The progression from chronic kidney disease (CKD) to end-stage kidney disease (ESKD) and its complications appears to be linked to the accumulation of toxins in the blood, many of which are thought to originate in the gut microbiota. However, the microbial origins of these metabolites–which include uremic toxins–and the mechanisms underlying them remain unclear. A large international study (223 ESKD patients and 69 control subjects) was carried out to characterize the relationship between microbial composition, uremic toxins and ESKD symptoms.

Fecal and serum metabolites mirror clinical status

Serum and fecal metabolites of the ESKD patients differed from those of the control subjects and were highly correlated with each other. The feces of the ESKD patients contained more secondary bile acids (SBAs)–precursors to uremic toxins–and fewer short chain fatty acids. Serum metabolites in the patient group were characterized by an increased level of nine uremic toxins and bile acid imbalance, with these characteristics closely related to patients’ clinical status. Therefore, intestinal metabolic alterations in ESKD patients are thought to contribute significantly to the accumulation of uremic toxins in the serum. This hypothesis was validated in a study on an independent second cohort (12 ESKD patients and 12 control subjects).

Gut dysbiosis

A shotgun metagenomic analysis identified an intestinal dysbiosis in the ESKD patients, with an increase in certain bacterial species. These bacteria included genes that code for the synthesis of uremic toxins and the biosynthesis of SBAs. Indeed, microbial composition was correlated not only to clinical variables in the patients, but also to the production of uremic toxins and SBAs. The authors believe that the intestinal microbiota speeds up the production of toxins, thereby contributing to the aggravation of the disease.

Involvement of the microbiota confirmed in rodents

When the feces of ESKD patients were transplanted into germ-free mice, the mice displayed an increase in serum levels of uremic toxins, an aggravation of renal fibrosis and oxidative stress. Intestinal dysbioses are therefore partly responsible for kidney disease via the production of uremic toxins. Two species that produce precursors to these toxins, Eggerthella lenta and Fusobacterium nucleatum, seem to be responsible. Lastly, the administration of a probiotic (a strain of Bifidobacterium animalis) reduced both toxin levels and the severity of the disease in rats. In sum, intestinal dysbioses in CKD patients generate harmful metabolites that aggravate the disease. This suggests that targeting the gut microbiota could reduce uremic toxicity in these patients.

Numerous studies have shown that, in addition to its other benefits, regular moderate physical exercise increases diversity among the bacteria in the intestine, favoring beneficial species. However, this is only the case for regular exercise, since ceasing all activity may lead to an imbalance in the intestinal microbiota (dysbiosis).

Avoid excessive exercise

The opposite situation also has its dangers. Whether you are an amateur or a professional, training too intensely or disproportionately to your level may lead to a dysbiosis, which can be all the more sudden and acute the more intense the activity. Such dysbioses may result in increased intestinal permeability, which, by allowing bacteria and their components to pass into the bloodstream, can lead to inflammation in the body. They may also be the cause of abdominal pain, nausea and diarrhea that certain people experience during extreme exertion.

A gut-muscle axis?

The most likely hypothesis is that the muscles and intestinal bacteria communicate via a gut-muscle axis. This communication is thought to work both ways: the gut microbiota influences muscular health and physical exercise modulates the composition of the microbiota. In humans, although supported by the link between intestinal dysbioses and various muscle-related metabolic alterations (protein synthesis, release of molecules promoting muscle development, etc.), this hypothesis remains tentative.

The immune system: at the crossroads of the gut-muscle axis?

Shaped by the intestinal bacteria, the immune system may also play a key role in muscular health. By helping to build a strong immune system, a “healthy” gut microbiota may influence the gut-muscle axis and the health of our muscles, especially among people having an active lifestyle. Conversely, a dysbiosis caused by a negative interaction with the immune system may promote muscular disorders. This is one more hypothesis that needs to be verified if we are to finally understand the relationship between exercise, the immune system, the gut microbiota and muscular health.

Sjӧgren syndrome (SS) is an autoimmune epithelitis characterized by dry mouth and dry eyes. The epithelial cells in the salivary glands act both as agents and targets by transforming into cells capable of activating the immune system (T cells, dendritic cells, then B cells) and synthesizing chemokines that cause lymphocytic infiltration. The inflammation of the salivary glands associated with these infiltrates is one of the diagnostic criteria for SS. However, it is not yet known what causes the disease. Among the suspects is a dysbiosis of the oral microbiota, already implicated in several autoimmune diseases (systemic lupus, Crohn’s disease, rheumatoid arthritis). The study described below sought to characterize the oral microbiota of patients with SS and to identify whether it had any role in the onset of the disease.

Dysbiosis of the oral microbiota

Oral bacterial communities were sampled via full mouth washing in 25 patients with a primary form of SS (17 with dry mouth and 8 without) and in 25 control subjects (11 with dry mouth and 14 without). These subgroups were selected in order to characterize the changes in the oral microbiota associated with SS, while controlling for the effects of dry mouth. Compared to that of control subjects, the oral microbiota of the SS patients had a higher bacterial load and, in correlation, was more diverse, with bacterial diversity even more pronounced in those not suffering from dry mouth.

The role of Prevotella melaninogenica

In order to assess whether bacterial species associated with the syndrome act as pathogens, the researchers tested in vitro three of the oral bacteria species that signal dysbiosis in SS patients, selecting those that express porins (proteins that allow membrane exchanges). Of these species, P. melaninogenica is able to induce functional (secretion of interferon λ by tumor cells, causing inflammation) and phenotypic (presentation of antigens) changes in the epithelial cells of the salivary glands. The question remained as to whether this bacterium could reach the salivary glands, and this was confirmed by a series of biopsies revealing its presence in salivary ductal cells and infiltration areas. This is thought to result from a rupture of the epithelial barrier due to inflammation and/or fibrosis. In this first scenario, the bacterial infection aggravates the inflammation and the deregulation already underway within the epithelial cells of the salivary glands. However, since the bacterium is also present in non-inflamed areas, another scenario is also possible, in which bacterial infection precedes lymphocyte infiltration. In short, a dysbiosis of the oral microbiota may initiate deregulation of the epithelial cells in the salivary glands. This would lead to a bacterial invasion of the ductal cells able to fuel the inflammation by itself.

Against the current pandemic backdrop, everyone would want a stronger immune system and develop better resistance to infections. Numerous articles have highlighted the key role played by nutrition in immunity, but what can we really expect from nutrition in this regard? In fact, no study to date has shown that an improved diet can help fight viruses^1,2, while protective measures and social distancing remain the most effective means of doing so. However, a well-chosen diet can optimize our immune defenses.

Two levers of action

Our food provides essential nutrients that contribute to the proper functioning of the immune system³, particularly zinc⁴, vitamin D^5,6, vitamin A⁷ and antioxidants such as vitamin C⁵. Moreover, food affects the immune system by shaping the intestinal microbiota^8,9. The billions of bacteria living in the gut are in constant dialogue with immune cells³ and play an important role in the immune response triggered by infections^{10 12}. A well-balanced microbiota also helps regulate the immune system, preventing it from “overreacting”^10,11 (i.e. maintaining a state of alert harmful to the body when it should return to standby once its mission is accomplished). For this reason, the aim is to “strengthen” rather than “boost” the immune system.

Which foods to choose?

In practice, which foods should be consumed? Fruit and vegetables–which are a source of antioxidant vitamins–, and vitamin D-rich oily fish (supplemented if possible by exposure to the sun, which favors vitamin D synthesis by the skin) provide the immune system with all its basic requirements¹. In addition, a varied diet rich in fiber and probiotics such as yogurt or cheese strengthens the microbiota, promoting health and immunity^14,15. Conversely, a diet too rich in calories, fats and processed foods containing additives depletes the microbiota^1,8,14.

Childhood asthma affects 8% of young Americans and Canadians. Its prevalence doubled in the second half of the 20^th century, but the trend seems to be reversing. Is this decline linked to a reduction in antibiotic prescription and to the resulting beneficial effects on the intestinal microbial community? To test this hypothesis, the authors analyzed government data on asthma diagnoses and antibiotic prescriptions in British Columbia (sidenote: Data from the BC PharmaNet government database, which collects data from all health centers in the province (database population: 4.7 million) )  (Canada), as well as the intestinal microbiota of 2,644 children participating in the Canadian CHILD Cohort Study (sidenote: Canadian CHILD Cohort Study Canadian Healthy Infant Longitudinal Development study, a prospective study of children recruited before birth between 2008 and 2012 ) .

Fewer antibiotics means less asthma

At population level, between 2000 and 2014, the incidence of asthma among one- to four-year-old children fell by 7.1% in absolute terms, from 27.3% to 20.2%, based on Canadian government data. In the same period, the prescription of antibiotics to children under the age of one decreased significantly (from 1,253.8‰ to 489.1‰). In 2014, one in three children (34.8%) was prescribed antibiotics at least once before the age of one, compared to two in three children (66.9%) in 2000. Statistical analysis shows a link between antibiotic prescription and asthma: the incidence of asthma increases by 24% with each 10% increase in antibiotic prescription. This trend observed at population level was also found at individual level in the CHILD cohort. After excluding children who had received antibiotics for respiratory problems, the diagnosis of asthma at five years of age was more frequent among children prescribed antibiotics before the age of one. Furthermore, the incidence of asthma increased with the number of prescriptions: 5.2% for no prescription, 8.1% for one, 10.2% for two and 17.6% for three or more.

Role of the microbiota

According to the authors, a dysbiosis of the intestinal microbiota in infants could explain the link between antibiotic exposure and childhood asthma. Children with asthma at five years of age showed less diversity in their gut microbiota at the age of one. This diversity decreased with the number of antibiotic treatments and the earlier the age of prescription (with a sharp reduction if taken before three months). The lower diversity was associated to a decrease in five key bacterial groups, particularly two species involved in the production of immunomodulating short-chain fatty acids. Therefore, the reduction of certain bacterial species may influence the development of children’s immune systems, making them susceptible to allergies. Hence the potential value of strategies aimed at maintaining the diversity of the microbiota after antibiotic use and the need for prudent use of antibiotics before the age of one.

Endometriosis is a chronic gynecological disease which happens when tissue similar to the lining of the uterus grows outside the uterus (womb). This abnormal migration results in inflammation and intense pain. The exact causes of endometriosis remain unknown, but genetic, hormonal, environmental and immune system factors seem to be involved.  A team has attempted to develop a non-invasive diagnostic test able to characterize vaginal and intestinal microbiota of women suffering from endometriosis.

Vaginal microbiota: a predictive tool

To this end, vaginal secretions and rectal samples were taken from 35 patients with endometriosis and 24 control subjects aged between 21 and 49 years, at two different time points: during menstruation and outside this period. The results showed no difference in the composition of the gut and vaginal microbiota of the two groups, regardless of the phase of menstrual cycle. However, differences in the vaginal microbiota were observed within the group of women with endometriosis. During menstruation, the bacterial genus Anaerococcus was found in abundance in women with severe forms of the disease when compared to women with less advanced forms, which suggests that Anaerococcus may predict the severity of endometriosis.

Further research

The team’s findings may prove especially useful for future research on the role of the vaginal microbiota, and more specifically for the diagnosis of advanced stages of endometriosis, although these results require confirmation on larger cohorts. All in all, these preliminary results open up new research avenues that will allow a better understanding of the causes of endometriosis and help in the development of new non-invasive diagnostic tools for the disease.

The human papillomavirus (HPV) is the most common sexually transmitted infectious agent. While for most women HPV clears up quickly, a small fraction develops persistent infection with a high risk of progression towards precancerous lesions and cervical cancer. Certain environmental (smoking, hormonal contraception) and clinical (genetics, immune system, parity) factors have been linked to the progression or elimination of HPV. The cervicovaginal microbiota (CVM) has been shown to be involved in the prevalence of the disease but its influence on whether HPV is eliminated or progresses towards moderate to severe dysplasia (CIN2+, CIN3+ (sidenote: Cervical intraepithelial neoplasia (CIN). CIN2+ involves Grade II precancerous lesions or moderate dysplasia, while CIN3+ entails high-grade precancerous lesions or severe dysplasia ) ) is not yet known.

Lactobacillus iners: a sign of HPV clearance

Taking advantage of a clinical trial in Costa Rica evaluating an HPV vaccine, researchers¹ analyzed the microbial composition of cervical samples from the study’s placebo group. They studied the microbiota of 273 women with high-risk oncogenic HPV (HR-HPV) and assessed the changes one year later. At the first visit (V1), virus clearance was correlated with the presence of L. iners. On the other hand, progression of the disease was correlated with the presence of Gardnerella at V1 and with that of a polymicrobial vaginal community at the second visit (V2).

Gardnerella: a key role in the progression of HPV

The researchers then modelled the course of the disease by combining clinical features (age, smoking, virus genotype, etc.) with data on the structure of the CVM obtained at V1 and V2. Their bioinformatics analysis suggests that Gardnerella is involved in the development of precancerous lesions. However, instead of a direct role, Gardnerella is thought to induce an increase in bacterial diversity which in turn leads to the progression of infection towards precancerous lesions.

A strategy to prevent HPV progression?

A separate team had published similar results a few weeks earlier². Both studies hypothesize that a vaginal dysbiosis may facilitate the progression of oncogenic HPV towards precancerous lesions. They also point out that the CVM contains biomarkers which help identify patients at risk. If future studies confirm a central role for the CVM in the evolution of HPV infection, therapeutic strategies to prevent the progression of the disease based on modulating the CVM could be contemplated.

Each winter, millions of French people catch the flu. Despite vaccination campaigns and treatment, the most vulnerable can develop complications which at times prove fatal. These severe forms are generally linked to pneumonia caused by bacterial superinfections. A recent study published in a prestigious journal suggests that the gut microbiota is involved.

Imbalance of intestinal flora

It is now accepted that the intestinal flora plays a key role in the proper functioning of the immune system. In this study, flu-infected mice showed a transitory imbalance in the composition and activity of their gut microbiota (dysbiosis (sidenote: Dysbiosis Generally defined as an alteration in the composition and function of the microbiota caused by a combination of environmental and individual-specific factors. Levy M, Kolodziejczyk AA, Thaiss CA, et al. Dysbiosis and the immune system. Nat Rev Immunol. 2017;17(4):219-232.   ) ). In addition, the production of short-chain fatty acids (SCFAs (sidenote: SCFAs Short Chain Fatty Acids are a source of energy (fuel) for the cells of the individual. They interact with the immune system and are involved in the communication between the intestine and the brain. Sources:
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. ) ) was greatly reduced. SCFAs, and especially acetate, have the ability to act at a distance from the intestines on certain immune cells in the lungs (macrophages) by stimulating their antibacterial activity. In short, a dysbiosis of intestinal microbiota associated with flu is thought to reduce acetate production, compromising the lungs’ immune defenses against bacteria.

The role of diet

This intestinal imbalance is not caused directly by the virus itself, but instead seems to be the result of a reduction in food intake due to loss of appetite, a frequent flu symptom. Accordingly, in order to preserve the integrity of intestinal microbiota and strengthen immune defenses, it is recommended to consume foods that are rich in dietary fiber (e.g. vegetables, fruits and pulses). Similarly, reducing calorie intake or fasting are strongly advised against during flu outbreaks.

New therapeutic strategies

It has been shown in mice that this susceptibility to bacterial superinfection can be corrected by acetate treatment. Based on these findings, a treatment based on acetate or similar compounds is a potentially valuable therapeutic approach. Furthermore, therapeutic strategies based on the use of prebiotics and probiotics should be assessed.

Sources:

^{Sencio V, Barthelemy A, Tavares LP, et al. Gut Dysbiosis during Influenza Contributes to Pulmonary Pneumococcal Superinfection through Altered Short-Chain Fatty Acid Production. Cell Rep. 2020;30(9):2934–2947.e6.} 

Allogeneic hematopoietic stem cell transplantations, or allografts, are one treatment option for blood cancer (sidenote: The patient receives stem cells from a histocompatible donor ) . However, the risks involved are significant, foremost among them the potentially lethal graft-versus-host disease (sidenote: Graft-versus-host disease  Immune response directed against host cells initiated by cells transplanted from the donor ) . It remains difficult to foresee when such complications will arise in a given patient. The intestinal microbiota, which plays a role in immunity and whose balance is disturbed in patients undergoing HSCT, could prove useful in this regard.

A multicenter study spanning three continents

A team sought to characterize the potential links between microbial composition and post-transplant prognosis, at the same time testing whether its findings were dependent on the patient’s place of care. Although alterations in the intestinal microbiota had already been linked to HSCT and its prognosis, it remained unclear whether these links were consistent in nature. A study was therefore carried out on 1,362 allograft patients (average age of 53 years) from four medical centers (New York and Durham, USA; Regensburg, Germany; Sapporo, Japan), allowing for between-center comparisons.

Survival linked to post-op diversity of microbiota

The study showed that greater diversity in the gut microbiota (α diversity), measured 7 21 days after the transplant (neutrophil development period), was associated with a lower risk of death (approximately 30%-50% lower, depending on the center and model) within 24 months from the procedure. In some patient subgroups, greater diversity was also associated with a reduction in transplant-related mortality and GvHD-related mortality.

Certain taxa are over-represented in the postoperative setting

The loss of diversity in the microbiota has also been associated with the over-representation of certain taxa of Enterococcus, Klebsiella, Escherichia, Staphylococcus and Streptococcus genera. This predominance of a specific taxon in the microbiota of transplant patients had already been reported in a previous study. Although not found in all patients, it was observed in all four centers. In short, allografts are frequently associated with an alteration of the microbiota and characteristic microbial profiles.

Pre-operative microbiota: a predictive tool?

The researchers also looked at the microbial profile of patients prior to transplant. By comparing patients to healthy control subjects, the researchers showed that their microbiota already presented a dysbiosis pre-transplant. Moreover, in the New York center, greater pre-operative diversity predicted successful outcomes. Ultimately, these results may lead to the development of clinical strategies to improve post-transplant prognosis by regulating the microbiota at two key moments, either before the transplant or during the neutrophil development period.

While immune checkpoint inhibitors (ICIs)–monoclonal antibodies directed against immune system checkpoints–have revolutionized cancer treatment, they only work in a small number of patients and can produce a multitude of unwanted side effects (e.g. fatigue, skin rashes, endocrine disorders and hepatotoxicity). In addition, although combinations of several inhibitors can prove more effective, they may have higher toxicity, hence the reluctance to use them. In order to provide a more localized, more durable, and less invasive therapeutic option, it is therefore crucial to improve their method of administration. Due to their colonization method and preferential growth within tumors, bacteria may prove to be an ideal solution to deliver these cancer treatments locally.

A single dose for a prolonged effect

With this in mind, a team designed probiotic bacteria capable of releasing blockade nanobodies locally. These target two membrane receptors–the lymphocyte receptor CTLA-4 and the tumor receptor PD-L1–involved in the defense mechanisms activated by the tumor to prevent T cells from attacking it. Specifically, a single intravenous or intra-tumoral injection transports these probiotic bacteria to the heart of the tumor, where they multiply to a critical density and destroy the tumor cells by effectively and continuously releasing therapeutic nanobodies into the tumor’s microenvironment.

Effective on even the most aggressive tumors

The research team subsequently injected the probiotic into murine models for lymphoma and colorectal cancer. For lymphomas, a single intra-tumoral or intravenous injection of the probiotic bacteria “carrying” the treatment proved more effective than standard immunotherapy, leading to a complete regression of the tumor and the prevention of metastasis in both early and advanced models. But what about cancers known to be more resistant to immunotherapy, such as colorectal cancer? A single intra-tumoral dose of a combination of nanobodies and a growth factor (GM-CSF, used to improve anti-tumor response) was enough to shrink the tumor without any side effects.

Bacteria: the ideal vehicle for the future?

This research should help advance immunotherapy by providing a “carrier”, i.e. bacteria, with many advantages: possibility of combination therapies; continuous production of therapeutic substances; minimized toxicity; localized treatment distribution close to control points; and of course, use among a larger number of cancer patients.