# Fecal Microbiota Transplantation for Glycemic Control in Type 2 Diabetes: A Comprehensive Literature Review of HbA1c Durability at Six Months and Beyond

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### Background and Context

Type 2 diabetes mellitus (T2DM) represents one of the most consequential metabolic pandemics of the twenty-first century. According to figures synthesized across the reviewed literature, approximately 463–536.6 million adults worldwide were living with diabetes as of 2019–2021, with T2DM accounting for an estimated 90–96% of all cases (PMC12376105, PMC11527334). The International Diabetes Federation projects that this burden will reach 700 million by 2045, driven by aging populations, rising obesity rates, urbanization, and sedentary lifestyles (PMC11597803, PMC12376105). The economic toll is staggering: the United States alone spent approximately $412.9 billion on diabetes-related care in 2022, while the United Kingdom's National Health Service allocates roughly £10 billion annually — approximately 10% of its total budget — to diabetes management (PMC11527334). Beyond financial costs, T2DM imposes a profound burden of microvascular complications (nephropathy, retinopathy, neuropathy) and macrovascular events (cardiovascular disease, stroke, peripheral vascular disease), which together account for the majority of diabetes-related morbidity and premature mortality (PMC11597803, PMC12376105).

Despite a pharmacological armamentarium that has expanded substantially over the past two decades — encompassing metformin, sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors — glycemic control remains suboptimal in a large proportion of patients. Current therapies do not adequately address the underlying pathophysiological mechanisms of T2DM, particularly the progressive deterioration of pancreatic β-cell function and the multifactorial nature of insulin resistance (PMC12376105). Adverse effects, hypoglycemia risk, and the financial burden of newer agents further limit their universal applicability. This therapeutic gap has catalyzed intense interest in novel, mechanism-targeting approaches that might complement or even partially substitute for conventional pharmacotherapy.

The gut microbiota has emerged as a compelling candidate therapeutic target. The microbial ecosystem in the human gut is highly complex, harboring an estimated 1,000–1,500 distinct bacterial species and 10¹³–10¹⁴ total microorganisms that are essential to human health (PMC12376105, PMC8886906). Mounting evidence from metagenomics, metabolomics, and interventional studies has established that gut microbial dysbiosis — characterized by reduced diversity, depletion of butyrate-producing taxa, and enrichment of pro-inflammatory species — is not merely a correlate but an active participant in the pathogenesis of T2DM (PMC8886906, PMC11597803). Fecal microbiota transplantation (FMT), the transfer of fecal material from a healthy donor into the gastrointestinal tract of a recipient, offers a theoretically elegant means of correcting this dysbiosis wholesale, rather than targeting individual microbial taxa or metabolic pathways. FMT has demonstrated remarkable efficacy (80–90% cure rates) for recurrent *Clostridioides difficile* infection (CDI), establishing its proof-of-concept as a microbiome-modulating intervention (PMC11464302, PMC11671274). The central clinical question addressed in this review is whether allogenic FMT from healthy donors produces a durable — defined here as persisting for six months or longer — reduction in glycated hemoglobin (HbA1c) in human adults with T2DM, compared with autologous FMT or placebo controls. This question is clinically urgent because HbA1c reduction is the primary surrogate endpoint for long-term glycemic control and the metric most directly linked to prevention of diabetic complications.

The historical context of FMT in metabolic disease is brief but rapidly evolving. The first modern RCT of FMT for a metabolic indication in humans was conducted by Vrieze et al. in 2012 (n=18 men with metabolic syndrome), demonstrating improved insulin sensitivity after allogenic FMT from lean donors over six weeks — a finding that galvanized the field (PMC7693552, PMC11671274). Since then, a small but growing number of RCTs, non-randomized controlled trials, observational studies, and systematic reviews have examined FMT's effects on glycemic parameters in T2DM, with follow-up durations ranging from four weeks to six months. The evidence base, while promising, remains heterogeneous in design, FMT protocol, patient population, and outcome measurement, and the specific question of HbA1c durability at or beyond six months has received only limited direct investigation. This review synthesizes the available human clinical evidence — excluding all rodent and animal data per the stated scope — to provide a rigorous, quantitative assessment of what is currently known, what remains contested, and what future research must address.

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### Molecular and Mechanistic Pathways

Understanding why FMT might improve glycemic control in T2DM requires a detailed appreciation of the mechanistic links between gut microbial composition and host glucose metabolism. The reviewed literature identifies several distinct, partially overlapping pathways through which the gut microbiota influences insulin sensitivity, β-cell function, and systemic inflammation. These pathways are not mutually exclusive, and their relative contributions to the glycemic phenotype of T2DM remain incompletely characterized.

#### Short-Chain Fatty Acid Production and GLP-1/PYY Signaling

The most extensively documented mechanistic pathway linking gut microbiota to glycemic control involves the production of short-chain fatty acids (SCFAs) — principally butyrate, propionate, and acetate — through microbial fermentation of dietary fibers in the colon. In T2DM, the abundance of SCFA-producing bacteria, including *Faecalibacterium prausnitzii* and *Roseburia intestinalis*, is consistently reduced compared with healthy controls, as documented across multiple human metagenomics studies (PMC11597803, PMC11671274). This depletion translates into lower circulating and fecal SCFA concentrations, with downstream consequences for multiple metabolic pathways.

SCFAs exert their metabolic effects through activation of G protein-coupled receptors (GPCRs), specifically GPR41 (FFAR3) and GPR43 (FFAR2). Upon activation by SCFAs, these receptors execute crucial physiological functions including regulation of fat and glucose metabolism and the production of peptide YY (PYY), which in turn regulates intestinal motility and nutrient absorption and modulates adipose-insulin signal transduction (PMC11671274). Intestinal SCFAs also contribute to reducing inflammation in adipocytes by stimulating the production of glucagon-like peptide-1 (GLP-1), thereby suppressing NF-κB activity (PMC11671274). The incretin effect — attributable to GLP-1 and gastric inhibitory polypeptide (GIP) — accounts for 50–60% of postprandial insulin release in healthy individuals; this effect is substantially impaired in T2DM, and reduced SCFA production may contribute to this impairment (PMC12376105). Butyrate additionally serves as the primary energy substrate for colonocytes and strengthens tight junction proteins, thereby reducing intestinal permeability; it also modulates inflammatory gene expression through inhibition of histone deacetylases (HDACs) (PMC11597803, PMC8886906).

The clinical relevance of this pathway is supported by the observation that allogenic FMT from lean donors in the Vrieze et al. trial produced notable increases in *Roseburia intestinalis* and *Eubacterium hallii* — both butyrate producers — coinciding with improved insulin sensitivity at six weeks (PMC7693552, PMC11671274). Similarly, the Wu et al. randomized controlled trial (n=29) demonstrated that FMT-containing arms significantly increased microbial alpha diversity and shifted the Firmicutes/Bacteroidetes ratio in a direction consistent with enhanced SCFA production capacity, while the metformin-only arm showed no such change (PMC9872724). Propionate supplementation in overweight adults has been shown to prevent weight gain and worsening insulin sensitivity, and to increase postprandial GLP-1 and PYY levels, providing direct human evidence for the SCFA-incretin axis (PMC8886906). In the Ng et al. RCT, combining lifestyle interventions with FMT induced more favorable changes in recipients' microbiota — including increased butyrate-producing gut microbiota and improved lipid profiles and liver stiffness — compared with FMT alone; however, as reported in the reviewed literature, these microbiome and lipid changes did not translate into significant HbA1c reduction at 24 weeks, and slight improvements in HbA1c post-FMT were noted without reaching statistical significance (PMC11671274, PMC12028006).

#### Metabolic Endotoxemia, Intestinal Barrier Integrity, and Inflammatory Pathways

A second major mechanistic pathway involves the disruption of intestinal barrier integrity and the consequent translocation of lipopolysaccharide (LPS) — a potent endotoxin derived from the outer membrane of Gram-negative bacteria — into the systemic circulation, a phenomenon termed metabolic endotoxemia (PMC11597803, PMC11671274). In T2DM, hyperglycemia itself damages tight junction proteins (including zonula occludens-1 and E-cadherin), increasing intestinal permeability and creating a vicious cycle in which elevated blood glucose promotes further LPS translocation, which in turn worsens insulin resistance (PMC11671274, PMC8886906).

LPS binds to Toll-like receptor 4 (TLR4) on immune cells, triggering activation of the NF-κB signaling cascade and the release of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6 (PMC11671274, PMC12028006). Persistent activation of this inflammatory pathway promotes chronic low-grade inflammation, which impairs insulin signaling across multiple tissues and contributes to the development and progression of metabolic dysfunction (PMC12028006, PMC11671274). The result is a state of chronic, low-grade systemic inflammation that perpetuates and amplifies insulin resistance.

FMT is hypothesized to interrupt this cycle by restoring a microbial community capable of maintaining intestinal barrier integrity. *Akkermansia muciniphila*, a mucin-degrading Gram-negative bacterium consistently depleted in T2DM patients, enhances Mucin 2 gene expression, promotes tight junction protein expression, and reduces metabolic endotoxemia (PMC11597803, PMC11671274). The Kootte et al. RCT (n=38) found that allogenic FMT from lean donors significantly increased *Akkermansia muciniphila* and *Eubacterium* genus levels — which correlated negatively with hyperglycemia — and improved insulin sensitivity at six weeks, while *Roseburia* genus levels were paradoxically reduced in responders (PMC11527334, PMC12028006). FMT also reduces circulating IL-6 and TNF-α levels, which are mechanistically involved in islet cell injury and insulin resistance in the liver, muscles, and adipocytes (PMC11527334). The immunomodulatory effects of FMT extend to activation of the TLR pathway, leading to accelerated synthesis of immunoglobulins that protect the intestinal mucosa, and to modulation of the Th17/Treg balance, which is disrupted in metabolic disease (PMC11671274).

#### Bile Acid Metabolism and FXR/TGR5 Signaling

A third mechanistic pathway of considerable importance involves the gut microbiota's role in converting primary bile acids (produced in the liver from cholesterol) into secondary bile acids through deconjugation and 7α-dehydroxylation (PMC9785599, PMC11597803). The gut microbiota converts primary bile acids into secondary bile acids (principally deoxycholic acid and lithocholic acid) through deconjugation and 7α-dehydroxylation via bile salt hydrolase and bai gene cluster enzymes in bacteria including *Clostridium*, *Bacteroides*, *Bifidobacterium*, and *Faecalibacterium* (PMC9785599, PMC11597803). Secondary bile acids can activate TGR5, a G protein-coupled receptor expressed on intestinal L cells, to increase secretion of GLP-1, or inhibit it through the farnesoid X receptor (FXR), giving them dual regulatory effects on GLP-1 secretion (PMC11597803).

The clinical relevance of this pathway to FMT was directly investigated in a secondary metagenomics analysis of a double-blind, randomized, placebo-controlled pilot trial of FMT capsules in obese but metabolically healthy adults (n=19 at the 4-week time point) (PMC9785599). In this study, FMT significantly enriched *Paraprevotella* and *Longibaculum* at the genus level, and tended to increase *Clostridium hylemonae* — a species known to convert primary to secondary bile acids — at the species level. Correlation analyses identified *Phocaeicola dorei* and *Bacteroides ovatus* as positively correlated with unconjugated chenodeoxycholic acid (CDCA; p=7.47×10⁻⁴⁵ and p=2.50×10⁻⁸, respectively), *Bifidobacterium adolescentis* and *Collinsella aerofaciens* with glycine-conjugated DCA (GDCA; p=0.0123 and p=0.0634), and *Faecalibacterium prausnitzii* with LCA (p=0.0634) (PMC9785599). These findings suggest that FMT-induced shifts in bile acid metabolism — toward a profile resembling that of the lean donor — may contribute to the observed improvements in glucose tolerance, though the mechanistic chain from altered bile acid profile to sustained HbA1c reduction in established T2DM remains to be established in adequately powered human trials.

#### Branched-Chain Amino Acid Metabolism and TMAO Production

Two additional mechanistic pathways deserve mention, though the clinical evidence linking them specifically to FMT-induced HbA1c changes in T2DM is less direct. First, elevated circulating branched-chain amino acids (BCAAs — leucine, isoleucine, valine) are consistently associated with obesity, insulin resistance, and T2DM; specific bacterial taxa including *Prevotella* and *Alistipes* are positively correlated with BCAA levels, while *Bacteroides* species are negatively correlated (PMC11597803). Second, trimethylamine N-oxide (TMAO) — produced by gut bacterial metabolism of dietary choline and L-carnitine, followed by hepatic oxidation — is elevated in T2DM patients and associated with increased cardiovascular risk, impaired hepatic insulin signaling, and adipose tissue inflammation (PMC8886906, PMC11597803). Higher plasma TMAO concentrations are independently associated with increased T2DM risk, and gut dysbiosis amplifies TMAO production from the same dietary substrate compared with eubiosis (PMC11597803). Whether FMT durably reduces TMAO levels in T2DM patients has not been directly assessed in the reviewed trials, though one study found no change in TMA or TMAO levels after autologous FMT from a vegan donor (PMC12028006).

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### Dose-Response and Pharmacokinetics of FMT

#### FMT Preparation, Dosing, and Administration Routes

Unlike conventional pharmacotherapy, FMT does not have a defined dose-response relationship in the traditional pharmacokinetic sense. The "dose" of FMT is typically expressed in terms of the mass of donor stool processed (commonly 30–50 g per preparation), the volume of the resulting suspension (typically 200–500 mL for infusion-based delivery, or encapsulated equivalents), and the number and timing of administrations (PMC11671274, PMC11527334). Two alternative preparation methods are available: fresh preparation, which requires processing donor feces within six hours after defecation to preserve anaerobic bacteria integrity, and frozen preparation, which involves freezing the fecal suspension with glycerol at −80°C to maintain bacterial vitality during storage (PMC11671274). Frozen preparations are increasingly preferred for logistical reasons and have demonstrated comparable efficacy to fresh preparations in CDI treatment.

Administration routes used across the reviewed T2DM trials include nasoduodenal tube infusion (Vrieze et al., Kootte et al.), nasojejunal tube (Wu et al., 2023), transendoscopic enteral tube (Ding et al.), oral capsules (Ng et al., Allegretti et al., Su et al.), and colonoscopic delivery to the terminal ileum (Cai et al. case report) (PMC11527334, PMC9872724). In CDI treatment, colonoscopic administration achieves a 94.8% cure rate and capsular administration 92.1%, compared with 78.1% for nasogastric and 87.2% for enema routes (PMC7693552). Whether these route-specific efficacy differences translate to metabolic indications is unknown, as no head-to-head comparison of administration routes has been conducted in T2DM populations.

The number of FMT administrations varies substantially across trials. Single-dose protocols (Vrieze et al., Kootte et al., Ding et al.) have been compared with repeated-dose protocols (Ng et al.: multiple doses over 24 weeks; Wu et al., 2023: single dose at week 0; Su et al.: capsules on days 1, 8, and 15). The Ng et al. RCT specifically investigated whether repeated FMT enhances microbiota engraftment and metabolic outcomes, finding that repeated FMT over 24 weeks produced sustained increases in donor-derived microbial engraftment compared with single-dose protocols, though this did not translate into significant HbA1c reduction at 24 weeks (PMC11527334, PMC11671274). The Wu et al. (2023) randomized trial found that a single FMT dose via nasojejunal tube produced significant improvements in HOMA-IR and BMI within four weeks, with approximately 62.5–66.7% of recipients achieving ≥20% donor-derived microbial engraftment (PMC9872724). These data suggest that engraftment efficiency — rather than simply the number of doses — may be a critical determinant of metabolic response, though the relationship between engraftment percentage and HbA1c reduction at six months has not been formally characterized.

#### Clinically Achievable vs. Suprapharmacological Considerations

A critical distinction in interpreting FMT trial results is the difference between the immediate post-FMT microbial shift and the sustained engraftment of donor-derived taxa. Several reviewed studies note that the gut microbiota of recipients tends to revert toward its pre-FMT composition over time, particularly if the recipient's diet and lifestyle do not align with those of the donor (PMC11671274, PMC12028006). This "microbiota memory" effect means that the metabolic benefits of FMT may be transient unless reinforced by dietary modification, repeated FMT, or adjunctive probiotic/prebiotic supplementation. One long-term study found that microbiota diversity remained elevated for up to 12 months post-transplant, but no significant biochemical or anthropometric changes were sustained, partly attributed to loss of key anaerobic species including *Faecalibacterium prausnitzii* and *Akkermansia muciniphila* during the transfer process (PMC12028006). This observation is directly relevant to the question of HbA1c durability at six months: even if FMT produces early glycemic improvements, the durability of these effects may depend on factors that current protocols do not adequately address.

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### Clinical Evidence and Implications

#### The Foundational RCT: Vrieze et al. (2012)

The Vrieze et al. RCT (n=18 men with metabolic syndrome, six-week follow-up) found that allogenic FMT improved insulin sensitivity and increased microbial diversity compared with autologous FMT, but BMI did not change and HbA1c was not reported as a primary endpoint; the small sample size, exclusively male population, and short follow-up severely limit generalizability (PMC7693552, PMC11671274). Recipients of allogenic FMT demonstrated notable increases in *Roseburia intestinalis* and *Eubacterium hallii* — both butyrate-producing organisms — coinciding with improved insulin sensitivity. Not all participants responded to FMT. The six-week follow-up is substantially shorter than the six-month durability threshold of interest in this review. Nevertheless, this trial established the proof-of-concept that allogenic FMT can improve insulin sensitivity in humans with metabolic dysregulation, and it catalyzed subsequent, more rigorously designed investigations.

#### Kootte et al. (2017): The First RCT Specifically in Obese Patients with Metabolic Syndrome

The Kootte et al. RCT (n=38; 12 autologous, 26 allogenic) is the most frequently cited controlled trial of FMT in patients with obesity and metabolic syndrome (PMC11527334). FMT was delivered via nasoduodenal tube infusion at baseline and again at six weeks. The primary finding was that allogenic FMT from lean donors improved insulin sensitivity and HbA1c at six weeks and increased fasting triglycerides, while autologous FMT did not; overall glucose levels were not significantly reduced, and no effect on weight was observed (PMC11527334). Microbial analysis revealed increased *Akkermansia muciniphila* and *Eubacterium* genus levels in allogenic recipients, which correlated negatively with hyperglycemia, while *Roseburia* genus levels were paradoxically reduced in responders — a finding that contradicts earlier reports and remains unexplained (PMC12028006, PMC11527334). The Kootte et al. trial did not extend follow-up beyond six weeks, making it impossible to assess HbA1c durability at six months. The study was assessed as low risk of bias (64%) by the Cochrane tool in the systematic review by Iqbal et al. (PMC11527334). The trial's limitation of a six-week observation window is a critical gap in the evidence base for the durability question.

#### Ng et al. (2022): The Longest RCT Follow-Up in T2DM

The Ng et al. RCT (n=52; 17 FMT alone, 17 FMT plus lifestyle intervention [LSI], 18 sham plus LSI) represents the most extended randomized trial of FMT in obese patients with T2DM, with a follow-up duration of 24 weeks (PMC11527334, PMC11671274). FMT was delivered via esophageal gastric endoscopy as a single infusion. As reported in the reviewed literature, no significant difference in HbA1c was observed at week 24, though slight improvements in HbA1c post-FMT were noted; combining lifestyle interventions with FMT induced more favorable changes in recipients' microbiota, improving lipid profiles and liver stiffness, with increased butyrate-producing gut microbiota (PMC11671274, PMC12028006). Lipid profiles improved significantly in the FMT plus LSI group (decreased LDL and total cholesterol), and liver stiffness was reduced. The Ng et al. trial is the only RCT in the reviewed literature with a follow-up duration reaching or approaching six months, and its primary finding — no significant HbA1c reduction at 24 weeks — is the most directly relevant piece of evidence to the user's question. The trial was assessed as low risk of bias (71%) by the Cochrane tool (PMC11527334). Limitations include the relatively small group sizes (n=17–18 per arm) and the heterogeneity of the patient population.

#### Wu et al. (2023): FMT Reverses Insulin Resistance at Four Weeks

The Wu et al. randomized, controlled, prospective trial (n=29 completers; FMT plus metformin n=8, FMT alone n=9, metformin alone n=12) is the most methodologically detailed recent RCT of FMT in T2DM, conducted in a southeast Chinese population (PMC9872724). FMT was delivered as a single 200 mL infusion containing 50 g bacterial sludge via nasojejunal tube from a pool of ten healthy lean donors. All three groups showed significant (p<0.05) improvements in fasting blood glucose (FBG), postprandial blood glucose (PBG), HbA1c, and HOMA-HBCI at week 4. However, only the FMT-containing arms demonstrated significant reductions in HOMA-IR (FMT alone: 6.73±2.88 to 3.55±1.58, p<0.05; FMT plus metformin: 5.57±5.91 to 3.61±4.15, p=0.01) and BMI (p<0.05), while the metformin-only group showed no significant change in either. FBG and HbA1c decreased more in the FMT plus metformin group than in FMT alone. Approximately 66.7% of FMT-alone recipients and 62.5% of FMT plus metformin recipients achieved ≥20% donor-derived microbial engraftment. Microbial alpha diversity (Chao1, Shannon) improved significantly after FMT (p<0.05). Correlation analyses showed that *Bifidobacterium adolescentis*, *Chlorobium phaeovibrioides*, and *Synechococcus* sp. were strongly negatively correlated with HOMA-IR, while *Dysosomobacter welbionis* and *Lactobacillus ruminis* were positively correlated with HOMA-IR, and *Clostridium bolteae* was strongly positively correlated with PBG (PMC9872724). No adverse reactions were observed in any FMT recipient. The critical limitation of this trial is its four-week follow-up duration, which is far shorter than the six-month threshold of interest. The small sample sizes (n=8–12 per arm) further limit statistical power and generalizability.

#### Ding et al. (2022): Non-Randomized Controlled Trial at 12 Weeks

The Ding et al. non-randomized controlled trial (NRCT; n=37; 17 T2DM patients, 20 controls) assessed FMT delivered via transendoscopic enteral tube over two days, with a 12-week follow-up (PMC11527334). After 12 weeks, FMT had a positive effect on FBG, postprandial glucose, HbA1c, and C-peptide, as well as lipid profile (decreased LDL and TG). No significant weight loss or blood pressure reduction occurred in any group. Microbial analysis revealed that *Rikenellaceae* and the genus *Anaerotruncus* significantly decreased to healthy levels after FMT in the responder group — these taxa had been elevated pre-FMT and were identified as predictors of favorable response (PMC11527334, PMC12028006). The 12-week follow-up of this trial is closer to the six-month threshold than most other studies but still falls short. The non-randomized design introduces significant selection bias, and the absence of a placebo or sham-FMT control limits causal inference. The Newcastle-Ottawa scale assessment yielded a score of 75% for this study (PMC11527334).

#### Wu et al. (2022): Observational Study with Six-Month Follow-Up

The Wu et al. (2022) observational study (n=195; 20 with high blood glucose, 175 with normal blood glucose) assessed washed microbiota transplantation (WMT) — a refined FMT preparation using microfiltration and repeated centrifugation — delivered via nasojejunal tube and transendoscopic enteral tube over two courses of three days each, with follow-up at one month, two months, and six months (PMC11527334). In the high blood glucose subgroup, WMT had a positive effect on FBG, HbA1c, fasting insulin, and HOMA-IR at one and two months. However, the levels of FBG and HOMA-IR did not significantly decrease in the long term (six months). BMI decreased but not significantly. Blood pressure and lipid profiles also improved in the short and medium term. This observational study is the only reviewed study with a six-month follow-up that directly addresses the durability question for HbA1c and related glycemic parameters. Its finding — that short- and medium-term improvements in FBG and HOMA-IR were not sustained at six months — is a critical piece of evidence suggesting that FMT-induced glycemic benefits may not be durable at the six-month threshold. However, the observational design, the mixed population (only 20 of 195 participants had high blood glucose), and the absence of a control group severely limit the strength of this conclusion (PMC11527334).

#### Su et al. (2022): FMT Combined with Dietary Modification

The Su et al. (2022) observational study (n=13; 8 in diet-only group, 5 in diet plus FMT group) assessed FMT delivered via oral capsules on days 1, 8, and 15, with follow-up at days 20 and 90 (PMC11527334). On days 20 and 90, there was improvement in FBG, HbA1c, lipid profile, blood pressure, and weight in both groups, but the improvement was greater in the FMT group. Significant and earlier weight loss was observed at day 20 in the FMT plus diet group. The study concluded that FMT has beneficial effects on glycemic control and weight; however, alteration of diet is necessary to maintain the long-term effects of FMT (PMC11527334). This conclusion is mechanistically plausible and consistent with the broader literature on microbiota-diet interactions (PMC11671274). However, the extremely small sample size (n=5 in the FMT group), the non-randomized design, and the 90-day maximum follow-up preclude any conclusions about six-month HbA1c durability.

#### Meta-Analytic Evidence: Short-Term Glycemic Benefits

A meta-analysis of nine studies (n=303) found FMT associated with lower fasting blood glucose, HbA1c, and insulin levels compared to placebo in short-term metabolic outcomes (PMC11464302). This pooled evidence provides the strongest available signal for short-term glycemic benefits of FMT, but its restriction to outcomes assessed within six weeks means it cannot address the durability question. The heterogeneity of included studies — varying FMT protocols, patient populations, and outcome definitions — limits the precision of the pooled estimates.

#### Cai et al. (2018): Case Report with Diabetic Neuropathy

A case report described a 46-year-old female T2DM patient who received FMT twice within three months via endoscopy, with successful alleviation of blood glucose control, reduction of depressive symptoms, and relief of neuropathic pain; no adverse reactions were observed (PMC11671274). While this case report is hypothesis-generating and suggests that FMT may have benefits beyond glycemic control, its n=1 design precludes any generalizable conclusions.

#### The Allegretti et al. Oral Capsule FMT Study

A study of oral FMT capsules in obese patients (follow-up up to 26 weeks) found increased insulin sensitivity, increased gut microbial diversity, and elevated butyrate production post-FMT (PMC11671274). This study is notable for its 26-week follow-up duration, which approaches the six-month threshold, and for its use of oral capsule delivery — a more patient-acceptable route than nasoduodenal infusion. However, the study was conducted in obese patients without confirmed T2DM, limiting its direct applicability to the question of HbA1c durability in established T2DM. Specific HbA1c data from this study were not reported in the reviewed papers.

#### Autologous FMT Post-Weight Loss: Metabolic Memory

One RCT examined the application of autologous FMT capsules after diet-induced weight loss, with a six-month follow-up (PMC11671274). This study found that autologous FMT preserved favorable metabolic attributes in participants, reduced weight regain, and improved blood glucose control, with altered gut microbiome composition and retention of "metabolic memory." This finding is particularly interesting because it suggests that the microbiome composition achieved during successful weight loss can be preserved through autologous FMT, potentially extending the metabolic benefits of dietary intervention. However, this study does not directly address allogenic FMT from healthy donors in T2DM patients.

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### Safety Profile and Adverse Events

#### General Safety of FMT

FMT is generally considered a safe procedure, with the majority of adverse events being mild, transient, and gastrointestinal in nature. FMT-related adverse effects are usually short-term and gastrointestinal; the most commonly reported include abdominal discomfort, diarrhea, nausea, bloating, and flatulence (PMC11464302, PMC11671274). FMT proves to be a safe therapeutic approach, with mild clinical symptoms being the most common adverse reactions observed in existing clinical cases; despite the low occurrence and mild nature of short-term adverse events, long-term safety assessments are considered essential (PMC11671274). A systematic review and meta-analysis cited in the reviewed literature found that serious adverse events of FMT occur in less than 1% of patients and include colectomies, bacteremia/infections, hospitalizations, life-threatening complications, and deaths (PMC11464302). A separate review reported a total adverse event incidence rate of 28.5%, with abdominal discomfort being the most common (PMC11464302). In the Wu et al. (2023) RCT specifically in T2DM patients, no adverse reactions were observed in any FMT recipient across all three groups (PMC9872724). The Ding et al. NRCT similarly reported no significant adverse events (PMC11527334).

#### Serious and Rare Adverse Events

Despite its generally favorable safety profile, FMT carries real risks that must be weighed against potential benefits, particularly in the context of metabolic indications where the risk-benefit calculus differs from life-threatening CDI. Serious complications such as perforation, bacteremia, sepsis, multi-organ failure, and death have been reported in the broader FMT literature (PMC11464302). Two cases of FMT patients who contracted extended-spectrum beta-lactamase (ESBL)-producing *Escherichia coli* bacteremia have been documented — one of which was fatal — with genome sequencing identifying the donor sample as the reservoir for the infection, highlighting that standard screening protocols cannot eliminate all transmission risks (PMC7693552). The FDA has issued safety warnings following patient deaths associated with FMT, and regulatory approval for FMT outside of CDI remains limited in most countries (PMC12028006). A case of Shiga toxin-producing *Escherichia coli* transmission following FMT has also been reported (PMC11464302).

In the T2DM-specific trials reviewed, the most notable safety signal was a transient leukocytosis observed in both patients in the Cai et al. T1DM case series. In Patient 1, white blood cell counts rose acutely to 21.2×10⁹/L on the first day after transplantation and then decreased to normal after two days, while other inflammatory indices did not change; in Patient 2, a similar abnormal increase in leukocytes occurred on the first day after the first transplantation, resolving within two days, with no recurrence after the second FMT session (PMC9414079). The authors interpreted this pattern as consistent with a transient immune reaction triggered by the initial exposure to transplanted microbiota, to which the patient subsequently adapted. No infectious complications, hepatic or renal toxicity, or autoimmune events were observed in either patient. The theoretical risk of transmitting obesity or chronic autoimmune disease through FMT from an obese or immunologically compromised donor has been raised in the literature, though direct human evidence for this risk remains limited (PMC7693552).

#### Safety in Special Populations

The safety of FMT has not been confirmed in immunocompromised recipients in the context of metabolic disease, and most T2DM FMT trials have excluded patients with severe comorbidities. A review of 44 studies on FMT for CDI found that 88% of immunocompromised patients achieved successful treatment, with serious adverse event rates comparable to immunocompetent patients (PMC11464302). However, the risk of transferring live microorganisms to recipients with underlying illnesses remains higher in this population. Pregnancy is considered a contraindication for FMT in most guidelines, though a case of successful FMT in a pregnant patient with CDI has been reported (PMC11464302). Elderly patients and those with inflammatory bowel disease may be at increased risk for side effects after FMT (PMC11527334).

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### Unresolved Controversies and Disagreements

#### Does Allogenic FMT Produce Durable HbA1c Reduction at Six Months?

The central controversy in this literature is whether allogenic FMT from healthy donors produces a clinically meaningful and durable reduction in HbA1c at six months or beyond in T2DM patients. The available evidence is directly contradictory across studies. On one hand, the meta-analysis of nine studies (n=303) found that FMT was associated with lower HbA1c within six weeks (PMC11464302), and the Wu et al. (2023) RCT found significant HbA1c reductions at four weeks in FMT-containing arms (PMC9872724). The Ding et al. NRCT found positive effects on HbA1c at 12 weeks (PMC11527334), and the Su et al. observational study found improvements at 90 days (PMC11527334). On the other hand, the Ng et al. RCT — the only randomized trial with a follow-up approaching six months (24 weeks) — found no significant change in HbA1c in any group compared with baseline at week 24 (PMC11527334, PMC11671274). The Wu et al. (2022) observational study found that FBG and HOMA-IR improvements were not sustained at six months (PMC11527334). The long-term study cited in the PMC12028006 review found that microbiota diversity remained elevated for up to 12 months post-transplant, but no significant biochemical or anthropometric changes were sustained. These contradictory findings cannot be reconciled by simple pooling, as they reflect genuine differences in study design, patient population, FMT protocol, and follow-up duration.

#### Autologous vs. Allogenic FMT: Which Is Superior?

A second major controversy concerns the relative efficacy of autologous versus allogenic FMT. The Kootte et al. RCT found that allogenic FMT from lean donors improved insulin sensitivity and HbA1c at six weeks, while autologous FMT did not (PMC11527334). In contrast, a study in T1DM patients found that autologous FMT prolonged residual beta-cell function compared with allogenic FMT, with changes in CD4+ CXCR3+ and CD8+ CXCR3+ T cells identified as potential mediators — suggesting that autologous FMT may be more immunologically compatible with the host in autoimmune diabetes contexts (PMC7967220). In the T2DM context, the Wu et al. (2023) RCT did not include an autologous FMT arm, making direct comparison impossible (PMC9872724). The mechanistic basis for why autologous FMT might be superior in some contexts (T1DM) but inferior in others (metabolic syndrome) is not established, and the optimal donor strategy for T2DM remains unresolved.

#### The Role of Roseburia in FMT Response

A specific microbiological controversy concerns the role of *Roseburia* species in mediating FMT's metabolic benefits. The Vrieze et al. trial found that increases in *Roseburia intestinalis* — a butyrate producer — were among the most notable microbial changes after allogenic FMT and were associated with improved insulin sensitivity (PMC7693552, PMC11671274). This finding was widely cited as evidence for the SCFA-mediated mechanism of FMT's metabolic effects. However, the Kootte et al. study found a reduced presence of *Roseburia* in responders to allogenic FMT, even though insulin sensitivity improved — a finding that appears to contradict the earlier report (PMC12028006, PMC11527334). The authors of the Kootte et al. study noted that other beneficial bacteria, including *Akkermansia muciniphila* and *Eubacterium*, were prevalent in responders' microbiota, suggesting that multiple microbial taxa may contribute to metabolic improvement through different mechanisms. This discrepancy has not been resolved and highlights the complexity of attributing metabolic outcomes to specific microbial taxa.

#### FMT Alone vs. FMT Combined with Lifestyle Intervention or Metformin

A third controversy concerns whether FMT's metabolic benefits are enhanced by combination with lifestyle intervention or pharmacotherapy. The Ng et al. RCT found that FMT combined with lifestyle intervention (LSI) produced greater improvements in lipid profiles and liver stiffness than FMT alone, but neither arm achieved significant HbA1c reduction at 24 weeks (PMC11527334, PMC11671274). The Wu et al. (2023) RCT found that FMT plus metformin produced greater reductions in FBG and HbA1c than FMT alone at four weeks, while FMT alone produced greater improvements in HOMA-HBCI, HbA1c, AST, TBA, and TP than metformin alone (PMC9872724). The Su et al. observational study found that FMT combined with dietary modification produced greater improvements than diet alone, and concluded that dietary alteration is necessary to maintain the long-term effects of FMT (PMC11527334). These findings collectively suggest that FMT alone is insufficient for sustained blood glucose control and should be combined with lifestyle modifications and established pharmacotherapies (PMC11671274). However, the optimal combination strategy — which pharmacotherapy, which dietary approach, and at what timing relative to FMT — has not been established in adequately powered trials.

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### Limitations of the Evidence Base

The evidence base for FMT in T2DM is characterized by numerous methodological limitations that collectively preclude definitive conclusions about HbA1c durability at six months.

**Paucity of randomized controlled trials with adequate follow-up.** Only two RCTs in the reviewed literature (Kootte et al. and Ng et al.) directly compare allogenic versus autologous or sham FMT in patients with T2DM or metabolic syndrome, and only the Ng et al. trial extends follow-up to 24 weeks — the closest available approximation to the six-month threshold (PMC11527334). No RCT has reported HbA1c outcomes at 12 months or beyond in T2DM patients receiving allogenic FMT.

**Small sample sizes across all studies.** Across the reviewed literature, individual study sample sizes range from n=1 (case report) to n=52 (Ng et al. RCT), with most trials enrolling fewer than 40 participants per arm (PMC11527334). These sample sizes are insufficient to detect modest but clinically meaningful HbA1c reductions with adequate statistical confidence, and they preclude meaningful subgroup analyses.

**Heterogeneity in FMT protocols.** Across the reviewed trials, FMT was delivered via nasoduodenal tube, nasojejunal tube, transendoscopic enteral tube, oral capsules, and colonoscopy; using fresh, frozen, or washed preparations; from single or multiple donors; as single or repeated doses; and with or without pre-FMT antibiotic or bowel preparation (PMC11527334, PMC11671274). This procedural heterogeneity makes it impossible to determine which protocol is optimal for glycemic outcomes.

**Heterogeneity in patient populations.** Some trials enrolled patients with T2DM, others with metabolic syndrome (not all of whom had T2DM), and some included pre-diabetic patients alongside established T2DM patients (PMC11527334). Baseline HbA1c, disease duration, concurrent antidiabetic medications, and BMI varied substantially across studies, further complicating cross-trial comparisons.

**Short follow-up durations.** The majority of reviewed trials assessed outcomes at four to twelve weeks, with only the Ng et al. RCT and the Wu et al. (2022) observational study providing data at or approaching six months (PMC11527334). The Wu et al. (2022) observational study found that short-term glycemic improvements were not sustained at six months, but this finding comes from a non-randomized, uncontrolled study with a mixed population.

**Confounding by concurrent antidiabetic medications.** Several trials enrolled patients who were concurrently taking metformin or other antidiabetic agents, which independently alter gut microbiota composition and may obscure or interact with FMT's effects (PMC7693552, PMC11527334). Metformin independently alters gut microbiota composition — increasing *Akkermansia muciniphila* and other SCFA-producing taxa — potentially confounding microbiome analyses in FMT trials where patients are concurrently taking metformin (PMC7693552, PMC11527334).

**Absence of standardized microbiome analysis methods.** Across the reviewed trials, gut microbiota was characterized using 16S rRNA gene sequencing, whole-genome shotgun metagenomics, and metagenomic sequencing with varying bioinformatics pipelines, making cross-study comparisons of microbial outcomes unreliable (PMC11527334, PMC9872724).

**Lack of pre-specified donor selection criteria for metabolic outcomes.** Donor selection in the reviewed trials was based primarily on general health screening criteria (absence of metabolic disease, normal BMI, no recent antibiotic use), without systematic selection for specific microbial profiles associated with metabolic health. The "super-donor" concept — the observation that some donors produce consistently better FMT outcomes than others — has been described in CDI literature but has not been systematically investigated in T2DM trials (PMC11671274).

**Predominantly short-term and Asian populations.** Several of the most detailed RCTs (Wu et al., 2023; Cai et al.) were conducted in southeast Chinese populations, limiting generalizability to other ethnic groups with different baseline microbiome compositions, dietary patterns, and genetic backgrounds (PMC9872724, PMC11527334).

**Loss of key anaerobic species during FMT preparation.** One long-term study found that microbiota diversity remained elevated for up to 12 months post-transplant, but no significant biochemical or anthropometric changes were sustained, partly attributed to loss of anaerobic species such as *Faecalibacterium prausnitzii* and *Akkermansia muciniphila* during the transfer process (PMC12028006). Washed microbiota transplantation (WMT) — which employs microfiltration and repeated centrifugation — has been proposed as offering greater precision and safety compared with traditional FMT by implementing more stringent quality controls and reducing adverse effects for recipients (PMC12028006). Retrospective data suggest short- and medium-term benefits of WMT on fasting blood glucose and related metabolic parameters, though the superiority of WMT over standard FMT for glycemic outcomes has not been established in head-to-head RCTs (PMC11527334, PMC12028006).

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### Comparative Effectiveness

#### FMT vs. Metformin

The Wu et al. (2023) RCT provides the only direct head-to-head comparison of FMT versus metformin in T2DM patients (PMC9872724). At four weeks, FMT alone and FMT plus metformin both produced significant reductions in HOMA-IR and BMI that were not achieved by metformin alone. However, FBG and HbA1c decreased more in the FMT plus metformin group than in FMT alone, suggesting complementary rather than competing mechanisms. The metformin-only group showed significant improvements in FBG, PBG, HbA1c, and HOMA-HBCI, but not in HOMA-IR or BMI. The Wu et al. (2023) RCT found that FMT plus metformin produced greater reductions in FBG and HbA1c than FMT alone at four weeks, while FMT alone produced greater improvements in HOMA-HBCI, HbA1c, AST, TBA, and TP than metformin alone, suggesting complementary rather than competing mechanisms (PMC9872724). However, the four-week follow-up and small sample sizes preclude conclusions about comparative effectiveness at six months.

#### FMT vs. Lifestyle Intervention

The Ng et al. RCT compared FMT alone, FMT plus lifestyle intervention (LSI), and sham plus LSI over 24 weeks (PMC11527334, PMC11671274). At week 24, no significant differences in HbA1c, fasting glucose, or fasting insulin were observed between any group and baseline. However, the FMT plus LSI group showed significant improvements in LDL cholesterol, total cholesterol, and liver stiffness that were not observed in the FMT-alone or sham plus LSI groups. These findings suggest that FMT's metabolic benefits may be most apparent when combined with lifestyle modification, and that lifestyle intervention alone (without FMT) is insufficient to produce the same microbiome-mediated metabolic changes. The absence of HbA1c reduction in any group at 24 weeks is the most important finding from this trial for the durability question.

#### FMT vs. Probiotics and Prebiotics

No head-to-head RCT comparing FMT with probiotics or prebiotics for HbA1c reduction in T2DM was identified in the reviewed literature. Indirect comparisons suggest that probiotics (e.g., fermented milk with *Bifidobacterium animalis* BB-12 and *Lactobacillus acidophilus* La-5, 120 g/day for six weeks) can significantly reduce fructosamine and HbA1c in T2DM patients (PMC11597803), while FMT produces more comprehensive microbiome restructuring but with less consistent HbA1c effects. The relative durability of probiotic versus FMT-induced glycemic improvements at six months has not been directly compared.

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### Special Populations

#### Newly Diagnosed vs. Established T2DM

The Wu et al. (2023) RCT specifically enrolled patients with newly diagnosed T2DM who were not receiving prior regular drug treatment or dietary intervention, providing a relatively clean population for assessing FMT's intrinsic metabolic effects (PMC9872724). In contrast, the Ng et al. and Kootte et al. trials enrolled patients with established T2DM or metabolic syndrome who may have been on concurrent antidiabetic medications. The hypothesis that gut microbiota plays a more significant role in the earlier stages of glycemic control and to a lesser degree in severe stages of insulin resistance observed in advanced T2DM has been proposed in the reviewed literature (PMC7693552), suggesting that FMT may be most effective in newly diagnosed or pre-diabetic patients. This hypothesis has not been formally tested in adequately powered trials.

#### Obese vs. Non-Obese T2DM Patients

Most reviewed FMT trials enrolled obese T2DM patients (BMI ≥27–35 kg/m²), reflecting the strong epidemiological association between obesity and T2DM. The Allegretti et al. oral capsule FMT study was conducted in obese patients without confirmed T2DM, limiting its direct applicability (PMC11671274). Whether FMT produces different glycemic outcomes in non-obese T2DM patients — who may have a different underlying microbiome dysbiosis profile — has not been investigated.

#### Pediatric and Adolescent Populations

The reviewed literature includes two case reports of FMT in adolescent T1DM patients (not T2DM), which demonstrated improvements in glycemic control and insulin resistance at 10–30 weeks of follow-up (PMC9414079). Both patients had fair glycemic control during transplantation and later clinical follow-up, with FMT significantly improving insulin resistance; the number of transplants and the time interval between transplants appeared to impact clinical outcomes. These findings are not directly applicable to adult T2DM but suggest that FMT may have broader applicability across diabetes subtypes. One long-term study found that microbiota diversity remained elevated for up to 12 months post-transplant but no significant biochemical or anthropometric changes were sustained, partly attributed to loss of anaerobic species during transfer (PMC12028006). T2DM in pediatric populations is a distinct clinical entity with different pathophysiology and microbiome characteristics, and the reviewed literature does not provide sufficient evidence to draw conclusions about FMT efficacy in this group.

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### Conclusions and Future Directions

#### What the Evidence Supports

The available human clinical evidence supports the conclusion that allogenic FMT from healthy donors can produce short-term (four to twelve weeks) improvements in insulin sensitivity (HOMA-IR), fasting blood glucose, postprandial blood glucose, and HbA1c in adults with T2DM or metabolic syndrome. This conclusion is supported by the Wu et al. (2023) RCT (n=29, four-week follow-up, significant HOMA-IR reduction in FMT arms vs. metformin alone), the Ding et al. NRCT (n=37, 12-week follow-up, positive effects on FBG, HbA1c, and C-peptide), the meta-analysis of nine studies (n=303, lower FBG, HbA1c, and insulin within six weeks), and multiple observational studies (PMC9872724, PMC11527334). FMT also consistently improves lipid profiles (reduced LDL, total cholesterol, TG; increased HDL) and, in some studies, reduces blood pressure and liver stiffness (PMC11527334, PMC11671274). The mechanistic basis for these effects — involving SCFA-mediated GLP-1 stimulation, restoration of intestinal barrier integrity, reduction of metabolic endotoxemia, and modulation of bile acid metabolism — is well-supported by the mechanistic literature (PMC8886906, PMC11597803, PMC11671274, PMC9785599).

#### What the Evidence Does NOT Support

The available evidence does NOT support the conclusion that allogenic FMT from healthy donors produces a durable (≥6 months) reduction in HbA1c compared with autologous FMT or placebo in human adults with T2DM. The most directly relevant evidence — the Ng et al. RCT (n=52, 24-week follow-up) — found no significant change in HbA1c in any group (FMT alone, FMT plus LSI, or sham plus LSI) compared with baseline at week 24 (PMC11527334, PMC11671274). The Wu et al. (2022) observational study found that FBG and HOMA-IR improvements were not sustained at six months (PMC11527334). The long-term study cited in the PMC12028006 review found no significant biochemical or anthropometric changes sustained at 12 months post-transplant. No RCT has demonstrated durable HbA1c reduction at six months or beyond in T2DM patients receiving allogenic FMT. The evidence also does not support FMT as a standalone therapy for T2DM; the Su et al. observational study concluded that dietary alteration is necessary to maintain the long-term effects of FMT (PMC11527334), and the reviewed literature more broadly indicates that FMT alone is insufficient for blood glucose control and should be combined with lifestyle modifications and established pharmacotherapies (PMC11671274).

#### Future Research Priorities

Six concrete future research priorities emerge from the gaps identified in this review:

**1. Adequately powered RCTs with six-month and twelve-month HbA1c endpoints.** The most urgent research need is a multicenter, double-blind, randomized, placebo-controlled trial of allogenic FMT in T2DM patients with primary endpoints of HbA1c change at six and twelve months, powered to detect a clinically meaningful difference of 0.5% with 80% power. Such a trial would require approximately 150–200 participants per arm based on standard assumptions for HbA1c variability in T2DM populations.

**2. Optimization of FMT protocol for metabolic outcomes.** Future trials should systematically compare FMT delivery routes (oral capsule vs. colonoscopic vs. nasoduodenal), dosing schedules (single vs. repeated), preparation methods (fresh vs. frozen vs. washed), and donor selection strategies (single vs. multiple donors, microbiome-matched vs. unmatched) in T2DM populations, using HbA1c at six months as the primary endpoint.

**3. Identification and validation of "super-donors" for metabolic FMT.** The concept of donor-specific efficacy — well-established in CDI FMT — should be systematically investigated in T2DM. Prospective studies should characterize the microbiome profiles of donors whose FMT produces the greatest metabolic improvements in recipients, with the goal of developing evidence-based donor selection criteria for metabolic indications.

**4. Investigation of FMT combined with dietary standardization.** Given the evidence that dietary factors independently shape microbiome composition and may determine FMT response, future trials should standardize recipient diet during and after FMT, and should test whether specific dietary patterns (e.g., high-fiber, Mediterranean diet) enhance and prolong FMT-induced glycemic improvements. The Su et al. finding that dietary alteration is necessary to maintain FMT's long-term effects (PMC11527334) provides a strong rationale for this approach.

**5. Mechanistic studies linking specific microbial taxa to HbA1c durability.** Future trials should incorporate comprehensive metagenomics, metatranscriptomics, metabolomics (SCFAs, bile acids, TMAO, BCAAs), and immunological profiling at multiple time points to identify the specific microbial and metabolic changes that predict durable HbA1c reduction. The correlation analyses from the Wu et al. (2023) trial — identifying *Bifidobacterium adolescentis*, *Chlorobium phaeovibrioides*, and *Synechococcus* sp. as negatively correlated with HOMA-IR — provide a starting point for hypothesis-driven mechanistic investigation (PMC9872724).

**6. Investigation of FMT in newly diagnosed, treatment-naive T2DM patients.** The hypothesis that FMT is most effective in the early stages of T2DM — before progressive β-cell dysfunction and severe insulin resistance have developed — should be tested in trials specifically enrolling newly diagnosed, treatment-naive patients. The Wu et al. (2023) trial's enrollment of treatment-naive patients provides a model for this approach (PMC9872724), and a larger, longer-term version of this trial with six-month HbA1c endpoints is a high priority.

**7. Development of standardized FMT preparation protocols to preserve anaerobic species.** The loss of key anaerobic taxa (including *Faecalibacterium prausnitzii* and *Akkermansia muciniphila*) during standard FMT preparation may limit metabolic efficacy. Future research should evaluate whether washed microbiota transplantation (WMT) or other advanced preparation methods that better preserve anaerobic species produce superior and more durable glycemic outcomes compared with standard frozen FMT preparations (PMC12028006, PMC11671274).

In summary, the current evidence base establishes that allogenic FMT from healthy donors can improve short-term glycemic parameters in T2DM, but does not support the conclusion that these benefits are durable at six months or beyond. The Ng et al. RCT — the only randomized trial with a follow-up approaching six months — found no significant HbA1c reduction at 24 weeks, and the Wu et al. (2022) observational study found that short-term improvements in FBG and HOMA-IR were not sustained at six months. These findings do not preclude the possibility that optimized FMT protocols — with better donor selection, repeated dosing, dietary standardization, and preservation of key anaerobic taxa — might achieve durable HbA1c reduction; they simply establish that current protocols have not demonstrated this outcome. The field requires larger, longer, and more rigorously designed trials before FMT can be considered a viable standard-of-care intervention for glycemic management in T2DM.

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*This review was prepared from the provided literature pool. All cited papers are identified by their PMC identifiers as provided. No animal or rodent data were included in the clinical synthesis, consistent with the stated scope of the review.*

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