The development of the gut microbiome is crucial to human health, particularly during the first three years of life. Given its role in immune development, disturbances in the establishment process of the gut microbiome may have long term consequences. This review summarizes evidence for these claims, highlighting compositional changes of the gut microbiome during this critical period of life as well as factors that affect gut microbiome development. Based on human and animal data, we conclude that the early-life microbiome is a determinant of long-term health, impacting physiological, metabolic, and immune processes. The early-life gut microbiome field faces challenges. Some of these challenges are technical, such as lack of standardized stool collection protocols, inconsistent DNA extraction methods, and outdated sequencing technologies. Other challenges are methodological: small sample sizes, lack of longitudinal studies, and poor control of confounding variables. To address these limitations, we advocate for more robust research methodologies to better understand the microbiome's role in health and disease. Improved methods will lead to more reliable microbiome studies and a deeper understanding of its impact on health outcomes.

Type 1 diabetes (T1D) results from T cell-mediated destruction of pancreatic β-cells, requiring lifelong insulin therapy and glycemic monitoring. While genetic risk, particularly HLA class II, is well established, rising T1D incidence and earlier onset suggest environmental modifiers. Mouse models show that microbiome alterations influence β-cell autoimmunity, and human studies link microbiome composition to T1D, though specific microbial regulators remain unidentified. We examine host-microbiome interactions, including studies implicating enteroviruses in modulating islet autoimmunity. Mechanistic discoveries of microbial effects on diabetes have emerged from mouse model studies. We consider clinical applications, including microbiota-targeted therapies and biomarkers of microbiome-immune crosstalk. Future research should integrate microbial, genetic, environmental, and immune data using multi-omic approaches. Collaborative efforts combining immunology, microbiology, and clinical metadata will drive discovery and precision medicine in T1D.

The infant gut microbiome, which develops from birth, has profound and lasting effects on human health. Its establishment in early life is influenced by events such as delivery mode and feeding type. This study examined the effects of formula milk enriched with sn-2 palmitate on the gut microbiota of healthy term infants. We conducted a 16-week comparative analysis of three feeding groups: infants receiving high sn-2 palmitate formula (n = 30), regular vegetable oil formula (n = 32), and breast milk (n = 30). Using shotgun metagenomic sequencing of fecal samples, we performed a comprehensive assessment of the gut microbiota. While overall microbial composition and diversity were comparable across groups, the functional profile of the microbiome in infants receiving sn-2 palmitate-enriched formula more closely resembled that of breastfed infants compared to the control formula group. This similarity extended to microbial species interactions, virulence gene abundance, and metabolic pathway expression patterns. In addition, sn-2 palmitate promoted the proliferation of Bifidobacterium breve and enhanced the robustness of the gut microbial ecology. Notably, the phylogenetic analysis of B. breve strains in the sn-2 palmitate group showed closer alignment with the breastfed group compared to the control group. These findings suggest that sn-2 palmitate-enriched formula may confer gut microbiota functional benefits that more closely resemble those of breast milk compared to control formula milk. This study provides scientific evidence for the development of future functional infant formulas.

The gut microbiota plays a pivotal role in human life and undergoes dynamic changes throughout the human lifespan, from infancy to old age. During our life, the gut microbiota influences health and disease across life stages. This review summarizes the discussions and presentations from the symposium "Gut microbiota development from infancy to old age" held in collaboration with the Journal of Internal Medicine. In early infancy, microbial colonization is shaped by factors such as mode of delivery, antibiotic exposure, and milk-feeding practices, laying the foundation for subsequent increased microbial diversity and maturation. Throughout childhood and adolescence, microbial maturation continues, influencing immune development and metabolic health. In adulthood, the gut microbiota reaches a relatively stable state, influenced by genetics, diet, and lifestyle. Notably, disruptions in gut microbiota composition have been implicated in various inflammatory diseases-including inflammatory bowel disease, Type 1 diabetes, and allergies. Furthermore, emerging evidence suggests a connection between gut dysbiosis and neurodegenerative disorders such as Alzheimer's disease. Understanding the role of the gut microbiota in disease pathogenesis across life stages provides insights into potential therapeutic interventions. Probiotics, prebiotics, and dietary modifications, as well as fecal microbiota transplantation, are being explored as promising strategies to promote a healthy gut microbiota and mitigate disease risks. This review focuses on the gut microbiota's role in infancy, adulthood, and aging, addressing its development, stability, and alterations linked to health and disease across these critical life stages. It outlines future research directions aimed at optimizing the gut microbiota composition to improve health.

Obese individuals are categorized as either "Metabolically Abnormal Obesity" (MAO) or "Metabolically Healthy Obesity" (MHO) based on their insulin resistance and metabolic disorders. However, the intrinsic mechanism remains largely unknown. Through examining gut microbiota and fecal metabolome of MAO and MHO patients, we identified intestinal microorganism Ruminococcus torques (R. torques) and its metabolite mevalonolactone (MVL) as risk factors for insulin resistance and metabolic disorders. Both R. torques and MVL administration results in MAO phenotype in mice. In general, MVL is an intermediate metabolite in the eukaryotic mevalonate (MVA) pathway, however we found that prokaryote R. torques, has the potential to produce MVL. We further showed that MVL could directly bind to the transcription factor ZNF384, triggering its nucleation and subsequent binding to the promoter regions of Ggps1. Ggps1 enhance Ras prenylation and promotes insulin resistance. In conclusion, the abnormal colonization of R. torques in gut leads to an increased level of MVL in patients. This, in turn, affects the expression of Ggps1 via ZNF384, ultimately contributing to the development of MAO.

Despite the different pathologies and genetic susceptibilities of childhood ALL, T1DM and allergies, these conditions share epidemiological risk factors related to timing of infectious exposures and acquisition of the gut microbiome in infancy. We have assessed whether lower microbiome diversity (Shannon Index) and shared genus/species profiles are associated with pediatric ALL, allergies, and T1DM.

Literature search was performed using PubMed, Embase, Cochrane, and Web of Science databases. Case-control, meta-analyses, and cohort studies were considered for inclusion. Inclusion criteria: (i) subjects age 1-18 years at diagnosis, (ii) reports effect of microbiome measured prior to/at time of diagnosis/first intervention (iii) outcome of ALL, allergies, asthma, or T1DM, (iv) English text. Exclusion criteria: (i) age < 1 or >18 years at diagnosis, (ii) Down Syndrome-associated ALL, (iii) non-English text, (iv) reviews, pre-print, or abstracts, (v) heavily biased studies. Abstract and full text screening were performed by two independent reviewers. Data extraction was performed by one reviewer following PRISMA guidelines. Data were pooled using a random-effects model. Eighty-eight studies were included in the analysis, with seventy-seven in the qualitative analysis and 54 in the meta-analysis. Cases were found to have lower alpha-diversity than controls in ALL (SMD:-0.78, 95%CI:-1.21, -0.34), T1DM (SMD:-1.26, 95%CI:-3.49, 0.96), eczema (SMD:-0.34, 95%CI:-0.56, -0.12), atopy (SMD:-0.06, 95%CI:-0.34, 0.22), asthma (SMD:-0.37, 95%CI:-1.16, 0.42), and food allergy (SMD:-0.11, 95%CI:-0.63, 0.41).

These results highlight similarities in the microbiome diversity and composition of children with ALL, T1DM, and allergies. This is compatible with a common risk factor related to immune priming in infancy and highlights the gut microbiome as a potentially modifiable risk factor and preventative strategy for these childhood diseases.

This study investigates the roles of gut microbiome and secondary bile acid dysfunctions in type 1 diabetes (T1D) and explores targeted interventions to address them. It finds that T1D is associated with reduced gut microbial diversity and imbalance favoring harmful bacteria over beneficial ones. Additionally, patients with T1D exhibited impaired secondary bile acid metabolism. Interventions aimed at modulating the gut microbiome and metabolites are safe and improve glycemic control, reduce daily insulin dose, and reduce inflammation. These interventions reshape the gut microbiome toward a healthier state and enhance secondary bile acid production. Responders to the interventions show increased levels of beneficial bacteria and secondary bile acids, along with improved C-peptide responses. Overall, these findings suggest that targeted modulation of the gut microbiome and secondary bile acid metabolism could be a promising therapeutic approach for T1D management. The trial is registered at Chinese Clinical Trial Registry (ChiCTR-ONN-17011279).

Type 1 diabetes (T1D) results from the destruction of pancreatic beta cells by autoreactive T lymphocytes, leading to insulin deficiency and lifelong insulin dependence. It develops in genetically predisposed individuals, triggered by environmental or immunological factors. Although the exact causes of T1D remain unknown, the autoimmune pathogenesis of the disease is clearly indicated by the genetic risk conferred by allelic human leukocyte antigens (HLA), the almost obligatory presence of islet cell autoantibodies (AAbs) and immune cell infiltration of pancreatic islets from patients. At the same time, epidemiological data point to a role of environmental factors, notably enteroviral infections, in the disease, although precise causative links between specific pathogens and T1D have been difficult to establish. Studies of human pancreas organs from patients made available through repositories and the advent of high-dimensional high-throughput technologies for genomic and proteomic studies have significantly elucidated our understanding of the disease in recent years and provided mechanistic insights that can be exploited for innovative targeted therapeutic approaches. This short overview will summarise current salient knowledge on immune cell and beta cell dysfunction in T1D pathogenesis. PLAIN LANGUAGE SUMMARY: Type 1 diabetes (T1D) is a chronic disease where the body's own immune system attacks and destroys the insulin-producing beta cells in the pancreas. This leads to a lack of insulin, a hormone essential for regulating blood sugar, which means people with T1D need insulin for life. The disease can develop at any age but is most diagnosed in children and young adults. Despite advances in treatment, T1D still significantly reduces life expectancy, especially in countries with fewer healthcare resources. T1D develops in people with a genetic predisposition, often triggered by environmental factors such as viral infections or changes in the gut microbiome. The disease progresses silently through three stages: Stage 1: Autoantibodies to beta cell components appear, signalling the immune system is reacting against the pancreas, but there are no symptoms; Stage 2: Beta cell function starts to decline, but fasting blood sugar is still normal; Stage 3: Enough beta cells are destroyed that fasting blood sugar rises, and symptoms of diabetes appear. The risk of progressing from stage 1 to full-blown diabetes is about 35-50% within five years, and even higher from stage 2. Over 60 genes are linked to T1D risk, most of which affect how the immune system works. The strongest genetic risk comes from specific versions of histocompatibility genes, which help the immune system distinguish between the body's own cells and invaders. Some types of these genes make it easier for the immune system to mistakenly attack beta cells. However, 90% of people diagnosed with T1D have no family member with T1D, showing that genetics is only part of the story. Environmental factors also play a big role. For example, certain viral infections, especially with viruses infecting the intestine, are associated with a higher risk of developing T1D. The gut microbiome - the community of bacteria living in our intestines - also influences risk, with healthier, more diverse microbiomes appearing to offer some protection. In T1D, immune cells - especially so-called T lymphocytes - mistake beta cells in the pancreas for threats and destroy them. This process is called autoimmunity. The attack is often reflected by the presence of autoantibodies against proteins found in beta cells. Over time, as more beta cells are lost, the body can no longer produce enough insulin, leading to the symptoms of diabetes. Interestingly, not all people with T1D have the same pattern of disease. For example, children diagnosed before age 7 often have more aggressive disease, more autoantibodies, and stronger genetic risk factors than those diagnosed later. Much of our understanding of T1D has come from studying animal models, but new technologies now allow researchers to study human pancreas tissue and blood immune cells in greater detail. Scientists are also exploring how the gut microbiome, diet, and environmental exposures contribute to T1D risk and progression. Treatment currently focuses on replacing insulin, but researchers are working on therapies that target the immune system or aim to protect or replace beta cells. Strategies include immunotherapy, gene therapy, and even modifying the gut microbiome. The goal is to prevent or reverse the disease, not just manage its symptoms. In summary, T1D is a complex autoimmune disease influenced by both genes and the environment. It progresses silently before symptoms appear, and while insulin therapy is life-saving, new research is paving the way for treatments that could one day halt or even prevent the disease.

Type 1 diabetes (T1D) is a chronic hyperglycemia disorder emerging from beta-cell (insulin secreting cells of the pancreas) targeted autoimmunity. As the blood glucose levels significantly increase and the insulin secretion is gradually lost, the entire body suffers from the complications. Although various advances in the insulin analogs, blood glucose monitoring and insulin application practices have been achieved in the last few decades, a cure for the disease is not obtained. Alternatively, pancreas/islet transplantation is an attractive therapeutic approach based on the patient prognosis, yet this treatment is also limited mainly by donor shortage, life-long use of immunosuppressive drugs and risk of disease transmission. In research and clinics, such drawbacks are addressed by the endocrine tissue engineering of the pancreas. One arm of this engineering is scaffold-free models which often utilize highly developed cell-cell junctions, soluble factors and 3D arrangement of islets with the cellular heterogeneity to prepare the transplant formulations. In this review, taking T1D as a model autoimmune disease, techniques to produce so-called pseudoislets and their applications are studied in detail with the aim of understanding the role of mimicry and pointing out the promising efforts which can be translated from benchside to bedside to achieve exogenous insulin-free patient treatment. Likewise, these developments in the pseudoislet formation are tools for the research to elucidate underlying mechanisms in pancreas (patho)biology, as platforms to screen drugs and to introduce immunoisolation barrier-based hybrid strategies.

The gastrointestinal tract plays a vital role in the occurrence and treatment of metabolic diseases. Recent studies have convincingly demonstrated a bidirectional axis of communication between the gut and islets, enabling the gut to influence glucose metabolism and energy homeostasis in animals strongly. The 'gut-islet axis' is an essential endocrine signal axis that regulates islet function through the dialogue between intestinal microecology and endocrine metabolism. The discovery of glucagon-like peptide-1 (GLP-1), gastric inhibitory peptide (GIP) and other gut hormones has initially set up a bridge between gut and islet cells. However, the influence of other factors remains largely unknown, such as the homeostasis of the gut microbiota and the integrity of the gut barrier. Although gut microbiota primarily resides and affect intestinal function, they also affect extra-intestinal organs by absorbing and transferring metabolites derived from microorganisms. As a result of this transfer, islets may be continuously exposed to gut-derived metabolites and components. Changes in the composition of gut microbiota can damage the intestinal barrier function to varying degrees, resulting in increased intestinal permeability to bacteria and their derivatives. All these changes contribute to the severe disturbance of critical metabolic pathways in peripheral tissues and organs. In this review, we have outlined the different gut-islet axis signalling mechanisms associated with metabolism and summarized the latest progress in the complex signalling molecules of the gut and gut microbiota. In addition, we will discuss the impact of the gut renin-angiotensin system (RAS) on the various components of the gut-islet axis that regulate energy and glucose homeostasis. This work also indicates that therapeutic approaches aiming to restore gut microbial homeostasis, such as probiotics and faecal microbiota transplantation (FMT), have shown great potential in improving treatment outcomes, enhancing patient prognosis and slowing down disease progression. Future research should further uncover the molecular links between the gut-islet axis and the gut microbiota and explore individualized microbial treatment strategies, which will provide an innovative perspective and approach for the diagnosis and treatment of metabolic diseases.

Background: The impact of maternal obesity on offspring health remains a major and pressing issue. We investigated its impact on the development of the infant gut microbiome during the first six months of life, examining the taxonomic composition, metabolic pathways, and antibiotic resistance genes. Methods: Twenty-four mother-infant pairs were divided into maternally obese (OB, BMI > 36) and normal weight (BM) groups. Shotgun metagenomic sequencing was performed on stool samples collected at birth and at 1, 3, and 6 months. A total of 12 maternal samples and 23 infant samples (n = 35) in the obese group and 12 maternal samples and 30 infant samples (n = 42) in the control group were sequenced. The analysis included taxonomic profiling (MetaPhlAn 4), metabolic pathway analysis (HUMAnN 3), and antibiotic resistance gene screening (CARD/ABRicate). Results: The OB group showed reduced alpha diversity in the first month (p ≤ 0.01) and an increased Firmicutes/Bacteroidetes ratio, peaking at 3 months (p ≤ 0.001). The metabolic profiling revealed enhanced carbohydrate breakdown (p ≤ 0.001) in the BM group and lipid biosynthesis (p ≤ 0.0001) in the OB group pathways. Strong correlations emerged between Lactobacillales and fatty acid biosynthesis (r = 0.7, p ≤ 0.0001) and between Firmicutes and lincosamide (r = 0.8, p ≤ 0.0001). Conclusions: The infants of obese mothers had significantly altered development of the infant gut microbiome, affecting both composition and metabolic potential. These changes may have long-term health consequences and suggest potential therapeutic targets for intervention.

The gut microbiome, a dynamic and integral component of human health, has co-evolved with its host, playing essential roles in metabolism, immunity, and disease prevention. Traditional microbiome studies, primarily focused on microbial composition, have provided limited insights into the functional and mechanistic interactions between microbiota and their host. The advent of multi-omics technologies has transformed microbiome research by integrating genomics, transcriptomics, proteomics, and metabolomics, offering a comprehensive, systems-level understanding of microbial ecology and host-microbiome interactions. These advances have propelled innovations in personalized medicine, enabling more precise diagnostics and targeted therapeutic strategies. This review highlights recent breakthroughs in microbiome research, demonstrating how these approaches have elucidated microbial functions and their implications for health and disease. Additionally, it underscores the necessity of standardizing multi-omics methodologies, conducting large-scale cohort studies, and developing novel platforms for mechanistic studies, which are critical steps toward translating microbiome research into clinical applications and advancing precision medicine.

Type 1 diabetes (T1D) is linked to an altered gut microbiota characterized by reduced short-chain fatty acid (SCFA) production. Oral delivery of a SCFA-yielding biotherapy in adults with T1D was followed by increased SCFAs, altered gut microbiota and immunoregulation, as well as delaying diabetes in preclinical models. Here, we show that SCFA-biotherapy in humans is accompanied by remodeling of the gut proteome and mucosal immune homeostasis. Metabolomics showed arginine, glutamate, nucleotide and tryptophan metabolism were enriched following the SCFA-biotherapy, and found metabolites that correlated with glycemic control. Fecal microbiota transfer demonstrated that the microbiota of SCFA-responders delayed diabetes progression in humanized gnotobiotic mice. The protected mice increased similar metabolite pathways to the humans including producing aryl-hydrocarbon receptor ligands and reducing inflammatory mucosal immunity and increasing IgA production in the gut. These data demonstrate that a potent SCFA immunomodulator promotes multiple beneficial pathways and supports targeting the microbiota as an approach against T1D. Trial registration: Australia New Zealand Clinical Trials Registry ACTRN12618001391268.

Earlier studies have implicated a crucial link between diabetic nephropathy (DN) and the gut microbiota (GM) by considering the gut-kidney axis; however, the specific cause-and-effect connections between these processes remain unclear.

To compare changes in the GM between DN patients and control subjects, a review of observational studies was performed. The examination focused on the phylum, family, genus, and species/genus categories. To delve deeper into the cause-effect relationship, instrumental variables for 211 GM taxa (9 phyla, 16 classes, 20 orders, 35 families, and 131 genera), which were eligible for the mbQTL (microbial quantitative trait locus) mapping analysis, were collected from the Genome Wide Association Study (GWAS). A Mendelian randomization investigation was then conducted to gauge their impact on DN susceptibility using data from the European Bioinformatics Institute (EBI) and the FinnGen consortium. The European Bioinformatics Institute data included 1032 DN patients and 451,248 controls, while the FinnGen consortium data consisted of 3283 DN patients and 210,463 controls. Two-sample Mendelian randomization (TSMR) was utilized to determine the link between the GM and DN. The primary method for analysis was the inverse variance weighted (IVW) approach. Moreover, a reverse Mendelian randomization analysis was carried out, and the findings were validated through sensitivity assessments.

This review examined 11 observational studies that satisfied the inclusion and exclusion criteria. There was a significant difference in the abundance of 144 GM taxa between DN patients and controls. By employing the MR technique, 13 bacteria were pinpointed as having a causal link to DN (including 3 unknown GM taxa). Even after Bonferroni correction, the protective impact of the phylum Proteobacteria and genus Dialister (Sequeira et al. Nat Microbiol. 5:304-313, 2020; Liu et al. EBioMedicine. 90:104527, 2023) and the harmful impact of the genus Akkermansia, family Verrucomicrobiaceae, order Verrucomicrobia and class Verrucomicrobiae on DN remained significant. No noticeable heterogeneity or horizontal pleiotropy was detected in the instrumental variables (IVs). However, reverse MR investigations have failed to reveal any substantial causal relationship between DN and the GM.

Differences in the GM among DN patients and healthy controls are explored in observational studies. We verified the possible connection between certain genetically modified genera and DN, thereby emphasizing the connection between the "gut-kidney" axis and new insights into the GM's role in DN pathogenesis underlying DN. Investigations into this association are necessary, and novel biomarkers for the development of targeted preventive strategies against DN are needed.

Liver fibrosis, a complex process resulting from most chronic liver diseases, remains devoid of effective treatments. An increasing body of evidence links liver fibrosis to the "gut-liver axis", with disruptions in the gut microbiota-host balance emerging as a critical contributor to its progression. Cinnamaldehyde (Cin), a natural compound with antioxidant, anti-inflammatory, and anticytotoxic properties, has shown potential in counteracting hepatic stellate cell (HSC) activation. Additionally, Cin has been shown to promote probiotics in the intestine, thereby restoring a healthy microbial community. These characteristics position Cin as a promising candidate for liver fibrosis treatment through modulation of the gut-liver axis. In this study, a Vitamin A (Va)-formulated Cin Nanoemulsion (Va-Cin@NM) was developed to enhance the physicochemical stability of Cin while preserving intestinal homeostasis and facilitating targeted liver deposition. In bile duct ligation (BDL)-induced liver fibrosis in rats, Va-Cin@NM intervention significantly reduced bile duct-like structure proliferation and collagen deposition in the liver. These effects are likely attributed to the restoration of gut microbiota, increased short-chain fatty acid (SCFA) concentrations, and improved intestinal integrity. Moreover, Va-Cin@NM treatment suppressed harmful bacterial populations in the liver, thus mitigating immune injury and inflammatory cell recruitment. Consequently, oxidative stress and HSC activation were attenuated. Overall, Va-Cin@NM demonstrates significant potential as a nanotherapeutic approach for liver fibrosis by modulating the gut-liver axis.

Pancreatic cancer ranks among the most lethal digestive malignancies, exhibiting a steadily increasing incidence and mortality worldwide. Despite significant advances in cancer research, the 5-year survival rate remains below 10%, predominantly due to delayed diagnosis and limited therapeutic options. Concurrently, the gut microbiota-an integral component of host physiology-has emerged as a crucial player in the pathogenesis of pancreatic cancer. Mounting evidence indicates that alterations in gut microbial composition and function may influence tumor initiation, progression, and response to therapy. This review provides an in-depth examination of the intricate interplay between the gut microbiome and pancreatic cancer, highlighting potential diagnostic biomarkers and exploring microbiome-targeted therapeutic strategies to improve patient outcomes.

The healthy human infant gut microbiome undergoes stereotypical changes in taxonomic composition between birth and maturation to an adult-like stable state. During this time, extensive communication between microbiota and the host immune system contributes to health status later in life. Although there are many reported associations between microbiota compositional alterations and disease in adults, less is known about how microbiome development is altered in pediatric diseases. One pediatric disease linked to altered gut microbiota composition is cystic fibrosis (CF), a multi-organ genetic disease involving impaired chloride secretion across epithelia and heightened inflammation both in the gut and at other body sites. Here, we use shotgun metagenomics to profile the strain-level composition and developmental dynamics of the infant fecal microbiota from several CF and non-CF longitudinal cohorts spanning from birth to greater than 36 months of life. We identify a set of keystone species that define microbiota development in early life in non-CF infants but are missing or decreased in relative abundance in infants with CF, resulting in a delayed pattern of microbiota maturation, persistent entrenchment in a transitional developmental phase, and subsequent failure to attain an adult-like stable microbiota. Delayed maturation is strongly associated with cumulative antibiotic treatments, and we also detect the increased relative abundance of oral-derived bacteria and higher levels of fungi in infants with CF, features that are associated with decreased gut bacterial density. These findings suggest the potential for future directed therapies targeted at overcoming developmental delays in microbiota maturation for infants with CF.IMPORTANCEThe human gastrointestinal tract harbors a diversity of microbes that colonize upon birth and collectively contribute to host health throughout life. Infants with the disease cystic fibrosis (CF) harbor altered gut microbiota compared to non-CF counterparts, with lower levels of beneficial bacteria. How this altered population is established in infants with CF and how it develops over the first years of life is not well understood. By leveraging multiple large non-CF infant fecal metagenomic data sets and samples from a CF cohort collected prior to highly effective modulator therapy, we define microbiome maturation in infants up to 3 years of age. Our findings identify conserved age-diagnostic species in the non-CF infant microbiome that are diminished in abundance in CF counterparts that instead exhibit an enrichment of oral-derived bacteria and fungi associated with antibiotic exposure. Together, our study builds toward microbiota-targeted therapy to restore healthy microbiota dynamics in infants with CF.

Loss of early-life microbial diversity is correlated with diabetes, yet mechanisms by which microbes influence disease remain elusive. We report a critical neonatal window in mice when microbiota disruption results in lifelong metabolic consequences stemming from reduced β cell development. We show evidence for the existence of a similar program in humans and identify specific fungi and bacteria that are sufficient for β cell growth. The microbiota also plays an important role in seeding islet-resident macrophages, and macrophage depletion during development reduces β cells. Candida dubliniensis increases β cells in a macrophage-dependent manner through distinctive cell wall composition and reduces murine diabetes incidence. Provision of C. dubliniensis after β cell ablation or antibiotic treatment improves β cell function. These data identify fungi as critical early-life commensals that promote long-term metabolic health.

The goal of the TEDDY (The Environmental Determinants of Diabetes in the Young) study is to elucidate factors leading to the initiation of islet autoimmunity (first primary outcome) and those related to progression to type 1 diabetes mellitus (T1DM; second primary outcome). This Review outlines the key findings so far, particularly related to the first primary outcome. The background, history and organization of the study are discussed. Recruitment and follow-up (from age 4 months to 15 years) of 8,667 children showed high retention and compliance. End points of the presence of autoantibodies against insulin, GAD65, IA-2 and ZnT8 revealed the HLA-associated early appearance of insulin autoantibodies (1-3 years of age) and the later appearance of GAD65 autoantibodies. Competing autoantibodies against tissue transglutaminase (marking coeliac disease autoimmunity) also appeared early (2-4 years). Genetic and environmental factors, including enterovirus infection and gastroenteritis, support mechanistic differences underlying one phenotype of autoimmunity against insulin and another against GAD65. Infant growth and both probiotics and high protein intake affect the two phenotypes differently, as do serious life events during pregnancy. As the end of the TEDDY sampling phase is approaching, major omics approaches are in progress to further dissect the mechanisms that might explain the two possible endotypes of T1DM.

People with type 1 diabetes (T1D) have a significantly elevated risk of stroke, but the mechanism through which T1D worsens ischemic stroke remains unclear. This study was aimed at investigating the roles of T1D-associated changes in the gut microbiota in aggravating ischemic stroke and the underlying mechanism. Fecal 16SrRNA sequencing indicated that T1D mice and mice with transplantation of T1D mouse gut microbiota had lower relative abundance of butyric acid producers, f_Erysipelotrichaceae and g_Allobaculum, and lower content of butyric acid in feces. After middle cerebral artery occlusion (MCAO), these mice had poorer neurological outcomes and more severe inflammation, but higher expression of myeloid differentiation factor 88 (MyD88) in the ischemic penumbra; moreover, the microglia were inclined to polarize toward the pro-inflammatory type. Administration of butyrate to T1D mice in the drinking water alleviated the neurological damage after MCAO. Butyrate influenced the response and polarization of BV2 and decreased the production of inflammatory cytokines via MyD88 after oxygen-glucose deprivation/reoxygenation. Knocking down MyD88 in the brain alleviated neurological outcomes and decreased the concentrations of inflammatory cytokines in the brain after stroke in mice with transplantation of T1D mouse gut microbiota. Poor neurological outcomes and aggravated inflammatory responses of T1D mice after ischemic stroke may be partly due to differences in microglial polarization mediated by the gut microbiota-butyrate-MyD88 pathway. These findings provide new ideas and potential intervention targets for alleviating neurological damage after ischemic stroke in T1D.

Food sensitization (FS) develops in early infancy and is a risk factor for subsequent food allergy (FA). Recent evidence suggests relationships of gut microbiota with FS and FA. However, little is known about the role of neonatal gut microbiota in the pathobiology of these manifestations.

We sought to characterize gut microbiota in children using an enterotyping approach and determine the association of gut microbiota and the enterotypes with the development of FS and FA.

We combined gut microbiome and fecal short-chain fatty acid data from 2 longitudinal birth-cohort studies in Japan, clustered the microbiome data from children who were 1 week to 7 years old and their mothers and identified enterotypes. We also determined the associations of gut microbiota and enterotypes with risks of developing FS and FA across the 2 studies using multivariable regression models.

Data from the 2563 microbiomes identified 6 enterotypes. More gut bacteria (eg, Bifidobacterium) in 1-month-old children showed significant relationships with the development of FS and FA than in 1-week-old children. Enterotypes at 1 month old consisted of Bacteroides-dominant, Klebsiella-dominant, and Bifidobacterium-dominant enterotypes. Bifidobacterium-dominant enterotypes with the highest fecal propionate concentration had the lowest risks of developing FS and FA, especially of hen egg white sensitization. Bifidobacterium-dominant enterotypes had lower risks at 2 years old in one study (vs Bacteroides-dominant enterotype, adjusted odds ratio [adjOR]: 0.10, 95% CI: 0.01-0.78; vs Klebsiella-dominant enterotype, adjOR: 0.10, 95% CI: 0.01-0.77) and at 9 months old in the other study (vs Bacteroides-dominant enterotype, adjOR: 0.33, 95% CI: 0.11-0.91).

In these birth-cohort studies, gut microbiome clustering identified distinct neonatal enterotypes with differential risks of developing FS and FA.

Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy with an incidence rate of up to 8% worldwide. However, the complete pathogenesis is still unknown. Obesity increases the risk of developing PE threefold. To better understand the relationship of maternal risk factors, the BPH/5 mouse was described as a model of superimposed PE. Previous research demonstrated that adult BPH/5 female mice have an adverse cardiometabolic phenotype characterized by hypertension, obesity with increased white adipose tissue, and dyslipidemia, exaggerated by pregnancy. We hypothesize that BPH/5 mice have gut dysbiosis characterized by changes in alpha and beta diversity of bacterial community structure as well as perturbed short-chain fatty acids (SCFAs) compared with controls in pregnancy. Fecal samples were used for Illumina sequencing of 16S v4 rRNA amplicons. Microbial community composition of the pregnant BPH/5 mice compared with C57 controls was different using permutational multivariate analysis of variance (PERMANOVA) with Bray-Curtis dissimilarity. Alpha diversity was increased in pregnant BPH/5 dams compared with controls. Alistipes and Helicobacter were increased, whereas Bacteroides, Lactobacillus, Parasutterella, and Parabacteroides were decreased compared with controls. Fecal SCFAs were not different between groups, but BPH/5 serum acetic and butyric acids were decreased, whereas isobutyric and isovaleric acids were increased specifically in pregnancy. BPH/5 pregnant colons had decreased expression of free fatty acid receptor, GPR41. In conclusion, the BPH/5 maternal fecal microbiome demonstrates microbial dysbiosis characterized by community structure and diversity changes before and after the onset of pregnancy. Gut dysbiosis may be a key mechanism linking SCFA signaling and obesity to the BPH/5 PE-like phenotype.NEW & NOTEWORTHY This is the first time the pregnant fecal microbiome has been identified in the BPH/5 spontaneous mouse model of superimposed PE. Community composition changed with the onset of pregnancy in this model. BPH/5 showed an altered colonic signaling with decreased GPR41 expression, suggesting that gut dysbiosis may link SCFA signaling to the PE phenotype. This data highlights the importance of the maternal obesogenic gut microbiome in pregnancy.

The neonatal microbiome has been the focus of considerable research over the past two decades and studies have added fascinating information in terms of early microbial patterns and how these relate to various disease processes. One difficulty with the interpretation of these relationships is that such data is associative and provides little in terms of proof of causality or the underpinning mechanisms. Integrating microbiome data with other omics such as the proteome, inflammatory mediators, and the metabolome is an emerging approach to address this gap. Here we discuss these omics, their integration, and how they can be applied to improve our understanding, treatment, and prevention of disease. IMPACT: This review introduces the concept of multiomics in neonatology and how emerging technologies can be integrated improve understanding, treatment, and prevention of disease. We highlight considerations for performing multiomic research in neonates and the need for validation in separate cohorts and/or relevant model systems. We summarise how the use of multiomics is expanding and lay out steps to bring this to the clinic to enable precision medicine.

Background: Type 1 diabetes (T1D) is a severe chronic T-cell mediated autoimmune disease that attacks the insulin-producing beta cells of the pancreas. The multifactorial nature of T1D involves both genetic and environmental components, with recent research focusing on the gut microbiome as a crucial environmental factor in T1D pathogenesis. The gut microbiome and its metabolites play an important role in modulating immunity and autoimmunity. In recent years, studies have revealed significant alterations in the taxonomic and functional composition of the gut microbiome associated with the development of islet autoimmunity and T1D. These changes include reduced production of short-chain fatty acids, altered bile acid and tryptophan metabolism, and increased intestinal permeability with consequent perturbations of host (auto)immune responses. Methods/Results: In this review, we summarize and discuss recent observational, mechanistic and etiological studies investigating the gut microbiome in T1D and elucidating the intricate role of gut microbes in T1D pathogenesis. Moreover, we highlight the recent advances in intervention studies targeting the microbiota for the prevention or treatment of human T1D. Conclusions: A deeper understanding of the evolution of the gut microbiome before and after T1D onset and of the microbial signals conditioning host immunity may provide us with essential insights for exploiting the microbiome as a prognostic and therapeutic tool.

Dairy consumption has been associated with various health outcomes that may be mediated by changes in gut microbiota.

This cross-sectional study investigated the association between the colonic mucosa-associated gut microbiota and the self-reported intake of total dairy, milk, cheese, and yogurt. A total of 97 colonic mucosal biopsies collected from 34 polyp-free individuals were analyzed. Dairy consumption in the past year was assessed using a food frequency questionnaire. The 16S rRNA gene V4 region was amplified and sequenced. Operational taxonomic unit (OTU) classification was performed using the UPARSE and SILVA databases. OTU diversity and relative abundance were compared between lower vs. higher dairy consumption groups. Multivariable negative binomial regression models for panel data were used to estimate the incidence rate ratio and 95% confidence interval for bacterial counts and dairy consumption. False discovery rate-adjusted p values (q value) < 0.05 indicated statistical significance.

Higher total dairy and milk consumption and lower cheese consumption were associated with higher alpha microbial diversity (adjusted p values < 0.05). Higher total dairy and milk consumption was also associated with higher relative abundance of Faecalibacterium. Higher milk consumption was associated with higher relative abundance of Akkermansia. Higher total dairy and cheese consumption was associated with lower relative abundance of Bacteroides.

Dairy consumption may influence host health by modulating the structure and composition of the colonic adherent gut microbiota.

Type 1 diabetes (T1D) is a complex disease triggered by a combination of genetic and environmental factors, where abnormal autoimmune responses lead to progressive damage of the pancreatic β cells and severe glucose metabolism disorder. Recent studies have increasingly highlighted the close link between gut microbiota dysbiosis and the development of T1D. This review delves into existing population studies to explore the intricate interactions between the gut microbiota and the immune and metabolic homeostasis in T1D. It summarizes how changes in the structure and function of the gut microbiota are closely associated with the onset and progression of T1D across its natural course and clinical stages. More importantly, based on evidence accumulated from clinical observations and trials, we pioneer the discussion on gut microbiota-based T1D prevention and treatment strategies, this not only enriches our understanding of the complex pathological mechanisms of T1D but also provides potential directions for developing novel prevention and treatment strategies.

The global prevalence of autoimmune diseases has surged in recent decades. Consequently, environmental triggers have emerged as crucial contributors to autoimmune diseases, equally relevant to classical risk factors, such as genetic polymorphisms, infections, and smoking. Sequencing-based approaches have demonstrated distinct gut microbiota compositions in individuals with autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, type 1 diabetes mellitus (T1D), and systemic lupus erythematosus, compared to healthy controls. Furthermore, fecal microbiota transplantation and microbial inoculation experiments have supported the hypothesis that alterations in the gut microbiota can influence autoimmune responses and disease outcomes. Herein, we propose that intestinal helminths may serve as a critical factor in inducing alterations in the gut microbiota. The concept of helminth-mediated suppression of autoimmune diseases in humans is supported by substantial evidence, aligning with the long-standing "hygiene hypothesis." This review focused on T1D to explore the interactions between parasites, gut microbiota, and the immune system-a topic that remains a black box within this intricate triangular relationship.

Type 1 diabetes (T1D) is an autoimmune-mediated disorder caused by the destruction of pancreatic beta cells. Although there is an underlying genetic predisposition to developing T1D, the trigger is multifactorial and likely includes environmental factors. The intestinal microbiome has been identified as one such factor. Previous studies have illustrated differences in the microbiota of people with T1D compared with healthy controls. This study aims to describe the evolution of the microbiome and metabolome during the first year of clinical T1D, or stage 3 T1D diagnosis, and investigate whether there are differences in the microbiome and metabolome of children who present with and without diabetic ketoacidosis. The study will also explore possible associations between the microbiome, metabolome, glycaemic control and beta cell reserve.

This prospective cohort study will include children with newly diagnosed T1D and sibling controls (n=100, males and females) and their faecal microbiome will be characterised using shotgun metagenomic sequencing at multiple time points during the first year of diagnosis. We will develop a microbial culture biobank based on culturomic studies of stool samples from the healthy controls that will support future investigation. Metabolomic analysis will aim to identify additional biomarkers which may be involved in disease presentation and progression. Through this initial exploratory study, we aim to identify specific microbial biomarkers which may be used as future interventional targets throughout the various stages of T1D progression.

This study has been approved by the Clinical Research Ethics Committee of the Cork Teaching Hospitals. Study results will be available to patients with T1D and their families, carers, support networks and microbiome societies and other researchers.

The clinicaltrials.gov registration number for this trial is NCT06157736.

The initial colonization of the infant gut is a complex process that defines the foundation for a healthy microbiome development. Bifidobacterium longum is one of the first colonizers of newborns' gut, playing a crucial role in the healthy development of both the host and its microbiome. However, B. longum exhibits significant genomic diversity, with subspecies (e.g., Bifidobacterium longum subsp. infantis and subsp. longum) displaying distinct ecological and metabolic strategies including differential capabilities to break down human milk glycans (HMGs). To promote healthy infant microbiome development, a good understanding of the factors governing infant microbiome dynamics is required.

We analyzed newly sequenced gut microbiome samples of mother-infant pairs from the Amsterdam Infant Microbiome Study (AIMS) and four publicly available datasets to identify important environmental and bifidobacterial features associated with the colonization success and succession outcomes of B. longum subspecies. Metagenome-assembled genomes (MAGs) were generated and assessed to identify characteristics of B. longum subspecies in relation to early-life gut colonization. We further implemented machine learning tools to identify significant features associated with B. longum subspecies abundance.

B. longum subsp. longum was the most abundant and prevalent gut Bifidobacterium at one month, being replaced by B. longum subsp. infantis at six months of age. By utilizing metagenome-assembled genomes (MAGs), we reveal significant differences between and within B. longum subspecies in their potential to break down HMGs. We further combined strain-tracking, meta-pangenomics and machine learning to understand these abundance dynamics and found an interplay of priority effects, milk-feeding type and HMG-utilization potential to govern them across the first six months of life. We find higher abundances of B. longum subsp. longum in the maternal gut microbiome, vertical transmission, breast milk and a broader range of HMG-utilizing genes to promote its abundance at one month of age. Eventually, we find B. longum subsp. longum to be replaced by B. longum subsp. infantis at six months of age due to a combination of nutritional intake, HMG-utilization potential and a diminishment of priority effects.

Our results establish a strain-level ecological framework explaining early-life abundance dynamics of B. longum subspecies. We highlight the role of priority effects, nutrition and significant variability in HMG-utilization potential in determining the predictable colonization and succession trajectories of B. longum subspecies, with potential implications for promoting infant health and well-being.

Characterizing the dynamics of microbial community succession in the infant gut microbiome is crucial for understanding child health and development, but no normative model currently exists. Here, we estimate child age using gut microbial taxonomic relative abundances from metagenomes, with high temporal resolution (±3 months) for the first 1.5 years of life. Using 3154 samples from 1827 infants across 12 countries, we trained a random forest model, achieving a root mean square error of 2.56 months. We identified key taxonomic predictors of age, including declines in Bifidobacterium spp. and increases in Faecalibacterium prausnitzii and Lachnospiraceae. Microbial succession patterns are conserved across infants from diverse human populations, suggesting universal developmental trajectories. Functional analysis confirmed trends in key microbial genes involved in feeding transitions and dietary exposures. This model provides a normative benchmark of "microbiome age" for assessing early gut maturation that may be used alongside other measures of child development.

Type 1 Diabetes (T1D) is a progressive autoimmune disease often identified in childhood or adolescence, with early stages detectable through pre-diabetic markers such as autoantibodies and subclinical beta-cell dysfunction. The identification of the pre-T1D stage is critical for preventing complications, such as diabetic ketoacidosis, and for enabling timely interventions that may alter disease progression. This review examines the multifaceted approach to managing T1D risk in adolescents and teens, emphasizing early detection, nutritional interventions, beta-cell preservation strategies, and psychosocial support. Screening for T1D-associated autoantibodies offers predictive insight into disease risk, particularly when combined with education and family resources that promote lifestyle adjustments. Although nutritional interventions alone are not capable of preventing T1D, certain lifestyle interventions, such as weight management and specific nutritional choices, have shown the potential to preserve insulin sensitivity, reduce inflammation, and mitigate metabolic strain. Pharmacological strategies, including immune-modulating drugs like teplizumab, alongside emerging regenerative and cell-based therapies, offer the potential to delay disease onset by protecting beta-cell function. The social and psychological impacts of a T1D risk diagnosis are also significant, affecting adolescents' quality of life, family dynamics, and mental health. Supportive interventions, including counseling, cognitive-behavioral therapy (CBT), and group support, are recommended for managing the emotional burden of pre-diabetes. Future directions call for integrating universal or targeted screening programs within schools or primary care, advancing research into nutrition and psychosocial support, and promoting policies that enhance access to preventive resources. Advocacy for the insurance coverage of screening, nutritional counseling, and mental health services is also crucial to support families in managing T1D risk. By addressing these areas, healthcare systems can promote early intervention, improve beta-cell preservation, and support the overall well-being of adolescents at risk of T1D.

Antibiotics, as the most commonly prescribed class of drugs in neonatal intensive care units, have an important impact on the developing neonatal gut microbiota. Therefore, comprehending the effects of commonly used antibiotic therapy on the gut microbiota and butyrate-producers in early infants could provide information for therapeutic decision-making in the NICU.

To explore the effects of antibiotic therapy on the early development of gut microbiota and butyrate-producers in early infants.

A total of 72 infants were included in the study. We performed 16S rRNA sequencing on stool swab samples collected from neonatal intensive care unit patients who received amoxicillin-clavulanic acid (AC, n = 10), moxalactam (ML, n = 28) and non-antibiotics (NA, n = 34). We then compared the taxonomic composition between treatment regimens, focusing on differences in butyrate-producers.

Our study showed that there were significant differences in Shannon index (p = 0.033) and Beta diversity (p = 0.014) among the three groups. At the family level, compared with the other two groups, the relative abundance of Clostridiaceae (p < 0.001) and Veillonellaceae (p = 0.004) were significantly higher, while the relative abundance of Enterococcidae (p < 0.001) was significantly lower in the NA group. The relative abundance of Enterobacteriaceae (p = 0.022) in the AC group was greater than that in the other two groups. Additionally, butyrate-producers (p < 0.001), especially Clostridiaceae (p < 0.001), were noticeably more abundant in the NA group. The relative abundance of Clostridiaceae and butyrate-producers were the lowest in the ML group (p < 0.001).

We found that antibiotic therapy had an adverse impact on the initial development of gut microbiota and leaded to a reduction in the abundance of butyrate-producers, particularly Clostridiaceae. Furthermore, moxalactam had a more pronounced effect on the gut microbiota compared to amoxicillin-clavulanic acid.

Diabetes mellitus represents a significant global health problem. The number of people suffering from this metabolic disease is constantly rising and although the incidence is heterogeneous depending on region, country, economic situation, lifestyle, diet and level of medical care, it is increasing worldwide, especially among youths and children, mainly due to lifestyle and environmental changes. The pathogenesis of the two most common subtypes of diabetes mellitus, type 1 (T1DM) and type 2 (T2DM), is substantially different, so each form is characterized by a different causation, etiology, pathophysiology, presentation, and treatment. Research in recent decades increasingly indicates the potential role of the gut microbiome in the initiation, development, and progression of this disease. Intestinal microbes and their fermentation products have an important impact on host metabolism, immune system, nutrient digestion and absorption, gut barrier integrity and protection against pathogens. This review summarizes the current evidence on the changes in gut microbial populations in both types of diabetes mellitus. Attention is focused on changes in the abundance of specific bacterial groups at different taxonomic levels in humans, and microbiome shift is also assessed in relation to geographic location, age, diet and antidiabetic drug. The causal relationship between gut bacteria and diabetes is still unclear, and future studies applying new methodological approaches to a broader range of microorganisms inhabiting the digestive tract are urgently needed. This would not only provide a better understanding of the role of the gut microbiome in this metabolic disease, but also the use of beneficial bacterial species in the form of probiotics for the treatment of diabetes.

The human microbiota-associated (HMA) mice model, especially the germ-free (GF)-humanized mice, has been widely used to probe the causal relationships between gut microbiota and human diseases such as type 1 diabetes (T1D). However, most studies have not clarified the extent to which the reconstruction of the human donor microbiota in recipient mice correlates with corresponding phenotypic reproducibility. In this study, we transplanted fecal microbiota from five patients with T1D and four healthy people into GF mice, and microbiota from each donor were transplanted into 10 mice. Mice with similar microbiota structure to the donor exhibited better phenotypic reproducibility. The characteristics of the microbial community assembly of donors also influenced the phenotypic reproducibility in mice, and individuals with a higher proportion of stochastic processes showed more severe disorders. Microbes enriched in patients with T1D had a stronger colonization potential in mice with impaired glucose metabolism, and microbiota functional features related to T1D were better reproduced in these mice. This indicates that assembly traits and colonization efficacy of microbiota influence phenotypic reproducibility in GF-humanized mice. Our findings provide important insights for using HMA mice models to explore links between gut microbiota and human diseases.