Artificial Sweeteners Induce Glucose Intolerance by Altering the Gut Microbiota
Abstract
Non-caloric artificial sweeteners (NAS) are among the most widely used food additives worldwide, regularly consumed by lean and obese individuals alike. NAS consumption is considered safe and beneficial owing to their low caloric content, yet supporting scientific data remain sparse and controversial. Here we demonstrate that consumption of commonly used NAS formulations drives the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota. These NAS-mediated deleterious metabolic effects are abrogated by antibiotic treatment, and are fully transferrable to germ-free mice upon faecal transplantation of microbiota configurations from NAS-consuming mice, or of microbiota anaerobically incubated in the presence of NAS. We identify NAS-altered microbial metabolic pathways that are linked to host susceptibility to metabolic disease, and demonstrate similar NAS-induced dysbiosis and glucose intolerance in healthy human subjects. Collectively, our results link NAS consumption, dysbiosis and metabolic abnormalities, thereby calling for a reassessment of massive NAS usage.
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All content in this area was uploaded by Ilana Kolodkin-Gal on Oct 06, 2014
- ... The consumption of NNSs, mainly in diet sodas, has been related to an increased risk of obesity, metabolic syndrome, and T2D (8)(9)(10)(11)(12), although some studies did not find any association (13,14). The consumption of typically used nonnutritive artificial sweetener formulations drives the development of glucose intolerance through the induction of compositional and functional alterations to the intestinal microbiota (15). In contrast, the consumption of NNSs reduces blood glucose, which is attributed to the lower carbohydrate load rather than the activation of sweet taste receptors (16). ...... In that week, the volunteers consumed the maximal ADI of saccharin (5 mg/kg). Compared with their individual glycemic response on days 1-4, the volunteers in the NAS group showed decreased glycemic responses at days 5 and 7 (15). The magnitude of the difference was >30%. ...The consumption of sugar-free foods is growing because of their low-calorie content and the health concerns about products with high sugar content. Sweeteners that are frequently several hundred thousand times sweeter than sucrose are being consumed as sugar substitutes. Although nonnutritive sweeteners (NNSs) are considered safe and well tolerated, their effects on glucose intolerance, the activation of sweet taste receptors, and alterations to the composition of the intestinal microbiota are controversial. This review critically discusses the evidence supporting the effects of NNSs, both synthetic sweeteners (acesulfame K, aspartame, cyclamate, saccharin, neotame, advantame, and sucralose) and natural sweeteners (NSs; thaumatin, steviol glucosides, monellin, neohesperidin dihydrochalcone, and glycyrrhizin) and nutritive sweeteners (polyols or sugar alcohols) on the composition of microbiota in the human gut. So far, only saccharin and sucralose (NNSs) and stevia (NS) change the composition of the gut microbiota. By definition, a prebiotic is a nondigestible food ingredient, but some polyols can be absorbed, at least partially, in the small intestine by passive diffusion: however, a number of them, such as isomaltose, maltitol, lactitol, and xylitol, can reach the large bowel and increase the numbers of bifidobacteria in humans. Further research on the effects of sweeteners on the composition of the human gut microbiome is necessary. Adv Nutr 2019;10:S31-S48.
- ... These responses resulted in a 28% decline in the composite ISI, an indicator of glucose disposal relative to insulin levels. The FB employed in the present study, 5h Energy Decaffeinated, contained several insulino- genic ingredients including sucralose and free amino acids [25,26]. Higher insulin concentra- tions without altered glycemia with acute sucralose consumption has been previously reported [27]. ...... Higher insulin concentra- tions without altered glycemia with acute sucralose consumption has been previously reported [27]. Likewise, there is a growing body of evidence showing that the consumption of artificial sweeteners may disrupt glucose homeostasis and is positively associated with host metabolic derangements including obesity, diabetes and cardiovascular disease with chronic consump- tion [26,28,29]. ...Over the past decade, there has been a substantial increase in the number of beverage products containing added vitamins and minerals. Often viewed as a healthier choice by consumers, the metabolic impacts of excessive vitamin consumption are relatively unknown, especially in children. The aim of this study was to examine the effects of a widely available, vitamin fortified beverage (5h Energy Decaffeinated) on insulin sensitivity, metabolic hormones and serum metabolomic responses in adolescents. Twenty adolescents (13-19y, 10M/10F) completed two randomized trials, consuming either coloured water as placebo (PL) or a vitamin fortified, sugar free beverage (FB, 1.5ml/kg) 40min prior to a modified oral glucose tolerance test (OGTT, 1.75g/kg glucose). Samples were collected at baseline and at 30, 45, 60, 90 and 120min during the OGTT. No differences in blood glucose response were observed between the treatments. However, compared to PL, postprandial plasma C-peptide and insulin excursion was significantly greater with FB, resulting in a 28% decline in the insulin sensitivity index. This was accompanied by elevated GLP-1, glucagon and PYY responses with FB compared to PL. Serum metabolomics (¹H-NMR) analysis also revealed perturbations to vitamin B-linked one carbon metabolism flux with FB consumption that became more pronounced over time. These included a transient reduction in homocysteine flux accompanied by increases in betaine, vitamin B6, vitamin B12, choline, folate and taurine. Although these impacts are likely short-lived, results show that beverages fortified with excessive amounts of vitamins are not metabolically inert, but likely result in greater insulin secretion, differential gut hormone secretion and elevated one-carbon flux to process the excessive vitamin loads.
- ... There were reports on the carcenogenic pro- perties of saccharin and risk of development of cancer of the urinary bladder, but further studies disproved this (Weihrauch & Diehl, 2004;Vasconcelos et al., 2017). Non-calory sweeteners stimulate the develop- ment of intolerance of glucose by change in the microflora of the intesti- nes and subsequent development of inflammatory processes in the organs ( Suez et al., 2014;Nettleton et al., 2016;Qin, 2016;Bian et al., 2017b), and significantly reduce the sense of taste ( Bakali et al., 2016;Sclafani & Ackroff, 2017;Dess et al., 2017;Choo & Dando, 2018). Despite these data, nowadays, saccharin is approved for ubiquitous usage in over 90 countries. ...Herbicides and food additives are included in many food products for humans. Non-used products or products beyond their expiry date are deposited in places of utilizatioin of solid municipal wastes, where they can take effects on the organisms of mouse-like rodents. Among the herbicides, glyphosphate takes first place in the world for volume of production, and is the most intensely used in agricultural farming. The discussion about negative impact on the organisms of mammals, especially against the background of using various substances and environmental factors, continues. In this study, we determined the combined effect of glyphosphate and food additives on the organism of laboratory animals, which manifested in changes in body weight, condition and indices of mass of the internal organs and blood parameters. Four groups of laboratory male rats were formed, which over 42 days received: unlimited access to clean water; 1% aqueous solution of glyphosate; 1% solution of glyphosphate and 1% solution sodium benzoate; 1% solution of glyphosphate with 1% solution of saccharin. Glyphosphate and glyphosphate with sodium benzoate and saccharin significantly reduced the daily increases in body weight of animals compared to the control group. The studied substances have notable suppressive effect on the immune system and haematopoiesis in general, which is manifested in reduce of relative mass of the thymus and spleen against the background of increase in the amount of lymphocytes in the peripheral blood. The inhibition of haematopoiesis is indicated by decrease in the amount of erythrocytes, neurophils and hemoglobin of blood of animals from the experimental groups. The impact on the digestive system of glyphosphate and food additives is indicated by occurance of the effect of “irritation” of mucous membranes, and, as a result, disorders in absorption followed by the disorder in metabolic processes. A dysbalance occurs in enzymic systems of the organism, which is manifested in distrophic processes, especially in the liver parenchyma, indicated by the activity of blood enzymes (ALT, AST, alkaline phosphatase), total number and ratio of proteins of blood plasma. We determined the impact of glyphosphate and its mixes with benzoate and saccharin on the pancreas, which manifests in severe pancreatitis with steep increase in the level of glucose of blood. The results of the study allow us to state that mixture of glyphosphate and food additives can cause toxic effect in animals and humans, which often contact with herbicides.
- ... Dlatego też w niektórych badaniach stwierdzono insulinogenne działanie niecukrowych sub- stancji słodzących [11]. Są także badania, które wskazują, że sztuczne słodziki zmieniają metabolizm glukozy po- przez oddziaływanie na mikrobiotę jelitową [17]. Jednak w przypadku ksylitolu ta strefa wciąż wymaga większej liczby badań. ...W powszechnie dostępnych informacjach medialnych i marketingowych powielana jest opinia, że ksylitol jako środek słodzący jest związkiem naturalnym wykazującym działanie przeciwpróchnicze, bakteriobójcze, grzybobójcze, zasadotwórcze i ogólnie prozdrowotne. Przegląd dostępnego piśmiennictwa pozwolił zweryfikować, które z powyższych cech przypisywanych ksylitolowi znajdują potwierdzenie w wynikach badań naukowych, a które z nich to jedynie mity. In media and marketing information, xylitol as a sweetener is depicted as a natural compound with anti-caries, bactericidal, fungicidal, alkaline and generally pro-health properties. Unfortunately not all of this information is the review of the available literature allowed to verify which of the above attributes of xylitol are confirmed by the research and which ones are only myths.
- ... Importantly, the negative impact of dietary emulsifiers is not observed in GF mice, suggesting that the compositional and functional modulation of the gut microbiota by emulsifiers play a key role in their adverse effect (177). Other food additives, for example artificial sweeteners, also induce gut dysbiosis (179,180). The consumption of artificial sweeteners promotes the expansion of Proteobacteria and increases the infiltration of bacteria into the ileal lamina propria in CD- like ileitis model mice (180). ...Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disease of the gastrointestinal tract. Although the precise etiology of IBD remains incompletely understood, accumulating evidence suggests that various environmental factors, including dietary nutrients, contribute to its pathogenesis. Dietary nutrients are known to have an impact on host physiology and diseases. The interactions between dietary nutrients and intestinal immunity are complex. Dietary nutrients directly regulate the immuno-modulatory function of gut-resident immune cells. Likewise, dietary nutrients shape the composition of the gut microbiota. Therefore, a well-balanced diet is crucial for good health. In contrast, the relationships among dietary nutrients, host immunity and/or the gut microbiota may be perturbed in the context of IBD. Genetic predispositions and gut dysbiosis may affect the utilization of dietary nutrients. Moreover, the metabolism of nutrients in host cells and the gut microbiota may be altered by intestinal inflammation, thereby increasing or decreasing the demand for certain nutrients necessary for the maintenance of immune and microbial homeostasis. Herein, we review the current knowledge of the role dietary nutrients play in the development and the treatment of IBD, focusing on the interplay among dietary nutrients, the gut microbiota and host immune cells. We also discuss alterations in the nutritional metabolism of the gut microbiota and host cells in IBD that can influence the outcome of nutritional intervention. A better understanding of the diet-host-microbiota interactions may lead to new therapeutic approaches for the treatment of IBD.
- Resveratrol (RSV) is a natural polyphenol with putative anti-obesity effects; however, its mechanisms of action remain unclear due to its low bioavailability. Microbial functions in the physiology result from the microbiota–host coevolution has profoundly affected host metabolism. Here, we sought to determine how beneficial microbiome caused by RSV interventions affects antiobesity. C57BL/6J mice were fed either standard diet (SD) or RSV (300 mg/kg/day) diet for 16 weeks. The composition of the gut microbiota was assessed by analyzing 16S rRNA gene sequences. Then, transplant the RSV-microbiota to high-fat diet (HFD)-fed mice (HFD-RSVT) to explore the function of microbiota. Body weight and food intake were monitored. Markers of lipid metabolism, inflammation, gut microbiota compostion, and intestinal barrier were determined. Mice treated with RSV shows a remarkable alteration in microbiota composition compared with that of SD-fed mice and is characterized by an enrichment of Bacteroides, Lachnospiraceae_NK4A136_group, Blautia, Lachnoclostridium, Parabacteroides, and Ruminiclostridium_9, collectively referred to as RSV-microbiota. We further explored whether RSV-microbiota has anti-obesity functions. Transplantation of the RSV-microbiota to high-fat diet (HFD)-fed mice (HFD-RSVT) was sufficient to decrease their weight gain and increase their insulin sensitivity. Moreover, RSV-microbiota was able to modulate lipid metabolism, stimulate the development of beige adipocytes in WAT, reduce inflammation and improve intestinal barrier function. Our study demonstrates that RSV-induced microbiota plays a key role in controlling obesity development and brings new insights to a potential therapy based on host–microbe interactions.
- Gut microbiota (GM) located within the intestinal tract lumen comprises the largest number of cells (10E14) in the human body. The gut microbiome refers to the collection of genomes and genes present in gut microbiota. GM can vary according to age, sex, genetic background, immune status, geography, diet, prebiotics, which are non-digestible fibers metabolized in the distal part of the gastrointestinal tract, probiotics, which are micro-organisms conferring a health benefit on the host when administered in adequate amounts, living conditions, diseases and drugs. A source of probiotics is fortified fermented dairy products, which in addition provide calcium, protein, phosphorus and various micronutrients. Bone homeostasis is influenced by GM composition and/or products. GM appears to be a major player in the various determinants of bone health. However, it remains to be demonstrated in well conducted long-term randomized controlled trials, whether interventions changing GM composition and/or function are capable of reducing fracture risk.
- Background Although clinical data support an association between paternal alcohol use and deficits in child neurocognitive development, the relationship between paternal drinking and alcohol-induced growth phenotypes remains challenging to define. Using an established mouse model of chronic exposure, previous work by our group has linked preconception paternal alcohol use to sex-specific patterns of fetal growth restriction and placental dysfunction. The aim of the present study was to investigate the long-term impact of chronic preconception paternal alcohol use on offspring growth and metabolic programming. Results Preconception paternal alcohol exposure induced a prolonged period of fetal gestation and an increased incidence of intrauterine growth restriction, which affected the male offspring to a greater extent than the females. While the female offspring of ethanol-exposed males were able to match the body weights of the controls within the first 2 weeks of postnatal life, male offspring continued to display an 11% reduction in weight at 5 weeks of age and a 6% reduction at 8 weeks of age. The observed growth deficits associated with insulin hypersensitivity in the male offspring, while in contrast, females displayed a modest lag in their glucose tolerance test. These metabolic defects were associated with an up-regulation of genes within the pro-fibrotic TGF-β signaling pathway and increased levels of cellular hydroxyproline within the livers of the male offspring. We observed suppressed cytokine profiles within the liver and pancreas of both the male and female offspring, which correlated with the up-regulation of genes in the LiverX/RetinoidX/FarnesoidX receptor pathways. However, patterns of gene expression were highly variable between the offspring of alcohol-exposed sires. In the adult offspring of alcohol-exposed males, we did not observe any differences in the allelic expression of Igf2 or any other imprinted genes. Conclusions The impact of paternal alcohol use on child development is poorly explored and represents a significant gap in our understanding of the teratogenic effects of ethanol. Our studies implicate paternal exposure history as an additional and important modifier of alcohol-induced growth phenotypes and challenge the current maternal-centric exposure paradigm. Electronic supplementary material The online version of this article (10.1186/s13072-019-0254-0) contains supplementary material, which is available to authorized users.
- Si bien los edulcorantes no calóricos (ENC) son aditivos de los alimentos que han sido utilizados como una posible herramienta para reducir el consumo de azúcares y la ingesta energética total actualmente existe un debate científico en torno a los beneficios reales de su uso. Los ENC están entre las sustancias más evaluadas en la literatura científica. Su seguridad ha sido revisada por agencias internacionales regulatorias en salud. La educación de los profesionales de la salud y los consumidores sobre estos productos debe fortalecerse de manera rigurosa y objetiva, basándose en la mejor evidencia científica y en los procesos reglamentarios, aunados al juicio clínico. Desde que existen, los ENC han sido utilizados como sustitutos de la sacarosa, particularmente por personas con diabetes mellitus y obesidad. La controversia acerca de si pueden favorecer el desarrollo de intolerancia a la glucosa o la ganancia de peso hace necesaria una revisión crítica de la literatura. Este consenso de la Asociación Latinoamericana de Diabetes presenta una revisión de las preguntas que más habitualmente se hacen al respecto los profesionales de la salud, las personas con diabetes y el consumidor en general. En este documento se condensan diversas publicaciones científicas bajoel tamiz de la medicina basada en evidencia, para dilucidar si el uso de ENC en planes de nutrición sustituyendo azúcares simples puede o no favorecer la reducción y el mantenimiento de peso y, en particular, si su uso en los programas de control de pacientes diabéticos puede o no contribuir a un mejor control glucémico. También se evalúan algunos otros temas sensibles, como su utilización en la edad pediátrica, durante el embarazo y la lactancia, así como el impacto en la microbiota intestinal.
- Assessment and characterization of gut microbiota has become a major research area in human disease, including type 2 diabetes, the most prevalent endocrine disease worldwide. To carry out analysis on gut microbial content in patients with type 2 diabetes, we developed a protocol for a metagenome-wide association study (MGWAS) and undertook a two-stage MGWAS based on deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals. We identified and validated approximately 60,000 type-2-diabetes-associated markers and established the concept of a metagenomic linkage group, enabling taxonomic species-level analyses. MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. An analysis of 23 additional individuals demonstrated that these gut microbial markers might be useful for classifying type 2 diabetes.
- Symbiotic microorganisms that reside in the human intestine are adept at foraging glycans and polysaccharides, including those in dietary plants (starch, hemicellulose and pectin), animal-derived cartilage and tissue (glycosaminoglycans and N-linked glycans), and host mucus (O-linked glycans). Fluctuations in the abundance of dietary and endogenous glycans, combined with the immense chemical variation among these molecules, create a dynamic and heterogeneous environment in which gut microorganisms proliferate. In this Review, we describe how glycans shape the composition of the gut microbiota over various periods of time, the mechanisms by which individual microorganisms degrade these glycans, and potential opportunities to intentionally influence this ecosystem for better health and nutrition.
- To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.
- Long-term dietary intake influences the structure and activity of the trillions of microorganisms residing in the human gut, but it remains unclear how rapidly and reproducibly the human gut microbiome responds to short-term macronutrient change. Here we show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii). Microbial activity mirrored differences between herbivorous and carnivorous mammals, reflecting trade-offs between carbohydrate and protein fermentation. Foodborne microbes from both diets transiently colonized the gut, including bacteria, fungi and even viruses. Finally, increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease. In concert, these results demonstrate that the gut microbiome can rapidly respond to altered diet, potentially facilitating the diversity of human dietary lifestyles.
- Emerging next-generation sequencing technologies have revolutionized the collection of genomic data for applications in bioforensics, biosurveillance, and for use in clinical settings. However, to make the most of these new data, new methodology needs to be developed that can accommodate large volumes of genetic data in a computationally efficient manner. We present a statistical framework to analyze raw next-generation sequence reads from purified or mixed environmental or targeted infected tissue samples for rapid species identification and strain attribution against a robust database of known biological agents. Our method, Pathoscope, capitalizes on a Bayesian statistical framework that accommodates information on sequence quality, mapping quality and provides posterior probabilities of matches to a known database of target genomes. Importantly, our approach also incorporates the possibility that multiple species can be present in the sample and considers cases when the sample species/strain is not in the reference database. Furthermore, our approach can accurately discriminate between very closely related strains of the same species with very little coverage of the genome and without the need for multiple alignment steps, extensive homology searches, or genome assembly- which are time consuming and labor intensive steps. We demonstrate the utility of our approach on genomic data from purified and in silico 'environmental' samples from known bacterial agents impacting human health for accuracy assessment and comparison with other approaches.
- A 16S rRNA gene database (http://greengenes.lbl.gov) addresses limitations of public repositories by providing chimera screening, standard alignment, and taxonomic classification using multiple published taxonomies. It was found that there is incongruent taxonomic nomenclature among curators even at the phylum level. Putative chimeras were identified in 3% of environmental sequences and in 0.2% of records derived from isolates. Environmental sequences were classified into 100 phylum-level lineages in the Archaea and Bacteria.
- Type 2 diabetes (T2D) is a result of complex gene-environment interactions, and several risk factors have been identified, including age, family history, diet, sedentary lifestyle and obesity. Statistical models that combine known risk factors for T2D can partly identify individuals at high risk of developing the disease. However, these studies have so far indicated that human genetics contributes little to the models, whereas socio-demographic and environmental factors have greater influence. Recent evidence suggests the importance of the gut microbiota as an environmental factor, and an altered gut microbiota has been linked to metabolic diseases including obesity, diabetes and cardiovascular disease. Here we use shotgun sequencing to characterize the faecal metagenome of 145 European women with normal, impaired or diabetic glucose control. We observe compositional and functional alterations in the metagenomes of women with T2D, and develop a mathematical model based on metagenomic profiles that identified T2D with high accuracy. We applied this model to women with impaired glucose tolerance, and show that it can identify women who have a diabetes-like metabolism. Furthermore, glucose control and medication were unlikely to have major confounding effects. We also applied our model to a recently described Chinese cohort and show that the discriminant metagenomic markers for T2D differ between the European and Chinese cohorts. Therefore, metagenomic predictive tools for T2D should be specific for the age and geographical location of the populations studied.
- Dynamic protein binding to DNA elements regulates genome function and cell fate. Although methods for mapping in vivo protein-DNA interactions are becoming crucial for every aspect of genomic research, they are laborious and costly, thereby limiting progress. Here we present a protocol for mapping in vivo protein-DNA interactions using a high-throughput chromatin immunoprecipitation (HT-ChIP) approach. By using paramagnetic beads, we streamline the entire ChIP and indexed library construction process: sample transfer and loss is minimized and the need for manually labor-intensive procedures such as washes, gel extraction and DNA precipitation is eliminated. All of this allows for fully automated, cost effective and highly sensitive 96-well ChIP sequencing (ChIP-seq). Sample preparation takes 3 d from cultured cells to pooled libraries. Compared with previous methods, HT-ChIP is more suitable for large-scale in vivo studies, specifically those measuring the dynamics of a large number of different chromatin modifications/transcription factors or multiple perturbations.
- Kwashiorkor, an enigmatic form of severe acute malnutrition, is the consequence of inadequate nutrient intake plus additional environmental insults. To investigate the role of the gut microbiome, we studied 317 Malawian twin pairs during the first 3 years of life. During this time, half of the twin pairs remained well nourished, whereas 43% became discordant, and 7% manifested concordance for acute malnutrition. Both children in twin pairs discordant for kwashiorkor were treated with a peanut-based, ready-to-use therapeutic food (RUTF). Time-series metagenomic studies revealed that RUTF produced a transient maturation of metabolic functions in kwashiorkor gut microbiomes that regressed when administration of RUTF was stopped. Previously frozen fecal communities from several discordant pairs were each transplanted into gnotobiotic mice. The combination of Malawian diet and kwashiorkor microbiome produced marked weight loss in recipient mice, accompanied by perturbations in amino acid, carbohydrate, and intermediary metabolism that were only transiently ameliorated with RUTF. These findings implicate the gut microbiome as a causal factor in kwashiorkor.
- Microbial exposures and sex hormones exert potent effects on autoimmune diseases, many of which are more prevalent in women. We demonstrate that early-life microbial exposures determine sex hormone levels and modify progression to autoimmunity in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D). Colonization by commensal microbes elevated serum testosterone and protected NOD males from T1D. Transfer of gut microbiota from adult males to immature females altered the recipient's microbiota, resulting in elevated testosterone and metabolomic changes, reduced islet inflammation and autoantibody production, and robust T1D protection. These effects were dependent on androgen receptor activity. Thus, the commensal microbial community alters sex hormone levels and regulates autoimmune disease fate in individuals with high genetic risk.
