Microbiome-based Therapeutics Research Articles

Necrotizing enterocolitis is preceded by increased gut bacterial replication, Klebsiella, and fimbriae-encoding bacteria.

Necrotizing enterocolitis (NEC) is a devastating intestinal disease that occurs primarily in premature infants. We performed genome-resolved metagenomic analysis of 1163 fecal samples from premature infants to identify microbial features predictive of NEC. Features considered include genes, bacterial strain types, eukaryotes, bacteriophages, plasmids, and growth rates. A machine learning classifier found that samples collected before NEC diagnosis harbored significantly more Klebsiella, bacteria encoding fimbriae, and bacteria encoding secondary metabolite gene clusters related to quorum sensing and bacteriocin production. Notably, replication rates of all bacteria, especially Enterobacteriaceae, were significantly higher 2 days before NEC diagnosis. The findings uncover biomarkers that could lead to early detection of NEC and targets for microbiome-based therapeutics.

BioForte Technology for in Silico Identification of Candidates for a New Microbiome-based Therapeutics and Diagnostics

BioForte Technology for in Silico Identification of Candidates for a New Microbiome-based Therapeutics and Diagnostics

Moving Microbiome Science from the Bench to the Bedside: a Physician-Scientist Perspective.

The recognition over the past decade that nearly all diseases are associated with changes in the microbiome has raised hope that microbiome-based therapeutics may cure many human ailments. Billions of dollars are being poured into microbiome-oriented biotech companies, and the coming years will undoubtedly witness the approval of the first generation of these products. However, significant hurdles remain in expanding the pipeline and advancing these first-generation therapies. In this perspective, I will discuss the challenges related to identifying causal microbes, determining their mechanism of action, and characterizing the specific bacterial molecules required for disease protection. We are approaching these issues through a combination of clinical sampling, animal models, classic microbiology methodologies, and systems-based approaches. The field of microbiome research is on the cusp of being able to identify clinically actionable host-microbe relationships; increasing attention on identifying causal microbes and their bioactive factors will usher in the next generation of microbiome-based therapies.

Cervicovaginal microbiota and local immune response modulate the risk of spontaneous preterm delivery

Failure to predict and understand the causes of preterm birth, the leading cause of neonatal morbidity and mortality, have limited effective interventions and therapeutics. From a cohort of 2000 pregnant women, we performed a nested case control study on 107 well-phenotyped cases of spontaneous preterm birth (sPTB) and 432 women delivering at term. Using innovative Bayesian modeling of cervicovaginal microbiota, seven bacterial taxa were significantly associated with increased risk of sPTB, with a stronger effect in African American women. However, higher vaginal levels of β-defensin-2 lowered the risk of sPTB associated with cervicovaginal microbiota in an ethnicity-dependent manner. Surprisingly, even in Lactobacillus spp. dominated cervicovaginal microbiota, low β-defensin-2 was associated with increased risk of sPTB. These findings hold promise for diagnostics to accurately identify women at risk for sPTB early in pregnancy. Therapeutic strategies could include immune modulators and microbiome-based therapeutics to reduce this significant health burden.

Fusobacterium and Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer worldwide and its pathogenesis has been extensively explored over the past decades. Recently, microorganisms in the gastrointestinal tract have emerged as potential etiological agents. In particular, a direct proportional association between Fusobacterium and CRC has been described. Since then, the functional impact of Fusobacterium in CRC development has been studied using various mouse models. Although some epidemiologic studies did not establish an obvious relationship between Fusobacterium and CRC, numerous pathogenic mechanisms leading to the disease have been described. For instance, Fusobacterium can activate the E-cadherin/β-catenin signaling pathway and is associated with particular epigenetic phenotype, such as microsatellite instability (MSI) and hypermethylation, via its strong adhesive and invasive abilities resulting in malignant transformation of epithelial cells. Also, Fusobacterium could alter the tumor microenvironment (TME) significantly by myeloid-derived suppressor cells (MDSCs), tumor associated macrophages (TAMs), and tumor associated neutrophils (TANs) recruitment and local immune suppression. Herein, we provide an in-depth review of the relationship between Fusobacterium and colorectal cancer. In light of the emergence of microbiome-based therapeutics, potential therapies and preventive strategies for colorectal cancer related to Fusobacterium are also discussed.

Management of refractory cirrhotic ascites: challenges and solutions

Among the various risky complications of liver cirrhosis, refractory ascites is associated with poor survival of cirrhotics and persistently worsens their quality of life (QOL). Major clinical guidelines worldwide define refractory ascites as ascites that cannot be managed by medical therapy either because of a lack of response to maximum doses of diuretics or because patients develop complications related to diuretic therapy that preclude the use of an effective dose of diuretics. Due to the difficulty in receiving a liver transplantation (LT), the ultimate solution for refractory ascites, most cirrhotic patients have selected the palliative therapy such as repeated serial paracentesis, transjugular intrahepatic portosystemic shunt, or peritoneovenous shunt to improve their QOL. During the past several decades, new interventions and methodologies, such as indwelling peritoneal catheter, peritoneal-urinary drainage, and cell-free and concentrated ascites reinfusion therapy, have been introduced. In addition, new medical treatments with vasoconstrictors or vasopressin V2 receptor antagonists have been proposed. Both the benefits and risks of these old and new modalities have been extensively studied in relation to the pathophysiological changes in ascites formation. Although the best solution for refractory ascites is to eliminate hepatic failure either by LT or by causal treatment, the selection of the best palliative therapy for individual patients is of utmost importance, aiming at achieving the longest possible, comfortable life. This review briefly summarizes the changing landscape of variable treatment modalities for cirrhotic patients with refractory ascites, aiming at clarifying their possibilities and limitations. Evolving issues with regard to the impact of gut-derived systemic and local infection on the clinical course of cirrhotic patients have paved the way for the development of a new gut microbiome-based therapeutics. Thus, it should be further investigated whether the early therapeutic approach to gut dysbiosis provides a better solution for the management of cirrhotic ascites.

Gut Microbiome-based Therapeutics in Liver Cirrhosis: Basic Consideration for the Next Step

Infections account for significant morbidity and mortality in liver cirrhosis and most are related to the gut microbiome. Fecal dysbiosis, characterized by an overgrowth of potentially pathogenic bacteria and a decrease in autochthonous non-pathogenic bacteria, becomes prominent with the progression of liver cirrhosis. In cirrhotic patients, disruption of the intestinal barrier causes intestinal hyperpermeability (i.e. leaky gut), which is closely related to gut dysmotility, dysbiosis and small intestinal bacterial overgrowth and may induce pathological bacterial translocation. Although the involved microbial taxa are somewhat different between the cirrhotic patients from the East and the West, the common manifestation of a shortage of bacteria that contribute to the production of short-chain fatty acids and secondary bile acids may facilitate intestinal inflammation, leaky gut and gut dysbiosis. Translocated endotoxin and bacterial DNA are capable of provoking potent inflammation and affecting the metabolic and hemodynamic systems, which may ultimately enhance the progression of liver cirrhosis and its various complications, such as hepatic encephalopathy (HE), variceal bleeding, infection and renal disturbances. Among studies on the microbiome-based therapeutics, findings of probiotic effects on HE have been contradictory in spite of several supportive results. However, the effects of synbiotics and prebiotics are substantially documented. The background of their effectiveness should be evaluated again in relation to the cirrhosis-related changes in gut microbiome and their metabolic effects. Strict indications for the antibiotic rifaximin remain unestablished, although its effect is promising, improving HE and other complications with little influence on microbial populations. The final goal of microbiome-based therapeutics is to adjust the gut-liver axis to the maximal benefit of cirrhotic patients, with the aid of evolving metagenomic and metabolomic analyses.

Short Course in the Microbiome.

Over the past decade, it has become evident that the microbiome is an important environmental factor that affects many physiological processes, such as cell proliferation and differentiation, behaviour, immune function and metabolism. More importantly, it may contribute to a wide variety of diseases, including cancer, inflammatory diseases, metabolic diseases and responses to pathogens. We expect that international, integrative and interdisciplinary translational research teams, along with the emergence of FDA-approved platforms, will set the framework for microbiome-based therapeutics and diagnostics. We recognize that the microbiome ecosystem offers new promise for personalized/precision medicine and targeted treatment for a variety of diseases.The short course was held as a four-session webinar series in April 2015, taught by pioneers and experts in the microbiome ecosystem, covering a broad range of topics from the healthy microbiome to the effects of an altered microbiome from neonates to adults and the long term effects as it is related to disease, from asthma to cancer. We have learned to appreciate how beneficial our microbes are in breaking down our food, fighting off infections and nurturing our immune system, and this information provides us with ideas as to how we can manipulate our microbiome to prevent certain diseases. However, given the variety of applications, there are scientific challenges, though there are very promising areas in reference to the clinical benefits of understanding more about our microbiome, whether in our gut or on our skin: the outlook is bright. A summary of the short course is presented as a meeting dispatch.

Immune homeostasis, dysbiosis and therapeutic modulation of the gut microbiota.

The distal gut harbours ∼10(13) bacteria, representing the most densely populated ecosystem known. The functional diversity expressed by these communities is enormous and relatively unexplored. The past decade of research has unveiled the profound influence that the resident microbial populations bestow to host immunity and metabolism. The evolution of these communities from birth generates a highly adapted and highly personalized microbiota that is stable in healthy individuals. Immune homeostasis is achieved and maintained due in part to the extensive interplay between the gut microbiota and host mucosal immune system. Imbalances of gut microbiota may lead to a number of pathologies such as obesity, type I and type II diabetes, inflammatory bowel disease (IBD), colorectal cancer (CRC) and inflammaging/immunosenscence in the elderly. In-depth understanding of the underlying mechanisms that control homeostasis and dysbiosis of the gut microbiota represents an important step in our ability to reliably modulate the gut microbiota with positive clinical outcomes. The potential of microbiome-based therapeutics to treat epidemic human disease is of great interest. New therapeutic paradigms, including second-generation personalized probiotics, prebiotics, narrow spectrum antibiotic treatment and faecal microbiome transplantation, may provide safer and natural alternatives to traditional clinical interventions for chronic diseases. This review discusses host-microbiota homeostasis, consequences of its perturbation and the associated challenges in therapeutic developments that lie ahead.