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

Fecal microbiota transplant allows patients to receive approximatively 10¹¹ bacteria per gram of stool, but also fungi, viruses and archaea. Its objective is to correct gut dysbiosis. The number of necessary attempts and results vary according to the individuals and their pathology, and the protocol requires seamless controls.¹³

Gut microbiota modulation is a potential treatment for IBD. In practice, this strategy could be carried out through fecal microbiota transplant (FMT). The fecal matter comes from one or several healthy donors and is then transplanted into the distal gastrointestinal tract of the patient thanks to a nasogastric tube, during a colonoscopic enema, or more recently through oral capsules. This protocol is already being successfully used in case of recurrent Clostridium difficile infections. But what about IBD?

Ulcerative Colitis

Although safety conditions of the first tests were satisfying and the therapy led to partial or total remission in some patients with ulcerative colitis (UC), other attempts were more controversial.¹⁴ The donor’s fecal composition quality, the number of transplants and early therapeutic care, could modulate the chances of success and appear as a post-hoc explanation of heterogeneity of results.

Crohn's disease (CD)

Studies conducted on Crohn’s disease (CD), although fewer in number, produced either positive (clinical and endoscopic remission) or neutral results.In the only study that did not show a significant disease reduction, patients still reported an improvement in their quality of life.¹⁴ To confirm the clinical efficacy of fecal transplant in Crohn’s disease, additional studies are still necessary.

Many pending issues

Whatever the disease, several questions remain unanswered regarding: FMT engraftment, which could require several fecal transplants; the quality of the transplanted microbiota often obtained from donors living in countries where IBD prevalence rate is high; the restoration of microbiota altered functions after the transplant (for instance, production of protective short-chain fatty acids such as butyrate); and of course, the role of inflammation, either as a cause or consequence of dysbiosis.¹⁴

Defensins play a major role in innate immunity. Ten defensins have been identified in humans: six α-defensins that are mainly secreted by Paneth cells, neutrophils and some populations of small intestine macrophages; and four β-defensins that are secreted by epithelial cells.⁵

Mechanisms of action

Mechanisms of action of antimicrobial peptides are variable:⁸ some puncture bacterial membranes and cause ion and nutrient efflux, loss of structure, or even bacterial lysis; other “bind” to bacteria and limit they passage through the gut epithelium without killing them; in other words, they reduce pathogen colonization and change the composition and density of bacterial communities in the intestinal lumen.

Crohn's disease and decrease in defensins

When CD affects the ileum, the production of some α-defensins decreases, which reduces antibacterial activity and promotes pathogenic bacteria penetration⁵. Among possible explanations there is NOD² gene mutation, involved in the recognition of bacterial surface and onset of defensin production; and impaired signaling pathways, whose dysregulation is involved in the development of many human cancers. Some researchers believe that the decrease in α defensin content is not the cause but the consequence of inflammation.⁴ In colonic CD, only β-defensin rates are disrupted5: increase in secretion of β-defensin type 2 and decrease in type 1. Some scientists believe that the smaller number of copies of the gene located on chromosome 8 in affected patients (3 instead of 4) is at fault.

The alteration of the intestinal barrier observed in patients with IBD could explain the pathophysiology of dysbiosis: not only would this mechanical frontier be altered, but also its first line of immune defense.

Besides its role in the absorption of ions, water and other nutrients, the intestinal barrier serves as a wall and prevents the entry of bacteria into the gut lumen. But its permeability increases in acute phases of Crohn’s disease (CD), which promotes translocation of bacteria through the mucus as well as local inflammation.⁵

The role of the instestinal barrier

Potential causes: alteration of the tight junctions of intestinal epithelial cadherins (glycoproteins playing a key role in intracellular adherence); involvement of some transcription factors¹¹ related to epithelial regeneration. Other mechanisms under discussion involve the gut mucus, whose thickness keeps pathogenic bacteria at bay, but which is considerably decreased in patients with IBD. This phenomenon could be explained by the alteration of mucus- producing goblet cells whose disruption induces the development of colitis in murine models. It could also be explained in patients with CD by the impairment of Paneth cells located at the bottom of small intestinal crypts, known to be involved in homeostasis and with a defensive role of the gut mucus through antimicrobial secretion.^5,11

First line of defense of the immune system

The scientific literature also mentions several mechanisms involving innate immunity, and more precisely dendritic cells, macrophages, innate lymphoid cells and neutrophils. These cells, which complete the previously described system, act as the first line of defense of the immune system. In the intestines of healthy subjects, macrophages are hyporeactive (reduced proliferation and activity) and can produce anti-inflammatory cytokines.¹¹ On the contrary, in patients with IBD, the imbalance in innate immunity cell populations could be associated to several phenomena:¹¹ bacteria crossing the mucus which became permeable due to macrophage activity decrease and defective neutrophil recruitment; inflammation induced by the production of large quantities of pro-inflammatory cytokines (TNF-α and IL-6) by specific macrophages; and inflammatory T-cell recruitment through the accumulation of dendritic cells which induce an adaptive immune response.

It appears that the bacterial and viral components of the microbiota are not the only ones to be affected in patients with IBD. The mycobiota, i.e. all fungi present in the gut ecosystem, also seems to be disrupted.

Disrupted microbiota

A study conducted in 235 patients with IBD and 38 healthy controls brought to light the presence of a fungal dysbiosis in affected patients: increase of the Basidiomycetes/Ascomycetes ratio, decrease in the proportion of Saccharomyces cerevisiae, and increase in that of Candida albicans.⁹ In patients with CD, it is believed that the development of fungi occurs to the detriment of bacteria, triggering a loss of diversity. Moreover, interactions between these two kingdoms (bacteria and fungi) also seem to be degraded compared to those observed in healthy subjects, thus revealing inter-kingdom alterations specific to IBD. Although data on the fungal portion of the microbiota are still very fragmented, these initial results suggest that the mycobiota plays a role in the pathogenesis of IBD. This dysbiosis, characterized by alterations in biodiversity and composition, adds itself to the bacterial dysbiosis.

Urbanization as a cause of this dysbiosis?

Meanwhile, some research teams focused on the link observed between rapid urbanization and increased incidence of autoimmune diseases, including IBD.⁷ Several hypotheses were suggested, including one involving the mycobiota: the Western diet, rich in carbohydrates, which promotes the development of Candida in the intestines; the impact of atmospheric pollution in urban areas which could reduce fungal biodiversity; and quality of urban air, less rich in some spores (Actinomyces, Botrytis…) than rural air. It seems that urbanization does not only impact the mycobiota but could also be related to the dysbiosis of other microorganism communities (bacteria, viruses, parasites...).