RESUMO
Dietary emulsifiers, including carboxymethylcellulose (CMC) and polysorbate 80 (P80), perturb gut microbiota composition and gene expression, resulting in a microbiota with enhanced capacity to activate host pro-inflammatory gene expression and invade the intestine's inner mucus layer. Such microbiota alterations promote intestinal inflammation, which can have a variety of phenotypic consequences including increased adiposity. Bacterial flagellin is a key mediator of emulsifiers' impact in that this molecule enables motility and is itself a pro-inflammatory agonist. Hence, we reasoned that training the adaptive mucosal immune system to exclude microbes that express flagellin might protect against emulsifiers. Investigating this notion found that immunizing mice with flagellin elicited an increase in mucosal anti-flagellin IgA and IgA-coated microbiota that would have otherwise developed in response to CMC and P80 consumption. Yet, eliciting these responses in advance via flagellin immunization prevented CMC/P80-induced increases in microbiota expression of pro-inflammatory agonists including LPS and flagellin. Furthermore, such immunization prevented CMC/P80-induced microbiota encroachment and deleterious pro-inflammatory consequences associated therewith, including colon shortening and increased adiposity. Hence, eliciting mucosal immune responses to pathobiont surface components, including flagellin, may be a means of combatting the array of inflammatory diseases that are promoted by emulsifiers and perhaps other modern microbiota stressors.
Assuntos
Microbiota , Vacinação , Animais , Camundongos , Imunização , Dieta , Obesidade , Flagelina , Polissorbatos/farmacologia , Imunoglobulina ARESUMO
BACKGROUND & AIMS: Epidemiologic and murine studies suggest that dietary emulsifiers promote development of diseases associated with microbiota dysbiosis. Although the detrimental impact of these compounds on the intestinal microbiota and intestinal health have been demonstrated in animal and in vitro models, impact of these food additives in healthy humans remains poorly characterized. METHODS: To examine this notion in humans, we performed a double-blind controlled-feeding study of the ubiquitous synthetic emulsifier carboxymethylcellulose (CMC) in which healthy adults consumed only emulsifier-free diets (n = 9) or an identical diet enriched with 15 g per day of CMC (n = 7) for 11 days. RESULTS: Relative to control subjects, CMC consumption modestly increased postprandial abdominal discomfort and perturbed gut microbiota composition in a way that reduced its diversity. Moreover, CMC-fed subjects exhibited changes in the fecal metabolome, particularly reductions in short-chain fatty acids and free amino acids. Furthermore, we identified 2 subjects consuming CMC who exhibited increased microbiota encroachment into the normally sterile inner mucus layer, a central feature of gut inflammation, as well as stark alterations in microbiota composition. CONCLUSIONS: These results support the notion that the broad use of CMC in processed foods may be contributing to increased prevalence of an array of chronic inflammatory diseases by altering the gut microbiome and metabolome (ClinicalTrials.gov, number NCT03440229).
Assuntos
Carboximetilcelulose Sódica/efeitos adversos , Dieta/efeitos adversos , Emulsificantes/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Animais , Método Duplo-Cego , Disbiose/etiologia , Fezes , Feminino , Voluntários Saudáveis , Humanos , Masculino , CamundongosRESUMO
The rapidly increasing prevalence of type 1 diabetes (T1D) underscores the role of environmental (i.e. non-genetic) determinants of T1D development. Such factors include industrialized diets as well as the intestinal microbiota with which they interact. One component of industrialized diets that deleteriously impact gut microbiota is dietary emulsifiers, which perturb intestinal microbiota to encroach upon their host promoting chronic low-grade intestinal inflammation and metabolic syndrome. Hence, we investigated whether 2 dietary emulsifiers, carboxymethylcellulose (CMC) and polysorbate-80 (P80), might influence the development of T1D in NOD mice, which spontaneously develop this disorder. We observed that chronic emulsifier exposure accelerated T1D development in NOD mice, which was associated with increased insulin autoantibody levels. Such accelerated T1D development was accompanied by compositional and functional alterations of the intestinal microbiota as well as low-grade intestinal inflammation. Moreover, machine learning found that the severity of emulsifier-induced microbiota disruption had partial power to predict subsequent disease development, suggesting that complex interactions occur between the host, dietary factors, and the intestinal microbiota. Thus, perturbation of host-microbiota homeostasis by dietary emulsifiers may have contributed to the post-mid-20th-century increase in T1D.
Assuntos
Diabetes Mellitus Tipo 1 , Microbioma Gastrointestinal , Camundongos , Animais , Diabetes Mellitus Tipo 1/etiologia , Camundongos Endogâmicos NOD , Dieta , InflamaçãoRESUMO
Tryptophan (Trp) is an essential amino acid, whose metabolism is a key gatekeeper of intestinal homeostasis. Yet, its systemic effects, particularly on atherosclerosis, remain unknown. Here we show that high-fat diet (HFD) increases the activity of intestinal indoleamine 2, 3-dioxygenase 1 (IDO), which shifts Trp metabolism from the production of microbiota-derived indole metabolites towards kynurenine production. Under HFD, the specific deletion of IDO in intestinal epithelial cells leads to intestinal inflammation, impaired intestinal barrier, augmented lesional T lymphocytes and atherosclerosis. This is associated with an increase in serotonin production and a decrease in indole metabolites, thus hijacking Trp for the serotonin pathway. Inhibition of intestinal serotonin production or supplementation with indole derivatives alleviates plaque inflammation and atherosclerosis. In summary, we uncover a pivotal role of intestinal IDO in the fine-tuning of Trp metabolism with systemic effects on atherosclerosis, paving the way for new therapeutic strategies to relieve gut-associated inflammatory diseases.
Assuntos
Aterosclerose , Dieta Hiperlipídica , Indolamina-Pirrol 2,3,-Dioxigenase , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Serotonina , Triptofano , Animais , Triptofano/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/genética , Aterosclerose/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Camundongos , Serotonina/metabolismo , Mucosa Intestinal/metabolismo , Cinurenina/metabolismo , Masculino , Microbioma Gastrointestinal , Indóis/farmacologia , Inflamação/metabolismo , Camundongos Knockout , Intestinos/patologia , Linfócitos T/metabolismo , Linfócitos T/imunologia , Modelos Animais de DoençasRESUMO
Aims: Metformin is the broadly accepted the first-line medication for diabetes. Its use, however, is limited by gastrointestinal side effects present in approximately 25% of patients. This study aimed to better understand the interplay between metformin intolerance and gut microbiota among Black individuals with diabetes. Methods: We performed a cross-sectional study among 29 Black individuals living with diabetes with or without metformin intolerance. Participants with mean age 59±11, 58% female, were stratified into three groups: 1)intolerant: metformin intolerance in the past, not on metformin; 2)partially intolerant: mild to moderate gastrointestinal symptoms, currently taking metformin 3)tolerant: using metformin without symptoms. We collected and analyzed rectal swabs and analyzed microbiota composition using V3-V4 regions of the 16s rRNA. Results: Metformin intolerant subjects trended towards having greatest alpha diversity, followed by tolerant and partially tolerant (Intolerant:4.9; Tolerant:4.2; Partially tolerant:3.9). Mean difference in alpha diversity for intolerant versus partially tolerant was 1.0 (95% CI-0.1,2.1) and intolerant versus tolerant were 0.7 (95% CI -0.4,1.8). Conclusion: This was the first study to evaluate the role of microbiota and metformin intolerance among Black individuals. We report on differences in alpha diversity as well as microbiota composition.
RESUMO
The human gut microbiota is highly heterogenous between individuals and also exhibits considerable day-to-day variation within individuals. We hypothesized that diet contributed to such inter- and/or intra-individual variance. Hence, we investigated the extent to which diet normalization impacted microbiota heterogeneity. We leveraged the control arm of our recently reported controlled-feeding study in which nine healthy individuals consumed a standardized additive-free diet for 10 days. Diet normalization did not impact inter-individual differences but reduced the extent of intra-individual day-to-day variation in fecal microbiota composition. Such decreased heterogeneity reflected individual-specific enrichment and depletion of an array of taxa microbiota members and was paralleled by a trend toward reduced intra-individual variance in fecal LPS and flagellin, which, collectively, reflect microbiota's pro-inflammatory potential. Yet, the microbiota of some subjects did not change significantly over the course of the study, suggesting heterogeneity in microbiota resilience to dietary stress or that baseline diets of some subjects were perhaps similar to our study's standardized diet. Collectively, our results indicate that short-term diet heterogeneity contributes to day-to-day intra-individual microbiota composition variance.
Assuntos
Microbioma Gastrointestinal , Microbiota , Humanos , Dieta , Fezes , Padrões de ReferênciaRESUMO
BACKGROUND & AIMS: Hyperbaric oxygen therapy (HBOT) is a promising treatment for moderate-to-severe ulcerative colitis. However, our current understanding of the host and microbial response to HBOT remains unclear. This study examined the molecular mechanisms underpinning HBOT using a multi-omic strategy. METHODS: Pre- and post-intervention mucosal biopsies, tissue, and fecal samples were collected from HBOT phase 2 clinical trials. Biopsies and fecal samples were subjected to shotgun metaproteomics, metabolomics, 16s rRNA sequencing, and metagenomics. Tissue was subjected to bulk RNA sequencing and digital spatial profiling (DSP) for single-cell RNA and protein analysis, and immunohistochemistry was performed. Fecal samples were also used for colonization experiments in IL10-/- germ-free UC mouse models. RESULTS: Proteomics identified negative associations between HBOT response and neutrophil azurophilic granule abundance. DSP identified an HBOT-specific reduction of neutrophil STAT3, which was confirmed by immunohistochemistry. HBOT decreased microbial diversity with a proportional increase in Firmicutes and a secondary bile acid lithocholic acid. A major source of the reduction in diversity was the loss of mucus-adherent taxa, resulting in increased MUC2 levels post-HBOT. Targeted database searching revealed strain-level associations between Akkermansia muciniphila and HBOT response status. Colonization of IL10-/- with stool obtained from HBOT responders resulted in lower colitis activity compared with non-responders, with no differences in STAT3 expression, suggesting complementary but independent host and microbial responses. CONCLUSIONS: HBOT reduces host neutrophil STAT3 and azurophilic granule activity in UC patients and changes in microbial composition and metabolism in ways that improve colitis activity. Intestinal microbiota, especially strain level variations in A muciniphila, may contribute to HBOT non-response.
Assuntos
Colite Ulcerativa , Oxigenoterapia Hiperbárica , Microbiota , Animais , Colite Ulcerativa/terapia , Humanos , Interleucina-10 , Camundongos , RNA Ribossômico 16S/genéticaRESUMO
An array of chronic inflammatory diseases, including metabolic diseases such as obesity and diabetes, are thought to be promoted by disturbance of the intestinal microbiota. Such diseases disproportionately impact low-income communities, which are frequently afflicted by chronic stress and increased density housing. Hence, we hypothesized that overcrowded housing might promote stress, microbiota dysbiosis, inflammation, and, consequently, metabolic diseases. We tested this hypothesis in a tractable murine model of social overcrowding (SOC), in which mice were housed at twice normal density. SOC moderately impacted behavior in some widely used assays (Open Field, Elevated Plus Maze and Light/Dark tests) and resulted in a stark increase in corticosterone levels. Such indices of stress were associated with mild chronic gut inflammation, hyperglycemia, elevations in colonic cytokines, and alterations in gut microbiota composition. All of these consequences of SOC were eliminated by broad spectrum antibiotics, while some (inflammation and hyperglycemia) were transmitted by microbiota transplantation from SOC mice to germfree mice housed at normal density. Altogether, these results suggest a central role for intestinal microbiota in driving stress, inflammation, and chronic diseases that are promoted by overcrowded housing.