus, a harmful dysbiosis ¹³.

Antibiotics to eradicate H. pylori

According to the American College of Gastroenterology and the Canadian Association of Gastroenterology, functional dyspepsia patients under 60 years of age should first be screened for H. pylori. If the test proves positive, antibiotics should be prescribed to eradicate the bacteria.

However, this strategy has its limits: only 1 in 10 patients will experience an improvement in their symptoms, while the remainder will see their symptoms worsen ¹⁴.

Probiotics

Since dysbiosis of the gastrointestinal microbiota is closely linked to the onset and progression of functional dyspepsia, regulating the gastrointestinal microbiota has logically been put forward as a potential treatment ². The role of probiotics may be multifactorial ¹⁵ :

• restoration of commensal flora eliminated by pathogens
• restoration of gut barrier permeability
• reduction of visceral hypersensitivity
• local and systemic anti-inflammatory action
• regulation of intestinal motility

All these benefits are thought to reduce symptoms of functional dyspepsia ¹⁵.

Alternative therapies

Various alternative therapies have been recognized as safe and effective treatments for functional dyspepsia:

• cognitive behavioral therapy, commonly used to treat stress and anxiety, helps the patient identify the thoughts or behaviors that lead to or exacerbate the expression of symptoms
• hypnotherapy, where the patient, in a state of hypnosis, is more receptive to therapeutic suggestions
• The potential of virtual reality is also being explored ¹⁴.

Introduction

We're about to dive into the fascinating world of "biotics." Now, you might be thinking, "What in the world are 'biotics'?" Well, it all goes back to an ancient Greek word, "bíos," which simply means "life." From that root word, we get terms like probiotics, prebiotics, postbiotics, synbiotics. These aren't just fancy scientific names – they're like the different parts that make up a lively neighborhood, each playing a unique role in keeping things running smoothly.

Imagine you're the new resident on the block, and a friendly neighbor offers to show you around, pointing out all the key people and places that make the community tick. That's what we're doing here – getting a local's tour of the "biotics" neighborhood inside your body.

In our city of health, probiotics are like our visiting beneficial friends – live microorganisms that take up residence within us and contribute to our well-being. As defined by the World Health Organization (WHO) and the International Scientific Association for Probiotics and Prebiotics (ISAPP), probiotics are "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host." ¹

In simpler terms, they are beneficial microbes such as bacteria, yeast, … that support our overall well-being. Probiotics contribute to our health in various ways, such as:

• promoting a balanced microbiome ²
• inhibiting the growth of pathogens inside the human body ³
• improvement in barrier and metabolic functions of targeted organs ^{4, 5, 6}
• supporting immune function ⁷
• and modulation of diverse signaling and metabolic pathways ⁸

One widespread misconception is that all fermented foods, such as yogurt, kefir, or kombucha, are inherently probiotic. ⁹ While fermentation can introduce beneficial bacteria, not all fermented products contain live, probiotic strains that meet the criteria set forth by health authorities. ¹⁰ However, some fermented foods are fermented using a microbe proven to be a probiotic, or have been supplemented with probiotics in sufficient quantities to offer health benefits.

It's essential to carefully read labels and rely on reputable sources to ensure you're consuming products with scientifically and clinically validated probiotic cultures. Additionally, some assume that probiotics are a one-size-fits-all solution, but different strains can have varying effects on different individuals and health conditions. ^{1, 11} Consulting with healthcare professionals and following evidence-based guidelines is crucial for optimizing the benefits of probiotics based on your unique needs and circumstances.

If you want to learn more about probiotics, you can read our dedicated section here:

Prebiotics are defined as "a substrate that is selectively utilized by host microorganisms conferring a health benefit." ^{12, 13} Unlike probiotics, prebiotics themselves are not live microbes but rather serve as fuel for the existing beneficial bacteria in our microbiome. It's a common oversimplification to describe prebiotics as "food for probiotics."

While prebiotics do support probiotic growth, their beneficial effects stem from the activity of the resident gut microbiota, which metabolize these compounds, indirectly conferring physiological advantages to the host – us! Moreover, not all dietary fibers are prebiotics, and not all prebiotics are fibers. ¹⁴ This distinction is often overlooked, leading to misconceptions about their definitions and functions.

Imagine prebiotics as favorite restaurants for your helpful bacteria. Foods like bananas, onions, and garlic are rich in substances such as inulin and galacto-oligosaccharides (GOS) that act as prebiotics. When your beneficial bacteria dine on these foods, they can increase the production of molecules, i.e. metabolites, such as short-chain fatty acids (SCFAs) (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. ) acetate, propionate, and butyrate which in turn can improve your health. ¹⁵

Beyond supporting gut health, prebiotics have been linked to re-balancing the microbiota for better defense against pathogens, ¹⁶ weight management, ¹⁷ better mineral absorption, ¹⁸ etc. Their benefits extend beyond just the gut. ¹⁹

We have also prepared a dedicated section about prebiotics and their health benefits here:

After probiotics have completed their visit of the city, they leave behind gifts known as postbiotics. These are like the products and services that businesses in a city provide after taking in raw materials. Postbiotics include beneficial substances like vitamins and 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. ) . They're the rewards your body gets from the probiotics' hard work.

This definition was revised many times, and the Scientific Community have now reached a consensus: “postbiotic is a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host.” This means that postbiotics are not just the “re-purposed” waste of the probiotics (or their end-products), but they are also the “dead” probiotics themselves and fragment components! ²⁰

Such as probiotics, postbiotics have been shown to strengthen the barrier function, reduce inflammation, and exhibit antimicrobial activity against pathogens, thereby promoting overall health. ²¹ Their beneficial properties also extend beyond the gut with benefits for skin and vaginal health and potentially addressing skin and vaginal conditions. ^{22, 23}

You may have heard additional names such as Parabiotics, Paraprobiotic or Proteobiotics. Indeed, some researchers have tried to define further the different elements or body parts of the postbiotic component, meaning dead cells, components of the cells and the metabolites produced by those microbial cells.

• While Parabiotics and Paraprobiotic are synonymous, they’re used to describe the inactivated microbial cells, either intact or broken; think of them as the "ghosts" of those helpful microbes still being able to lend a hand. ²⁴
• On the other hand, Proteobiotics are natural metabolites produced by the probiotic during fermentation. ^{25, 26}

However, there is no consensus agreement on these possible definitions, and they all fall under the ISAPP definition of Postbiotic. ²⁰

Synbiotics are like community projects that bring everyone together for a common goal. ²⁷ They combine probiotics and prebiotics in a single product, ensuring that the good bacteria not only have a place to live but also plenty of their favorite food right from the start. This combination can be found in some yogurts and dietary supplements, designed to work together to provide an even greater health benefit.

On the other hand, Psychobiotics are a whole new category of probiotics and prebiotics that can actually benefit your mental health when consumed properly. ²⁸ They work through something called the gut-brain axis. Basically, your gut and brain are physically connected and are in constant communication. The microbes living in your intestines can send signals to your brain that impact your mood, cognition, and even behaviors.

Researchers are really excited about the potential of psychobiotics. Early studies show they may help prevent or improve conditions like neurodegenerative diseases like Alzheimer's or Parkinson's. Some evidence even suggests psychobiotics could play a therapeutic role in treating psychiatric disorders like depression or anxiety. ²⁹

You can find out more about the interaction between the gut and the brain here:

What about antibiotics?

Finally, it's essential to differentiate antibiotics from the other "biotics." While antibiotics are crucial life-saving medications for treating bacterial infections, their indiscriminate or excessive use can severely disrupt the delicate balance of the microbiome, potentially causing unintended and far-reaching consequences. ^{30, 31} These powerful drugs don't discriminate between harmful and beneficial bacteria, which means they can decimate the vital microbial populations that promote health and immunity.

Maintaining a healthy, diverse microbiome through probiotics, prebiotics, and other "biotics" can help counteract some of the collateral damage caused by antibiotics and support overall well-being.

You can find here a dedicated section about the effects of antibiotics on the microbiota and on your health:

Recommended by our community

Intestinal parasites can be broadly classified into protozoa (single cell organisms) and helminths (multicellular, known as worms).³⁹ Globally, there are an estimated 895 million people infected with soil transmitted helminths (STH). Intestinal protozoa (IP) have a lower overall prevalence rate, but still, over 350 million people are believed to be infected with 3 of the most common protozoan parasites40. Protozoan infections are common in low and middle income countries (LMICs). Food-chain globalisation, international travel and migration are leading to an increase in protozoan infections in high income countries, where they are more common than intestinal helminth infections.³⁹ 

DIARRHEAS CAUSED BY PROTOZOAN PARASITES

The most common intestinal protozoan parasites are Giardia intestinalis (Giardia duodenalis or Giardia lamblia), Entamoeba histolytica, Cyclospora cayetanensis, and Cryptosporidium spp. Diarrheal diseases caused by these pathogens are known respectively as giardiasis, amebiasis, cyclosporiasis and cryptosporidiosis.⁴¹​​​​​​​

DIARRHEAS CAUSED BY SOIL-TRANSMITTED HELMINTHS

Globally, the principal soil-transmitted helminths are the roundworm (Ascaris lumbricoides), the whipworm (Trichuris trichiura) and hookworms (Necator americanus and Ancylostoma duodenale). Symptoms experienced following helminth infection are related to the number of worms harboured: people with infections of light intensity (few worms) do not usually experience discomfort, whereas heavier infections can cause a range of symptoms including some that manifest in the intestine (diarrhea and abdominal pain), malnutrition, general malaise and weakness, and impaired growth and physical development. Soiltransmitted helminths contribute to the burden of diseases by impairing the nutritional status of the people they infect in a variety of ways: they feed on host tissues, cause intestinal blood loss and hamper the absorption of nutrients.⁴²

• Ascaris lumbricoides is the most common intestinal nematode that infects humans, with an estimated 807 - 1,221 million people infected each year. ⁴³ Infection commonly occurs without symptoms. The symptomatic form is characterized by an early lung phase followed by a later intestinal phase, which is characterized by diarrhea, mild abdominal pain, anorexia, nausea and vomiting.⁴¹
   
• An estimated 604-795 million people in the world are infected with Trichuris trichiura. People with heavy infections can experience frequent painful bowel movements that contain a mixture of mucus, water and blood.⁴⁴
   
• An estimated 576-740 million people in the world are infected with hookworms, usually without symptoms. Few people, especially those infected for the first time, experience gastrointestinal symptoms. The most common and serious effects of hookworm infection are intestinal blood loss leading to anaemia, in addition to protein loss.⁴⁵

MICROBIOTA: A ROLE IN THE MARKED CLINICAL VARIABILITY OF PARASITIC DIARRHEA?

Parasitic protozoan infections are characterized by marked variability in their clinical presentation: they can be asymptomatic or cause diarrhea, abdominal pain, weight loss, etc. Recent studies have highlighted the potential contribution of the intestinal microbiota to this clinical variation: for instance, an abundance of Prevotella copri in the gut microbiota predicted diarrhea in the context of Entamoeba histolytica infection;⁴⁶ low Megasphaera abundance prior to and at the time of Cryptosporidium detection was associated with parasitic diarrhea in infants in Bangladesh, suggesting that the gut microbiota may play a role in determining the severity of a Cryptosporidium infection.⁴⁷ In turn, infection by protozoan parasites alters the gut microbiome.^48,49

Regarding helminths, the complex interactions between worms and the microbiota (“two of humans’ old friends” ⁵⁰) are currently under study⁵⁰ (Figure7). Authors agree on the existence of a complex and dynamic interplay between parasite(s), the host microbiota and host immunity, capable of shaping the clinical outcomes of parasitic infections. ^46,48

Rotaviruses, norovirus, sapovirus, astrovirus, and adenovirus: five virus types are currently recognized as the main causes of viral diarrhea.²¹

Of the 2 billion plus episodes of diarrheal disease that occur across the world each year, as estimated by the 2016 Global Burden of Disease (GBD) Study,2 almost 900 millions of the moderate-to-severe episodes were attributed to just three of these viruses: rotavirus, norovirus and adenovirus²².

ROTAVIRUS, THE NUMBER ONE DIARRHEAL KILLER IN CHILDREN

Despite the development and availability of rotavirus vaccines since 2006,²² this virus, which causes more severe symptoms than most other enteric pathogens,²² was still responsible for over 228,000 deaths worldwide in 2016, of which over 128,000 occurred in children below the age of 5² – making rotavirus the leading cause of diarrhearelated mortalities among this segment of the population (Figure 4).

WATERY DIARRHEA

Whatever the virus that triggers an episode of diarrhea, the process of infection is broadly the same: the virus infects the epithelial cells of the small intestine and causes damage that hampers the absorption of fluid.²¹ Viral diarrhea usually manifests itself in the form of a watery (non-bloody) diarrhea. It can be accompanied by other symptoms, i.e. nausea, abdominal cramps, vomiting and fever,²² resulting in what is known as viral gastroenteritis.

REHYDRATION… AND PROBIOTICS

Just as for the other etiologies (bacterial or parasitic) of infectious diarrhea, management of viral diarrhea relies on oral or intravenous fluid replacement therapy, depending on the degree of dehydration.²¹ In addition, according to the latest conclusions of the ESPGHAN committee (2023),²⁰ healthcare professionals may recommend some probiotic strains (L. rhamnosus, S. boulardii and L. reuteri) for the management of acute gastroenteritis in children, since there is some evidence (certainty of evidence: low; grade of recommendation: weak) of reduced duration of diarrhea, and/or length of hospitalization, and/or and stool output.

IMPROVING ROTAVIRUS VACCINE EFFICACY, A CHALLENGE YET TO OVERCOME

Regarding prevention, the usual preventive measures apply (ensuring safe drinking water, adequate sanitation and frequent handwashing, limiting contact with infected people, etc.). Given the considerable burden of rotavirus diarrheal disease, rotavirus vaccines are another important preventive measure. ^22,23

These were estimated to have prevented 139,000 deaths from rotavirus among under-fives during the period 2006 to 2019, and to have prevented 15% of under-five rotavirus deaths in 2019.²⁴ However, vaccine efficacy is region-specific and displays poor seroconversion in low-and middle-income countries. Human clinical trial data have suggested a possible link between the gut microbiota and the enteric immune system’s response to rotavirus vaccine²⁵ (Figure 5).

MICROBIOTA: FRIEND OR FOE IN THE ONSET OF VIRAL DIARRHEA?

In cases of viral diarrhea, as with infectious diarrhea in general, the outcome of the confrontation between pathogen and host depends on complex balances that in large part involve the microbiota.

The gut microbiota displays bidirectional interactions with rotavirus and norovirus infections:¹⁴ it can either protect against or predispose the host to infection; in turn, an infection can alter the gut microbiota. Some bacteria seem able to inhibit viral infection. For example, one study shows segmented filamentous bacteria preventing and curing rotavirus infection in mouse colonies³⁵ (Figure 6). On the other hand, in vitro and in vivo studies indicate the gut microbiota’s involvement in facilitating viral infection: certain gut microbes (e.g. Enterobacter cloacae) stimulate the ability of human norovirus to infect human B cells in vitro; microbiota elimination by antibiotics delays infection, reduces infectivity and/or viral titer of norovirus and rotavirus in mice.^8,36

Therefore, any invasive pathogens might have different effects depending on the state of the gut microbiota. ³ The optimal microbiota profile and microbiota-targeting strategies that would lower the risk of infection and the following viral diarrhea remain to be characterized.³⁷

As to the effect of viral infection on gut microbiota composition, numerous studies have documented specific patterns of dysbiosis in patients suffering from viral diarrhea compared to healthy controls^25,38. A reduction of microbiota (alpha) diversity is often reported, but specific taxa increases or decreases vary widely across the studies.¹⁴ And one question remains: does the dysbiosis observed during viral diarrhea reflect a prior disposition that might have facilitated the infection, is it a state caused by the virus, or is it a combination of both?

Antibiotics are a powerful tool in the fight against bacterial infections, however they also disrupt the protective intestinal microbiota and this can lead to unintended consequences including antibiotic-associated diarrhea (AAD) in as much as 35% of patients.^17,18,19 The incidence of AAD depends on several factors: ^17,18,19 age (among children this percentage can reach up to 80%) ¹⁵, setting, type of antibiotic, etc. Most of the time, AAD is caused by antibiotic-induced dysbiosis, is of mild intensity and is self-limiting, lasting between 1 and 5 days.

While the etiologies for AAD are diverse, approximately one-third of AAD cases are attributed to C. difficile. Under certain conditions, C. difficile will trigger an inflammatory response leading to a range of clinical outlooks, from mild diarrhea to pseudomembranous colitis, toxic megacolon and/or death.¹⁷

Underlying how lethal bacterial diarrhea can be, these 8 bacteria were responsible for more than a third of the over 1.65 million deaths from infectious diarrhea recorded worldwide in 2016.²

FROM INFECTION TO DIARRHEA

The mechanisms that lead to bacterial diarrhea depend on the bacteria involved. Transmitted via contaminated food, water or by personto-person contact, Shigella infests the gastrointestinal tract, produces an enterotoxin and serotype toxin 1, destroying the intestinal epithelium and leading to severe bloody and mucous diarrhea.^3,5
Pathogenic variants of Vibrio cholerae produce a cholera toxin that activates anion secretion, inhibits absorption of electroneutral NaCl and destroys the intestinal barrier function, thereby inducing massive fluid secretion in the lumen of the small intestine and the loss of large amounts of water, sodium, chloride, bicarbonate and potassium.3,5,13 Different pathogenic E. coli strains, classified into different pathotypes (Table 1), cause mild to severe diarrhea usually accompanied by fever. E. coli adheres to the intestinal epithelial cells through the adherent fimbriae, produces toxins and exerts its pathogenic effects.^3,5

EFFECT OF PATHOGENS AND DIARRHEA ON MICROBIOTA

Bacterial diarrheas are accompanied by dysbiosis, usually with an overabundance of facultative anaerobes (Escherichia, Streptococcus, Enterococcus, etc.) in dysenteric diarrhea, and a depletion in bacteria of known immuno-modulatory effects (Lactobacillus ruminis, Bifidobacterium pseudocatenulatum)⁷ (Figure 3).

For example, in cholera, the gut microbiota is substantially modified both during and after infection, this as a consequence of the removal of the mucus layer along with the residing gut microbial community and of the delivery of toxin by V. cholerae. ¹³ During recovery, the gut microbiota of cholera patients slowly repopulates via an accumulation pattern similar to that of the maturation of the gut microbiota observed in children.³
In the same way, children infected with diarrheagenic E. coli (DEC) display a distinctive gut microbial composition, with a high fraction of Bacteroidetes and Proteobacteria and a reduced abundance of Firmicutes. ¹³ Increases in Proteobacteria could be partially explained by an increase in Escherichia/ Shigella species (as the cause of diarrhea) and in other members of Enterobacteriaceae, such as Citrobacter and Enterobacter (related to histamine production induced by proinflammatory environments and associated with E. coli adherence).¹⁴ Frequent antimicrobial use can also partly explain the observed dysbiosis.⁷

GUT MICROBIOTA PROTECTION AGAINST INFECTIONS

Symmetrically, the gut microbiota has demonstrated effects on bacterial infection. In germ-free animals, their lack of a gut microbiota and the absence of ecological competition results in an immature immune system that renders them highly susceptible to diarrheal pathogens: 10 colony-forming units (CFU) of Salmonella are enough to cause a lethal infection, whereas to kill 50% of mice with an intact gut microbiota 10³ –10⁹ CFU are required.⁸

In humans, Prevotella, Bifidobacterium and Blautia have been shown to reduce colonization of V. cholerae. Conversely, Paracoccus is believed to support the growth of the pathogen.¹³ This is the reason why promoting a ‘healthy’ gut microbiome has been considered a useful approach in the intervention and prevention of cholera.¹³

BACTERIAL AND YEAST PROBIOTICS, PREBIOTICS AND FMT

The severity of several bacterial infections could be reduced by probiotics: for example, probiotic E. coli inhibits the biofilm formation of other E. coli strains and likewise those of the pathogenic Staphylococcus aureus and S. epidermidis. ³ Regarding dysentery, a combination of Lactobacillus and Bifidobacterium strains and a Streptococcus strain reduces both the duration of blood-affected diarrhea and the time spent in hospital.³
Numerous mechanisms could explain why probiotics alleviate diarrhea:³ production of antimicrobial substances, competitive exclusion, competition with cell binding sites, production of acids and metabolites that lower the surrounding pH, strengthening of the gut mucosal barrier, modulation of gut mucosal immunity and gut microbiota diversity. For example, the probiotic yeast Saccharomyces boulardii may facilitate gut microbiota restoration in children with acute diarrhea.¹⁵

Prebiotics can also have a positive impact on diarrhea: by increasing the bacterial production of short-chain fatty acids (SCFAs) such as butyrate, which contribute to the gut barrier integrity; and by antagonizing the adherence of pathogens to epithelial cells, thus inhibiting colonization and promoting gut pathogen elimination.³

Fecal microbiota transplantation (FMT), which aims to restore a healthy gut microbiota, has proven effective and is only indicated in the treatment of recurrent C. difficile in both adults and children.¹⁴

INFECTIOUS DIARRHEA, ONE OF THE LEADING CAUSES OF INFANT MORTALITY WORLDWIDE

The passage of 3 or more loose or liquid stools per day corresponds to the common definition of diarrhea as set out by the WHO.1 Both criteria (frequency and consistency) are necessary: frequent passing of formed stools is not diarrhea, nor is the passing of loose stools by breastfed babies (Figure 1). 1.6 million deaths were attributed to diarrhea in 2016.² Children are particularly at risk: diarrheal disease is the 3rd leading cause of death in children under 5 years of age. A large part of the mortality used to be attributed to severe dehydration linked to fluid loss but today, septic bacterial infections account for an increasing proportion of all diarrhea-associated deaths.¹ Malnourished or immunity-impaired children are the most at risk of life-threatening diarrhea, as well as people living with HIV.¹

PATHOPHYSIOLOGICAL SYNDROMES OF DIARRHEA

From the clinical perspective, diarrheagenic pathogens can cause 2 pathophysiological syndromes:⁴

• Noninflammatory diarrhea (NID): patients present with nausea, vomiting, watery and voluminous stools, and abdominal cramping resulting from intestinal secretion (the intestinal mucosa remains intact). This milder course of disease is usually viral (Rotavirus, Norovirus…) but it can also be bacterial (enterotoxigenic Escherichia coli, Clostridium perfringens…) or parasitic (Giardia, …);
• Inflammatory diarrhea (ID): patients present with fever, abdominal pain, tenesmus and bloody stools of smaller volume than in NID. This severe course of disease is usually caused by invasive or toxinproducing bacterial strains (Shigella, Salmonella species…) that lead to mucosal barrier disruption and tissue destruction.

BEHIND THE SCENES OF DIARRHEA: THE MICROBIOTA

VICIOUS CIRCLE: WHEN DIARRHEA LEADS TO GUT DYSBIOSIS

Infectious diarrhea is regarded as a major dysbiotic event resulting from:

• increased bowel movements and disruption to mucosal integrity, ³
• increased proportion of water in the fecal matter and reduced transit time which contributes to taxonomic scarcity, ³
• and possible oral rehydration, zinc supplements, probiotics and even antimicrobials (in the case of dysentery or bacterial infections) which also contribute to an imbalance in the intestinal microbiota.⁷

Depending of the type of infection, infectious diarrheas are usually accompanied by dysbiotic states: ⁷ bacteria-induced diarrhea is generally linked to an elevation in Escherichia, Streptococcus and oral bacteria; viral infections lead to a less pronounced reduction in anaerobic commensals in the gut (higher abundance in Bifidobacterium); giardia-induced diarrhea is linked to a decrease in Gammaproteobacteria and an enrichment in Prevotella.

VIRTUOUS CIRCLE: WHEN THE GUT MICROBIOTA OFFERS PROTECTION

Mechanisms by which the gut microbiota provides colonization resistance can be both direct and indirect. The microbiota directly inhibits diarrheal pathogens mainly via competition for nutrients, but also by limiting in a variety of ways the growth of diarrheal pathogens: secreting bacteriocins (antimicrobial peptides), cell contact-dependent inhibitory structures (type VI secretion system), producing molecules that reduce the pathogens’ virulence…

The microbiota also indirectly inhibits diarrheal pathogens via its effects on the host: by promoting gut barrier maintenance and by stimulating both the innate and the adaptive immune system.⁸

HOW TO MANAGE INFECTIOUS DIARRHEA?

The majority of intestinal infections are self-limiting in immunocompetent individuals. Nevertheless, some patients (with severe dehydration, more severe illness, persistent fever, bloody stools, immunosuppression…) require specific diagnostic investigation. These can include a complete blood count, a creatinine and electrolytes assessment, verification of leukocytes and lactoferrin presence in the stools, stool culture, along with C. difficile testing, PCR, ova and parasites search, endoscopy and abdominal imaging¹¹. The American College of Gastroenterology (ACG) guideline¹² provides recommendations for the diagnosis and management of adult patients presenting with acute diarrhea of suspect infectious etiology (Figure 2). Clinical investigation in children is based on the same principles.²³ In 2023, World Gastroenterology Organisation Global Guidelines included probiotics in the prevention and treatment of some infectious diarrhea⁵⁷.