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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.

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 .

Environmental factors driving the development of type 1 diabetes (T1D) are still largely unknown. Both animal and human studies have shown an association between altered fecal microbiota composition, impaired production of short-chain fatty acids (SCFA) and T1D onset. However, observational evidence on SCFA and fecal and oral microbiota in adults with longstanding T1D vs healthy controls (HC) is lacking. We included 53 T1D patients without complications or medication and 50 HC matched for age, sex and BMI. Oral and fecal microbiota, fecal and plasma SCFA levels, markers of intestinal inflammation (fecal IgA and calprotectin) and markers of low-grade systemic inflammation were measured. Oral microbiota were markedly different in T1D (eg abundance of Streptococci) compared to HC. Fecal analysis showed decreased butyrate producing species in T1D and less butyryl-CoA transferase genes. Also, plasma levels of acetate and propionate were lower in T1D, with similar fecal SCFA. Finally, fecal strains Christensenella and Subdoligranulum correlated with glycemic control, inflammatory parameters and SCFA. We conclude that T1D patients harbor a different amount of intestinal SCFA (butyrate) producers and different plasma acetate and propionate levels. Future research should disentangle cause and effect and whether supplementation of SCFA-producing bacteria or SCFA alone can have disease-modifying effects in T1D.

Aims/hypothesisThe general population is ageing, involving an enhanced incidence of chronic diseases such as type 2 diabetes. With ageing, DNA methylation of FHL2 increases, as well as expression of the four and a half LIM domains 2 (FHL2) protein in human pancreatic islets. We hypothesised that FHL2 is actively involved in glucose metabolism.MethodsPublicly available microarray datasets from human pancreatic islets were analysed for FHL2 expression. In FHL2-deficient mice, we studied glucose clearance and insulin secretion. Gene expression analysis and glucose-stimulated insulin secretion (GSIS) were determined in isolated murine FHL2-deficient islets to evaluate insulin-secretory capacity. Moreover, knockdown and overexpression of FHL2 were accomplished in MIN6 cells to delineate the underlying mechanism of FHL2 function.ResultsTranscriptomics of human pancreatic islets revealed that individuals with elevated levels of HbA1c displayed increased FHL2 expression, which correlated negatively with insulin secretion pathways. In line with this observation, FHL2-deficient mice cleared glucose more efficiently than wild-type littermates through increased plasma insulin levels. Insulin sensitivity was comparable between these genotypes. Interestingly, pancreatic islets isolated from FHL2-deficient mice secreted more insulin in GSIS assays than wild-type mouse islets even though insulin content and islet size was similar. To support this observation, we demonstrated increased expression of the transcription factor crucial in insulin secretion, MAF BZIP transcription factor A (MafA), higher expression of GLUT2 and reduced expression of the adverse factor c-Jun in FHL2-deficient islets. The underlying mechanism of FHL2 was further delineated in MIN6 cells. FHL2-knockdown led to enhanced activation of forkhead box protein O1 (FOXO1) and its downstream genes such as Mafa and Pdx1 (encoding pancreatic and duodenal homeobox 1), as well as increased glucose uptake. On the other hand, FHL2 overexpression in MIN6 cells blocked GSIS, increased the formation of reactive oxygen species and increased c-Jun activity.Conclusions/interpretationOur data demonstrate that FHL2 deficiency improves insulin secretion from beta cells and improves glucose tolerance in mice. Given that FHL2 expression in humans increases with age and that high expression levels of FHL2 are associated with beta cell dysfunction, we propose that enhanced FHL2 expression in elderly individuals contributes to glucose intolerance and the development of type 2 diabetes.Data availabilityThe human islet microarray datasets used are publicly available and can be found on https://www.ncbi.nlm.nih.gov/geo/.

Derivatives from yeast including yeast extracts and yeast cell walls are sustainable sources of valuable nutrients, including dietary fibers and proteins. Previous studies have shown that certain components from these yeast derivatives can inhibit the growth of harmful intestinal bacteria and promote the growth of beneficial bacteria. However, the effects of yeast derivatives on oral health have not yet been investigated. An oral biofilm model was employed to examine the impacts of yeast derivatives on the oral microbiota and their potential benefits for maintaining oral homeostasis. The model incorporated dental plaque donor material from both healthy and periodontitis diagnosed individuals. Biofilm formation, density, and microbial composition were quantified. Additionally, the production of short-chain fatty acids in the biofilm supernatants was measured. Yeast extracts had only minor effects on oral biofilm formation. In contrast, yeast cell wall derivatives, which are rich in polysaccharides such as beta-glucans and mannans, significantly reduced the density of the oral biofilms . This reduction in biofilm density was associated with an overall shift in the bacterial community composition, including an increase in beneficial bacteria and a decrease in the abundance of , an important species involved in bacterial coaggregation and the development and maturation of the oral biofilm. Furthermore, the yeast cell wall derivatives decreased the production of short-chain fatty acids, including acetic and butyric acid. These findings were consistent across both healthy and periodontitis microbiomes. This study has demonstrated the potential of yeast cell wall derivatives to positively impact oral health by significantly reducing biofilm density, modulating the oral microbial composition, and decreasing the production of short-chain fatty acids. The observed effects highlight the promising applications of these yeast-based compounds as an approach to managing oral diseases. Further research is needed to fully elucidate the mechanisms of action and explore the clinical potential of yeast cell wall derivatives in promoting and maintaining oral health.

Increasing evidence indicates that the development of type 2 diabetes is driven by chronic low grade beta-cell inflammation. However, it is unclear whether pancreatic inflammation can be noninvasively visualized in type 2 diabetes patients. We aimed to assess pancreatic 18F-FDG uptake in type 2 diabetes patients and controls using 18F-fluorodeoxylglucose positron emission tomography/computed tomography (18F-FDG PET/CT). In this retrospective cross-sectional study, we enrolled 20 type 2 diabetes patients and 65 controls who had undergone a diagnostic 18F-FDG PET/CT scan and obtained standardized uptake values (SUVs) of pancreas and muscle. Pancreatic SUV was adjusted for background uptake in muscle and for fasting blood glucose concentrations. The maximum pancreatic SUVs adjusted for background muscle uptake (SUVmax.m) and fasting blood glucose concentration (SUVglucose) were significantly higher in diabetes patients compared to controls (median 2.86 [IQR 2.24-4.36] compared to 2.15 [IQR 1.51-2.83], p = 0.006 and median 2.76 [IQR 1.18-4.34] compared to 1.91 [IQR 1.27-2.55], p<0.001, respectively). In linear regression adjusting for age and body mass index, diabetes remained the main predictor of SUVmax.m and SUVglucose. Pancreatic 18F-FDG uptake adjusted for background muscle uptake and fasting blood glucose concentration was significantly increased in type 2 diabetes patients.

Increasing evidence indicates that the development of type 2 diabetes is driven by chronic low grade beta-cell inflammation. However, it is unclear whether pancreatic inflammation can be noninvasively visualized in type 2 diabetes patients. We aimed to assess pancreatic .sup.18 F-FDG uptake in type 2 diabetes patients and controls using .sup.18 F-fluorodeoxylglucose positron emission tomography/computed tomography (.sup.18 F-FDG PET/CT). In this retrospective cross-sectional study, we enrolled 20 type 2 diabetes patients and 65 controls who had undergone a diagnostic .sup.18 F-FDG PET/CT scan and obtained standardized uptake values (SUVs) of pancreas and muscle. Pancreatic SUV was adjusted for background uptake in muscle and for fasting blood glucose concentrations. The maximum pancreatic SUVs adjusted for background muscle uptake (SUV.sub.max.m) and fasting blood glucose concentration (SUV.sub.glucose) were significantly higher in diabetes patients compared to controls (median 2.86 [IQR 2.24-4.36] compared to 2.15 [IQR 1.51-2.83], p = 0.006 and median 2.76 [IQR 1.18-4.34] compared to 1.91 [IQR 1.27-2.55], p<0.001, respectively). In linear regression adjusting for age and body mass index, diabetes remained the main predictor of SUV.sub.max.m and SUV.sub.glucose. Pancreatic .sup.18 F-FDG uptake adjusted for background muscle uptake and fasting blood glucose concentration was significantly increased in type 2 diabetes patients.

Aims Visceral adipose tissue inflammation is a fundamental mechanism of insulin resistance in obesity and type 2 diabetes. Translocation of intestinal bacteria has been suggested as a driving factor for the inflammation. However, although bacterial DNA was detected in visceral adipose tissue of humans with obesity, it is unclear to what extent this is contamination or whether the gut microbiota is causally involved. Effects of fecal microbiota transplantation (FMT) on bacterial translocation and visceral adipose tissue inflammation in individuals with obesity and insulin resistance were assessed. Material and Methods Eight individuals with clinically severe obesity (body mass index [BMI] >35 kg/m2) and metabolic syndrome received lean donor FMT 4 weeks prior to elective bariatric surgery. The participants were age‐, sex‐, and BMI‐matched to 16 controls that underwent no fecal transplantation. Visceral adipose tissue was collected during surgery. Bacterial translocation was assessed by 16S rRNA gene sequencing of adipose tissue and feces. Pro‐inflammatory cytokine expression and histopathological analyses of visceral adipose tissue were performed to assess inflammation. Results Fecal microbiota transplantation significantly altered gut microbiota composition. Visceral adipose tissue contained a very low quantity of bacterial DNA in both groups. No difference in visceral bacterial DNA content between groups was observed. Also, visceral expression of pro‐inflammatory cytokines and macrophage infiltration did not differ between groups. No correlation between inflammatory tone and bacterial translocation was observed. Conclusions Visceral bacterial DNA content and level of inflammation were not altered upon FMT. Thus, bacterial translocation may not be the main driver of visceral adipose tissue inflammation in obesity.

Intake of a high‐fat meal induces a systemic inflammatory response in the postprandial which is augmented in obese subjects. However, the underlying mechanisms of this response have not been fully elucidated. We aimed to assess the effect of gut microbiota modulation on postprandial inflammatory response in lean and obese subjects. Ten lean and ten obese subjects with metabolic syndrome received oral vancomycin 500 mg four times per day for 7 days. Oral high‐fat meal tests (50 g fat/m2 body surface area) were performed before and after vancomycin intervention. Gut microbiota composition, leukocyte counts, plasma lipopolysaccharides (LPS), LPS‐binding protein (LBP), IL‐6 and MCP‐1 concentrations and monocyte CCR2 and cytokine expression were determined before and after the high‐fat meal. Oral vancomycin treatment resulted in profound changes in gut microbiota composition and significantly decreased bacterial diversity in both groups (phylogenetic diversity pre‐ versus post‐intervention: lean, 56.9 ± 7.8 vs. 21.4 ± 6.6, P < 0.001; obese, 53.9 ± 7.8 vs. 21.0 ± 5.9, P < 0.001). After intervention, fasting plasma LPS significantly increased (lean, median [IQR] 0.81 [0.63–1.45] EU/mL vs. 2.23 [1.33–3.83] EU/mL, P = 0.017; obese, median [IQR] 0.76 [0.45–1.03] EU/mL vs. 1.44 [1.11–4.24], P = 0.014). However, postprandial increases in leukocytes and plasma LPS were unaffected by vancomycin in both groups. Moreover, we found no changes in plasma LBP, IL‐6 and MCP‐1 or in monocyte CCR2 expression. Despite major vancomycin‐induced disruption of the gut microbiota and increased fasting plasma LPS, the postprandial inflammatory phenotype in lean and obese subjects was unaffected in this study. Translocation of intestinal bacteria into the blood is implicated in the systemic inflammatory response that occurs after a high fat meal. We showed that after gut microbiota manipulation with vancomycin, the postprandial inflammatory phenotype in lean and obese subjects is unaffected, despite major vancomycin‐induced disruption of the gut microbiota and increased fasting plasma LPS. This suggests that bacterial translocation may not play a large role in postprandial inflammation.