CHANGE IN STATUS

Viewed as shameful in many cultures, functional GI disorders were long regarded as a private matter and related to stress and feelings rather than an easily identifiable organic trouble. The perception changed in the years 1960’s thanks to technical and scientific advances: works on etiology and pathophysiology provided a foundation for an organic understanding of FGIDs. In the following decades, the “all physiological” vision was gradually abandoned and the related psychosocial processes were deepened, before the standard modern biopsychological model was ultimately reached.

ROME, CRADLE OF CLASSIFICATION

In the fourth edition of its work of reference (Rome IV), the Rome Foundation proposes a definition of FGIDs collaboratively designed by a panel of experts: they include disorders of the gut-brain axis, i.e. a “group of disorders classified based on gastrointestinal symptoms, related to a combination of the following: motility disturbance, visceral hypersensitivity, deterioration of the mucosa and immune functions, change in intestinal microbiota and alteration of central nervous system functions”. The result of that review is a precise categorization of FGIDs as well as a rationale for their study and treatment.

53 DIFFERENT TYPES OF FGID

The Rome IV classification is based on symptomatic criteria grouped by anatomic region (esophageal, gastroduodenal, intestinal, biliary and anorectal). However, symptom location by itself is not enough, especially regarding irritable bowel syndrome (IBS), functional dyspepsia, or abdominal pain syndrome (hard to place and influenced by global effects resulting from deregulation of signaling pathways between central and enteric nervous systems) mediated by the central nervous system. Its 33 items for adults and 20 for newborns, children and teenagers ensure a precise diagnosis and facilitate the implementation of targeted patient care. In this regard, the Rome Foundation insisted on the importance of not limiting therapeutic approaches to medication alone and recommends a biopsychosocial approach to face the variability of cases and individual expectations of patients suffering from FGIDs.

MICROBIOTA: A MAJOR INTESTINAL PLAYER

The intestinal microbiota has a complex influence on the metabolism, nutrition and immune functions of the host. Its alteration plays a central role in FGIDs.^3,4 Dysbiosis has been specifically studied regarding IBS and studies in animals have shown that this imbalance might be involved in the observed visceral hypersensitivity (via endoluminal bile acids), as well as in gastrointestinal dysmotility through the expression of enzymes involved in the synthesis of neuromodulators (gamma-aminobutyric acid [GABA], for instance) and products of colonic fermentation (gas or short-chain fatty acids, SCFA). Finally, dysbiosis seems to promote the disruption of the intestinal barrier: increased intestinal permeability would thus improve the crossing of bacterial antigens responsible for low-grade inflammation leading to sensitization of sensory afferent fibers of the enteric nervous system.^3,4

PROMISING APPROACH

Heterogeneity of FGIDs and contradictory results in terms of bacterial composition depending on studies and methods do not allow microbiota and its metabolites to be used as relevant markers for diagnosis, monitoring of the progression of the disease, or treatment response. Literature confirms however the importance of diversity and composition of the intestinal microbiota in the pathophysiology of FGIDs, and consequently the potential impact of approaches related to modulations of intestinal bacterial populations.

Although alcohol abuse is detrimental to health, the discussion regarding the impact of moderate consumption is still ongoing, as well as the negative impact of alcohol on the oral flora, according to recent works. In a new study, Mexican researchers tested the effects of beer (with and without alcohol) on the gut microbiota.

A beer at lunch to keep the doctor away?

For a month, around thirty volunteers were told to drink one 335-ml non-alcoholic beer (0.5º) at lunch, without changing any other dietary habit. Five months later, they had to follow the same protocol but with a classic beer (4.9º). On Days 1, 15 and 30 of the experiment, samples of blood and stool were collected and a series of body measurements (hip circumference, body mass index, blood pressure...).

Non-alcoholic beer provides more benefits

Bad news for hop lovers, but maybe also some good news... On the plus side, both types of beer led to a strong increase in the proportion of Bacteroidetes and decrease in species from the Firmicutes phylum; and such a ratio is also found in healthy people. However, the match between non-alcoholic beer and alcoholic beer turned in favor of the former: no weight gain, no increase in hip or waist circumference, no change in liver enzymes or blood lipids, and even decrease in blood sugar levels coupled with a better insulin resistance. But let’s be fair play: all these parameters remained within the normal range for drinkers of “true” beer.

A new superfood?

At the intestinal level, non-alcoholic beer also has the upper hand: the bacterial flora is more diversified and with a higher content in beneficial bacteria such as lactobacilli (barrier against obesity and insulin resistance in mice), Streptococcus (promoting the regulation of immune reaction), and other types of bacteria associated with weight loss in humans. One month after the beginning of the experiment, non-alcoholic beer also tripled the amount of bacteria capable of producing polyphenols–already present in beer (with or without alcohol)–and phenolic acids such as resveratrol, which are potentially beneficial components against cancer, diabetes or even neurodegenerative diseases. A convincing argument in support of happy sobriety.

Through which mechanisms does the microbiota influence the efficacy of chemotherapy or immunotherapy?

We have shown that chemotherapy leads to intestinal permeability, which facilitates the spread of bacteria into the immune system. Although this downside is the source of many adverse events (nausea, diarrhea, vomiting), it is also paradoxically very useful since it stimulates the immune system and boosts the effect of the antitumor drug.

As for immunotherapy, its aim is to mobilize the immune system against tumors, and its success also seems to depend on the intestinal microbiota which acts on three main mechanisms:

• Its composition impacts the distribution of lymphocytes (white blood cells) in the digestive tube, and thus impacts the endogenous defense system, as was recently shown in several articles.
• Some of its metabolites could activate the immune system, although it has yet to be demonstrated.
• It activates mechanisms of intestinal barrier repair which contribute to treatment efficacy.

How are these findings going to change the management of cancers treated by chemotherapy or immunotherapy?

Probiotics used as complement to the existing therapeutic arsenal (surgery, radiotherapy, chemotherapy, hormone therapy, immunotherapy) could become a sixth therapeutic modality against cancer. When there is no infection, we will avoid prescribing prophylactic antibiotics (preventive treatment), while in case of infection, we will postpone immunotherapy. Our objective is to identify patients with an intestinal dysbiosis and to restore their microbiota before starting immunotherapy or chemotherapy.

What are the research avenues currently considered to modulate the composition of the intestinal microbiota?

Probiotics administration and fecal transplant (transplant of the microbiota from a healthy individual into the patient’s digestive tract) are the main avenues under investigation to restore a microbiota which is likely to hinder treatment. These bacteria, called “oncomicrobiotics” are not intended to increase the efficacy of chemotherapy or immunotherapy on their own. Their aim is to prepare the organism of a patient with dysbiosis to respond positively to these immunomodulating treatments. More and more biotechnology companies dedicate part of their research efforts to the development of “anticancer” probiotics. However, only multidisciplinary research followed by large-scale clinical trials will be able to identify which are the “friendly” bacteria and to assess their efficacy within the context of chemotherapy or immunotherapy. We can expect progress in the foreseeable future.

Before menopause, estrogens are synthesized by ovaries and later, other tissues take over (fatty tissue, brain, hypothalamus). A portion of estrogens produced are subject to chemical reactions of detoxification by the liver (which makes molecules harmless to the body) and then excreted in the bile. They are then transferred to the intestines where they are deconjugated by the microbiota before being reabsorbed by the tissues or released into the blood flow. Depending on the composition of the microbiota, this reabsorption means that hormonal metabolites with differentiated estrogenic activity are released back into the blood flow. It seems that breast cancer risk is contingent, as least partly, on the nature and ratio between metabolites and estrogens.

This “deconjugation” is led by bacterial genes, mainly an enzyme which is involved in the degradation of complex sugars and whose activity can be modulated by diet and by the intestinal microbiota. Blocking the actions of this enzyme could thus decrease the level of active estrogens released back into the blood flow and reduce breast cancer risk. This is precisely the hypothesis that a team of American scientists is currently testing in mice.

Breast microbiota

Some researchers also discovered a microbiota in the breast tissue. Its composition, and more specifically the abundance or lack of specific bacterial families, seems to be different whether the host is suffering from breast cancer or not. Other researchers made a similar finding in the intestinal microbiota, whose composition seems to vary depending on the stage of cancer. The alteration of the intestinal microbiota (dysbiosis) as a starting point for breast cancer is an avenue seriously considered by researchers

Is there a link between the different microbiotas?

At this time, all these assumptions are leads worthwhile to be investigated. Further research should focus on determining if there are links between the different microbiotas, and whether these links lead them to act together to generate an environment favoring the development of breast cancer.

KEY FIGURES - BREAST CANCER:

Many women complain about dry mouth during menopause. According to an international team of researchers¹², this lack of saliva, associated to the drop in estrogen levels, could have harmful effects such as changes in composition of the oral microbiota, dysbiosis (imbalance of the microbial flora) and onset of inflammatory disorders (e.g. gingivitis or periodontitis) which create a loss of tooth support that potentially leads to tooth loss.

Drop in estrogen levels and diseases

Since female sexual hormones affect the composition of the different body floras, especially the intestine microbiota, a drop in estrogen levels impairs the microbial balance and promotes the onset of autoimmune diseases. This could explain why some autoimmune diseases affect women more than men (lupus, Sjögren syndrome,rheumatoid arthritis) or why they occur at specific moments of their hormonal lives, i.e. after their menstrual period or during their reproductive period (asthma). Moreover, microbiota alteration due to estrogen deficiency leads to metabolic changes. The one most feared by women is abdominal weight gain, which is a proven risk factor for type 2 diabetes. Finally, intestinal microbiota could affect breast cancer risk through its effects on estrogens produced by fatty tissue in menopausal women.

Composition of oral and/or intestinal microbiota and estrogen deficiency have been successfully linked to all these disorders that are likely to occur during menopause. That is why researchers are encouraged to continue investigating and study the effect of prebiotics and probiotics and their potential use as a monotherapy or in combination with HRT.

To prevent the risk of osteoporosis and fracture, menopausal women can decide between HRT or a treatment combining calcium and vitamin D. But in the US, where the types of hormones and their doses are different from those used in France, THM remains controversial since it is suspected to increase the risk of some female hormone-dependent cancers, including breast cancer. What are the alternatives?

According to a Chinese study¹⁰, probiotics associated with isoflavones (naturally occurring plant compound) could be a low-risk and effective alternative treatment for osteoporosis.

Efficacy of probiotics has been demonstrated in mice

Non-clinical tests have shown that the intestinal microbiota plays a role in bone metabolism regulation. First possible mode of action: through an interaction with the immune and/or endocrine (i.e. hormones) systems, both involved in bone metabolism. Second possible mode of action: by aiding calcium absorption, a mineral essential to bone formation and strength. The microbiota could thus promote bone formation as well as limit bone loss, although to a lesser extent.

All these results have led researchers to assess the benefits of probiotics to prevent osteoporosis and evaluate their efficacy in an animal model. Probiotics play a role at two levels: on the one hand, they increase microbiota diversity by restoring the intestinal barrier and modulating the immune response; and on the other hand, they stimulate calcium absorption and production of estrogen-like compounds. These promising results still have to be confirmed in women.

Combination with isoflavones

Isoflavones are compounds naturally found in some plants, especially soy and red clover. They have anti-osteoporotic effects which are boosted by the concomitant administration of probiotics. They mimic certain modes of action of estrogens while counteracting others, i.e. they limit disorders associated with menopause while still protecting against breast cancer. A Danish study¹¹ showed that the combination of isoflavones and probiotics associated with calcium and vitamin D supplementation was more effective than calcium and vitamin D supplementation alone to reduce osteopenia (loss of bone density). As a monotherapy or as a combination therapy with an anti-osteoporosis drug, probiotics could offer an alternative treatment to women who would rather use natural remedies to limit the progression of osteoporosis.

Key figures - Osteoporosis:

For the first time⁹, scientific data were obtained regarding the cervicovaginal microbiota in postpartum HIV-positive women. They showed that postpartum HIV-positive women have a highly diverse microbiota, just like postpartum HIV-negative women. They also showed that immunodeficiency caused by HIV and cervicovaginal dysbiosis are suspected to play a role in the onset of precancerous lesions.

HIV and increased risk of lesions

Vaginal microbiota dominated by Lactobacillus crispatus is associated with a decreased risk of HIV infection and, in HIV-positive women, to a decreased risk of HPV infection. On the contrary, vaginal dysbiosis with higher bacterial diversity and decreased levels of lactobacilli increases the risk of HIV and HPV acquisition, cervical precancerous lesions and cervical cancer. It is also known that a change in vaginal microbiota composition occurs during the postpartum period: higher bacterial diversity and decreased levels of Lactobacillus crispatus. As a result, postpartum HIV-positive women have a vaginal microbiota that could expose them to a higher risk of HVP infection and thus to a higher risk of cervical precancerous lesions and cervical cancer.

What is the role of the microbiota?

To test this hypothesis, Brazilian researchers analyzed the vaginal microbiota of 80 young HIV-positive women on antiretroviral therapy at 6 and 12 months postpartum: four types of microbiota were identified, including three with a high microbial diversity, but none dominated by Lactobacillus crispatus. The researchers observed an overabundance of specific bacteria in cases of cervical precancerous lesions, especially Moryella and Schlegellela. They also detected an increased content of Gardnerella vaginalis in women whose lesions had regressed during the monitoring period, but not in women who had developed lesions

It is not clear from these findings whether the identified bacteria are the cause or the result of cervical precancerous lesions, but this study still highlighted HIV-positive women’ susceptibility and described the type of microorganisms involved. Their exact role in the development of lesions has yet to be determined, bearing in mind that cervical cancer is the 4th most common type of female cancer, causing more than 200,000 deaths every year in the world.

The composition of the vaginal microbiota changes throughout women’s lives: while it has a particularly low content of Gardnerella vaginalis, Prevotella and lactobacilli before puberty, it becomes almost exclusively colonized by lactobacilli after puberty. Lactobacilli ensure women’s health by fighting against pathogens. Their decrease is associated to various gynecological disorders, such as premature delivery, infertility, sexually transmitted infections or even pelvic inflammatory diseases. Shortly before menopause, hormonal variations cause significant changes in the composition of the vaginal microbiota which finds a different balance after menopause.

Microbes and reproduction

Vaginal microbiota also seems to play a role in conception, whether it is natural or by means of in vitro fertilization (IVF). The presence of Gardnerella vaginalis and Atopobium vaginae in the vaginal microbiota was associated to lower success rates, while treatment of bacterial vaginosis, which is frequent in infertile women, improves pregnancy rate. Success also depends on the proportion of lactobacilli in seminal fluids as well as the presence of some species in the Fallopian tubes and the uterine mucosa (endometrium), whose microbiota could either favor or limit chances of embryo implantation.

The baby’s health starts in the uterus

The baby’s immune and metabolic systems could be determined during intrauterine life through its exposure to maternal microbes which are present in the placenta and amniotic liquid and can also be found in the newborn’s first stools (meconium). At present, it is unknown if the placenta hosts its own microbiota. It is known however, that it is similar to the maternal oral flora, which could explain why pregnant women with periodontal diseases have an increased risk of facing pregnancy-related complications. Moreover, changes in its composition are associated to premature births.

Risks and benefits

Although the mother is a source of microbes for her baby, other factors come into play to modulate the baby’s microbiota. Use of antibiotics by the mother (especially in the second or third trimesters of pregnancy) as well as cesarean delivery (because the newborn does not come into contact with the mother’s vaginal microbiota) are associated with an increased risk of childhood obesity. On the contrary, probiotics seem to benefit the mother and her unborn child, according to the researcher Jessica Younes. In pregnant women, they could reduce the risk of premature delivery, gestational diabetes, postpartum depression or urinary and vaginal infections; whereas in the newborn child they could limit colic, predisposition to developing allergies (atopy), resistance to antibiotics and could also reduce— or even eliminate—the risk of necrotizing enterocolitis which is a fatal disease. Finally, breastfeeding or formula feeding could play a significant role in the child’s microbiota composition, although its impact on childhood health remains unknown.

A healthy vaginal microbiota is composed of various microorganisms, where lactobacilli generally predominate. However, advances in molecular biology have shown that not all lactobacilli provide the same degree of protection: Lactobacillus crispatus, for example, is associated to an anti-inflammatory profile and seems to afford protection against pathogenic germs. On the contrary, Lactobacillus iners seems to promote an imbalance of the vaginal microbiota (dysbiosis) favorable to bacterial vaginosis, similarly to pathogenic bacteria

Microbiota, vaginosis and STIs: dangerous liaisons

Vaginosis, vaginal candidiasis, colonization of the vaginal microbiota by pathogens, and STIs share many biological and behavioral factors which could explain their interrelationships. Although vaginosis and vaginal candidiasis are not STIs per se (since they can occur without intercourse), a study by Janneke Van de Wijgert showed that sexual transmission of the responsible organisms most certainly plays a role in their development. Moreover, dysbiosis and vaginosis weaken the vaginal mucosal barrier and leads to cervicovaginal inflammation, which increases the risk of HIV infection. The risk of contracting sexually transmitted infections thus depends, at least in part, on the health of the vaginal microbiota. By preserving their microbial flora, women could limit their risk of developing STI. Future research needs to focus on determining how the vaginal microbiota can expose women to a higher risk of STI, in order to better screen and treat them, especially with local probiotics.