Shifts In Gut Microbiome Research Articles

Metagenomic profiling reveals dominance of gram-positive bacteria in the gut microbiome shifts associated with immunoglobulin A vasculitis (Henoch-Schönlein Purpura).

ObjectivesImmunoglobulin A vasculitis (IgAV), previously known as Henoch–Schönlein purpura, is the most common vasculitis that has a classical skin manifestation of palpable purpuric rash. Factors pertinent to IgAV remain inadequately understood. Here, we aimed to examine the gut microbiome shifts associated with IgAV and its recovery.MethodsStool samples were collected from 10 children with IgAV (6–14 years old) before and after a multi‐drug therapy, along with 9 age‐matched healthy children. The samples were subjected to metagenomic analyses to investigate the taxonomic and functional shifts of the gut microbiome.ResultsThe analyses revealed that compared with healthy controls, treatment‐naïve patients exhibited substantial taxonomic and functional alterations of gut microbiota, including 104 IgAV‐depleted species and 7 IgAV‐elevated species (FDR < 0.05). After treatment, the IgAV patients displayed a partial restoration of the microbiota shifts, as the relative abundances of some biomarkers (e.g. 9 genera and 22 species) became comparable (FDR > 0.1) between the patients and healthy controls. The treatment‐responsive features included Weissella, Faecalibacterium prausnitzii and Bifidobacterium pseudocatenulatum and three components of a putative glutamine transport system. Importantly, gram‐positive bacteria accounted for over 85% of the numbers and total relative abundance of the species that were associated with IgAV and responsive to the treatment. In addition, of the 122 IgAV‐depleted bacterial genes, 82 were mainly contributed by gram‐positive bacteria and 12 by gram‐negative bacteria.ConclusionsGram‐positive bacteria are the main drivers underlying the gut microbiome shifts of IgAV, which may assist rational management of the disease.

Shifts in gut microbiome and metabolome are associated with risk of recurrent atrial fibrillation.

Alternations of gut microbiota (GM) in atrial fibrillation (AF) with elevated diversity, perturbed composition and function have been described previously. The current work aimed to assess the association of GM composition with AF recurrence (RAF) after ablation based on metagenomic sequencing and metabolomic analyses and to construct a GM‐based predictive model for RAF. Compared with non‐AF controls (50 individuals), GM composition and metabolomic profile were significantly altered between patients with recurrent AF (17 individuals) and non‐RAF group (23 individuals). Notably, discriminative taxa between the non‐RAF and RAF groups, including the families Nitrosomonadaceae and Lentisphaeraceae, the genera Marinitoga and Rufibacter and the species Faecalibacterium spCAG:82, Bacillus gobiensis and Desulfobacterales bacterium PC51MH44, were selected to construct a taxonomic scoring system based on LASSO analysis. After incorporating the clinical factors of RAF, taxonomic score retained a significant association with RAF incidence (HR = 2.647, P = .041). An elevated AUC (0.954) and positive NRI (1.5601) for predicting RAF compared with traditional clinical scoring (AUC = 0.6918) were obtained. The GM‐based taxonomic scoring system theoretically improves the model performance, and the nomogram and decision curve analysis validated the clinical value of the predicting model. These data provide novel possibility that incorporating the GM factor into future recurrent risk stratification.

Type I IFNs and CD8 T cells increase intestinal barrier permeability after chronic viral infection.

Intestinal barrier leakage constitutes a potential therapeutic target for many inflammatory diseases and represents a disease progression marker during chronic viral infections. However, the causes of altered gut barrier remain mostly unknown. Using murine infection with lymphocytic choriomeningitis virus, we demonstrate that, in contrast to an acute viral strain, a persistent viral isolate leads to long-term viral replication in hematopoietic and mesenchymal cells, but not epithelial cells (IECs), in the intestine. Viral persistence drove sustained intestinal epithelial barrier leakage, which was characterized by increased paracellular flux of small molecules and was associated with enhanced colitis susceptibility. Type I IFN signaling caused tight junction dysregulation in IECs, promoted gut microbiome shifts and enhanced intestinal CD8 T cell responses. Notably, both type I IFN receptor blockade and CD8 T cell depletion prevented infection-induced barrier leakage. Our study demonstrates that infection with a virus that persistently replicates in the intestinal mucosa increases epithelial barrier permeability and reveals type I IFNs and CD8 T cells as causative factors of intestinal leakage during chronic infections.

Dietary Lipids Influence Bioaccessibility of Polyphenols from Black Carrots and Affect Microbial Diversity under Simulated Gastrointestinal Digestion.

The bioaccessibility and activity of polyphenols is dependent on their structure and entrapment in the food matrix. While dietary lipids are known to transit into the colon, the impact of different lipids on the microbiome, and their interactions with dietary polyphenols are largely unknown. Here, we investigated the effect of dietary lipids on the bioaccessibility of polyphenols from purple/black carrots and adaptation of the gut microbiome in a simulated in vitro digestion-fermentation. Coconut oil, sunflower oil, and beef tallow were selected to represent common dietary sources of medium-chain fatty acids (MCFAs), long-chain polyunsaturated fatty acids (PUFAs), and long-chain polysaturated fatty acids (SFAs), respectively. All lipids promoted the bioaccessibility of both anthocyanins and phenolic acids during intestinal digestion with coconut oil exhibiting the greatest protection of anthocyanins. Similar trends were shown in antioxidant assays (2,2-Diphenyl-1-pricrylhydrazyl (DPPH), ferric reducing ability (FRAP), and total phenolic content (TPC)) with higher phytochemical bioactivities observed with the addition of dietary lipids. Most bioactive polyphenols were decomposed during colonic fermentation. Black carrot modulated diversity and composition of a simulated gut microbiome. Dramatic shifts in gut microbiome were caused by coconut oil. Inclusion of sunflower oil improved the production of butyrate, potentially due to the presence of PUFAs. The results show that the impact of polyphenols in the digestive tract should be considered in the context of other components of the diet, particularly lipids.

Eicosapentaenoic and Docosahexaenoic Acids Differentially Alter Gut Microbiome and Reverse High-Fat Diet-Induced Insulin Resistance.

To assess the individual effects of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on insulin resistance (IR), gut microbiome, and gut metabolites in high-fat-diet-induced obese (DIO) mice. DIO mice are fed an either high-fat diet (HFD), EPA (1%w/w) enriched HFD, or DHA (1%wt/wt) enriched HFD for 15 weeks. Both EPA and DHA supplements reverse hyperglycemia and IR but do not affect body weight in DIO mice while DHA exhibits a more pronounced ameliorative effect in male mice. Both EPA- and DHA-enriched Lactobacillus and short-chain fatty acids (SCFAs)-producing species from Lachnospiraceae while reduced lipopolysaccharide (LPS)-producing Bilophila and Escherichia/Shigella. Compared with EPA, DHA-supplemented mice have more abundant propionic/butyric acid-producing bacteria, including Coprococcus, Butyricimonas synergistica, Bacteroides acidifaciens, and Intestinimonas, and less-abundant LPS-correlated species Streptococcus and p-75-a5. The shifts in gut microbiome co-occurred with the changes in levels of propionic/butyric acid, circulating LPS, and serotonin. Additionally, EPA/DHA supplementation attenuates adipose inflammation with upregulated glucose transporter 4 and Akt phosphorylation, indicating the improvement of insulin signaling. EPA and DHA differentially reverse IR and relieve adipose inflammation while modulating gut microbiome and SCFAs/LPS production, underscoring the gut-adipose axis as a primary target of EPA/DHA.

Prior Toxoplasma Gondii Infection Ameliorates Liver Fibrosis Induced by Schistosoma Japonicum through Inhibiting Th2 Response and Improving Balance of Intestinal Flora in Mice.

Schistosomiasis is an immunopathogenic disease in which a T helper (Th) cell type 2-like response plays vital roles. Hepatic fibrosis is its main pathologic manifestations, which is the leading cause of hepatic cirrhosis. Co-infections of Schistosoma japonicum (Sj) with other pathogens are frequently encountered but are easily ignored in clinical studies, and effective therapeutic interventions are lacking. In this study, we explored the effect of Toxoplasma gondii (Tg) prior infection on Th1/Th2 response, community shifts in gut microbiome (GM), and the pathogenesis of schistosomiasis in murine hosts. Mice were prior infected with Tg before Sj infection. The effects of co-infection on Th1/Th2 response and hepatic fibrosis were analyzed. Furthermore, we investigated this issue by sequencing 16S rRNA from fecal specimens to define the GM profiles during co-infection. Tg prior infection markedly reduced the granuloma size and collagen deposit in livers against Sj infection. Prior infection promoted a shift toward Th1 immune response instead of Th2. Furthermore, Tg infection promoted the expansion of preponderant flora and Clostridiaceae was identified as a feature marker in the GM of the co-infection group. Redundancy analysis (RDA)/canonical correspondence analysis (CCA) results showed that liver fibrosis, Th1/Th2 cytokines were significantly correlated (P < 0.05) with the GM compositions. Tg infection inhibits hepatic fibrosis by downregulating Th2 immune response against Sj infection, and further promotes the GM shifts through “gut–liver axis” in the murine hosts. Our study may provide insights into potential anti-fibrosis strategies in co-infection individuals.

Distinct murine cartilage microbial DNA signatures are seen in high fat diet-induced obesity and aging

Purpose: The strongest nongenetic risk factors for primary knee OA are advanced age and obesity. We have previously demonstrated that human cartilage exhibits a microbial DNA signature which changes in association with the development and progression of knee OA. In this study, we hypothesized that aging and obesity, known to cause gut microbiome shifts, would also produce shifts in cartilage microbial DNA patterns in mice.

Gut microbiome shifts with urbanization and potentially facilitates a zoonotic pathogen in a wading bird.

Microbial communities in the gastrointestinal tract influence many aspects of host health, including metabolism and susceptibility to pathogen colonization. These relationships and the environmental and individual factors that drive them are relatively unexplored for free-living wildlife. We quantified the relationships between urban habitat use, diet, and age with microbiome composition and diversity for 82 American white ibises (Eudocimus albus) captured along an urban gradient in south Florida and tested whether gut microbial diversity was associated with Salmonella enterica prevalence. Shifts in community composition were significantly associated with urban land cover and, to a lesser extent, diets higher in provisioned food. The diversity of genera was negatively associated with community composition associated with urban land cover, positively associated with age class, and negatively associated with Salmonella shedding. Our results suggest that shifts in both habitat use and diet for urban birds significantly alter gut microbial composition and diversity in ways that may influence health and pathogen susceptibility as species adapt to urban habitats.

Bariatric Surgery-Induced Shift in Gut Microbiome and NAFLD

Bariatric Surgery-Induced Shift in Gut Microbiome and NAFLD

Gastrointestinal (non-systemic) antibiotic rifaximin differentially affects chronic stress-induced changes in colon microbiome and gut permeability without effect on behavior

Chronic stress is often accompanied by gastrointestinal symptoms, which might be due to stress-induced shift of gut microbiome to pathogenic bacteria. It has been hypothesized that stress alters gut permeability and results in mild endotoxemia which exaggerates HPA activity and contributes to anxiety and depression. To reveal the relationship between microbiome composition, stress-induced gastrointestinal functions and behavior, we treated chronically stressed mice with non-absorbable antibiotic, rifaximin. The “two hits” stress paradigm was used, where newborn mice were separated from their mothers for 3 h daily as early life adversity (maternal separation, MS) and exposed to 4 weeks chronic variable stress (CVS) as adults. 16S rRNA based analysis of gut microbiome revealed increases of Bacteroidetes and Proteobacteria and more specifically, Clostridium species in chronically stressed animals. In mice exposed to MS + CVS, we found extenuation of colonic mucosa, increased bacterial translocation to mesenteric lymph node, elevation of plasma LPS levels and infiltration of F4/80 positive macrophages into the colon lamina propria. Chronically stressed mice displayed behavioral signs of anxiety-like behavior and neophobia. Rifaximin treatment decreased Clostridium concentration, gut permeability and LPS plasma concentration and increased colonic expression of tight junction proteins (TJP1, TJP2) and occludin. However, these beneficial effects of rifaximin in chronically stressed mice was not accompanied by positive changes in behavior. Our results suggest that non-absorbable antibiotic treatment alleviates stress-induced local pathologies, however, does not affect stress-induced behavior.

Gut Microbiome in Psoriasis is Perturbed Differently During Secukinumab and Ustekinumab Therapy and Associated with Response to Treatment.

Immunotherapy could change the complex host-microbial interactions. We aimed to investigate the dynamics of gut microbiome in response to secukinumab [an interleukin (IL)-17 inhibitor] and ustekinumab (an IL-12/23 inhibitor) therapy and its association with treatment response in psoriasis. This observational, longitudinal study collected a total of 114 fecal samples from 12 healthy controls and 34 patients with psoriasis at baseline and 3 and 6months after secukinumab (n = 24) or ustekinumab treatment (n = 10) and gut microbiomes were investigated using next-generation sequencing targeting 16S ribosomal RNA. Secukinumab treatment causes more profound alterations in gut microbiome, including increases in the relative abundance of phylum Proteobacteria and decreases in Bacteroidetes and Firmicutes, than ustekinumab treatment. The relative abundance of family Pseudomonadaceae, family Enterobacteriaceae and order Pseudomonadales also increased significantly following secukinumab therapy. In contrast, there was no significant change in gut microbiome composition following ustekinumab treatment, and only genus Coprococcus significantly increased after 6months of ustekinumab therapy. Moreover, we observed significant differences in baseline gut microbiome between responders and non-responders to secukinumab treatment. These results indicate that gut microbiome is altered differently after anti-IL17 and anti-IL12/23 treatment. Secukinumab (anti-IL17) therapy is associated with distinct and more profound gut microbiome shifts than ustekinumab therapy (anti-IL 12/23) in patients with psoriasis. Moreover, gut microbiome would serve as potential biomarkers of response to secukinumab treatment.

Antiobesogenic Potential of Seaweed Dulse (Palmaria palmata) in High-fat Fed C57BL/6 J Mice (P21-014-19)

ObjectivesThe growing obesity challenge around the world continues to warrant interventions that could mitigate disease onset and progression. This study aimed to evaluate the potential of seaweed supplementation using dulse (Palmaria palmata) and wakame (Undaria pinnatifida), in improving caloric management and insulin resistance, and mitigating inflammation and gut microbiome shifts in diet-induced obesity in C57BL/6 J mice. MethodsTwenty-four individually-caged C57BL/6 J mice were fed ad libitum with a high-fat diet (HFD) with and without seaweed inclusion, and another 8 mice for low-fat control (n = 8). Freeze-dried dulse and wakame were incorporated in the test diets at 5% inclusion level. Glucose tolerance test was performed during week 4 to assess insulin resistance state of test animals. After 9 weeks, fresh fecal samples were collected from all 32 mice prior to necropsy. These were used for the gut microbiome analysis using MiSeq. Fecal triglyceride levels were determined using Infinity Triglycerides Kit while plasma Monocyte Chemoattractant Protein-1 (MCP-1) was quantified using ELISA. ResultsDespite higher feed intake, dulse-fed mice had lower feed efficiency, indicating less weight gain from same amount of diet. This group also showed improved early-phase insulin response compared to HFD and wakame-fed groups. Plasma inflammatory marker MCP-1 levels were also significantly reduced in dulse-fed mice. While liver triglyceride levels were not affected with the dietary inclusion, fecal samples showed that there was higher lipid being excreted in dulse-fed group. This suggests that caloric excess and inflammatory progression may have been mitigated by increased lipid excretion in the feces. Gut microbiome analysis showed that dulse-fed mice retained microflora composition that is comparable to those fed with low-fat diet. ConclusionsOur work reveals that dulse supplementation improved obesity and associated metabolic parameters by increasing lipid excretion, improving early-phase insulin response, and mitigating both inflammation and gut microbiome shifts associated with HFD, more effectively than wakame. These provide initial evidences that dietary inclusion of dulse holds therapeutic promise in mitigating diet-induced obesity. Funding SourcesOregon State University Agricultural Research Foundation. Supporting Tables, Images and/or Graphs▪▪▪▪

Combination Therapy of TGF-β Blockade and Commensal-derived Probiotics Provides Enhanced Antitumor Immune Response and Tumor Suppression.

Galunisertib (Gal) is a transforming growth factor (TGF-β) blockade which is being investigated as a potential tumor immunotherapy candidate drug in clinical trials. However, primary or acquired resistance is often found in the recruited cancer patients, which limits its clinical application. Tumor immune microenvironment can be regulated by intestinal microbiota, leading to different therapeutic outcomes. It is hypothesized that manipulation of cancer patients' intestinal microbiome in the early stage of therapy may be a promising strategy to improve the therapeutic efficacy of Gal.Methods: 4T1 and H22 subcutaneous tumor bearing mice were used to evaluate the therapeutic effect. Escherichia coli strain Nissle 1917 (EcN), a widely used probiotic bacteria, was orally delivered to the tumor bearing mice daily along with Gal treatment. Antitumor effect of the combination therapy was evaluated by tumor volume, histological staining of tumor tissues. Furthermore, flow cytometry was performed to analyze the alteration of immune microenvironment in tumor bed after treatment. The suppressing effect of the combination therapy on tumor invasiveness and metastasis was evaluated in both mice and zebrafish xenografts models. Fecal sample 16S rRNA gene sequencing was conducted to analyze changes of intestinal microbial diversity. The effect of intestinal microbiota on tumor suppression after receiving EcN was further tested by fecal transplant.Results: The therapeutic outcomes in tumor growth inhibition and metastasis suppression of Gal were significantly potentiated by EcN, resulting from the strengthened antitumor immunity. EcN was able to relieve the immunosuppressive tumor microenvironment, which was evidenced by enhanced tumor-specific effector T cells infiltration and dendritic cells activation. Intestinal microbiota was modulated by EcN, illustrated by a shift of gut microbiome toward certain beneficial bacteria.Conclusion: These results suggested that Gal combined with EcN might be a novel therapeutic approach with great potential of clinical implications for cancer prevention or treatment.

The Gut Metagenome Changes in Parallel to Waist Circumference, Brain Iron Deposition, and Cognitive Function.

Microbiota perturbations seem to exert modulatory effects on emotional behavior, stress-, and pain-modulation systems in adult animals; however, limited information is available in humans. To study potential relationships among the gut metagenome, brain microstructure, and cognitive performance in middle-aged, apparently healthy, obese and nonobese subjects after weight changes. This is a longitudinal study over a 2-year period. A tertiary public hospital. Thirty-five (18 obese) apparently healthy subjects. Diet counseling was provided to all subjects. Obese subjects were followed every 6 months. Brain relaxometry (using magnetic resonance R2*), cognitive performance (by means of cognitive tests), and gut microbiome composition (shotgun). R2* increased in both obese and nonobese subjects, independent of weight variations. Changes in waist circumference, but not in body mass index, were associated with brain iron deposition (R2*) in the striatum, amygdala, and hippocampus in parallel to visual-spatial constructional ability and circulating beta amyloid Aβ42 levels. These changes were linked to shifts in gut microbiome in which the relative abundance of bacteria belonging to Caldiserica and Thermodesulfobacteria phyla were reciprocally associated with raised R2* in different brain nuclei. Of note, the increase in bacteria belonging to Tenericutes phylum was parallel to decreased R2* gain in the striatum, serum Aβ42 levels, and spared visual-spatial constructional ability. Interestingly, metagenome functions associated with circulating and brain iron stores are involved in bacterial generation of siderophores. Changes in the gut metagenome are associated longitudinally with cognitive function and brain iron deposition.

Sleeve gastrectomy drives persistent shifts in the gut microbiome

BackgroundChanges in the gut microbiome following bariatric surgery have been causally linked to metabolic benefits. ObjectivesWe sought to characterize and assess the stability of gut microbiome shifts following sleeve gastrectomy (SG). SettingUniversity laboratories. MethodsDiet-induced obese mice were randomized to SG or sham surgery. Mice were housed individually or cohoused such that one SG mouse was housed with one weight-matched, sham-operated mouse. Fecal samples were collected before and on postoperative days 7 and 28. Bacterial composition in feces was characterized by using next-generation Illumina sequencing of 16 S rRNA. ResultsSG mice lost more weight and were more insulin sensitive than sham mice independent of housing status (P<.05). One week following surgery, fecal samples from all mice showed shifts in the microbiome that only persisted in SG-operated mice. Cohousing did not alter the microbial composition of SG-operated mice. Cohoused sham-operated mice showed a unique shift in microbial composition on postoperative day 28 that differed from individually housed, sham-operated mice (P<.001). Cohousing did not affect metabolic outcomes of either SG or sham surgeries. ConclusionSG results in acute and sustained shifts in the gut microbiome. SG associated shifts are not altered by reexposure to obesity-associated gut microbiota.

Energy-dense diet triggers changes in gut microbiota, reorganization of gut‑brain vagal communication and increases body fat accumulation.

Obesity is associated with consumption of energy-dense diets and development of systemic inflammation. Gut microbiota play a role in energy harvest and inflammation and can influence the change from lean to obese phenotypes. The nucleus of the solitary tract (NTS) is a brain target for gastrointestinal signals modulating satiety and alterations in gut-brain vagal pathway may promote overeating and obesity. Therefore, we tested the hypothesis that high-fat diet‑induced changes in gut microbiota alter vagal gut-brain communication associated with increased body fat accumulation. Sprague-Dawley rats consumed a low energy‑dense rodent diet (LFD; 3.1 kcal/g) or high energy‑dense diet (HFD, 5.24 kcal/g). Minocycline was used to manipulate gut microbiota composition. 16S Sequencing was used to determine microbiota composition. Immunofluorescence against IB4 and Iba1 was used to determine NTS reorganization and microglia activation. Nodose ganglia from LFD rats were isolated and co-cultured with different bacteria strains to determine neurotoxicity. HFD altered gut microbiota with increases in Firmicutes/Bacteriodetes ratio and in pro-inflammatory Proteobacteria proliferation. HFD triggered reorganization of vagal afferents and microglia activation in the NTS, associated with weight gain. Minocycline-treated HFD rats exhibited microbiota profile comparable to LFD animals. Minocycline suppressed HFD‑induced reorganization of vagal afferents and microglia activation in the NTS, and reduced body fat accumulation. Proteobacteria isolated from cecum of HFD rats were toxic to vagal afferent neurons in culture. Our findings show that diet‑induced shift in gut microbiome may disrupt vagal gut‑brain communication resulting in microglia activation and increased body fat accumulation.

Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota.

In recent years, several associations between common chronic human disorders and altered gut microbiome composition and function have been reported. In most of these reports, treatment regimens were not controlled for and conclusions could thus be confounded by the effects of various drugs on the microbiota, which may obscure microbial causes, protective factors or diagnostically relevant signals. Our study addresses disease and drug signatures in the human gut microbiome of type 2 diabetes mellitus (T2D). Two previous quantitative gut metagenomics studies of T2D patients that were unstratified for treatment yielded divergent conclusions regarding its associated gut microbial dysbiosis. Here we show, using 784 available human gut metagenomes, how antidiabetic medication confounds these results, and analyse in detail the effects of the most widely used antidiabetic drug metformin. We provide support for microbial mediation of the therapeutic effects of metformin through short-chain fatty acid production, as well as for potential microbiota-mediated mechanisms behind known intestinal adverse effects in the form of a relative increase in abundance of Escherichia species. Controlling for metformin treatment, we report a unified signature of gut microbiome shifts in T2D with a depletion of butyrate-producing taxa. These in turn cause functional microbiome shifts, in part alleviated by metformin-induced changes. Overall, the present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication.