Microbial Tryptophan Metabolism Tunes Host Immunity, Metabolism, and Extraintestinal Disorders

The trillions of commensal microorganisms comprising the gut microbiota have received growing attention owing to their impact on host physiology. Recent advances in our understandings of the host–microbiota crosstalk support a pivotal role of microbiota-derived metabolites in various physiological processes, as they serve as messengers in the complex dialogue between commensals and host immune and endocrine cells. In this review, we highlight the importance of tryptophan-derived metabolites in host physiology, and summarize the recent findings on the role of tryptophan catabolites in preserving intestinal homeostasis and fine-tuning immune and metabolic responses. Furthermore, we discuss the latest evidence on the effects of microbial tryptophan catabolites, describe their mechanisms of action, and discuss how perturbations of microbial tryptophan metabolism may affect the course of intestinal and extraintestinal disorders, including inflammatory bowel diseases, metabolic disorders, chronic kidney diseases, and cardiovascular diseases

Microbial Tryptophan Metabolism Tunes Host Immunity, Metabolism, and Extraintestinal Disorders

The trillions of commensal microorganisms comprising the gut microbiota have received growing attention owing to their impact on host physiology. Recent advances in our understandings of the host–microbiota crosstalk support a pivotal role of microbiota-derived metabolites in various physiological processes, as they serve as messengers in the complex dialogue between commensals and host immune and endocrine cells. In this review, we highlight the importance of tryptophan-derived metabolites in host physiology, and summarize the recent findings on the role of tryptophan catabolites in preserving intestinal homeostasis and fine-tuning immune and metabolic responses. Furthermore, we discuss the latest evidence on the effects of microbial tryptophan catabolites, describe their mechanisms of action, and discuss how perturbations of microbial tryptophan metabolism may affect the course of intestinal and extraintestinal disorders, including inflammatory bowel diseases, metabolic disorders, chronic kidney diseases, and cardiovascular diseases

Fecal microbiota transplantation in human metabolic diseases: From a murky past to a bright future?

Fecal microbiota transplantation (FMT) is gaining considerable traction as a therapeutic approach to influence the course of a plethora of chronic conditions, ranging from metabolic syndrome and malignancies to auto-immune and neurological diseases, and helped to establish the contribution of the gut microbiome to these conditions. Although FMT procedures have yielded important mechanistic insights, their use in clinical practice may be limited due to practical objections in the setting of metabolic diseases. While its applicability is established to treat recurrent Clostridiodes difficile, FMT is emerging in ulcerative colitis and various other diseases. A particularly new insight is that FMTs may not only alter insulin sensitivity but may also alter the course of type 1 diabetes by attenuating underlying auto-immunity. In this review, we will outline the major principles and pitfalls of FMT and where optimization of study design and the procedure itself will further advance the field of cardiometabolic medicine.Peer reviewe

From fecal microbiota transplantation toward next-generation beneficial microbes: The case of Anaerobutyricum soehngenii

The commensal gut microbiota is important for human health and well-being whereas deviations of the gut microbiota have been associated with a multitude of diseases. Restoration of a balanced and diverse microbiota by fecal microbiota transplantation (FMT) has emerged as a potential treatment strategy and promising tool to study causality of the microbiota in disease pathogenesis. However, FMT comes with logistical challenges and potential safety risks, such as the transfer of pathogenic microorganisms, undesired phenotypes or an increased risk of developing disease later in life. Therefore, a more controlled, personalized mixture of cultured beneficial microbes might prove a better alternative. Most of these beneficial microbes will be endogenous commensals to the host without a long history of safe and beneficial use and are therefore commonly referred to as next-generation probiotics (NGP) or live biotherapeutic products (LBP). Following a previous FMT study within our group, the commensal butyrate producer Anaerobutyricum spp. (previously named Eubacterium hallii) was found to be associated with improved insulin-sensitivity in subjects with the metabolic syndrome. After the preclinical testing with Anaerobutyricum soehngenii in mice models was completed, the strain was produced under controlled conditions and several clinical studies evaluating its safety and efficacy in humans were performed. Here, we describe and reflect on the development of A. soehngenii for clinical use, providing practical guidance for the development and testing of NGPs and reflecting on the current regulatory framework

Acupuncture as multi-targeted therapy for the multifactorial disease obesity: a complex neuro-endocrine-immune interplay

The prevalence of obesity has reached pandemic dimensions. It is associated with multiple comorbidities and is becoming a clinical and public health threat. Obesity is a multifactorial disease with a complex pathophysiology and interplay of various systems. A strong interplay exists between the neuro-endocrine system, the immune system with systemic chronic low-grade inflammation, and microbiome dysbiosis that can lead to the development of obesity, which in turn can exacerbate each of these factors, hence creating a vicious cycle. The conventional treatment with lifestyle modifications such as diet, physical exercise, pharmacotherapy, and bariatric surgery does not always result in sufficient weight control thus paving the way for other strategies. As one such strategy, acupuncture is increasingly used worldwide to treat obesity. This narrative review outlines the evidence for this neuro-endocrine-immune interplay in the pathophysiology of obesity. Furthermore, the existing experimental and clinical evidence of acupuncture as a multi-targeted therapy for obesity is explained and future research perspectives are discussed

Gut microbiota, metabolism and psychopathology:A critical review and novel perspectives

Psychiatric disorders are often associated with metabolic comorbidities. However, the mechanisms through which metabolic and psychiatric disorders are connected remain unclear. Pre-clinical studies in rodents indicate that the bidirectional signaling between the intestine and the brain, the so-called microbiome-gut-brain axis, plays an important role in the regulation of both metabolism and behavior. The gut microbiome produces a vast number of metabolites that may be transported into the host and play a part in homeostatic control of metabolism as well as brain function. In addition to short chain fatty acids, many of these metabolites have been identified in recent years. To what extent both microbiota and their products control human metabolism and behavior is a subject of intense investigation. In this review, we will discuss the most recent findings concerning alterations in the gut microbiota as a possible pathophysiological factor for the co-occurrence of metabolic comorbidities in psychiatric disorders

From fecal microbiota transplantation toward next-generation beneficial microbes : The case of Anaerobutyricum soehngenii

The commensal gut microbiota is important for human health and well-being whereas deviations of the gut microbiota have been associated with a multitude of diseases. Restoration of a balanced and diverse microbiota by fecal microbiota transplantation (FMT) has emerged as a potential treatment strategy and promising tool to study causality of the microbiota in disease pathogenesis. However, FMT comes with logistical challenges and potential safety risks, such as the transfer of pathogenic microorganisms, undesired phenotypes or an increased risk of developing disease later in life. Therefore, a more controlled, personalized mixture of cultured beneficial microbes might prove a better alternative. Most of these beneficial microbes will be endogenous commensals to the host without a long history of safe and beneficial use and are therefore commonly referred to as next-generation probiotics (NGP) or live biotherapeutic products (LBP). Following a previous FMT study within our group, the commensal butyrate producer Anaerobutyricum spp. (previously named Eubacterium hallii) was found to be associated with improved insulin-sensitivity in subjects with the metabolic syndrome. After the preclinical testing with Anaerobutyricum soehngenii in mice models was completed, the strain was produced under controlled conditions and several clinical studies evaluating its safety and efficacy in humans were performed. Here, we describe and reflect on the development of A. soehngenii for clinical use, providing practical guidance for the development and testing of NGPs and reflecting on the current regulatory framework.Peer reviewe

Gut bacteriophage dynamics during fecal microbial transplantation in subjects with metabolic syndrome

Publisher Copyright: © 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.Metabolic Syndrome (MetS) is a growing public health concern worldwide. Individuals with MetS have an increased risk for cardiovascular (CV) disease and type 2 diabetes (T2D). These diseases–in part preventable with the treatment of MetS–increase the chances of premature death and pose a great economic burden to health systems. A healthy gut microbiota is associated with a reduction in MetS, T2D, and CV disease. Treatment of MetS with fecal microbiota transplantation (FMT) can be effective, however, its success rate is intermediate and difficult to predict. Because bacteriophages significantly affect the microbiota membership and function, the aim of this pilot study was to explore the dynamics of the gut bacteriophage community after FMT in MetS subjects. We performed a longitudinal study of stool bacteriophages from healthy donors and MetS subjects before and after FMT treatment. Subjects were assigned to either a control group (self-stool transplant, n = 3) or a treatment group (healthy-donor-stool transplant; n-recipients = 6, n-donors = 5). Stool samples were collected over an 18-week period and bacteriophage-like particles were purified and sequenced. We found that FMT from healthy donors significantly alters the gut bacteriophage community. Subjects with better clinical outcome clustered closer to the heathy donor group, suggesting that throughout the treatment, their bacteriophage community was more similar to healthy donors. Finally, we identified bacteriophage groups that could explain these differences and we examined their prevalence in individuals from a larger cohort of MetS FMT trial. Trial information- http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2705; NTR 2705.Peer reviewe

How strong is the evidence that gut microbiota composition can be influenced by lifestyle interventions in a cardio-protective way?

Alterations in composition and function of the gut microbiota have been demonstrated in diseases involving the cardiovascular system, particularly coronary heart disease and atherosclerosis. The data are still limited but the typical altered genera include Roseburia and Faecalibacterium. Plausible mechanisms by which microbiota may mediate cardio-protective effects have been postulated, including the production of metabolites like trimethylamine (TMA), as well as immunomodulatory functions. This raises the question of whether it is possible to modify the gut microbiota by lifestyle interventions and thereby improve cardiovascular health. Nevertheless, lifestyle intervention studies that have involved modifications of dietary intake and/or physical activity, as well as investigating changes in the gut microbiota and subsequent modifications of the cardioprotective markers, are still scarce, and the results have been inconclusive. Current evidence points to benefits of consuming high-fibre foods, nuts and an overall healthy dietary pattern to achieve beneficial effects on both gut microbiota and serum cardiovascular markers, primarily lipids. The relationship between physical exercise and gut microbiota is probably complex and may be dependent on the intensity of exercise. In this article, we review the available evidence on lifestyle, specifically diet, physical activity and smoking as modifiers of the gut microbiota, and subsequently as modifiers of serum cardiovascular health markers. We have attempted to elucidate the plausible mechanisms and further critically appraise the caveats and gaps in the research

Sickle cell patients are characterized by a reduced glycocalyx volume

The glycocalyx is an important anti-inflammatory and anti-adhesive barrier at the luminal side of endothelial cells. Glycocalyx volume was significantly reduced in sickle cell patients (HbSS/HbSβ0-thalassemia median 0.47L, IQR 0.27-0.66, HbSC/HbSβ+-thalassemia 0.23L, 0.0-0.58) compared with controls (1×109L, 0.52-1.77) (p=0.03). Reduced glycocalyx may be a new factor in the pathophysiology of sickle cell disease