Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by immune-mediated destruction of pancreatic β-cells, eventually leading to absolute insulin deficiency (1). In recent years, the incidence of T1DM has been increasing globally, particularly among children and adolescents (2). According to the International Diabetes Federation (IDF) 2025 report, approximately 9.2 million people are living with T1DM worldwide, with more than 80% of cases occurring in individuals under the age of 20 (3). The development of T1DM typically progresses through multiple stages, beginning with genetic susceptibility and environmental triggers, followed by immune activation, islet inflammation, and progressive loss of β-cell function. Based on its natural history, T1DM can be divided into three clinical stages: Stage 1 involves the presence of two or more islet autoantibodies with normal blood glucose; Stage 2 includes abnormal glucose metabolism without overt symptoms; and Stage 3 corresponds to the clinical onset of diabetes, meeting diagnostic criteria. Some newly diagnosed patients experience a transient “honeymoon phase”, during which measurable C-peptide levels indicate residual β-cell function. Individuals with longer disease duration typically exhibit near-complete β-cell exhaustion and rely entirely on exogenous insulin (4). These disease-stage–related pathological differences may influence how patients respond to adjunctive therapeutic interventions. Despite advances in current treatment strategies, many individuals still struggle to achieve sustained glycemic control, highlighting the need for novel approaches to optimize long-term management of T1DM.

Recent research has underscored the potential role of the gut microbiome in the pathogenesis and progression of T1DM, as well as in various immune-mediated disorders (5). Accumulating evidence suggests that individuals with T1DM commonly exhibit significant gut microbial dysbiosis, characterized by reduced diversity, a decreased abundance of beneficial microbes, and an increased presence of pro-inflammatory bacteria (6, 7). Such an imbalance can provoke autoimmune responses against pancreatic β-cells through multiple mechanisms, thereby fostering chronic inflammation and impairing insulin secretion (8). One major pathway involves increased intestinal permeability, which allows bacterial endotoxins such as lipopolysaccharides (LPS) to translocate into systemic circulation. This translocation may activate innate immune responses and promote inflammation-driven β-cell destruction (9). Additionally, the depletion of short-chain fatty acids (SCFAs)—key microbial metabolites with anti-inflammatory and regulatory properties—may impair mucosal immune homeostasis and reduce the number or function of regulatory T cells (Tregs), further exacerbating immune dysfunction (10). Moreover, Early-life factors such as cesarean delivery, lack of breastfeeding, and antibiotic exposure may further exacerbate dysbiosis, potentially increasing the risk of T1DM onset (11, 12). Together, these findings highlight that the gut microbiome may not simply reflect immune dysfunction in T1DM, but actively contribute to its onset and progression. Consequently, strategies aimed at restoring gut microbial balance have been proposed as a promising adjunctive approach to modulate immune responses, improve gut barrier function, and reduce systemic inflammation in individuals with T1DM.

Probiotics, defined as live microorganisms that confer health benefits to the host, have garnered increasing interest for their potential to modulate the gut–immune–metabolic axis in type 1 diabetes mellitus (T1DM). A growing body of evidence suggests that probiotics may protect pancreatic β-cells and improve glycemic control through a series of interrelated mechanisms. By reshaping the gut microbial landscape—enhancing the abundance of beneficial taxa such as Lactobacillus and Bifidobacterium while suppressing proinflammatory species like Escherichia coli—probiotics help reduce systemic endotoxin exposure and attenuate low-grade inflammation associated with islet autoimmunity. This microbial modulation supports a more balanced immune environment, mitigating the chronic immune responses that underlie β-cell destruction (13). Additionally, probiotic administration has been linked to increased production of SCFAs, particularly butyrate, which reinforces intestinal epithelial barrier function and plays a vital role in immune tolerance. Butyrate and other SCFAs also exert direct effects on β-cells by improving mitochondrial activity, reducing oxidative stress, and upregulating insulin gene expression, thereby supporting residual β-cell function in the early or partial stages of disease (14). Beyond local effects in the gut, probiotics modulate systemic immunity by promoting regulatory T cell (Treg) expansion and fostering tolerogenic dendritic cell phenotypes, which collectively downregulate pathogenic Th1/Th17 responses implicated in T1DM progression (15). These concerted actions not only reduce inflammatory burden but may also delay β-cell failure and extend the therapeutic window for intervention. Synbiotics and prebiotics, which further promote a favorable gut environment, are being explored as adjunctive strategies to sustain these benefits over time.

While some studies indicate potential benefits of probiotics for patients with T1DM, the majority of research has predominantly centered on adult populations, yielding inconsistent findings (16–18). Furthermore, there exists considerable debate regarding the effects of probiotics on glycemic control in pediatric and adolescent populations (19, 20). Research regarding the effects of probiotics on blood glucose regulation in pediatric T1DM remains in its preliminary stages, necessitating further systematic investigations to substantiate the clinical efficacy of probiotics in diabetes management. Consequently, this study conducted a systematic review and meta-analysis to assess the effects of probiotics and related supplements on glycemic control in children and adolescents with T1DM. In addition to assessing key clinical outcomes such as HbA1c, fasting blood glucose, C-peptide levels, and insulin requirements, we also performed detailed subgroup analyses to account for potential sources of heterogeneity across studies. This comprehensive approach aim to provide more definitive evidence to inform clinical treatment strategies.

This systematic review and meta-analysis focused on the adjunctive role of probiotics and related supplements in the management of T1DM among children and adolescents. With growing evidence on the relationship between gut microbiota and metabolic diseases, modulation of the gut microbiome has been recognized as a promising strategy in diabetes care. Following a systematic search and rigorous screening of the literature, eight randomized controlled trials involving pediatric and adolescent T1DM populations were included. Given the small number of trials, we did not perform Egger or Begg tests (underpowered and potentially misleading in small-k settings)Risk of bias (ROB) assessed using the Cochrane Handbook/ROB 2 framework indicated only one low-risk study, six with some concerns, and one at high risk; overall study quality was limited. According to GRADE, the certainty of evidence was low for HbA1c and very low for fasting blood glucose (FBG), C-peptide, and insulin requirements, warranting cautious interpretation. Pooled analyses showed a modest mean reduction in HbA1c (approximately 0.25%), with no consistent improvements in FBG, C-peptide, or insulin requirements. Given that a commonly cited threshold for clinically meaningful change in HbA1c is about 0.5% (34), the observed magnitude suggests limited clinical importance. Sensitivity analyses (excluding the high–risk-of-bias trial, leave-one-out analyses, and excluding prebiotic-only trials) yielded broadly consistent directions of effect on HbA1c but did not materially raise the certainty of evidence. These findings differ from some meta-analyses conducted in type 2 diabetes mellitus (T2DM) or gestational diabetes mellitus (GDM) (35–39), suggesting that T1DM may have distinct pathophysiological characteristics and responses to microbiota-targeted interventions. Importantly, our pooled estimate integrates heterogeneous probiotic regimens (strain composition and co-administration of prebiotics) and does not attribute effects to any specific strain or formulation; the implicit exchangeability assumption across formulations may not hold biologically. In view of the limited evidence base and between-study variability, overall certainty remains low, and routine clinical recommendations are not proposed.

Prior evidence suggests that when the intervention duration approaches or spans the HbA1c assessment window (approximately 2–3 months), reductions are more likely to be observed, whereas shorter follow-up may fail to capture changes (40). Accordingly, we conducted an exploratory subgroup analysis by duration: longer courses tended to show signals of HbA1c reduction, whereas shorter courses did not. To further parse heterogeneity, two additional exploratory subgroupings were performed. First, by disease duration (newly diagnosed/shorter duration vs. longer duration), the former more often showed favorable changes in HbA1c; however, definitions and reporting of “disease duration” varied across studies, limiting interpretability. Second, by probiotic formulation (single-strain vs. multi-strain), subgroup directions were broadly consistent, with multi-strain formulations showing a tendency toward larger HbA1c reductions; nonetheless, confidence intervals were wide and the exchangeability assumption across formulations was unverified, precluding comparative effectiveness inferences. All three subgroup analyses were exploratory with limited statistical power and do not support firm stratified conclusions.

At the mechanistic level, probiotics may influence glycemic control through multiple pathways. Microbiota-directed effects include increased abundance of beneficial taxa (e.g., Lactobacillus, Bifidobacterium), reductions in proinflammatory taxa (e.g., Proteobacteria), and restoration of diversity and homeostasis (41). Metabolically, increased short-chain fatty acid production (notably butyrate and propionate) may enhance gut barrier integrity via tight junction upregulation, attenuate translocation of lipopolysaccharide, and reduce low-grade inflammation (42–44). Immunomodulatory effects may include promotion of regulatory T-cell differentiation, suppression of Th1/Th17 activity, and a shift toward anti-inflammatory cytokine profiles, thereby potentially limiting immune-mediated β-cell injury. From a metabolic signaling perspective, short-chain fatty acids can activate G-protein–coupled receptors, stimulate GLP-1 secretion, slow gastric emptying, and improve insulin secretion and sensitivity (45), with potential antioxidant effects via enhanced antioxidant enzyme activity (46). These mechanisms, synthesized from the broader literature, represent plausible pathways that could partially account for the signal observed with multi-strain regimens; however, the included RCTs did not directly or systematically measure mechanistic endpoints, and these explanations remain hypothesis-generating.

Probiotic regimens showed no significant effects on FBG, C-peptide, or insulin requirements in children and adolescents with T1DM. This may reflect disease-specific pathophysiology: unlike T2DM, most individuals with T1DM have profound β-cell destruction and depend on exogenous insulin, so improvements in insulin sensitivity may be insufficient to produce measurable changes in glycemia among insulin-dependent patients (47). Moreover, probiotic effects may preferentially influence longer-term glycemic averages (HbA1c) rather than single time-point FBG or direct β-cell function indices such as C-peptide (48, 49). Statistically, the higher heterogeneity observed for FBG and C-peptide may stem from differences in formulations (e.g., prebiotics vs. multi-strain synbiotics), dosing, disease duration, and age distributions. Although most studies reported no statistically significant baseline imbalances, some baseline estimates (e.g., FBG) exhibited wide confidence intervals (e.g., −1.05–33.86 mg/dl), suggesting potential residual imbalance or measurement error that could affect the stability of effect estimates. Given the limited number of studies per outcome, we did not pursue additional subgroup analyses for these endpoints and downgraded GRADE for inconsistency and imprecision. No clinical recommendations are proposed for these outcomes on current evidence. This study has several limitations: (1) small overall sample size with uneven study quality and limited power; (2) marked clinical and methodological heterogeneity (strain composition and co-administration of prebiotics, dosing and duration, disease stage, outcome measurement and aggregation), with pooled estimates contingent on an exchangeability assumption across distinct formulations, limiting comparative effectiveness and causal inference; (3) generally short follow-up, with insufficient evidence on long-term efficacy and safety; (4) incomplete reporting on domains pertinent to risk of bias, including one high-risk study; (5) too few studies to perform robust publication bias assessments, so small-study and reporting biases cannot be excluded; and (6) wide confidence intervals in baseline estimates for some outcomes, suggesting potential residual imbalance. Overall, GRADE certainty ranged from low to very low. We therefore do not advance routine clinical recommendations. Therefore, future research should address these issues from several perspectives. First, larger sample sizes and multicenter collaborative studies employing rigorously designed RCTs with detailed subgroup analyses are warranted to elucidate the effects and underlying mechanisms of probiotic interventions on both long-term and short-term glycemic control in diverse patient populations. Second, refined selection of probiotic strains and dosage optimization represent critical directions for future investigations. Systematic comparisons of different strains, combinations, dosages, and intervention durations are necessary to provide a scientific basis for personalized treatment regimens. Third, exploring the synergistic effects of probiotics in conjunction with conventional hypoglycemic agents, dietary modifications, and exercise interventions may facilitate the development of a more comprehensive T1DM management strategy. Additionally, further basic research is required to elucidate the mechanisms by which probiotics influence glucose metabolism through modulation of gut microbiota composition, enhancement of intestinal barrier function, reduction of systemic inflammation, and regulation of short-chain fatty acid metabolism, as well as to develop predictive biomarkers. Finally, comprehensive evaluations of the long-term safety and tolerability of probiotic supplementation are essential to provide the necessary data for their clinical application.

This systematic review and meta-analysis observed a small, statistically significant reduction in HbA1c (≈0.25%) with probiotic supplementation in children and adolescents with type 1 diabetes; however, the certainty of this evidence is low, the clinical importance is uncertain (below commonly cited ≈0.5% thresholds), and no consistent effects were detected for fasting blood glucose, C-peptide, or insulin requirements. The evidence base is constrained by small sample sizes, risk of bias, and substantial clinical and methodological heterogeneity across strains, dosages, regimens, and follow-up, and too few trials to reliably assess publication bias. Sensitivity analyses showed broadly similar directions of effect but did not increase the GRADE certainty. While adequate dosing and longer intervention duration may favor gut colonization and downstream metabolic effects, whether probiotics can sustain long-term glycemic control remains unproven and requires trials with extended follow-up. Given the unverified exchangeability of different formulations, routine clinical recommendations are not proposed. Future research should include larger, rigorously designed multicenter RCTs using standardized, well-characterized strains with prespecified dosing and duration, ideally with head-to-head comparisons and mechanistic biomarker collection, to clarify comparative efficacy, underlying mechanisms, and optimized treatment protocols for T1DM management.