Microbiome applications: microbiomes contribute to inflammation and the onset of diseases
New opportunities to identify new biomarkers and novel therapeutic targets
Thanks to metagenomics development, the understanding of the human microbiome has opened the door for multiple microbiome applications.
Historically, microbiome therapeutic areas of interest have been gastrointestinal diseases (irritable bowel syndrome, inflammatory bowel disease, and Crohn’s disease) and metabolic diseases (obesity and diabetes). In recent years, the potential microbiome applications have extended to other therapeutic areas, the fastest progressing ones being central nervous system diseases, infectious diseases, and oncology.
The interest in microbiome is not limited to drug development: the Food industry is actively contributing to microbiome research. Yet some Food companies are developing their products as a drug and therefore follow the same path as Pharma companies with clinical studies to prove the efficiency of their products.
The pathophysiological mechanisms, along with the mode of action of drugs, are more and more often found to be microbiota related/mediated. Collecting microbiome samples from patients in all clinical trials, be it from the gut or other internal tissues, could help to enlighten the outcomes of such trials (mode of action, prospective interaction with the drugs, individual’s response to treatment, adverse effects, patient stratification) resulting in a significantly improved success of trials and treatments.
Gut microbiota, translocation and tissue low-grade inflammation
During the last 2 decades, the hypothesis has been validated that metabolic diseases, neurodegenerative diseases or cancer have their origin in chronic low grade inflammation. The mechanism through which the intestinal microbiota could specifically affect tissue inflammation has been suggested by Vaiomer founders in 2011 with the discovery of blood and tissue microbiota resulting from bacterial translocation.
The question of the circulating microbiome and its interactions with the host is under investigation in health and a variety of pathologies. A diversity of bacterial DNA and living bacteria has been described by several groups in the adipose tissue, the breast tumor or the pancreas, to name a few.
Identifying the bacterial taxa (from living bacteria to bacterial DNA) present within tissues will aid in elucidating the molecular mechanisms implicated in the control of cellular and physiological functions of the host, opening the way to the discovery of new biomarkers and new therapeutic strategies.
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Microbiota and cardiometabolic diseases
Cardiometabolic diseases are the number 1 cause of death globally. They encompass cardiovascular diseases (e.g. atherosclerosis, stroke, heart attack and heart failure) and type 2 diabetes. Obesity and hypertension are known risk factors of cardiometabolic disorders. Gut microbiota has been established as a major determinant of obesity, type 2 diabetes and cardiovascular diseases because of its capacities in lipid metabolism control and its metabolism of dietary compounds such as L-carnitine and choline.
All cardiometabolic diseases present a chronic low-grade inflammation that is central in the onset, progression and aggravation of these pathologies. Inflammation and diet, especially Western diets, have been shown to increase intestinal permeability thus aggravating bacterial translocation. Bacteria, bacterial compounds and metabolites leaking from the gut can induce a chronic or acute inflammatory response that can affect glucose homeostasis, insulin resistance, lipid metabolism, atherosclerosis and other cardio-metabolic outcomes. Bacteria and/or bacterial components can translocate from the gut to organs in close association, such as the adipose tissue and the liver, therefore have a direct action on the target organs of metabolic diseases. Bacterial translocation can also occur
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from the gut to the blood from where bacteria and/or bacterial compounds can reach more distant organs such as the heart. Cardiovascular diseases are also linked to periodontal diseases and the oral microbiome. Indeed, bacterial pathogens can enter the blood circulation from the mouth and affect heart valves.
Microbiomes and bacterial translocation are key to understand the pathogenesis of cardiometabolic diseases, especially due to their pivotal role in the development of chronic low-grade inflammation. To encompass all the complex interactions of cardiometabolic diseases, it is crucial to move beyond the analysis of the gut microbiota to explore the blood microbiome and the microbiomes of target metabolic tissues such as adipose tissues, liver, heart, muscles and blood vessels (e.g. carotid, aortic arch).
Microbiomes in liver diseases
The liver is in the closest contact with the gastrointestinal tract through the portal vein and thus with the gut microbiota. Unsurprisingly, chronic liver pathologies such as alcoholic liver diseases, non-alcoholic liver diseases and primary sclerosing cholangitis are associated with shifts in intestinal microbiome profile.
Although alcohol consumption is the primary causal factor in the onset of alcoholic liver diseases, microbiome is still an important factor and can play a critical role in the aggravation and the outcome of the disease. Indeed, while some individuals with over-consumption of alcohol develop severe hepatic complications, others maintain a rather healthy liver.
In non-alcoholic liver diseases, the causal role of the intestinal microbiota through bacterial translocation has been supported by several studies. The liver is particularly exposed to variations in gut microbiota composition through the translocation of bacteria or bacterial metabolites from the gut to the portal circulation. The fat build-up in the liver cells leading to steatosis and NAFLD (Non-Alcoholic Fatty Liver Disease) has several known risk factors such as dyslipidemia, insulin resistance, type 2 diabetes, obesity, metabolic syndrome and a Western diet. All of these risk factors are associated with gut microbiota dysbiosis and aggravation of bacterial translocation. These associated pathologies are
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also characterized by a chronic low-grade inflammation that can lead to the progression into NASH (Non-Alcoholic Steatohepatitis). The liver pathology can then evolve into cirrhosis due to the accumulation of hepatic lesions known as fibrosis. From the irreversible stage of cirrhosis, several complications may occur such as decompensation, ACLF (Acute on Chronic Liver Failure), hepatic encephalopathy and HCC (hepatocellular carcinoma). Microbiomes, and especially, liver and blood microbiomes are pivotal to understand the progression of non-alcoholic liver diseases and to better identify reversible stages in which modulation of the microbiome through antibiotics, prebiotics and probiotics can open the way to new therapeutics. Liver and blood microbiomes can also help for patient stratification and serve as biomarkers for disease prognosis.
Microbiome analysis can be highly informative to monitor portal hypertension and TIPS (Transjugular Intrahepatic Portosystemic Shunt) procedure. Blood and tissue microbiomes can help with the follow-up of liver transplantation by identifying new biomarkers and new therapeutic approaches such as microbiome management.
Therefore to provide a more complete picture of the complex liver diseases, to understand the liver-gut axis and how microbiome dysbiosis can trigger chronic inflammation, it is essential to investigate all tissue microbiomes (e.g. gut, liver, adipose tissues) and fluid microbiomes (e.g. blood, bile, ascites).
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Microbiota and gastrointestinal disorders
The gastrointestinal tract is the body part colonized by the largest bacterial biomass, so unsurprisingly intestinal microbiota plays a central role in the onset and the clinical course of gastrointestinal disorders.
Genetic factors only have a low contribution to the prevalence of Inflammatory Bowel Syndrome (IBS) and Inflammatory Bowel Diseases (IBD) including Crohn’s disease and ulcerative colitis. Several studies showed that environmental factors and the gut microbiome are decisive in the development and evolution of these inflammatory diseases. In particular, through its capacities to mediate inflammation the gut microbiome is pivotal to understand and prevent acute phases and relapses.
In industrialized countries, food allergies also called Adverse Reactions to Food (ARF) have been rising for the last two decades. These abnormal reactions to food ingestion can be related to immunologic or non-allergic processes and greatly vary in clinical presentation and severity. Among food allergies, celiac disease is a serious reaction to gluten ingestion leading to damage in the small intestine. The gut microbiota with its functional role in
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in food digestion and its capacities to modulate inflammation, is a key contributor to food allergies.
Dysbiosis of gastrointestinal microbiomes has also been linked to colorectal cancer (CRC) and other gastrointestinal cancers (e.g. esophagus cancer). The involvement of bacteria and bacterial metabolites is suspected in tumor progression and cancer outcome. The tumor environment creates a niche distinct from the intestinal environment which can lead to local rearrangement of the microbiota.
Modulation of the gut microbiota clearly appears as an innovative therapeutic strategy in gastrointestinal disorders. Fecal microbiota transplantation can be used to shift a pathological gut microbiome to a more beneficial microbiome by transferring fecal matter from a healthy donor to a sick recipient. So far, FMT has only been approved for the treatment of recurrent Clostridium difficile infections when all other treatments have failed. However, the effectiveness, long-term benefits and safety of FMT remain under investigation. Changes in gut microbiota have been shown to increase bacterial translocation in a pathological manner. Bacterial translocation can be involved in several other pathologies because it increases systemic and local inflammation.
Over the last decade, bacterial translocation from the gut to the blood circulation and adjacent tissues has increasingly been raising concerns. The intestinal permeability also referred to as leaky gut, can be aggravated by gut microbiota dysbiosis, diet, inflammation and other factors. Chemically-induced (e.g. DSS, dextran sodium sulfate) animal models have been developed to investigate the leaky gut effects.
Gut microbiota and more broadly all gastrointestinal microbiomes (e.g. oral, esophageal and stomacal) are pivotal to understand pathogenesis mechanisms, to monitor the clinical course and to predict disease outcome and prognosis. Microbiome analysis is not only limited to feces. Mucosa, tumor and blood samples are also relevant. Blood especially can allow to evaluate bacterial translocation, to monitor the safety of FMT and to identify predictive biomarkers. Additionally, stool specimen collection can be challenging, while blood sampling is commonly more acceptable to the patients.
Beyond the human gut microbiome
The microbiota is not only located in the gut . It expands to every part of the body , ranging from very high to very low bacterial biomass . Learn more by travelling through our microbiome atlas.
Cancer and microbiomes
Microbiomes are drawing more and more attention in cancer research. The pivotal role of microbiota in the interplay between the immune system and cancer has only recently been fully appreciated. Three aspects are particularly under investigation 1) the effects of local microbiota on carcinogenesis, 2) tumor microbiota and 3) the interactions between microbiomes and cancer therapies.
Microbiomes can affect cancer susceptibility and progression by modulating inflammation and by producing harmful metabolites involved in tumor progression. Several studies have associated gut microbiota dysbiosis with colorectal cancer and other cancers. Gut microbiota through bacterial translocation can alter the progression of remotely located tumors through the translocation of bacteria and bacterial content from the gut to the blood circulation. Tissue microbiomes are also essential to understand carcinogenesis. Microbiomes can negatively affect tumor progression but can also produce beneficial metabolites promoting tumor suppression and reducing cancer susceptibility.
The tumor microenvironment provides a favorable niche for bacterial proliferation because the immune system is suppressed. The blood flow is also increased and the blood vessels are unusually
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leaky bringing more nutrients and carrying more components from the bacterial translocation originating in the gut. Tumors have also been shown to recruit bacteria with immunosuppressive activities, thus promoting tumor progression.
Microbiomes are crucial for cancer therapies. Cancer patients undergoing chemotherapy frequently develop diarrhea linked to increased intestinal permeability and resulting in the aggravation of bacterial translocation. Bacteria translocating from the gut to the bloodstream can be responsible for life-threatening infections and other secondary effects due to increased systemic inflammation. Moreover, microbial metabolism of anticancer drugs may promote tumor chemoresistance. Early on, the immunotherapeutic effect of the gut microbiome had been suspected. In studies of total-body irradiation, the efficacy of tumor-specific T cell transfer has been enhanced through the translocation of bacterial products. Anticancer therapeutics also showed reduced efficiency in germ-free mice. The modulation of the tumor microbiota could therefore stimulate the anti-cancer immunity leading to synergic effects with radiochemotherapy.
Immune Checkpoint Inhibitors (ICI) have opened a new era for cancer therapeutics by targeting the tumor microenvironment and restoring the immune system activity. Although ICI therapies show promising results, response varies among patients. Studies have confirmed the central role of microbiota in the clinical response and outcomes of ICI therapies.
Consequently, determining the bacterial profiles of the gut microbiota but also tissue and blood microbiomes is key to understand the protective or promoting effect of bacteria on cancer progression. Microbiome analysis appears crucial in the major ongoing efforts to identify new biomarkers to predict the patient’s response and clinical outcome. The manipulation of the microbiota, from the gut or the local tumor environment, is triggering the development of new therapeutic approaches to improve anticancer response and to reduce treatment toxicity.
DOCUMENTARY RESOURCES
- Gut microbiota dysbiosis contributes to the tumorigenic process
- Resistance to anti-PD-1 immunotherapy can be attributed to the gut microbiome
- Microbiomes modulate the local immune response, immunotherapy & toxicity
- The human tumor microenvironment is colonized by cancer type–specific bacteria and fungi
- Probiotic strains translocate to the tumor and improve ICI efficacy through indole-3-aldehyde release
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Microbiota in neurodegenerative and mental disorders
In the last decades, gut microbiota has emerged as a key modulator of human health due to its role in maturating and regulating host physiology, including the central nervous system. The focus on the gut-brain axis has revolutionized neuroscience research and has shown the pivotal role of the gut microbiota in neurodevelopment, neuroinflammation, and behavior.
Gastrointestinal symptoms very often precede or are associated with neurodegenerative diseases and mood disorders such as autism, Parkinson’s disease and depression. This supports the involvement of the gut microbiota in the pathogenesis of these diseases. Moreover, several studies have shown that microbial transfer from sick human donors to healthy recipient mice is enough for the animals to exhibit the symptoms of the related neurodegenerative or mental disorders.
Studies also suggest that the cause of at least certain neurodegenerative disorders may originate in the gut. The gut microbiota appears implicated in the regulation of myelin production and thus in the pathogenesis of multiple sclerosis. Parkinson’s disease is characterized by the aggregation of the α-synuclein. This protein has been found in the
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mucosal and submucosal nerve fibers and may be transported to the brain via the vagus nerve. Several studies pointed to a possible microbial origin for Alzheimer’s disease. Some evidence even suggests that bacteria can produce amyloid-like proteins. As for Parkinson’s disease, the interplay between gut proteins and cognitive health is of growing interest.
The implication of the gut microbiota in other neurodegenerative diseases and mental disorders is yet to be confirmed but is drawing more and more attention like in epilepsy, amyotrophic lateral sclerosis and schizophrenia. In particular, a ketogenic diet has shown beneficial effects in the therapeutic management of epilepsy by reducing seizure frequency. Diet is a major, well-recognized, modulator of the gut microbiota.
The gut microbiota is emerging as a driving factor of the neuroinflammation associated with neurogenerative disorders and for most of these diseases, aging is a primary risk factor. Aging is also characterized by a low-grade inflammation commonly referred to as inflammaging in which the gut microbiota plays a key role. Inflammation is recognized to increase bacterial translocation from the gut to the blood or other tissues. Some evidence already suggests the transport of proteins produced by bacteria from the gut to the brain and their involvement in Parkinson’s disease. An infective cause of Alzheimer’s disease originating in the gut is also hypothesized. Moreover, a specific blood microbial signature has been reported in patients with schizophrenia.
All these elements highlight the importance of microbiomes in understanding these complex neurodegenerative diseases and mood disorders. Microbiome analysis thus appears crucial to elucidate pathogenesis mechanisms and to open new therapeutic approaches. Recent evidence also supports the need to move beyond the gut microbiota and to explore tissue microbiota and circulating microbiomes from blood or other body fluids (e.g. cerebrospinal fluid). These investigations are logistically and ethically challenging in humans and can often only be carried post-mortem. Animal models will remain instrumental to comprehend the role of microbiomes in the gut-brain axis and the pathogenesis of neurodegenerative and mental disorders.
Bacterial translocation and tissue microbiota: The missing link between gut microbiota, systemic inflammation and pathogenesis.
Microbiota in COVID, HIV and infectious diseases
The SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), responsible for the COVID-19 pandemic, has emerged in late 2019 and rapidly spread globally. SARS-CoV-2 primarily shows respiratory symptoms such as cough, pneumonia and Acute Respiratory Distress Syndrome (ARDS) but also presents many life-threatening complications ranging from encephalopathies to multiple organ failure. Interestingly, some COVID-19 patients report gastrointestinal symptoms like abdominal pain and diarrhea. Substantial evidence is showing that the SARS-CoV-2 not only transmits through the respiratory route but also through the fecal-oral route. This virus can infect host cells by using the ACE2 (angiotensin-converting enzyme II) as the entry receptor into cells and the serine protease TMPRSS2 for S protein priming. ACE2 is abundantly expressed in the lung and the small intestine. In the latter, ACE2 regulates the renin-angiotensin system (RAS) and thus the intestinal inflammation. The SARS-CoV-2 has been found in gastric, duodenal and rectal epithelial cells. Viral particles are also present in feces, even when the virus is no longer detectable in the respiratory tract. The SARS-CoV-2 gastrointestinal infections result in the reduction of ACE2 activity increasing the intestinal inflammation and resulting in gut microbiota dysbiosis. Both inflammation and dysbiosis are known to increase bacterial translocation from the gut to the blood leading to systemic inflammation. Intestinal microbiome but also other microbiomes such as blood and respiratory tract (e.g. nasal swab, lung, expectorations, bronchoalveolar lavages) appear crucial in elucidating the pathogenesis mechanisms, predicting life-threatening complications and the disease outcome. Additionally, targeting the microbiomes could open new therapeutic approaches.
Many other viral infections are associated with modification of the gut microbiota that can affect the clinical course and prognosis of the disease. Among these viral infections, several studies have
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shown that the gut microbiota plays a pivotal role in HIV pathogenesis. The alteration of gut microbiota in the initial stage of HIV infection induces mucosal damage causing the depletion of CD4+ T cells in the gut-associated lymphoid tissue and the increase of the intestinal barrier permeability. It results in an aggravated bacterial translocation which increases the production of inflammatory cytokines. Although, anti-retroviral therapy allows the recovery of CD4+ cells in peripheral blood, it fails to restore the depleted CD4+ intestinal cells and the gut microbiota. Bacterial translocation is suspected to play a crucial role in other viral infections such as the seasonal flu (influenza A virus). Recent evidence suggests that gut microbiota dysbiosis leads to bacterial superinfection in the lungs.
The influence of the microbiota on viral infection susceptibility and disease outcome is undisputable although varies among viruses. The purpose of understanding the interactions between microbiota, virus, and host is to identify practical, effective, and safe approaches targeting the microbiota for the prevention and treatment of viral diseases in humans and animals, as currently there are few effective and reliable antiviral therapies available. Moreover, considering that the bacterial translocation is aggravated in viral infection, the circulating microbiome appears crucial to investigate as well as target-tissue microbiomes.
Beyond the exploration of microbiomes, targeted metagenomics can be highly valuable to detect low grade infections, uncultured pathogens or polymicrobial infections. This approach opens new diagnostic perspectives for infective endocarditis, bone and joint infections, Lyme disease and more broadly for patients in ICU with infectious life-threatening complications.
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Microbiome in autoimmune and inflammatory diseases
The role of the gut microbiome is well-recognized in the development, maturation and maintenance of the immune system. Therefore, its involvement is unsurprising in autoimmune disorders which are caused by the deregulation of the immune system mistakenly attacking the body.
The link between gut microbiota dysbiosis and autoimmune diseases has so far mainly been investigated in rheumatoid arthritis affecting the synovial joints and being characterized by inflammation and hyperplasia. The exploration of the interplay between microbiome and rheumatoid arthritis pathogenesis has been primarily focused on the oral microbiota. Patients have an increased prevalence of periodontitis and the translocation of the pathogen Porphyromonas gingivalis is suspected to trigger the onset of rheumatoid arthritis. Several studies are also associating rheumatoid arthritis with the gut microbiota, more specifically the exposure to certain specific bacteria appears to stimulate Th17 expression and to depress Treg activity.
In children and adolescents, type 1 diabetes is the most prevalent autoimmune disorder and is associated with gut microbiota dysbiosis. Evidence suggests a causal role of increased intestinal permeability in type 1 diabetes.
There are over 100 autoimmune diseases and emerging evidence is associating these
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diseases with modification of the gut microbiota, especially for ankylosing spondylitis, enthesitis-related arthritis, psoriatic arthritis, systemic lupus erythematosus and allergies. The gut microbiota also appears to play a pivotal role in multiple sclerosis (see Neurodegenerative and mental disorders).
The deregulation of the immune system, inflammation and gut microbiota dysbiosis are all well-described factors leading to increased intestinal permeability, and thus to the aggravation of the bacterial translocation in a pathological manner. Bacteria, bacterial compounds and metabolites translocate from the gut to the blood circulation and travel to other tissues where they can cause local inflammation. Lipopolysaccharide (LPS) is probably the best characterized bacterial metabolite with inflammation-inducing properties. The increase of bacterial compounds and metabolites in the blood circulation is also suspected to be involved in vasculitis.
Targeted microbiome analyses are thus crucial to understand the pathogenesis mechanisms of autoimmune and inflammation disorders and to discover new biomarkers to monitor or predict disease progression and flare-up. Microbiomes can also be a source of new therapeutic targets and alternative therapies including prebiotics, probiotics and FMT that are already under investigation.
Nutrition and microbiota
Diet is the main modulator of gut microbiota composition and metabolism. Diet is also a key factor in the management of numerous chronic illnesses such as metabolic disorders (e.g. obesity, T2D), cardiovascular diseases (e.g. hypertension, atherosclerosis), gastrointestinal disorders (e.g. inflammatory bowel diseases and inflammatory bowel syndrome), neurodegenerative diseases (e.g. epilepsy) and cancer. The goal is to develop effective personalized nutrition based on the individual microbiota profile of each patient.
Personalized sport nutrition is a growing research area aimed at improving athlete performances through dietary changes and active food complements. The gut microbiota is central in the metabolism of nutrients and the response to prebiotics and probiotics in the so-called gut-muscle axis. The interplay between microbiota and the gut-muscle axis is also involved in pathology like sarcopenia characterized by muscle loss. Osteoporosis has been associated with changes in gut microbiota composition. Sarcopenia and osteoporosis are diseases linked to aging.
Aging has been associated with gut microbiota dysbiosis. Elderlies in long-stay have a distinct microbial signature compared to their counterparts living in the community and this microbial signature is
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correlated with frailty. With old age, systemic low-grade inflammation is occurring: this phenomenon is known as inflammaging. Gut microbiota dysbiosis and inflammation are known to aggravate bacterial translocation from gut to blood, leading to increased systemic inflammation and relating to other health complications in elderlies.
In the agri-food sector, advances in animal nutrition can improve animal performance with more animal welfare-friendly practices. The synergy between microbiota and diet can help to lower the environmental impact of animal agriculture, especially by reducing greenhouse gas emissions.
The gut microbiota is highly responsive to dietary changes and is the key regulator of the effects of prebiotics and probiotics. Changes in gut microbiota are known to modulate inflammation and intestinal barrier permeability. Bacterial translocation is aggravated when these parameters are increased, permitting bacteria and bacterial compounds to migrate from the gut to the blood and other body parts. Other microbiomes than the gut microbiota may act as companion biomarkers to follow short- and long-term effects of food intervention. Microbiomes like the nasal microbiota, the oral microbiota or the microbiome of taste buds can play a central role in eating behavior and in the development of new organoleptic molecules by modulating the final taste perception.
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Microbiome and kidney diseases
Chronic Kidney Diseases (CKD) include heterogeneous disorders marked by kidney damage or prolonged decreased kidney functions. Shifts in intestinal microbiota have been associated with chronic kidney diseases. Many factors are suggested to explain these shifts such as uremic toxemia, metabolic acidosis, dietary restriction and drugs to name a few. Urea can be metabolized by bacterial urease, thus promoting the growth of certain members of the gut microbiota potentially at the expense of more beneficial intestinal bacteria. Diet is the main factor driving changes in gut microbiota composition and the dietary restrictions drastically reducing fiber intakes are likely to decrease the abundance of many essential members of the intestinal microbiome.
Gut microbiota dysbiosis is a well-known risk factor of intestinal barrier disruption. With increased intestinal permeability, bacterial translocation is also increased, triggering and maintaining systemic inflammation. Patients with chronic kidney diseases have persistent systemic inflammation linked to other complications such as acquired immune dysfunction, protein-energy wasting, and accelerated vascular aging. Therefore, the exploration of microbiomes beyond the gut microbiota such as blood and
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kidney, may provide insight into the pathogenesis mechanisms of chronic kidney diseases and may contribute to the discovery of new biomarkers for patient stratification and clinical course prediction.
Chronic Kidney Diseases (CKD) are classified into five stages from normal kidney function (stage 1) to end-stage kidney disease (stage 5). End-Stage Renal Disease (ESRD) requires heavy renal replacement therapy: hemodialysis, peritoneal dialysis, or kidney transplant. Microbiome analysis of blood, dialysis fluid or kidney can open the way to new biomarkers for treatment follow-up, for the prognosis of clinical outcome and transplantation rejection. Alternative treatments aiming to restore a healthy and well-balanced microbiome, such as prebiotics, probiotics and antibiotics, may improve chronic kidney disease management.
Microbiome in pregnancy and early life
Several immunological, hormonal and metabolic changes occur during pregnancy to support fetus growth and successful delivery. The gut microbiota is known to be drastically modulated by these changes and is also recognized as a key regulator of these bodily functions. Studies show that several modifications of the intestinal microbiota arise throughout the progression of the pregnancy and that gut microbiota can play a critical role in maternal and child health outcomes. In non-pregnancy, gut microbiota dysbioses are associated with numerous diseases such as cardiometabolic disorders including obesity, type 2 diabetes and hypertension. Unsurprisingly, the gut microbiota is also involved in the most common pregnancy complications, namely gestational diabetes mellitus and gestational hypertension. These pregnancy complications can lead to adverse pregnancy and perinatal outcomes. Gut microbiota dysbiosis is linked to increased bacterial translocation, causing the release of bacterial compounds and metabolites into the bloodstream, in turn inducing low-grade systemic inflammation. Studies have shown that increased inflammatory response is a main causal factor of the onset of insulin resistance.
The vaginal microbiome also changes throughout pregnancy corresponding with hormonal fluctuations and has shown to differ between pregnant and non-pregnant women. Recent evidence suggests that shifts in vaginal microbiota are associated with preterm birth, and thus can open the way
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to the discovery of new predictive biomarkers. Moreover, the increase of vaginal pathogens is linked to poor pregnancy outcomes such as preterm birth and spontaneous abortion. The oral microbiome is another source of potentially predictive biomarkers of pregnancy outcomes as recent studies show that periodontal disease is associated with preterm birth and preeclampsia.
Although microbial acquisition is suspected to start in utero, infants mainly acquire microbes during the delivery and the first years of life. Thus, delivery mode and feeding are the two main modulators for microbial colonization. Several studies showed that babies born through caesarian section have their gut microbiota resembling the maternal skin microbiome, whereas vaginally delivered newborns acquire microbial taxa found in the maternal vaginal microbiota. Breast milk contains human milk oligosaccharides (HMOs) that promote the growth of specific intestinal bacteria and support the maturation of a health-associated microbiota. Breast milk is also acting as an inoculum for the newborn as it can contain up to 10000 bacteria/mL although the origin of these bacteria remains elusive. Indeed, the microbiota composition of breast milk does not fully correspond to the composition of skin microbiota (in contact with the newborn mouth) and translocation of intestinal bacteria has been suggested. Delivery mode and feeding during infancy may influence the onset of chronic and complex diseases such as asthma, allergies, obesity, inflammatory bowel diseases, or type I diabetes mellitus.
The first years of life are critical for the colonization, ecological succession and the maturation of the gut microbiota. Therefore, exposure to known disruptors of the intestinal microbiota profile may have drastic effects on the future health of the infant. Currently, prolonged and/or repetitive use of antibiotics, pet exposure and environmental pollutants are amongst the most studied factors of gut microbiota variations.
Microbiome analyses, therefore, appear essential to understand health outcomes in mothers, children and adults. Exploring other microbiomes than the gut microbiota, for example oral, vaginal, meconium and blood, may open the way to the discovery of new biomarkers and new therapeutic strategies in poor pregnancy outcomes and related complications in infants such as preterm birth and low birth weight. Bacterial translocation is suggested to play a central role in increased inflammation in pregnancy complications and breast milk composition. Circulating and tissue microbiomes can thus unravel new mechanisms.
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