Lactulose Regulates Gut Microbiota Dysbiosis in Acute Pancreatitis with Intestinal Dysfunction Original paper

What was studied?

This prospective, open-label, randomized controlled trial investigated whether lactulose regulates gut microbiota dysbiosis in acute pancreatitis patients with intestinal dysfunction and whether its effects on gut function, systemic inflammation, and short-chain fatty acid (SCFA) production were comparable or superior to Chinese herb rhubarb. Moderate-severe acute pancreatitis (MSAP) patients with gastrointestinal dysfunction (score of gut dysfunction > 5) were randomized 1:1 within 72 hours of onset to receive lactulose or rhubarb for 1 week, alongside standard AP care. The primary endpoints were recovery of intestinal function, assessed by tolerance of complete enteral nutrition and normalization of the gut dysfunction score, with secondary endpoints including infectious complications, organ failure, inflammatory cytokines, gut permeability markers, gut microbiota composition, and fecal SCFAs. The investigators used 16S rRNA gene sequencing (V3–V4 region, 97 % OTU clustering, SILVA v138 taxonomy) and LEfSe analysis to characterize microbial shifts, and GC–MS to quantify acetate, propionate, and butyrate in stool samples, enabling integration of clinical outcomes with microbiome and metabolite data.

Who was studied?

The study enrolled 73 adult MSAP patients (18–75 years) with early intestinal dysfunction at a single tertiary pancreatic center in China, of whom 83 were initially randomized and 73 completed per-protocol analysis (36 lactulose, 37 rhubarb). Baseline characteristics, including etiology (predominantly biliary pancreatitis, followed by hypertriglyceridemia), APACHE II, SIRS, modified Marshall, and MCTSI scores, were balanced between groups. Exclusion criteria eliminated those with organ failure, gastrointestinal bleeding, fistulas, malignancy, autoimmune disease, pregnancy, or prior use of prebiotics/probiotics within 4 weeks, refining the cohort to a relatively homogeneous MSAP population with early gut involvement. In parallel, 28 healthy volunteers without AP served as microbiome and SCFA controls, permitting differentiation between AP-associated dysbiosis and treatment-induced changes. Approximately half of the AP patients received cephalosporins, allowing stratified analyses of antibiotic versus non-antibiotic subgroups for microbiome outcomes.

Most important findings

Clinically, lactulose and rhubarb were equivalent in restoring intestinal function: about 70 % of patients in each arm tolerated complete enteral nutrition by day 7, and the gut dysfunction score normalized after roughly 6 days in both groups. Rates of infectious complications, organ failure, minimally invasive interventions, and hospital stay length were also similar, indicating non-inferiority of lactulose to an established TCM therapy at the level of classical AP outcomes. However, lactulose demonstrated a stronger systemic anti-inflammatory profile; both treatments reduced TNF-α, IL-6, CRP, and procalcitonin by day 7, but TNF-α and IL-6 fell to significantly lower levels in the lactulose group, suggesting more effective dampening of the inflammatory cascade that drives AP severity. D-lactate, a marker of gut permeability, decreased comparably in both arms, while diamine oxidase remained unchanged, indicating partial but not complete restoration of barrier integrity.

Microbiome analyses revealed a characteristic AP signature with reduced diversity and overrepresentation of pathobionts relative to healthy controls, dominated by Proteobacteria and Firmicutes, particularly Escherichia-Shigella and Enterococcus. In non-antibiotic patients, lactulose shifted the community structure toward a more eubiotic profile: Actinobacteriota increased, driven by enrichment of Bifidobacterium, while pathogenic Escherichia-Shigella and Enterococcus were reduced. Lactobacillales also expanded, aligning the community toward health-associated SCFA producers. In contrast, rhubarb-treated patients without antibiotics showed higher abundances of Escherichia-Shigella and Staphylococcus, preserving or even amplifying AP-associated pathobionts as major microbial associations. Under antibiotic exposure, both lactulose and rhubarb groups converged on similar microbiota dominated by Enterococcus and Lactobacillales, indicating that systemic antibiotics largely overrode prebiotic or herbal differentiation.

Metabolically, total SCFAs (acetate, propionate, butyrate) were reduced in AP relative to healthy controls and increased after 1 week of treatment in both arms, but lactulose elicited a quantitatively stronger response. In antibiotic-free patients, lactulose produced higher total SCFAs, particularly acetate, than rhubarb, consistent with its prebiotic fermentation by Bifidobacterium and Lactobacillus species. This coupling of Bifidobacterium enrichment, suppression of Escherichia-Shigella and Enterococcus, and increased SCFA output defines a coherent microbiome signal for lactulose in AP, positioning Bifidobacterium (and possibly Lactobacillales) as beneficial MMAs and Escherichia-Shigella/Enterococcus as targetable pathogenic MMAs within a microbiome signatures framework.

Key implications

For clinicians managing AP with early intestinal dysfunction, this study indicates that lactulose is a viable alternative to rhubarb for promoting gut functional recovery, with the additional advantages of stronger systemic anti-inflammatory effects and favorable microbiome remodeling. From a microbiome medicine perspective, lactulose acts as a microbiome-targeted intervention that aligns clinical improvement with correction of dysbiosis: it selectively expands Bifidobacterium and Lactobacillales, suppresses Proteobacteria-dominated pathobionts such as Escherichia-Shigella and Enterococcus, and restores SCFA production toward a healthier profile. These changes are mechanistically relevant, given the known roles of SCFAs in enhancing epithelial barrier function and modulating immune responses. The findings also highlight antibiotics as a major modifier of microbiome outcomes, often flattening differences between interventions, which is critical when interpreting microbiome-based therapies in hospitalized AP cohorts. Limitations include single-center design, modest sample size, use of 16S rather than metagenomics, and absence of a placebo arm, so some microbiome shifts may reflect natural recovery. Nevertheless, the concordance between improved inflammation, beneficial taxa shifts, and SCFA restoration supports lactulose as a candidate microbiome-targeted intervention (MBTI) for AP-associated dysbiosis and provides concrete MMAs (Bifidobacterium, Lactobacillales vs Escherichia-Shigella, Enterococcus, Staphylococcus) for inclusion in a microbiome signatures database.

Citation

Wang J, Jiang M, Hu Y, Lei Y, Zhu Y, Xiong H, He C. Lactulose regulates gut microbiota dysbiosis and promotes short-chain fatty acids production in acute pancreatitis patients with intestinal dysfunction. Biomed Pharmacother. 2023;163:114769. doi:10.1016/j.biopha.2023.114769.