Changes in the composition and function of the gut microbiome accompany type 1 diabetes in pregnancy

BackgroundThe gut microbiome changes in response to a range of environmental conditions, life events and disease states. Pregnancy is a natural life event that involves major physiological adaptation yet studies of the microbiome in pregnancy are limited and their findings inconsistent. Pregnancy with type 1 diabetes (T1D) is associated with increased maternal and fetal risks but the gut microbiome in this context has not been characterized. By whole metagenome sequencing (WMS), we defined the taxonomic composition and function of the gut bacterial microbiome across 70 pregnancies, 36 in women with T1D.ResultsWomen with and without T1D exhibited compositional and functional changes in the gut microbiome across pregnancy. Profiles in women with T1D were distinct, with an increase in bacteria that produce lipopolysaccharides and a decrease in those that produce short-chain fatty acids, especially in the third trimester. In addition, women with T1D had elevated concentrations of fecal calprotectin, a marker of intestinal inflammation, and serum intestinal fatty acid-binding protein (I-FABP), a marker of intestinal epithelial damage.ConclusionsWomen with T1D exhibit a shift towards a more pro-inflammatory gut microbiome during pregnancy, associated with evidence of intestinal inflammation. These changes could contribute to the increased risk of pregnancy complications in women with T1D and are potentially modifiable by dietary means.9EttwuCftMDTXMZ-D9rhTqVideo abstract

Changes of Human Gut Microbiome Correlated with Metabolomics After Cranberry Juice Consumption in a Double-Blinded, Placebo Controlled, Crossover Study

Gut microbiota mediate vascular dysfunction in a murine model of sleep apnoea: effect of probiotics.

Intestinal microorganisms play important roles in maintaining host health, but their functions in aquatic animal hosts have yet to be fully elucidated. The Chinese mitten crab, Eriocheir sinensis, is one such example. We attempted to identify the shift of gut microbiota that occurred in response to infection of white spot syndrome virus (WSSV), an emerging viral pathogen in the crab aquaculture industry. The microbiota may exert some control over aspects of the viral pathogenesis. We investigated the changes in composition and structure of the crab gut microbiome during various WSSV infection stages of 6h post-infection (hpi) and 48hpi, using a 16S rRNA approach on the MiSeq Illumina sequencing platform. Four phyla (Firmicutes, Proteobacteria, Tenericutes and Bacteroidetes) were most dominant in the gut of E.sinensis regardless of the WSSV infection stages. However, further analysis revealed that over 12 bacterial phyla, 44 orders and 68 families were significantly different in abundance at various states of WSSV infection. Several intriguing aspects of E.sinensis gut bacteria that had not been previously reported were also uncovered, such as class Mollicutes was dominant here, but absent in crabs from Yangtze River estuary and Chongming Islands. Overall, this study provided the first evidence that changes in gut microbiome were closely associated with the severity of WSSV infection and that indicator taxa could be used to evaluate the crab health status.

Acetylated and butyrylated high amylose starch (HAMS-AB) is a prebiotic shown to be effective in type 1 diabetes (T1D) prevention in mouse models and is safe in adults with established T1D. HAMS-AB alters the gut microbiome profile with increased bacterial fermenters that produce short chain fatty acids (SCFAs) with anti-inflammatory and immune-modulatory effects. We performed a pilot study using a cross-over design to assess the safety and efficacy of 4 weeks of oral HAMS-AB consumption by recently diagnosed (< 2 years of diagnosis) youths with T1D. Seven individuals completed the study. The mean±SD age was 15.0±1.2 years, diabetes duration 19.5±6.3 months, 5/7 were female and 4/7 were White, all with a BMI of < 85th%. The prebiotic was safe. Following prebiotic intake, gut microbiome changes were seen, including a notable increase in the relative abundance of fermenters such as Bifidobacterium and Faecalibacterium. Treatment was also associated with changes in bacterial functional pathways associated with either improved energy metabolism (upregulation of tyrosine metabolism) or anti-inflammatory effects (reduced geraniol degradation). There were no differences in stool SCFA levels. Plasma metabolites associated with improved glycemia, such as hippurate, were significantly increased after treatment and there were positive and significant changes in the immune regulatory function of mucosal associated invariant T cells. There was a significant decrease in the area under the curve glucose but not C-peptide, as measured during a mixed meal tolerance testing, following the prebiotic consumption. In summary, the prebiotic HAMS-AB was safe in adolescents with T1D and showed promising effects on the gut microbiome composition, function and immune regulatory function.

Bariatric surgery is highly effective in achieving weight loss in children and adolescents with severe obesity, however the underlying mechanisms are incompletely understood, and gut microbiome changes are unknown. 1) To comprehensively examine gut microbiome and metabolome changes after laparoscopic vertical sleeve gastrectomy (VSG) in adolescents and 2) to assess whether the microbiome/metabolome changes observed with VSG influence phenotype using germ-free murine models. 1) A longitudinal observational study in adolescents undergoing VSG with serial stool samples undergoing shotgun metagenomic microbiome sequencing and metabolomics (polar metabolites, bile acids and short chain fatty acids) and 2) a human-to-mouse fecal transplant study. We show adolescents exhibit significant gut microbiome and metabolome shifts several months after VSG, with increased alpha diversity and notably with enrichment of oral-associated taxa. To assess causality of the microbiome/metabolome changes in phenotype, pre-VSG and post-VSG stool was transplanted into germ-free mice. Post-VSG stool was not associated with any beneficial outcomes such as adiposity reduction compared pre-VSG stool. However, post-VSG stool exhibited an inflammatory phenotype with increased intestinal Th17 and decreased regulatory T cells. Concomitantly, we found elevated fecal calprotectin and an enrichment of proinflammatory pathways in a subset of adolescents post-VSG. We show that in some adolescents, microbiome changes post-VSG may have inflammatory potential, which may be of importance considering the increased incidence of inflammatory bowel disease post-VSG.

Background: Taurine has been identified as a potential neuroprotective agent due to its potent antioxidant and anti-inflammatory properties. We found that delayed taurine supplementation after stroke decreased post-stroke depression (PSD) phenotypes seen in aged male mice, and this was independent of changes in infarct size. However, the mechanisms by which taurine contributes to post-stroke recovery remain elusive. Here, we investigated the effects of taurine in mice both male and female mice subjected to stroke. Hypothesis: We hypothesized that aged mice treated with taurine will have changes in microbial composition in the gut and changes in intestinal immune responses after stroke, and reduced PSD-like behavior compared to vehicle-treated mice. Methods: Aged C57BL/6 male and female mice (16-18 months) were subjected to a transient 60-minute middle cerebral artery occlusion. At 72h post-surgery mice were randomly assigned to one of two groups: 1). Taurine supplementation (in drinking water) or 2). Vehicle (drinking water without taurine). Neurologic deficit scores (NDS) and behavioral testing was performed at baseline and at regular intervals until euthanasia on post-stroke day 42. Flow cytometry was used to examine immune changes in the brain, blood, and spleen. 16S rRNA gene sequencing was used to determine changes in the gut microbiome composition. Results: Aged mice treated with taurine after stroke had significant reductions in stroke-induced weight loss (n=10/grp) compared to mice that received vehicle treatment (n=11/grp; p&lt;0.05). Taurine treated mice demonstrated improved NDS (p&lt;0.05) and higher grooming time in the sucrose splash test, indicative of reduced PSD (p&lt;0.05). Flow cytometry of gut tissue shows a reduction of stroke-associated cytotoxic T lymphocytes and increased B lymphocyte counts in taurine treated group compared to vehicle (**p&lt;0.01 n=16,18). 16S rRNA sequencing revealed taurine increased Enterocloster, a beneficial microbial genus, while depleting Bacteroides species (p&lt;0.05). Conclusion: Our results demonstrates that post-stroke taurine supplementation significantly changes the gut microbiome composition in parallel to enhancing overall recovery in aged mice. Although changes in gut microbiome appears to be a key contributor to taurine induced recovery, more studies are needed to further elucidate the underlying mechanisms before potentially translating taurine into a potential therapeutic strategy for adult stroke survivors.

Susceptibility to many human autoimmune diseases is under strong genetic control by class II human leukocyte antigen (HLA) allele combinations. These genes remain by far the greatest risk factors in the development of type 1 diabetes and celiac disease. Despite this, little is known about HLA influences on the composition of the human gut microbiome, a potential source of environmental influence on disease. Here, using a general population cohort from the All Babies in Southeast Sweden study, we report that genetic risk for developing type 1 diabetes autoimmunity is associated with distinct changes in the gut microbiome. Both the core microbiome and beta diversity differ with HLA risk group and genotype. In addition, protective HLA haplotypes are associated with bacterial genera Intestinibacter and Romboutsia. Thus, general population cohorts are valuable in identifying potential environmental triggers or protective factors for autoimmune diseases that may otherwise be masked by strong genetic control.

Preterm infants are often fed donor human milk (DHM) when the mother's own milk is insufficient or not available. Holder or Retort pasteurization is used to inactivate potential pathogens in DHM. The effects of DHM pasteurization methods on the infant gut microbiome are unknown. To compare the gut microbiome and clinical outcomes between preterm infants fed Holder- versus Retort-pasteurized DHM, we performed weekly collections of stool samples from infants born <34 weeks' gestation and/or <1500 g birth weight. We analyzed stool samples from 150 patients exclusively fed DHM [Retort (n = 80), Holder (n = 54)] or exclusively fed mother's own milk (n = 16). Whole-metagenome sequencing was performed to assess microbiome composition, diversity, and functional enrichment. Compared to infants fed Retort-pasteurized DHM, infants fed Holder-pasteurized DHM showed higher alpha-diversity (Chao-1 p = 0.007) and a higher abundance of beneficial anaerobes, such as Bacteroides thetaiotaomicron, Clostridium spp., and Bifidobacterium spp. Functional enrichment analysis revealed significant differences in carbohydrate metabolism, transport systems, and regulatory pathways between feeding groups. There were no statistically significant differences in short-term clinical outcomes, such as necrotizing enterocolitis, length of hospitalization or death. Differences in pasteurization methods for DHM resulted in measurable gut microbiome changes in preterm infants. It is known that the preterm infant gut microbiota is different in infants fed pasteurized donor milk compared to mother's own milk. However, the impact of different pasteurization methods for donor milk on the infant gut microbiome is unknown. We show that the type of pasteurization of donor human milk influences the gut microbiome and its function in preterm infants. In contrast to feeding Retort-pasteurized donor human milk, feeding Holder-pasteurized donor human milk generates an infant gut microbiome similar to feeding mother's own milk.

ObjectivesRecent studies pointed out that gut microbiome dysbiosis in HIV infection was possibly confounded in men who have sex with men (MSM), but there is a lack of evidence. It also remained unclear how MSM-associated gut microbiome dysbiosis affected human health. This study aimed to compare the differences in gut microbiome changes between HIV and MSM and reveal the potential impacts of MSM-associated gut microbiome dysbiosis on the immune system.MethodsWe searched available studies based on the PubMed database, and all gut microbiome changes associated with HIV infection and MSM were extracted from the enrolled studies. The gutMgene database was used to identify the target genes and metabolites of the gut microbiome. Bioinformatic technology and single-cell RNA sequencing data analysis were utilized to explore the impacts of these gut microbiome changes on human immunity.ResultsThe results showed significant overlaps between the gut microbiome associated with HIV and that of MSM. Moreover, bioinformatic analysis revealed that gut microbiome dysbiosis in MSM had an impact on several pathways related to immunity, including the IL-17 signaling pathway and Th17 cell differentiation. Additionally, target genes of MSM-associated gut microbiome were found to be highly expressed in monocytes and lymphocytes, suggesting their potential regulatory role in immune cells. Furthermore, we found that MSM-associated gut microbiome could produce acetate and butyrate which were reported to increase the level of inflammatory factors.ConclusionIn conclusion, this study highlighted that MSM-associated gut microbiome dysbiosis might increase the risk of HIV acquisition by activating the immune system. Further studies are expected to elucidate the mechanism by which gut microbiome dysbiosis in MSM modulates HIV susceptibility.

Alterations in the composition and function of the gut microbiome in women with fibromyalgia have recently been demonstrated, including changes in the relative abundance of certain bile acid-metabolizing bacteria. Bile acids can affect multiple physiological processes, including visceral pain, but have yet to be explored for association to the fibromyalgia gut microbiome. In this study, 16S rRNA sequencing and targeted metabolomic approaches were used to characterize the gut microbiome and circulating bile acids in a cohort of 42 women with fibromyalgia and 42 healthy controls. Alterations in the relative abundance of several bacterial species known to metabolize bile acids were observed in women with fibromyalgia, accompanied by significant alterations in the serum concentration of secondary bile acids, including a marked depletion of α-muricholic acid. Statistical learning algorithms could accurately detect individuals with fibromyalgia using the concentration of these serum bile acids. Serum α-muricholic acid was highly correlated with symptom severity, including pain intensity and fatigue. Taken together, these findings suggest serum bile acid alterations are implicated in nociplastic pain. The changes observed in the composition of the gut microbiota and the concentration of circulating secondary bile acids seem congruent with the phenotype of increased nociception and are quantitatively correlated with symptom severity. This is a first demonstration of circulating bile acid alteration in individuals with fibromyalgia, potentially secondary to upstream gut microbiome alterations. If corroborated in independent studies, these observations may allow for the development of molecular diagnostic aids for fibromyalgia as well as mechanistic insights into the syndrome.

PurposeIntestinal dysbiosis has been linked with the pathogenesis of several degenerative diseases. Moreover, the consumption of high‐fat diets (HFD) can drove to significant changes in the gut microbiome. Our purpose was to investigate changes in gut microbiome and retinal degeneration associated with the ingestion of HFD in a mice model of retinitis pigmentosa (RP).MethodsC57BL/6J mice and rd10 mice were fed either with normal chow (5.5% fat kcal) or with a HFD (61.6% fat kcal) for two weeks since P19. Retinal function was analyzed by electroretinography and optomotor test. Immunohistochemistry was employed to evaluate the structure and integrity of the retinal tissue. 16S rRNA gene sequencing was made to evaluate the gut microbiome.ResultsWe found a higher retinal degeneration in rd10 mice as compared to C57BL/6J mice, both fed with normal chow. Rd10 mice exhibited significantly reduced retinal responsiveness, as well as diminished visual acuity. This loss of retina function went with a decrease in the number of photoreceptor rows, and the remaining photoreceptors showed morphologic anomalies. The photoreceptor degeneration was accompanied by an inflammatory response of the retina, characterized by the proliferation of microglial cells and reactive gliosis of Müller cells. Likewise, the gut microbiome analysis revealed differences in alpha and beta diversity at the genera, species, and amplicon sequence variants levels. HFD generated a significant dysbiosis in the gut microbiome increasing potentially pro‐inflammatory bacteria as Bilophila sp., Alistipes sp. and Mucispirillum schaedleri, and drived the exacerbation of the retinal degeneration.ConclusionsIn retinitis pigmentosa, retinal dysfunction and degeneration are related to significant changes in the gut microbiome, which can be altered by diet, conducing to a worsening of the disease.SupportMINECOFEDER‐BFU2015‐67139‐R, FEDER‐PID2019‐106230RB‐I00, RETICS‐FEDER RD16/0008/0016, IDIFEDER/2017/064.

Background Type 1 Diabetes (T1D) is a severe autoimmune disease affecting the insulin-producing beta cells of the pancreas. T1D requires lifelong insulin treatment and is associated with increased mortality and morbidity. The cause is still unknown, but increasing incidence, clustering of new cases in space and time, seasonality and geographical differences suggest strong environmental influences. The genetic predisposition to T1D is mainly driven by the immune-related human leukocyte antigen (HLA) genes, where the HLA-DR3DQ2 and HLADR4DQ8 haplotypes confer the greatest risk. Clinical T1D can present at any age, often in early adolescence, but the autoimmune process driving the progressive loss of beta cells usually begins in early childhood. The gut microbiome is an important link between the environment and the immune system and is responsible for several metabolic and immunological functions. Different autoimmune disorders have been associated with alterations in microbiome composition and diversity, but the interaction between risk-associated HLA haplotypes, microbiome composition and T1D in the general population is still incompletely understood. Objective The overall aim of this thesis was to identify factors associated with development of type 1 diabetes in a general population cohort, with focus on early childhood infections and the early gut microbiome. Material and methodsThe All Babies In Southeast Sweden (ABIS) study is a prospective general population cohort followed from birth (1997-1999) to adulthood using questionnaires and biological samples. This thesis includes data from the birth (n=16 428), 1-year (n=11 093), 3-year (n=8 890) and 5-year questionnaires (n=7 445), blood samples sequenced for HLA haplotypes (n=3 947) and stool samples collected at 12 months of age (n=1 756). Logistic regression analyses and 16S rRNA sequencing were used to investigate the interaction between environmental exposures, microbiome composition and future T1D. As of December 2023, 168 individuals have been diagnosed with T1D according to the National Patient Register and validated by the National Drug Prescription Register. Results Maternal respiratory tract infection in the first trimester of pregnancy and a high frequency of gastroenteritis in the 1-3-year age interval were associated with increased risk of T1D. Other types of infection or antibiotic treatments during pregnancy or early childhood were not associated with T1D in this general population cohort. Presence or absence of risk-associated HLA haplotypes had significant effects on gut microbiome composition at 12 months of age. T1D in individuals with a neutral or decreased genetic risk was associated with a higher frequency of both viral and bacterial infections in early childhood, while T1D individuals with increased risk reported fewer episodes of the common cold compared to healthy controls. The core gut microbiome of infants with a future T1D diagnosis (n=16) had taxonomical and functional differences compared to matched controls (n=268) at 12 months of age. ConclusionsPerinatal or early childhood exposure to infections had a limited effect on the risk of developing T1D in this general population cohort. Individuals without risk-associated HLA haplotypes, possibly protected by a symbiotic (or “healthy”) microbiome, appear to require more environmental “triggers” to develop T1D compared to high-risk individuals. Differences in gut microbiome composition evident already at 12 months of age suggest that prevention of T1D requires modification of environmental influences in either pregnancy or infancy.

Type 2 diabetes (T2D) is a global epidemic that affects more than 8% of the world’s population and is a leading cause of death in Mexico. Diet and lifestyle are known to contribute to the onset of T2D. However, the role of the gut microbiome in T2D progression remains uncertain. Associations between microbiome composition and diabetes are confounded by medication use, diet, and obesity.Here we present data on a treatment-naive cohort of 405 Mexican individuals across varying stages of T2D severity. Associations between gut bacteria and more than 200 clinical variables revealed a defined set of bacterial genera that were consistent biomarkers of T2D prevalence and risk. Specifically, gradual increases in blood glucose levels, beta cell dysfunction, and the accumulation of measured T2D risk factors were correlated with the relative abundances of four bacterial genera. In a cohort of 25 individuals, T2D treatment—predominantly metformin—reliably returned the microbiome to the normoglycemic community state. Deep clinical characterization allowed us to broadly control for confounding variables, indicating that these microbiome patterns were independent of common T2D comorbidities, like obesity or cardiovascular disease. Our work provides the first solid evidence for a direct link between the gut microbiome and T2D in a critically high-risk population. In particular, we show that increased T2D risk is reflected in gradual changes in the gut microbiome. Whether or not these T2D-associated changes in the gut contribute to the etiology of T2D or its comorbidities remains to be seen.

We evaluated the impact of sex and mitochondrial-haplotype on the age-related changes in the fecal gut microbiome of the genetically heterogeneous rodent model, the OKC-HETB/W rat. Alpha-diversity, measuring richness and evenness of gut microbiome composition, did not change with age or mitochondrial-haplotype. However, beta-diversity, a measure of microbial differences among samples, was significantly modulated by age in male and female rats in both mitochondrial-haplotypes. The age-related changes in the microbiome differed markedly between male and female rats. Five microbial species changed significantly with age in male rats compared to nine microbial species in female rats. Only three of these microbes changed with age in both male and female rats. The mitochondrial-haplotype of the rats also affected how aging altered the microbiome. Interestingly, most of the microbial species that changed significantly with age were mitochondrial-haplotype and sex specific, i.e., changing in one sex and not the other. We also discovered that sex and mitochondrial-haplotype significantly affected the age-related variations in content of fecal short-chain fatty acids and plasma metabolites that influence or are regulated by the microbiome, e.g., tryptophan derived metabolites and bile acids. This study demonstrates that the host’s sex plays a significant role in how the gut microbiome evolves with age, even within a genetically diverse background. Importantly, this is the first study to show that the mitochondrial-haplotype of a host impacts the age-related changes in the microbiome and supports previous studies suggesting a bidirectional interaction between the gut microbiome and host mitochondria.