Gut microbiota-host co-metabolism in hypertriglyceridemia-associated acute pancreatitis: from causality to precision intervention
This narrative review synthesizes causal evidence — predominantly preclinical and from Mendelian randomization — that gut dysbiosis aggravates hypertriglyceridemia-associated acute pancreatitis (HTG-AP) through specific co-metabolic axes, but no microbiota-targeted intervention has demonstrated clinical benefit in humans with HTG-AP to date.
| Population | Patients with hypertriglyceridemia-associated acute pancreatitis (TG ≥ 500 mg/dL); review also includes murine models and Mendelian randomization data from European and East Asian populations |
|---|---|
| Intervention | Gut microbiota-targeted interventions (probiotics, postbiotics, fecal microbiota transplantation, prebiotics) and modulation of co-metabolic axes (SCFA-GPR43/HDAC, Trp-AhR, BA-FXR/TGR5, LPS-TLR4-LPC) |
| Comparator | No single comparator; narrative review without meta-analysis of clinical trials |
| Outcome | Mortality in HTG-AP vs. other AP etiologies; Global proportion of HTG-AP (meta-analysis); Microbiota-AP risk causality (Mendelian randomization); Microbiota-SCFA modulation in AP (animal models); Akkermansia muciniphila in HTG-AP (animal model); BA-FXR/TGR5 axis in AP (animal models); Microbiota-targeted interventions in HTG-AP in humans (clinical trials) |
Summary of findings
| Outcome | Effect | 95% CI | Certainty | Clinical relevance | Notes |
|---|---|---|---|---|---|
| Mortality in HTG-AP vs. other AP etiologies | OR 2.779, 95% CI 1.60-4.81 | — | Low | — | 1 studies |
| Global proportion of HTG-AP (meta-analysis) | 11.6% global; 16.3% Eastern; 5.4% Western (n=3,057,428, 110 studies) | — | Moderate | — | 110 studies |
| Microbiota-AP risk causality (Mendelian randomization) | MR signal: Odoribacter protective; Olsenella and Clostridium leptum risk-conferring; 24 mediation pathways identified across 473 taxa, 233 metabolites, 731 immune traits | — | Low | — | 10 studies |
| Microbiota-SCFA modulation in AP (animal models) | Protective effect lost in Gpr43 KO mice; in the human effect size reported | — | Very low | — | 2 studies |
| Akkermansia muciniphila in HTG-AP (animal model) | Attenuation of HTG-AP severity in murine model; in the quantitative effect size reported | — | Very low | — | 1 studies |
| BA-FXR/TGR5 axis in AP (animal models) | NF-kB/NLRP3 suppression via secondary bile acids in murine AP; in the human effect size reported | — | Very low | — | 2 studies |
| Microbiota-targeted interventions in HTG-AP in humans (clinical trials) | No completed RCTs; 2 trials recruiting (ChiCTR2500112068, ChiCTR2500108211); in the effect size available | — | Very low | — |
Context
HTG-AP accounts for 11.6% of global acute pancreatitis cases, rising to 16.3% in East Asian countries, with mortality four times higher than in Western settings (4.1% vs. 1.0%). Current therapeutic options are largely supportive, and triglyceride-lowering measures have questionable efficacy in altering disease course. Understanding how the gut microbiota modulates disease progression is clinically relevant for identifying precision therapeutic targets.
What the study showed
A meta-analysis of 110 studies (n = 3,057,428) estimated the global proportion of HTG-AP at 11.6% (16.3% in Eastern vs. 5.4% in Western countries). A Chinese multicenter cohort (n = 3,224) identified an OR of 2.779 (95% CI: 1.60–4.81) for mortality in HTG-AP vs. other etiologies. Mendelian randomization studies across European and East Asian populations indicate causality between microbiota composition and AP risk, with Odoribacter as protective and Olsenella/Clostridium leptum as risk-conferring taxa. All mechanistic and intervention evidence derives from animal models; no completed randomized clinical trials in humans with HTG-AP exist.
How it was done
Narrative review with systematic literature search of PubMed, Web of Science, and Cochrane Library through June 2026, using combined terms for HTG, acute pancreatitis, and microbiota/metabolites. Incorporates data from meta-analyses, Mendelian randomization studies, gnotobiotic mouse experiments, and recruiting clinical trials. No registered protocol or formal risk-of-bias assessment (AMSTAR-2 not applied).
Effect magnitude
The only direct clinical magnitude estimate is OR 2.779 (95% CI: 1.60–4.81) for mortality in HTG-AP vs. other AP etiologies. Effects of microbiota-targeted interventions are reported exclusively in animal models, with no translation to human effect sizes.
Risk of bias
Narrative review without registered protocol, without formal risk-of-bias assessment (AMSTAR-2 not applicable; RoB 2 and ROBINS-I not applied to included primary studies), and subject to publication and citation selection bias. Most mechanistic evidence is preclinical (murine models), with unvalidated extrapolation to humans. The two registered clinical trials (ChiCTR2500112068 and ChiCTR2500108211) are still recruiting, with no results available.
What this study does NOT prove
This review does not prove that any microbiota-targeted intervention improves clinical outcomes in HTG-AP patients. Mendelian randomization data establish causal associations between microbiota composition and AP risk but do not define which intervention is effective, at what dose, timing, or in which population.
In clinical practice
This review supports no change in clinical management of HTG-AP. Clinicians should maintain standard supportive care and await results from ongoing trials. Use of probiotics or postbiotics in HTG-AP during the acute phase lacks efficacy and safety evidence in humans.
Limitations
Narrative review without registered protocol, without formal risk-of-bias assessment (AMSTAR-2 not applicable; RoB 2 and ROBINS-I not applied to included primary studies), and subject to publication and citation selection bias. Most mechanistic evidence is preclinical (murine models), with unvalidated extrapolation to humans. The two registered clinical trials (ChiCTR2500112068 and ChiCTR2500108211) are still recruiting, with no results available.
What is still missing
Randomized clinical trials in humans with HTG-AP testing microbiota-targeted interventions (specific probiotics, SCFA mixtures, AhR ligands) with clinically relevant endpoints (mortality, complications, recurrence). Validation of co-metabolic axes identified in animal models in prospective human cohorts.
Technical appendix
Version history
- 1.0 · 2026-11-12 — Auto-generated under Evidence Standard v1.0