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Humans with the metabolic syndrome and type 2 diabetes have an altered gut microbiome. Emerging evidence indicates that it is not only the microorganisms and their structural components, but also their metabolites that influences the host and contributes to the development of the metabolic syndrome and type 2 diabetes. Here, we discuss some of the mechanisms underlying how microbial metabolites are recognised by the host or are further processed endogenously in the context of type 2 diabetes. We discuss the possibility that gut-derived microbial metabolites fuel the development of the metabolic syndrome and type 2 diabetes.

Abstract The pathophysiology of obesity and obesity-related diseases such as type 2 diabetes mellitus (T2DM) is complex and driven by many factors. One of the most recently identified factors in development of these metabolic pathologies is the gut microbiota. The introduction of affordable, high-throughput sequencing technologies has substantially expanded our understanding of the role of the gut microbiome in modulation of host metabolism and (cardio)metabolic disease development. Nevertheless, evidence for a role of the gut microbiome as a causal, driving factor in disease development mainly originates from studies in mouse models: data showing causality in humans are scarce. In this review, we will discuss the quality of evidence supporting a causal role for the gut microbiome in the development of obesity and diabetes, in particular T2DM, in humans. Considering overlap in potential mechanisms, the role of the gut microbiome in type 1 diabetes mellitus will also be addressed. We will elaborate on factors that drive microbiome composition in humans and discuss how alterations in microbial composition or microbial metabolite production contribute to disease development. Challenging aspects in determining causality in humans will be postulated together with strategies that might hold potential to overcome these challenges. Furthermore, we will discuss means to modify gut microbiome composition in humans to help establish causality and discuss systems biology approaches that might hold the key to unravelling the role of the gut microbiome in obesity and T2DM. We have reviewed the evidence of the gut microbiome as a driving force in the development of obesity and type 2 diabetes mellitus. Considering overlap in potential mechanisms, the role of the gut microbiome in type 1 diabetes mellitus will also be addressed.

The increasing interest to perform and investigate the efficacy of fecal microbiota transplantation (FMT) has generated an urge for feasible donor screening. We report our experience with stool donor recruitment, screening, follow-up, and associated costs in the context of clinical FMT trials. Potential stool donors, aged between 18-65 years, underwent a stepwise screening process starting with an extensive questionnaire followed by feces and blood investigations. When eligible, donors were rescreened for MDROs and SARS-CoV-2 every 60-days, and full rescreening every 4-6 months. The costs to find and retain a stool donor were calculated. From January 2018 to August 2021, 393 potential donors underwent prescreening, of which 202 (51.4%) did not proceed primarily due to loss to follow-up, medication use, or logistic reasons (e.g. COVID-19 measures). 191 potential donors filled in the questionnaire, of which 43 (22.5%) were excluded. The remaining 148 candidates underwent parasitology screening: 91 (61.5%) were excluded, mostly due to Dientamoeba fragilis and/or high amounts of Blastocystis spp. After additional feces investigations 18/57 (31.6%) potential donors were excluded (mainly for presence of Helicobacter Pylori and ESBL-producing organisms). One donor failed serum testing. Overall, 38 out of 393 (10%) potential donors were enrolled. The median participation time of active stool donors was 13 months. To recruit 38 stool donors, [euro]64.112 was spent. Recruitment of stool donors for FMT is challenging. In our Dutch cohort, failed eligibility of potential donors was often caused by the presence of the protozoa Dientamoeba fragilis and Blastocystis spp.. The exclusion of potential donors that carry these protozoa, especially Blastocystis spp., is questionable and deserves reconsideration. High-quality donor screening is associated with substantial costs.

The gut microbiota has been linked to the development of obesity and type 2 diabetes (T2D). The underlying mechanisms as to how intestinal microbiota may contribute to T2D are only partly understood. It becomes progressively clear that T2D is characterized by a chronic state of low-grade inflammation, which has been linked to the development of insulin resistance. Here, we review the current evidence that intestinal microbiota, and the metabolites they produce, could drive the development of insulin resistance in obesity and T2D, possibly by initiating an inflammatory response. First, we will summarize major findings about immunological and gut microbial changes in these metabolic diseases. Next, we will give a detailed view on how gut microbial changes have been implicated in low-grade inflammation. Lastly, we will critically discuss clinical studies that focus on the interaction between gut microbiota and the immune system in metabolic disease. Overall, there is strong evidence that the tripartite interaction between gut microbiota, host immune system and metabolism is a critical partaker in the pathophysiology of obesity and T2D.

Fecal microbiota transplantation (FMT) is a therapeutic intervention for inflammatory diseases of the gastrointestinal tract, but its clinical mode of action and subsequent microbiome dynamics remain poorly understood. Here we analyzed metagenomes from 316 FMTs, sampled pre and post intervention, for the treatment of ten different disease indications. We quantified strain-level dynamics of 1,089 microbial species, complemented by 47,548 newly constructed metagenome-assembled genomes. Donor strain colonization and recipient strain resilience were mostly independent of clinical outcomes, but accurately predictable using LASSO-regularized regression models that accounted for host, microbiome and procedural variables. Recipient factors and donor–recipient complementarity, encompassing entire microbial communities to individual strains, were the main determinants of strain population dynamics, providing insights into the underlying processes that shape the post-FMT gut microbiome. Applying an ecology-based framework to our findings indicated parameters that may inform the development of more effective, targeted microbiome therapies in the future, and suggested how patient stratification can be used to enhance donor microbiota colonization or the displacement of recipient microbes in clinical practice. Understanding the factors underlying colonization of donor microbes in recipients of fecal microbiota transplantation is a necessary first step to aid development of directed approaches that aim to couple colonization to clinical outcomes.

Bacteriophages (phages) are bacterial viruses that have been shown to shape microbial communities. Previous studies have shown that faecal virome transplantation can decrease weight gain and normalize blood glucose tolerance in diet-induced obese mice. Therefore, we performed a double-blind, randomised, placebo-controlled pilot study in which 24 individuals with metabolic syndrome were randomised to a faecal filtrate transplantation (FFT) from a lean healthy donor ( n  = 12) or placebo ( n  = 12). The primary outcome, change in glucose metabolism, and secondary outcomes, safety and longitudinal changes within the intestinal bacteriome and phageome, were assessed from baseline up to 28 days. All 24 included subjects completed the study and are included in the analyses. While the overall changes in glucose metabolism are not significantly different between both groups, the FFT is well-tolerated and without any serious adverse events. The phage virion composition is significantly altered two days after FFT as compared to placebo, which coincides with more virulent phage-microbe interactions. In conclusion, we provide evidence that gut phages can be safely administered to transiently alter the gut microbiota of recipients. Bacteriophages (phages) can modify the gut microbiome to benefit human health. Here, the authors report the results of a double blind, randomized, placebo-controlled trial, showing that faecal filtrate transplantation (FFT), containing phages from lean healthy donors, is safe and improves glycemic variability in patients with metabolic syndrome, while shifting the gut phage composition.

There is significant interest in altering the course of cardiometabolic disease development via gut microbiomes. Nevertheless, the highly abundant phage members of the complex gut ecosystem -which impact gut bacteria- remain understudied. Here, we show gut virome changes associated with metabolic syndrome (MetS), a highly prevalent clinical condition preceding cardiometabolic disease, in 196 participants by combined sequencing of bulk whole genome and virus like particle communities. MetS gut viromes exhibit decreased richness and diversity. They are enriched in phages infecting Streptococcaceae and Bacteroidaceae and depleted in those infecting Bifidobacteriaceae . Differential abundance analysis identifies eighteen viral clusters (VCs) as significantly associated with either MetS or healthy viromes. Among these are a MetS-associated Roseburia VC that is related to healthy control-associated Faecalibacterium and Oscillibacter VCs. Further analysis of these VCs revealed the Candidatus Heliusviridae , a highly widespread gut phage lineage found in 90+% of participants. The identification of the temperate Ca. Heliusviridae provides a starting point to studies of phage effects on gut bacteria and the role that this plays in MetS. Here, the authors characterize gut viromes in a cohort of individuals with metabolic syndrome, which they find associated with a highly widespread family of gut bacteriophages they name Candidatus Heliusviridae .

Chronic inflammation plays a central role in the pathophysiology of various non-communicable diseases. Dietary interventions can reduce inflammation, in part due to their effect on the gut microbiome. This systematic review aims to determine the effect of dietary interventions, specifically fiber intake, on chronic inflammatory diseases and the microbiome. It aims to form hypotheses on the potential mediating effects of the microbiome on disease outcomes after dietary changes. Included were clinical trials which performed a dietary intervention with a whole diet change or fiber supplement (>5 g/day) and investigated the gut microbiome in patients diagnosed with chronic inflammatory diseases such as cardiovascular disease (CVD), type 2 diabetes (T2DM), and autoimmune diseases (e.g., rheumatoid arthritis (RA), inflammatory bowel disease (IBD)). The 30 articles which met the inclusion criteria had an overall moderate to high risk of bias and were too heterogeneous to perform a meta-analysis. Dietary interventions were stratified based on fiber intake: low fiber, high fiber, and supplemental fiber. Overall, but most pronounced in patients with T2DM, high-fiber plant-based dietary interventions were consistently more effective at reducing disease-specific outcomes and pathogenic bacteria, as well as increasing microbiome alpha diversity and short-chain fatty acid (SCFA)-producing bacteria, compared to other diets and fiber supplements.

Cancer cachexia is a multi-organ and multifactorial syndrome characterized by muscle wasting (with or without adipose tissue loss) and systemic inflammation in patients with advanced malignancies. Gut microbiota dysbiosis, particularly the depletion of short-chain fatty acid (SCFA)-producing bacteria, may contribute to the progression of cancer cachexia. Studies in both murine models and humans consistently associate cachexia with a decline in SCFA-producing gut microbiota commensals and an overgrowth of pro-inflammatory pathobionts. These microbial imbalances may lead to reduced levels of SCFAs and branched-chain amino acids (BCAAs) and alter the normal bile acid profile. BCAAs and the maintenance of a normal bile acid profile are associated with muscle synthesis and decreased breakdown. While SCFAs (acetate, propionate, and butyrate), contribute to intestinal barrier integrity and immune regulation. SCFA depletion may increase gut permeability, allowing bacterial endotoxins, such as lipopolysaccharide (LPS), to enter the bloodstream. This may lead to chronic inflammation, muscle catabolism, and impairment of anabolic pathways. Interventions targeting gut microbiota in preclinical models have mitigated inflammation and muscle loss. While clinical data are limited, it suggests an improvement in immune functions and better tolerance to anticancer therapies. Current evidence is predominantly derived from cross-sectional studies suggesting associations without causality. Thus, future longitudinal studies are needed to identify biomarkers and optimize personalized therapy.

Viruses are core components of the human microbiome, impacting health through interactions with gut bacteria and the immune system. Most human microbiome viruses are bacteriophages, which exclusively infect bacteria. Until recently, most gut virome studies focused on low taxonomic resolution (e.g., viral operational taxonomic units), hampering population-level analyses. We previously identified an expansive and widespread bacteriophage lineage in inhabitants of Amsterdam, the Netherlands. Here, we study their biodiversity and evolution in various human populations. Based on a phylogeny using sequences from six viral genome databases, we propose the Candidatus order Heliusvirales . We identify heliusviruses in 82% of 5441 individuals across 39 studies, and in nine metagenomes from humans that lived in Europe and North America between 1000 and 5000 years ago. We show that a large lineage started to diversify when Homo sapiens first appeared some 300,000 years ago. Ancient peoples and modern hunter-gatherers have distinct Ca. Heliusvirales populations with lower richness than modern urbanized people. Urbanized people suffering from type 1 and type 2 diabetes, as well as inflammatory bowel disease, have higher Ca. Heliusvirales richness than healthy controls. We thus conclude that these ancient core members of the human gut virome have thrived with increasingly westernized lifestyles. Here, based on phylogeny analyses using sequences from six viral genome databases, the authors study the biodiversity and evolution of a new bacteriophage lineage, Candidatus order Heliusvirales , and identify heliusviruses in 82% of 5,441 individuals across 39 studies, and in nine metagenomes from humans that lived in Europe and North America between 1,000 and 5,000 years ago, revealing associations with human diseases.