Antibiotics not only eradicate pathogenic microorganisms responsible for infection, but they can also destroy some bacteria that are beneficial to the gut microbiota. They always cause a more or less significant imbalance within this ecosystem. This ecosystem becomes less rich and less diversified, and is no longer able to properly carry out its protective functions².

Antibiotics are not automatic anymore¹⁵  !

Between 10 and 30% of patients treated with antibiotics experience a change in their intestinal transit within 3-5 days of treatment, most often in the form of diarrhea¹⁶. Most of the time, this diarrhea is purely functional, caused by the antibiotic-induced dysbiosis. It usually presents without fever, it is short lived, not severe, and in most cases, it regresses once antibiotics are discontinued, or in the following weeks. However, dysbiosis starts in the first 24 hours of antibiotic treatment and lasts up to six weeks after its conclusion. New microorganisms, close to the initial strains but not necessarily identical, slowly re-colonize the intestines and create a new balance, although it often remains incomplete.

A new route for pathogens

But sometimes, the mucus layer, true line of defense of our intestines, has been so weakened that the body becomes more vulnerable to pathogens. In 10 to 20% of cases, diarrhea results from the colonization of the microbiota by Clostridium difficile. This bacterium is very widespread in hospitals and nursing homes, and elderly people are particularly vulnerable: in these facilities, up to 20% of residents (50% in cases of long-term stay) can host this bacterium in their intestines without showing any symptom (asymptomatic carriers). Although most cases of C. difficile diarrhea resolve once the antibiotics are discontinued, most severe forms could occur (pseudomembranous colitis and fulminant colitis, especially in people over 65 years old¹⁷). In the US, for instance, this infection is responsible for around 30,000 deaths/year18. The families of antibiotics that are often blamed are penicillins, some generations of cephalosporins, fluoroquinolones and clindamycins. To stop this vicious circle, stool transplant (transplant of healthy microbiota into the GI tract of a patient) could be a therapeutic alternative to antibiotics in order to repopulate the microbiota and restore the gut barrier.

Why are some people particularly sensitive when others are more resistant? “It depends on the microbiota”, answer the researchers, whose studies underline the impact of interactions between invasive pathogens and microorganism living in our intestines.

An uphill battle

To understand the infectious process of enteropathogenic bacteria, researchers reviewed the mechanisms employed by the body to fight the colonization of the digestive tract by Salmonella typhimurium¹⁴, a bacterium causing food poisoning with diarrhea, that is sometimes severe although short-lived. The first mechanism comes into play in the stomach where the acid environment destroys between 95 and 99% of ingested bacteria (through food). For bacteria that are able to reach the intestines, it is too early to claim victory: they can only grow if the level of resistance to colonization allows it. But the latter depends on the composition of the gut microbiota, specific to each person, that has an arsenal of tools to fight this colonization: secretion of components blocking the invader’s growth and virulence, competition for the same binding sites, creation of an oxygen-poor environment that is unfavorable to its growth…

A fierce fight

And our defenses have not said their last word: bacteria must be present in sufficient amounts to trigger diarrhea, and it only happens between 12 to 36 hours (sometimes 72 hours, depending on the number of ingested bacteria) after they cross the intestiWhen bacteria and parasites attack the gut microbiota nal barrier. Based on animal models, S. typhimurium accomplishes this by secreting toxic substances, thus allowing it to reach the mucosa and then the submucosa. The body reacts by expelling infected intestinal cells thus dividing the number of pathogenic bacteria in the tissues by 100– and sets off a massive inflammatory response which affects the enemy in two ways: by reducing the bacterial load in the body, while serving as fuel to the remaining bacteria.

Long-term consequences

There is another enemy: Giardia lamblia. This protozoan infects humans through the consumption of contaminated water or food. Although the frequency of giardiasis does not exceed 7% in developed countries, it can reach 30% in developing countries. In most cases, the infection takes a few weeks to resolve but it can sometimes last several months and become chronic. There is currently no vaccine and available treatments have different levels of effectiveness. Giardiasis is often asymptomatic, but it can cause diarrhea, cramps and nausea. In newborns, disease severity hinges on its long-term consequences: at the age of two, they show a significant growth deficit. And some people may develop post-infectious syndromes several years after the elimination of the parasite, such as irritable bowel syndrome or chronic fatigue. According to several papers, Giardia lamblia could act by decreasing the immune response and causing dysbiosis.

No matter what virus is responsible, viral gastroenteritis leads to a decrease in diversity of species composing the gut microbiota and impacts the abundance of three species¹² : Prevotella, Staphylococcus and Atopobium. The resulting imbalance (called “intestinal dysbiosis”) is the source of several symptoms observed in patients. For instance, abundant diarrhea that characterizes rotavirus-induced gastroenteritis is the result of disorganization of the microbiota that leads to the destruction of microbial barrier.

Is the gut microbiota a frenemy?

Dysbiosis alone cannot explain the whole story: for example, the norovirus can merge with “commensal” bacteria (i.e. beneficial and naturally present in the microbiota) or act together with “harmful” bacteria (pathogens) and cause inflammation. The body therefore produces natural antiviral substances, such as interferons. However, as a result of strong stimulation, these substances turn against the body and attack it, thus causing severe intestinal lesions. The underlying mechanisms ruling over the interactions between these agents are still poorly understood and are the subject of many research studies. But relations between norovirus and gut microbiota can also be beneficial: experiments in mice have shown that intestinal dysbiosis caused by antibiotics may prevent or mitigate norovirus infection.

The role of genetics

These findings give us an overview of the complex relations existing between viruses originating from our environment and microorganisms living in our intestines. In fact, they seem to depend on a third player: our genes. Based on studies carried out in rodents, we are not equal when it comes to fighting norovirus infections: there is an individual susceptibility which depends on our genetic makeup, our gut microbiota and the presence of concomitant infections, that leads to a great variety of symptoms and long-term effects.

Taking all ages together, the main cause of gastroenteritis is norovirus. However, in children under five, rotavirus-induced infections are the first cause of severe and acute diarrhea worldwide. Poor countries are the most affected, despite vaccines and antiviral drugs.

Rotavirus was identified in 1973 and owes its name to its distinctive wheellike structure³. There are ten different species of rotavirus, the most common one being species A. Besides diarrhea, which is non-bloody and short term, contrary to bacterial diarrhea, the infection causes vomiting that contributes to the patients’ dehydration and may hamper treatment efficacy. Rotavirus-induced infection is generally more severe than diarrhea caused by other infectious agents: fever, dizziness, fatigue are defensive reactions to the infection. If it persists for over a week or if diarrhea/vomiting worsen, medical consultation and specific treatment are required. Rotavirus transmission is possible year-long and mainly occur through direct or indirect contact with infected people. Complications are rare but possible: if it enters the blood stream, the virus can cause extraintestinal infections, mainly neurological (meningitis, encephalitis, encephalopathy). The introduction of vaccination in 2006 throughout the world had two consequences in rich countries: people infected are older (teenagers or people over 70), and outbreaks have become seasonal.

Pay attention to diet and close contact¹⁰ !

Norovirus is extremely contagious, highly infectious and relatively resistant to disinfectant agents. As such, it is mainly transmitted through the intake of infected food or water, or through contact with contaminated objects or people. Airborne contamination is also possible. Simple isolated cases can quickly lead to epidemics in confined spaces (cruise ships, health care facilities, hospitals…) and acute forms can cause severe intestinal complications (postinfectious irritable bowel syndrome, life-threatening dehydration…). Usually, norovirus-induced gastroenteritis lasts between one and four days and is associated to the same symptoms as rotavirus-induced gastroenteritis: abdominal pain, nausea, vomiting and non-bloody diarrhea. It generally resolves spontaneously, but several months may be needed to eradicate the virus in healthy carriers (infected but without any symptom), or sometimes even years in people with a weakened immune system; and since they become chronically ill, they probably also become disease reservoirs.

In the past several years, the use of probiotics has grown significantly. The increasing number of works on these “beneficial” microorganisms have largely contributed to this trend. But not all microorganisms can be called “probiotics”: they need to be able to survive in the GI tract, resist to gastric acid and digestive enzymes, temporarily populate the intestines and they must have proven effective. The term can only be applied to microorganisms that resist degradation, are harmless to the human body, and are able to alleviate symptoms. They are generally marketed as dietary supplements or drugs, depending on their efficacy to alleviate symptoms and their degree of safety. They are composed of one or several strains or a mix of several species, and are available in many forms: capsules, powders for oral solution, orally dispersible powders, tablets...

Two leading species

A review of scientific literature to assess the use of probiotics in the prevention and treatment of pediatric gastrointestinal disorders showed that the benefits are specific to each strain and depend on the type of infection⁸. At this time, two microorganisms seem to efficiently act on gastroenteritis symptoms by reducing their duration: Saccharomyces boulardii yeast as well as Lactobacillus rhamnosus GG (LGG) bacteria. More generally, these probiotics seem to improve symptoms, and even more so if they are administered at an early stage of the infection, and if the latter is of viral origin. In case of antibiotic-induced diarrhea, S. boulardii and L. rhamnosus GG could also have a beneficial effect. However, to prevent relapses of Clostridium difficile infections and traveler’s diarrhea, it seems that only S. boulardii has an effect on symptoms.

Quicker recovery!

In case of rotavirus-induced gastroenteritis, these probiotics reduce the duration of the episode by a day or two². They lower the levels of molecules that improve the inflammatory process, by stimulating the immune response and promoting proliferation and/or migration of intestine cells responsible for the transport of nutrients, thus facilitating glucose–and consequently water–absorption. Beyond the prevention of diarrhea in children receiving antibiotics or hospitalized children, these strains (S. boulardii among others) prevent 85% of diarrhea episodes related to the consumption of contaminated food or water⁹ (traveler’s diarrhea). To be effective, these treatments must be taken a few days before departure and during the entire journey, and even after.

The primary step in the treatment of any acute diarrhea is to counterbalance water and sodium losses, and slow down the intestinal transit (except in case of hemorrhagic diarrhea or high fever). It is also important to make sure that the amount of protein and calorie intake as well as micronutrient supplements are adequate.

Drink salty fluids^2,3 !

This rehydration process can be carried out either through diet, combining an increased consumption of drinks containing glucose, sodium, potassium and bicarbonates (still or sparkling water, some soft drinks) and salty high-glucose food (rice, pasta…), or through the intake of commercially available oral rehydration solutions (ORS) in case of nausea. Tap water should be avoided, as well as chicken broth, apple juice and most soft drinks. Special caution should be paid with older people who are less sensitive to thirst: in case of severe dehydration, intravenous rehydration may be required. In newborns, breastfeeding should be encouraged whenever possible. For formula-fed babies, the use of lactose-free milk is not recommended because it could jeopardize treatment effectiveness once an antibiotic is given.

Zinc for malnourished children

The World Health Organization recommends the daily use of zinc supplements for two weeks in malnourished children over six months; unfortunately, this recommendation is seldom applied in low-income countries where meat consumption (source of zinc)is low⁴. In the GI tract, zinc restores the integrity of the gut barrier and stimulates immunity against microorganisms responsible for gastrointestinal infections.

This twofold benefit has been confirmed in animal studies concluding that a chronic zinc deficit alters the composition and function of the gut microbiota and increases the risk of gastrointestinal infections. More specifically, giving zinc dietary supplements to children with severe diarrhea decreases the duration of the episode. However, according to scientists, this approach is of little use in children under five years old with severe diarrhea but no zinc deficit, especially considering that this supplementation may increase the risk of vomiting following the initial dose.

With around 15 million cases a year and a global incidence above 10%, preterm birth, i.e. before 37 weeks of amenorrhea (WA), is a public health issue and the second cause of neonatal mortality in the world. Environmental factors, especially the vaginal microbiota, could play an important role in preterm delivery: homogeneous bacterial vaginal composition, with a predominance of Lactobacillus, seems to be associated to a reduced risk of prematurity, while high diversity seems to be associated to an increased risk.

Risk signature

An American team tried to delve deeper into this issue by analyzing the vaginal microbiota of 45 women (mainly of African descent) who had preterm births (<32 WA) and comparing it to that of 90 women (of various ethnicities) who had full-term pregnancies (≥37 WA). The data obtained in this study together with the data from a large American database (12,000 samples) confirmed their hypothesis: greater diversity in vaginal bacteria as well as lower content in Lactobacillus crispatus associated to an overabundance of some bacteria (BVAB1, Sneathia amnii, and Prevotella cluster 2) are related to a higher risk of preterm birth. In these same patients, samples collected early on (between 6 and 24 WA) also brought to light the increased presence of Megasphaera type 1 and TM7 H1 taxa, that are already well known for being associated to a poor vaginal health.

Improving detection

A model predicting the risk of preterm birth was thus developed based on the presence of BVAB1, Sneathia amnii, and Prevotella cluster 2 at the beginning of the pregnancy (< 24 WA). The role of these bacteria still needs to be clarified, but they could be responsible for the increase of some proinflammatory cytokines that can potentially trigger labor prematurely. Although the microbial signature is found mainly in women of African descent involved in the study, additional work needs to be completed to generalize the link between vaginal flora and preterm birth. When associated to clinical data and potential genetic factors, bacterial, metabolic and immunological biomarkers could help the early detection of the risk of preterm birth and improve the management of high-risk pregnancies.

“The fetus grows in a sterile environment”. This belief–formerly unshakable–is called into question as experts have identified traces of bacterial DNA in the amniotic liquid and meconium (sidenote: Meconium Earliest “stool” of the newborn, containing the amniotic liquid absorbed in utero. The meconium helps identify microorganisms lining the gastrointestinal tract of the fetus.
  ) , both representative of the intrauterine environment. Identifying the presence of microorganisms is all the more important since they impact the development of the child’s immunity and build their microbiota.

Cutting-edge DNA analysis

In order to confirm the existence of microbes and identify them, Australian researchers analyzed the bacterial DNA present in the amniotic liquid of 50 pregnant women and that of the meconium of their children born via elective c-section. A specific procedure was able to minimize the risk of contamination (during a manipulation for instance) which might skew the results.

Bacteria everywhere...

DNA analyses finally revealed bacteria in a large majority of studied samples, sometimes common to both environments. One non-pathogenic species is dominant in the meconium: Pelomonas puraquae, although the reason why has not been explained (external contamination was considered, despite the measures taken). For its part, amniotic liquid contains DNA from skin commensal (“regular”) bacteria, mainly Propionibacterium acnes and staphylococci. Beneficial molecules produced by bacteria were also found in the meconium, especially short-chain fatty acids, known for their protective effects on health. All these findings show that fetal environment is not sterile and that the composition of its “microbiota” could impact the future health of the baby.

How is IBD diagnosed?

Because there is no specific test available, IBD diagnosis is based on an array of tests that the physician has to combine to confirm the inflammation and its chronic nature. In Crohn’s disease (CD) the inflammation may affect the entire gastrointestinal tract, while in ulcerative colitis (UC) it is confined to the rectum and colon. Usually, the diagnosis is made by a specialist. It is relatively simple and is supported by endoscopy and biopsies, and sometimes an MRI of the intestines. It should be reminded that 1 European out of 100 will develop IBD at one point in life, with Northern people being even more affected. IBDs are often detected in young patients: 28 years old on average for CD, and around thirty for UC–for which a second peak is also observed at around fifty years old, a few months after quitting smoking. (While smoking worsens CD, it paradoxically limits UC symptoms).

Which type of solutions can be offered to patients?

The difficulty of managing CD and UC lies on the adjustment of the background treatment that prevents anatomical damages caused by successive flares, and the need to delay as much as possible any surgical procedure. As for the treatment of exacerbations, it is important to avoid the use of corticosteroids, which are responsible for too many adverse effects, morbidity and mortality. In the absence of a reliable biomarker of clinical severity, finding a balance is quite a subtle exercise... Moreover, patients with colonic IBD must be closely monitored to confirm the absence of dysplasia (thus the absence of cancer over time) and to avoid any infection (tuberculosis, herpes...) when prescribing one or several immunosuppressants (vaccination schedule and serological surveillance for instance). And finally, patients must be accompanied on their everyday life: studies, travels, sexuality, marriage, children, diet... because IBD can be very disabling in some patients (30 to 50%).

The microbiota, a major therapeutic avenue for today and tomorrow?

Research surrounding IBD is very active and includes the search for new molecules, flare management and implementation of treatment strategies. Among them, the gut microbiota is undoubtedly a promising research avenue: we are starting to understand that the gut microbiota is responsible for triggering and maintaining the inflammation of the gastrointestinal system. The microbiota and its host communicate through many symbiotic actions related to species coevolution. But, for unknown reasons, these symbiotic relationships sometimes malfunction, which is why research is greatly needed to find mechanisms of action to modulate the microbiota and restore potentially impaired functions through the administration of probiotics, metabiotics (microbiota metabolites) or fecal microbiota transplant (a pragmatic method to replace the unbalanced microbiota by another one deemed healthy).

Probiotics are living microorganisms which, when ingested in adequate quantities, provide health benefits. Several mechanisms of action might underlie the beneficial effects of probiotics in IBD: inducing changes in the gut microbiota composition thus reducing gut dysbiosis; regulating metabolic activity of the gut microbiota; eliminating pro-inflammatory processes; and immunomodulation.¹²

Contrasted results depending on the disease

In UC, the efficacy of probiotics containing one and only strain (from the E. coli species), as well as milk fermented with Bifidobacterium, in inducing disease remission was comparable to that of standard anti-inflammatory treatments (mesalazine).¹² Different combinations of bacterial strains were also tested, but with no effect on disease remission, with one exception: a cocktail of 8 different strains¹⁵ induced a significant reduction in UC symptoms,^13,16 (rectal bleeding and stool frequency) and a study proved its efficacy in maintaining remission. This same cocktail also seems to be efficient in patients with pouchitis: it prevents inflammatory flares arising from coloproctectomy and maintains remission,^17,18 however, probiotics have not shown to be useful in CD so far. Results from the rare studies performed are weak and inconclusive, including with strains that have proven to be efficient against UC and pouchitis.^12,15

Further investigations

Heterogeneity of non-clinical and clinical results could be at least partially attributed to factors related to the host (age, gender, diet, disease location, severity, family history of IBD) and the probiotic preparations that were used (type of strain, concentration, mode of administration, potential colonization, and strain survival rate). Other factors, such as dose and duration of probiotics administration, are also supposed to play a primary role in the success of this therapeutic approach, whose adverse effects are minimal, or even nonexistent.¹²