Molecular mechanisms of trehalose in modulating glucose homeostasis in diabetes

Diabetes mellitus is the most prevalent metabolic disorder contributing to significant morbidity and mortality in humans. Many preventative and therapeutic agents have been developed for normalizing glycemic profile in patients with diabetes. In addition to various pharmacologic strategies, many non-pharmacological agents have also been suggested to improve glycemic control in patients with diabetes. Trehalose is a naturally occurring disaccharide which is not synthesized in human but is widely used in food industries. Some studies have provided evidence indicating that it can potentially modulate glucose metabolism and help to stabilize glucose homeostasis in patients with diabetes. Studies have shown that trehalose can significantly modulate insulin sensitivity via at least 7 molecular pathways leading to better control of hyperglycemia. In the current study, we concluded about possible anti-hyperglycemic effects of trehalose suggesting trehalose as a potentially potent non-pharmacological agent for the management of diabetes.     

Increasing intracellular trehalose is sufficient to confer desiccation tolerance to Saccharomyces cerevisiae

Diverse organisms capable of surviving desiccation, termed anhydrobiotes, include species from bacteria, yeast, plants, and invertebrates. However, most organisms are sensitive to desiccation, likely due to an assortment of different stresses such as protein misfolding and aggregation, hyperosmotic stress, membrane fracturing, and changes in cell volume and shape leading to an overcrowded cytoplasm and metabolic arrest. The exact stress(es) that cause lethality in desiccation-sensitive organisms and how the lethal stresses are mitigated in desiccation-tolerant organisms remain poorly understood. The presence of trehalose in anhydrobiotes has been strongly correlated with desiccation tolerance. In the yeast Saccharomyces cerevisiae, trehalose is essential for survival after long-term desiccation. Here, we establish that the elevation of intracellular trehalose in dividing yeast by its import from the media converts yeast from extreme desiccation sensitivity to a high level of desiccation tolerance. This trehalose-induced tolerance is independent of utilization of trehalose as an energy source, de novo synthesis of other stress effectors, or the metabolic effects of trehalose biosynthetic intermediates, indicating that a chemical property of trehalose is directly responsible for desiccation tolerance. Finally, we demonstrate that elevated intracellular maltose can also make dividing yeast tolerant to short-term desiccation, indicating that other disaccharides have stress effector activity. However, trehalose is much more effective than maltose at conferring tolerance to long-term desiccation. The effectiveness and sufficiency of trehalose as an antagonizer of desiccation-induced damage in yeast emphasizes its potential to confer desiccation tolerance to otherwise sensitive organisms.Water is an essential molecule whose absence can lead to a variety of detrimental and often lethal effects on cells and organisms (1–3). Severe water removal, termed desiccation, has been proposed to lead a variety of detrimental stresses (3). Which of these stresses leads to lethality in desiccation-sensitive organisms is unclear. Organisms capable of surviving desiccation, commonly termed anhydrobiotes, are found among bacteria, fungi, plants, and invertebrates (1, 3). Anhydrobiotes harbor stress effectors that are known or postulated to mitigate the different stresses associated with desiccation (2, 4). These stress effectors include osmolytes, heat shock proteins, redox balancing enzymes, nonreducing disaccharides (trehalose, sucrose), and hydrophilins (short unstructured hydrophilic proteins—also known as LEAs) (1). A reasonable assumption might be that many if not all of these stress effectors are necessary for desiccation tolerance given the multitude of stresses imposed by desiccation. However, this assumption is challenged by the uncertainty in the number and degree of lethal stresses generated by desiccation and the versatility and coordination/cooperation of multiple stress effectors in ameliorating such lethal stresses. Thus, a critical question in the anhydrobiosis field is whether a single stress effector is sufficient to promote desiccation tolerance.One of the most studied desiccation-associated stress effectors is the simple nonreducing disaccharide, trehalose (α,α-1,1-glucoside) (5). It is found in extremely high concentrations in most anhydrobiotes, including in the model organism Saccharomyces cerevisiae (6, 7). In this yeast, exponentially dividing cells have very low levels of trehalose and are extremely desiccation sensitive (8). However, in saturated cultures, yeast cells accumulate high levels of a number of stress effectors, including extremely high levels of trehalose (up to 15% of dry cell mass) (6, 7). We recently showed that high levels of trehalose are necessary for yeast cells in saturated cultures to survive weeks to months of desiccation (long term), but not a few days (short term) (9). Trehalose dispensability during short-term desiccation is due in part to overlapping functions with the heat shock factor Hsp104. This overlap led us to discover that trehalose functions as a chemical chaperone capable of preventing the aggregation of both membrane and cytoplasmic proteins (9). Work in the nematode Caenorhabditis elegans demonstrated that worms unable to synthesize trehalose display hallmarks of membrane damage, consistent with trehalose playing a role in preserving membrane structure (10). Indeed, trehalose has been found to be lipidated in nematodes and these “maradolipids” are required for efficient desiccation tolerance (11). Due to the different and versatile mechanisms by which trehalose confers desiccation tolerance in anhydrobiotes, we hypothesize that trehalose, in the absence of other stress effectors, will be sufficient in conferring desiccation tolerance.A simple way to address this hypothesis is to increase the intracellular levels of trehalose in desiccation/dehydration-sensitive cells or organisms then assess whether they acquire desiccation tolerance. Two strategies for increasing intracellular trehalose have been previously used. These were engineering high level expression of trehalose biosynthetic enzymes or importing extracellular trehalose via fusion with lipid vesicles (12–16). Both methods only generated small increases in trehalose levels and minor increases in dehydration but not desiccation tolerance. This weak effect could reflect the need for additional stress effectors. Alternatively, trehalose alone could indeed be sufficient for desiccation tolerance but was missed for two reasons. First, high physiological levels of trehalose observed in desiccation-tolerant organisms were not reached so a potential critical threshold level of trehalose was not met. Second, the biosynthetic strategy not only increased trehalose but also trehalose-6-phosphate, a potent regulator of glucose metabolism that has deleterious effects on cell and organism fitness. Thus, it remains untested whether trehalose alone is sufficient for generating desiccation tolerance.The correlative evidence for trehalose being sufficient for desiccation tolerance was provided from our previous study comparing desiccation sensitivity of saturated and exponentially dividing cultures of yeast (8). Cells in a saturated culture rapidly lose desiccation tolerance when they divide upon dilution into fresh media. Shortly, after dilution, the levels of many stress factors, including trehalose, diminish. Trehalose levels drop as a consequence of activation of two intracellular trehalases, NTH1 and NTH2, and the inhibition of the trehalose biosynthetic enzyme Tps1 (6, 7). The diluted cells retained their desiccation tolerance significantly longer when trehalose depletion was slowed by inactivation of the trehalases (9). This result is consistent with the notion that sustaining high trehalose levels, while reducing the levels of other stress effectors, is sufficient to promote desiccation tolerance. Encouraged by this result, we decided to investigate further the potential sufficiency of trehalose for desiccation tolerance, exploiting the ability of the AGT1 sugar transporter to import extracellular trehalose (17). Here, we show that when AGT1 overexpressing cells are grown in the presence of trehalose, they acquire high levels of intracellular trehalose and desiccation tolerance similar to that of saturated cultures. We characterize this novel acquisition of desiccation tolerance and provide important insights into the roles of trehalose concentration and trehalose structure in both short- and long-term desiccation tolerance.     

Trehalose transporter 1, a facilitated and high-capacity trehalose transporter, allows exogenous trehalose uptake into cells

Trehalose is potentially a useful cryo- or anhydroprotectant molecule for cells and biomolecules such as proteins and nucleotides. A major obstacle to application is that cellular membranes are impermeable to trehalose. In this study, we isolated and characterized the functions of a facilitated trehalose transporter [trehalose transporter 1 (TRET1)] from an anhydrobiotic insect, Polypedilum vanderplanki. Tret1 cDNA encodes a 504-aa protein with 12 predicted transmembrane structures. Tret1 expression was induced by either desiccation or salinity stress. Expression was predominant in the fat body and occurred concomitantly with the accumulation of trehalose, indicating that TRET1 is involved in transporting trehalose synthesized in the fat body into the hemolymph. Functional expression of TRET1 in Xenopus oocytes showed that transport activity was stereochemically specific for trehalose and independent of extracellular pH (between 4.0 and 9.0) and electrochemical membrane potential. These results indicate that TRET1 is a trehalose-specific facilitated transporter and that the direction of transport is reversible depending on the concentration gradient of trehalose. The extraordinarily high values for apparent Km (>or=100 mM) and Vmax (>or=500 pmol/min per oocyte) for trehalose both indicate that TRET1 is a high-capacity transporter of trehalose. Furthermore, TRET1 was found to function in mammalian cells, suggesting that it confers trehalose permeability on cells, including those of vertebrates as well as insects. These characteristic features imply that TRET1 in combination with trehalose has high potential for basic and practical applications in vivo.     

Impact of trehalose transporter knockdown on Anopheles gambiae stress adaptation and susceptibility to Plasmodium falciparum infection

Anopheles gambiae is a major vector mosquito for Plasmodium falciparum, the deadly pathogen causing most human malaria in sub-Saharan Africa. Synthesized in the fat body, trehalose is the predominant sugar in mosquito hemolymph. It not only provides energy but also protects the mosquito against desiccation and heat stresses. Trehalose enters the mosquito hemolymph by the trehalose transporter AgTreT1. In adult female A. gambiae, AgTreT1 is predominantly expressed in the fat body. We found that AgTreT1 expression is induced by environmental stresses such as low humidity or elevated temperature. AgTreT1 RNA silencing reduces the hemolymph trehalose concentration by 40%, and the mosquitoes succumb sooner after exposure to desiccation or heat. After an infectious blood meal, AgTreT1 RNA silencing reduces the number of P. falciparum oocysts in the mosquito midgut by over 70% compared with mock-injected mosquitoes. These data reveal important roles for AgTreT1 in stress adaptation and malaria pathogen development in a major vector mosquito. Thus, AgTreT1 may be a potential target for malaria vector control.Critical to the malaria transmission cycle, the mosquito Anopheles gambiae is a major vector for Plasmodium falciparum, the pathogen responsible for most malignant malaria in sub-Saharan Africa. In malaria endemic regions, vector mosquitoes survive harsh fluctuations of temperature and humidity (1). Mosquitoes adapt to environmental changes by adjusting expression levels of certain genes (2); however, most protective mechanisms apparently remain unknown. Recently, we characterized an aquaporin water channel from A. gambiae (AgAQP1) that is important for water homeostasis, because reduced expression protected against dehydration (3). Since water loss has profound effects on mosquito physiology, we investigated other candidate genes that may protect against environmental stress and may affect transmission of P. falciparum.Trehalose is a nonreducing disaccharide of two glucose molecules linked by an α-α-1,1-glycosidic bond. It is abundant in insects, crustaceans, nematodes, bacteria, fungi, and plants, but not vertebrates. As the major sugar in mosquito hemolymph, trehalose is concentrated more than 10 times higher than glucose or other sugars (4). Trehalose is a versatile molecule, serving as the principal energy storage but also as a stabilizer for dry membranes and proteins due to unique chemical and physical properties—high hydration volume, lack of internal hydrogen bonds, and nonreduction (5–8).Trehalose levels rise sharply during several stresses—desiccation (9–12), heat (13), freezing (14, 15), hyperosmolality (16), and oxidation (17). In yeast and plants, trehalose is also a signaling molecule in metabolic pathways affecting growth (18). Evidence is emerging that trehalose protects cultured cells. Increased trehalose in HEK-293 cells expressing Drosophila trehalose-phosphate synthase 1 protects the cells from hypoxic injury (17). Bovine endothelial cell line cultivated with trehalose followed by cryopreservation with trehalose in an optimized solution yielded over 80% viable cells (19). Trehalose levels in anhydrobiotic stage larvae of Polypedilum vanderplanki (sleeping chironomid) accumulate rapidly to ∼20% of the dry body mass, more than five times higher than that of larvae in fresh water (9, 20). Furthermore, a recent study has shown that injection of d-(+)-trehalose into the hemocoel of head-intact, starved cockroaches lowers the content of short neuropeptide F in hemolymph, suggesting novel roles of trehalose in regulating brain and midgut interplay in insect digestion and nutrition-associated behavior (21).Synthesized exclusively in the fat body of mosquitoes, trehalose is transported to the circulating hemolymph for delivery to other tissues. This process involves the specific movement of trehalose across cell membranes facilitated by the trehalose transporter, TreT (9, 22). The AgTreT1 cDNA from A. gambiae is an ortholog of PvTreT1 from P. vanderplanki. Only one TreT gene is present in the A. gambiae genome, and its trehalose-transport function was characterized by heterologous expression in Xenopus oocytes (22). PvTreT1 was proposed to contribute to the dehydration resistance of P. vanderplanki larvae in vivo (9). Nevertheless, no direct evidence has supported this role of AgTreT1 in the whole vector mosquito A. gambiae.Trehalose is a likely energy source for Plasmodium pathogens in A. gambiae mosquitoes. After ingesting an infected blood meal, Plasmodium gametocytes differentiate into male or female gametes and fuse to form ookinetes in the mosquito midgut. Mobile ookinetes then penetrate the gut lining to produce oocysts on the basal-lamina side. During the oocyst stage, malaria parasites amplify by several thousand fold, scavenging energy from the vector. Plasmodium infection has been reported to deplete sugars in vector hemolymph, suggesting that trehalose is used by parasites for rapid growth (23). Genes related to trehalose transport and metabolism may be related to the life cycle of Plasmodium spp. in mosquito vectors.In this study, we observed that AgTreT1 expression is induced by desiccation and heat. Reducing AgTreT1 expression in female A. gambiae by RNAi decreases hemolymph trehalose levels. Mosquitoes with reduced AgTreT1 levels die sooner than controls in dry or hot environments. Moreover, when AgTreT1 was silenced in A. gambiae infected with P. falciparum, significantly fewer parasite oocysts appear in the midguts than in midguts of control mosquitoes. These data suggest an important role of AgTreT1 in maintaining vector hemolymph sugar levels during desiccation and heat and reveal a unique function in P. falciparum propagation during the oocyst stage.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Plant genetic effects on microbial hubs impact host fitness in repeated field trials

Although complex interactions between hosts and microbial associates are increasingly well documented, we still know little about how and why hosts shape microbial communities in nature. In addition, host genetic effects on microbial communities vary widely depending on the environment, obscuring conclusions about which microbes are impacted and which plant functions are important. We characterized the leaf microbiota of 200 Arabidopsis thaliana genotypes in eight field experiments and detected consistent host effects on specific, broadly distributed microbial species (operational taxonomic unit [OTUs]). Host genetic effects disproportionately influenced central ecological hubs, with heritability of particular OTUs declining with their distance from the nearest hub within the microbial network. These host effects could reflect either OTUs preferentially associating with specific genotypes or differential microbial success within them. Host genetics associated with microbial hubs explained over 10% of the variation in lifetime seed production among host genotypes across sites and years. We successfully cultured one of these microbial hubs and demonstrated its growth-promoting effects on plants in sterile conditions. Finally, genome-wide association mapping identified many putatively causal genes with small effects on the relative abundance of microbial hubs across sites and years, and these genes were enriched for those involved in the synthesis of specialized metabolites, auxins, and the immune system. Using untargeted metabolomics, we corroborate the consistent association between variation in specialized metabolites and microbial hubs across field sites. Together, our results reveal that host genetic variation impacts the microbial communities in consistent ways across environments and that these effects contribute to fitness variation among host genotypes.

Hosts harbor complex microbial communities that are thought to impact health and development (1). Human microbiota has been implicated in a variety of diseases, including obesity and cancer (2). Efforts are thus underway to determine the host factors shaping these communities (3, 4), and to use next-generation probiotics to inhibit colonization by pathogens (5). Similarly, in agriculture, there is great hope that selection on plant traits shaping the composition of the microbiota will help mitigate disease and increase crop yield in a sustainable fashion. Indeed, the Food and Agriculture Organization of the United Nations has made the use of biological control and growth-promoting microbial associations a clear priority for improving food production (6).Plant-associated microbes can be beneficial in many ways, including improving access to nutrients, activating or priming the immune system, and competing with pathogens. For example, seeds inoculated with a combination of naturally occurring microbes were found to be protected from a sudden-wilt disease that emerged after continuous cropping (7). Thus, it would be advantageous to breed crops that promote the growth of beneficial microbes under a variety of field conditions, a prospect that is made more likely by the demonstration of host genotypic effects on their microbiota (8–11). However, microbial communities are complex entities that are influenced by the combined impact of host factors, the abiotic environment, and microbe–microbe interactions (12). Indeed, several studies have found a strong influence of the environment on estimates of host genotype effects (8, 13, 14). Although most, if not all, studies exploring the influence that host genotype exerts on microbial communities suggest that such plant control could be beneficial to plant performance, almost nothing is known about the relationship between host genotype effects on microbial communities and on plant performance or fitness. Consequently, the extent to which host plants can control microbial communities to their advantage, especially in a consistent manner across multiple environments, remains unclear.Here, we combine large-scale field experiments in natural environments, extensive microbial community analysis, and genome-wide association mapping to 1) determine how host genotype affects different microbial community members, and thus shapes the overall microbiome; 2) estimate host genotype effects on microbial communities across eight environments and investigate the contribution of those effects to the performance of plant genotypes; and 3) use genome-wide association mapping to identify key pathways that shape the leaf microbial communities across multiple environmental conditions.     

A mixed blessing for liver transplantation patients — Rapamycin

BackgroundLiver transplantation (LT) is an effective treatment option for end-stage liver disease. Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, are widely used post LT.Data sourcesIn this review, we focused on the anti-cancer activities and metabolic side effects of rapamycin after LT. The literature available on PubMed for the period of January 1999-September 2022 was reviewed. The key words were rapamycin, sirolimus, liver transplantation, hepatocellular carcinoma, diabetes, and lipid metabolism disorder.ResultsRapamycin has shown excellent effects and is safer than other immunosuppressive regimens. It has exhibited excellent anti-cancer activity and has the potential in preventing hepatocellular carcinoma (HCC) recurrence post LT. Rapamycin is closely related to two long-term complications after LT, diabetes and lipid metabolism disorders.ConclusionsRapamycin prevents HCC recurrence post LT in some patients, but it also induces metabolic disorders. Reasonable use of rapamycin benefits the liver recipients.     

The potential of gut microbiota and fecal volatile organic compounds analysis as early diagnostic biomarker for necrotizing enterocolitis and sepsis in preterm infants

Introduction: Although the exact pathophysiological mechanisms of both necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) in preterm infants are yet to be elucidated, evidence is emerging that the gut microbiota plays a key role in their pathophysiology.

Areas covered: In this review, initial microbial colonization and factors influencing microbiota composition are discussed. For both NEC and LOS, an overview of studies investigating preclinical alterations in gut microbiota composition and fecal volatile organic compounds (VOCs) is provided. Fecal VOCs are considered to reflect not only gut microbiota composition, but also their metabolic activity and concurrent interaction with the host.

Expert review: Heterogeneity in study protocols and applied analytical techniques hampers reliable comparison between outcomes of different microbiota studies, limiting the ability to draw firm conclusions. This dilemma is illustrated by the finding that study results often cannot be reproduced, or even contradict each other. A NEC- and sepsis specific microbial or metabolic signature has not yet been discovered. Identification of ‘disease-specific’ VOCs and microbiota composition may increase understanding on pathophysiological mechanisms and may allow for development of an accurate screening tool, opening avenues towards timely identification and initiation of targeted treatment for preterm infants at increased risk for NEC and sepsis.     

Trehalose activates autophagy and decreases proteasome inhibitor‐induced endoplasmic reticulum stress and oxidative stress‐mediated cytotoxicity in hepatocytes

Aim

Endoplasmic reticulum stress is associated with the pathophysiology of various liver diseases. Endoplasmic reticulum stress mediates the accumulation of abnormal proteins and leads to oxidative stress, cytoplasmic inclusion body formation, and apoptosis in hepatocytes. Autophagy is a bulk degradation pathway for long‐lived cytoplasmic proteins or damaged organelles and is also a major degradation pathway for many aggregate‐prone and disease‐causing proteins. We previously reported that rapamycin, a mammalian target of rapamycin inhibitor, activated autophagy and decreased proteasome inhibitor‐mediated ubiquitinated protein accumulation, cytoplasmic inclusion body formation, and apoptosis in hepatocytes. Trehalose is a non‐reducing disaccharide that has been shown to activate autophagy. It has been reported to decrease aggregate‐prone proteins and ameliorate cytotoxicity in neurodegenerative disease models. However, the effects of trehalose in hepatocytes are unclear.

Methods

We show here that trehalose activated autophagy and reduced endoplasmic reticulum stress, cytoplasmic inclusion body formation, and apoptosis in proteasome inhibitor‐treated liver‐derived cultured cells.

Conclusion

To our knowledge, this is the first report showing that trehalose activates autophagy and has cytoprotective effects in hepatocytes. Our findings suggest that trehalose can become a therapeutic agent for endoplasmic reticulum stress‐related liver diseases.     

Temporal and region-specific effects of sleep fragmentation on gut microbiota and intestinal morphology in Sprague Dawley rats

ABSTRACT

Sleep is a fundamental biological process, that when repeatedly disrupted, can result in severe health consequences. Recent studies suggest that both sleep fragmentation (SF) and dysbiosis of the gut microbiome can lead to metabolic disorders, though the underlying mechanisms are largely unclear. To better understand the consequences of SF, we investigated the effects of acute (6 days) and chronic (6 weeks) SF on rats by examining taxonomic profiles of microbiota in the distal ileum, cecum and proximal colon, as well as assessing structural and functional integrity of the gastrointestinal barrier. We further assayed the impact of SF on a host function by evaluating inflammation and immune response. Both acute and chronic SF induced microbial dysbiosis, more dramatically in the distal ileum (compared to other two regions studied), as noted by significant perturbations in alpha- and beta-diversity; though, specific microbial populations were significantly altered throughout each of the three regions. Furthermore, chronic SF resulted in increased crypt depth in the distal ileum and an increase in the number of villi lining both the cecum and proximal colon. Additional changes were noted with chronic SF, including: decreased microbial adhesion and penetration in the distal ileum and cecum, elevation in serum levels of the cytokine KC/GRO, and depressed levels of corticotropin. Importantly, our data show that perturbations to microbial ecology and intestinal morphology intensify in response to prolonged SF and these changes are habitat specific. Together, these results reveal consequences to gut microbiota homeostasis and host response following acute and chronic SF in rats.     

Maternal sucralose intake alters gut microbiota of offspring and exacerbates hepatic steatosis in adulthood

ABSTRACT

Background

Nonalcoholic fatty liver disease (NAFLD) is considered to be associated with diet and gut dysbiosis. Excessive sucralose can induce gut dysbiosis and negatively affect host health. Maternal diet shapes the microbial communities of neonate and this effect continues in later life. We aimed to investigate the effects of maternal sucralose (MS) intake on the susceptibility of offspring to hepatic steatosis in adulthood.     

Feeding strategy shapes gut metagenomic enrichment and functional specialization in captive lemurs

Many studies have demonstrated the effects of host diet on gut microbial membership, metagenomics, and fermentation individually; but few have attempted to interpret the relationship among these biological phenomena with respect to host features (e.g. gut morphology). We quantitatively compare the fecal microbial communities, metabolic pathways, and fermentation products associated with the nutritional intake of frugivorous (fruit-eating) and folivorous (leaf-eating) lemurs. Our results provide a uniquely multidimensional and comparative perspective on the adaptive dynamics between host and microbiome. Shotgun metagenomic sequencing revealed significant differential taxonomic and metabolic pathway enrichment, tailored to digest and detoxify different diets. Frugivorous metagenomes feature pathways to degrade simple carbohydrates and host-derived glycosaminoglycans, while folivorous metagenomes are equipped to break down phytic acid and other phytochemical compounds in an anaerobic environment. We used nuclear magnetic resonance based metabolic profiling of fecal samples to link metabolic pathways to fermentation products, confirming that the dissimilar substrates provided in each diet select for specific microbial functions. Fecal samples from frugivorous lemurs contained significantly different profiles of short chain fatty acids, alcohol fermentation products, amino acids, glucose, and glycerol compared to folivorous lemurs. We present the relationships between these datasets as an integrated visual framework, which we refer to as microbial geometry. We use microbial geometry to compare empirical gut microbial profiles across different feeding strategies, and suggest additional utility as a tool for hypothesis-generation.     

Variants in genes of innate immunity,appetite control and energy metabolism are associated with host cardiometabolic health and gut microbiota composition

ABSTRACT

Identifying the genetic and non-genetic determinants of obesity and related cardiometabolic dysfunctions is cornerstone for their prevention, treatment, and control. While genetic variants contribute to the cardiometabolic syndrome (CMS), non-genetic factors, such as the gut microbiota, also play key roles. Gut microbiota is intimately associated with CMS and its composition is heritable. However, associations between this microbial community and host genetics are understudied. We contribute filling this gap by genotyping 60 variants in 39 genes of three modules involved in CMS risk, measuring cardiometabolic risk factors, and characterizing gut microbiota in a cohort of 441 Colombians. We hypothesized that CMS risk variants were correlated with detrimental levels of clinical parameters and with the abundance of disease-associated microbes. We found several polymorphisms in genes of innate immunity, appetite control, and energy metabolism that were associated with metabolic dysregulation and microbiota composition; the associations between host genetics and cardiometabolic health were independent of the participants’ gut microbiota, and those between polymorphisms and gut microbes were independent of the CMS risk. Associations were also independent of the host genetic ancestry, diet and lifestyle. Most microbes explaining genetic-microbiota associations belonged to the families Lachnospiraceae and Ruminococcaceae. Multiple CMS risk alleles were correlated with increased abundance of beneficial microbiota, suggesting that the phenotypic outcome of the evaluated variants might depend upon the genetic background of the studied population and its environmental context. Our results provide additional evidence that the gut microbiota is under the host genetic control and present pathways of host–microbe interactions.     

Endoscopic and Percutaneous Biliary Interventions after Liver Transplantation: Nationwide Data in Korea

Background/AimsBiliary complications including biliary strictures and bile leaks are the most common complications that occur after liver transplantation (LT). Endoscopic treatment with endoscopic retrograde cholangiography (ERC) is considered the first-line treatment, and percutaneous transhepatic cholangiography (PTC) can serve as an alternative or rescue therapy. However, nationwide clinical data on the frequency of ERC and PTC following LT have not yet been investigated.MethodsUsing the nationwide claims database, we investigated patients who underwent LT between 2012 and 2014 in Korea and followed them until 2015. We analyzed the prevalence and characteristics of patients and biliary procedures, including ERC and PTC implemented after LT.ResultsA total of 3,481 patients underwent LT during the 3-year study period. Among them, 3.0% of patients underwent biliary intervention postoperatively during the same hospitalization period, and 21.4% of patients received biliary intervention later on after initially being discharged from the hospital following LT. A total of 16.9% and 12.1% of patients underwent ERC and PTC after LT, respectively. The median period from LT to the first biliary intervention was 7.8 months (interquartile range, 3.5 to 14.6 months), and these patients underwent an average of 3.2±2.8 biliary procedures during the follow-up period. Patients undergoing living donor LT were more than twice as likely to undergo biliary procedures as those undergoing deceased donor LT (25.5% vs 12.1%).ConclusionsApproximately one-fourth of patients in Korea who underwent LT subsequently underwent ERC or PTC. Compared with deceased donor LT patients, those undergoing living donor LT underwent more biliary interventions and were more difficult to treat.     

海藻糖对帕金森病氧化损伤保护作用及机制研究

目的研究海藻糖对1-甲基-4-苯基吡啶离子(MPP+)诱导的shsy5y细胞损伤的保护作用及机制。方法利用MPP+诱导损伤shsy5y建立帕金森病模型,分为对照组、损伤组、实验1组(海藻糖10mmol/L)、实验2组(海藻糖50mmol/L)和实验3组(海藻糖100mmol/L)。CCK-8法检测细胞存活率,利用二乙酰二氯氢化荧光素探针检测shsy5y细胞活性氧水平,hoechst 33342染色观察海藻糖对MPP+诱导的细胞凋亡保护作用,Western blot检测Nrf2、血红素氧化酶1(heme oxygenase-1,HO-1)抗氧化损伤蛋白表达。结果与对照组比较,损伤组shsy5y细胞存活率明显降低(P<0.01),Nrf2和HO-1表达明显降低(0.676±0.020 vs 1.000±0.067,P<0.05;0.546±0.049vs 1.000±0.048,P<0.01)。损伤组MPP+可以显著诱导shsy5y细胞发生凋亡,核碎裂,不同浓度实验组可以逆转这种诱导凋亡。实验1组Nrf2表达较损伤组明显升高,实验2组和实验3组Nrf2和HO-1表达较损伤组明显升高,差异有统计学意义(P<0.01)。损伤组shsy5y细胞内绿色荧光较对照组明显升高,不同浓度实验组随海藻糖浓度升高,shsy5y细胞内绿色荧光明显减少。结论海藻糖可以逆转MPP+作用的shsy5y细胞损伤,这一作用路径可能是通过促进Nrf2/HO-1信号通路激活,减少活性氧损伤,从而起到保护作用。     

Trehalose-recycling ABC transporter LpqY-SugA-SugB-SugC is essential for virulence of Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) is an exclusively human pathogen that proliferates within phagosomes of host phagocytes. Host lipids are believed to provide the major carbon and energy sources for Mtb, with only limited availability of carbohydrates. There is an apparent paradox because five putative carbohydrate uptake permeases are present in Mtb, but there are essentially no host carbohydrates inside phagosomes. Nevertheless, carbohydrate transporters have been implicated in Mtb pathogenesis, suggesting that acquisition of host sugars is important during some stages of infection. Here we show, however, that the LpqY-SugA-SugB-SugC ATP-binding cassette transporter is highly specific for uptake of the disaccharide trehalose, a sugar not present in mammals, thus refuting a role in nutrient acquisition from the host. Trehalose release is known to occur as a byproduct of the biosynthesis of the mycolic acid cell envelope by Mtb's antigen 85 complex. The antigen 85 complex constitutes a group of extracellular mycolyl transferases, which transfer the lipid moiety of the glycolipid trehalose monomycolate (TMM) to arabinogalactan or another molecule of TMM, yielding trehalose dimycolate. These reactions also lead to the concomitant extracellular release of the trehalose moiety of TMM. We found that the LpqY-SugA-SugB-SugC ATP-binding cassette transporter is a recycling system mediating the retrograde transport of released trehalose. Perturbations in trehalose recycling strongly impaired virulence of Mtb. This study reveals an unexpected accessory component involved in the formation of the mycolic acid cell envelope in mycobacteria and provides a previously unknown role for sugar transporters in bacterial pathogenesis.     

Nonalcoholic steatohepatitis before and after liver transplant: keeping up with the times

Introduction: In the last years, nonalcoholic steatohepatitis (NASH) has become a leading indication for liver transplant (LT). After transplant, both recurrent and de novo nonalcoholic fatty liver disease (NAFLD) can be commonly diagnosed. However, dedicated surveillance programs for patients with pre- or post-transplant NAFLD are not available.

Areas covered: Patients waiting for LT for NASH show specific peculiarities and would deserve targeted stratification of mortality risk. Obesity, hyperlipidemia, and diabetes mellitus can be often found after transplant. These conditions, together with immunosuppressive regimen, make LT recipients a high-risk population for both recurrent and de novo NAFLD. Development of fatty liver disease after LT has a relevant impact on both morbidity and mortality.

Expert commentary: A targeted stratification of neoplastic and cardiovascular risk for patients with NASH waiting for LT would be mandatory. In both pre- and post-transplant period, NAFLD should be considered not only a liver disease but also a cardiovascular risk factor. Patients within Transplant Program, especially those with known metabolic risk factors, should be followed with personalized diagnostic and life-style interventions before and after LT.     

Habitual intakes of sugar-sweetened beverages associated with gut microbiota-related metabolites and metabolic health outcomes in young Chinese adults

Background and aimsReducing consumption of sugar-sweetened beverages (SSBs) is a global public health priority because of their limited nutritional value and associations with increased risk of obesity and metabolic diseases. Gut microbiota-related metabolites emerged as quintessential effectors that may mediate impacts of dietary exposures on the modulation of host commensal microbiome and physiological status.Methods and resultsThis study assessed the associations among SSBs, circulating microbial metabolites, and gut microbiota–host co-metabolites, as well as metabolic health outcomes in young Chinese adults (n = 86), from the Carbohydrate Alternatives and Metabolic Phenotypes study in Shaanxi Province. Five principal component analysis-derived beverage drinking patterns were determined on self-reported SSB intakes, which were to a varying degree associated with 143 plasma levels of gut microbiota-related metabolites profiled by untargeted metabolomics. Moreover, carbonated beverages, fruit juice, energy drinks, and bubble tea exhibited positive associations with obesity-related markers and blood lipids, which were further validated in an independent cohort of 16,851 participants from the Regional Ethnic Cohort Study in Northwest China in Shaanxi Province. In contrast, presweetened coffee was negatively associated with the obesity-related traits. A total of 79 metabolites were associated with both SSBs and metabolic markers, particularly obesity markers. Pathway enrichment analysis identified the branched-chain amino acid catabolism and aminoacyl-tRNA biosynthesis as linking SSB intake with metabolic health outcomes.ConclusionOur findings demonstrate the associations between habitual intakes of SSBs and several metabolic markers relevant to noncommunicable diseases, and highlight the critical involvement of gut microbiota-related metabolites in mediating such associations.     

Environmental and intrinsic factors shaping gut microbiota composition and diversity and its relation to metabolic health in children and early adolescents: A population-based study

ABSTRACT

Background

Gut microbiota, by influencing multiple metabolic processes in the host, is an important determinant of human health and disease. However, gut dysbiosis associated with metabolic complications shows inconsistent patterns. This is likely driven by factors shaping gut microbial composition that have largely been under-evaluated, at a population level, in school-age children, especially from developing countries.