Letter to the Editor: Rhubarb enema for acute pancreatitis - encouraging gut-immune signals with unconfirmed clinical benefit

Abstract

Progress in acute pancreatitis management has mainly resulted from improvements in supportive care, while adjunctive therapies targeting intestinal function and immune-inflammatory responses remain unproven. In the recent issue of World Journal of Gastroenterology, Zhong et al conducted a randomized placebo-controlled trial evaluating rhubarb enema in acute pancreatitis. The intervention reduced pro-inflammatory cytokines, downregulated the Th17 cell/IL-17A pathway, increased interleukin-10 levels, and was associated with lower intra-abdominal pressure, collectively supporting the possibility that gut-directed interventions may influence systemic inflammation through modulation of the gut-immune axis. However, 28-day all-cause mortality was not significantly reduced, and the observed number of deaths was substantially lower than anticipated, reducing statistical power and increasing the risk of a type II error. Furthermore, the predominance of hypertriglyceridemic acute pancreatitis limits generalizability. Rhubarb enema should therefore be regarded as a promising but unconfirmed adjunctive intervention requiring validation in studies focused on patient-centered outcomes.

Key Words: Acute pancreatitis; Rhubarb enema; Gut-immune axis; Th17 cells; IL-17A; Intra-abdominal pressure; Randomized controlled trial; Patient-centered outcomes

Core Tip: Rhubarb enema has shown promising intestinal-immune regulatory signals in acute pancreatitis, including a decrease in pro-inflammatory factors, a downregulation of the Th17/IL-17A pathway, an increase in IL-10, and an improvement in intra-abdominal pressure. However, recent randomized controlled studies have not shown a significant reduction in all-cause mortality at 28 days, and the actual event rate is lower than expected, with a relatively specific study population, which limits the certainty and generalizability of the conclusions. Rhubarb enema should currently be regarded as a potentially promising but unproven adjunctive intervention rather than a standard treatment that can immediately change clinical practice. Its clinical value still needs to be further verified in standardized procedures, clear stratified populations, and patient-centered hard endpoints.

TO THE EDITOR

Acute pancreatitis is a common acute disease of the digestive system. Its clinical manifestations are diverse, ranging from mild self-limited disease to severe disease with organ failure[1]. Persistent organ failure, infected pancreatic necrosis, intra-abdominal hypertension, and systemic inflammatory responses remain major causes of morbidity and mortality in moderately severe and severe acute pancreatitis[2]. Improvements in outcomes in recent decades have been due largely to advances in supportive care rather than to the introduction of effective disease-modifying agents[3,4]. In this context, the gut is receiving increasing attention as a potential therapeutic target, as intestinal dysfunction appears to lead to amplification of systemic inflammation during disease progression[5,6]. Whether therapies targeting gut function and gut-derived inflammation provide additional benefit beyond standard supportive care remains an important clinical question. In the recent issue of World Journal of Gastroenterology, Zhong et al[7] conducted a randomized placebo-controlled trial, which evaluated rhubarb enema in patients with acute pancreatitis, therefore offers a valuable opportunity to reassess a traditional empirical therapy using modern randomized methodology and in the context of gut-immune regulation.

In that trial, rhubarb enema was compared with normal saline enema, both given in addition to standard treatment. Patients in the rhubarb enema group showed improvements in several biological and physiological indicators, including pro-inflammatory cytokines, the proportion of Th17 cells, and intra-abdominal pressure. Some secondary clinical endpoints also showed favorable trends, although these findings require cautious interpretation. The primary endpoint, 28-day all-cause mortality, however, was not significantly improved, and convincing benefits in major clinical outcomes were not demonstrated.

The main message of this trial is therefore not that rhubarb enema has been proven to improve the prognosis of acute pancreatitis. Rather, the study shows that a traditional empirical intervention can be evaluated through randomized controlled methods and interpreted in relation to immune mechanisms. At present, these findings should be regarded as encouraging biological signals, not as conclusive evidence sufficient to change clinical practice.

The contribution of the trial to current evidence

Chinese rhubarb-containing therapies have been in practice in China over several decades as adjuvant therapies for acute pancreatitis especially among those with abdominal distension or gut dysfunction. However, these mechanisms and prolonged clinical application are not enough to confirm clinical effectiveness. Improvement in patient-based results is still required[8,9].

Despite progress in supportive care, acute pancreatitis still lacks adjunctive treatments that consistently improve clinically meaningful outcomes[10-12]. The main contribution of the Zhong et al’s study[7] is that it shifted rhubarb enema from an empirical clinical application to a randomized, placebo-controlled, and mechanism-oriented evaluation. To the best of our knowledge, this is the first randomized placebo-controlled study to include Th17-related immunophenotype in the evaluation of rhubarb treatment in acute pancreatitis. Previous studies on interventions containing rhubarb have focused on gastrointestinal recovery, abdominal distension, bowel function, or conventional inflammatory markers[13]. Zhong et al[7] made new interpretations to further expand this assessment by looking at Th17 cell responses, IL-17A signaling, anti-inflammatory cytokine profiles, and intra-abdominal pressure. Meanwhile, the present study creatively connects gut interventions to the general immune regulation, which offers mechanistic support to the notion of the gut-immune axis in acute pancreatitis and enhances the credibility of the research. On top of the positive aspect, it is necessary to consider the negative aspect as well. This research should be viewed more as a biologically plausible hypothesis, instead of direct evidence of the routine clinical use.

Interpreting the discordance between immunological signals and clinical outcomes

Acute pancreatitis is not a disease entity per se. In reality, it is a heterogeneous syndrome[14]. Thus, varying etiologies, clinical presentations, and different phases of the disease can contribute to the ultimate treatment results. In the paper by Zhong et al[7], hypertriglyceridemia-induced acute pancreatitis (HTG-AP) was the most common etiology, whereas the biliary form of acute pancreatitis was underrepresented[15]. This design could potentially decrease the heterogeneity of causes and enhance the internal consistency of mechanistic analyses, yet it leads to a very significant question: Do the observed effects apply exclusively to HTG-AP or can they be extended to other forms of acute pancreatitis? It is especially important to remember that HTG-AP is pathophysiologically distinct in many ways as compared to biliary and alcoholic acute pancreatitis. Too much triglyceride and free fatty acid in the blood can lead to lipotoxicity, microcirculatory dysfunction, oxidative stress and systemic inflammatory activity, which cause damage to the pancreas. People with HTG-AP tend to be younger and have a greater risk of developing recurrent attacks compared to people with other causes. Such disparities indicate that the inflammatory characteristics and clinical progression of HTG-AP might not entirely coincide with those of biliary or alcoholic acute pancreatitis.

The role of gut dysfunction, barrier damage, and gut-immune interactions is not yet clear in acute pancreatitis of different etiological subtypes[16]. This implies that the mechanistic advantages of rhubarb enema noted in the current trial might apply better to those with hyperlipidemic acute pancreatitis than to all the patients with acute pancreatitis. The results can be regarded as initial data on a particular population and must be carefully extrapolated to other etiologies. Future studies ought to incorporate etiological stratification or, better yet, be designed as randomized studies focusing on specific causes since it would help establish if rhubarb enema has varying effects between acute pancreatitis subgroups.

A further significant concern is that the primary outcome occurrence was less than anticipated, and there is more to it than simply the fact that the sample size is too small. In the initial calculation of sample size, the number of deaths was assumed to be much higher, but the observed mortality rate was much lower, which undermines the statistical basis of the research. In this context, the sample size used in the study is insufficient to demonstrate the actual difference in 28-day all-cause mortality, and thus it is not able to show that the effect has clinical importance. Hence, a non-significant mortality finding can be better described as inconclusive and has a rather large probability of type II error. It is particularly important because, despite the fact that mortality is very important clinically, it is quite uncommon in acute pancreatitis, especially with current supportive treatment. With a low number of events, group comparisons may be statistically unstable, the confidence interval will be large, and the effect estimate may change due to one or two additional deaths. Therefore, the survival effect of rhubarb enema cannot be reliably confirmed or excluded in this trial. Therefore, the primary end point should be interpreted as underpowered and hypothesis-generating rather than as negative or definitive.

Whether 28-day mortality is the most appropriate primary end point in a predominantly HTG-AP population is also worth exploring. Compared with biliary or alcoholic acute pancreatitis, HTG-AP often affects younger patients and may be associated with relatively lower short-term mortality despite a higher inflammatory burden. In this case, mortality may be too insensitive to detect efficacy in a moderate-sized trial.

Other patient-centered outcomes, such as persistent organ failure, infected pancreatic necrosis, need for intervention, and number of intensive care unit (ICU) days, may be more sensitive measures of efficacy for intestinal intervention in acute pancreatitis[17].

More broadly, studies of acute pancreatitis have repeatedly shown that improvements in inflammatory mediators do not necessarily translate into reduced organ failure or mortality. The disconnect between substitute endpoints and real results remains an issue to be addressed in the future. Biomarker improvement may indicate some useful hints, yet it does not guarantee a particular clinical benefit[18].

Clinical contexts and remaining uncertainties of rhubarb enema therapy

The findings of Zhong et al[7] naturally lead to a more practical issue: At what stage does a rhubarb enema become most effective? The changes in inflammatory markers as well as intra-abdominal pressure indicate that some patient categories may react differently. Patients with clear gut dysfunction, high intra-abdominal pressure, or severe inflammation could benefit more from this intervention. It is also extremely critical. In terms of pathophysiology, interventions focused on the gut problem and immune activation can be more useful in the early inflammatory stage, prior to any current organ failure or infectious necrosis.

Also, it remains questionable as to whether the immune changes detected in the present study would be observed in a larger number of patients with various types of clinical conditions. In the future studies, the target populations need to be more defined, the optimal treatment duration needs to be determined and the presence of such biological changes should be confirmed by actual improvement of patient outcomes. Such problems are quite serious when planning further trials. However, if the influence of rhubarb enemas is determined by personal features of a patient, a stage of a disease and the moment of treatment, the mere increase in the amount of samples may not suffice. Future trials should not only assess the effectiveness of the treatment but also determine the clinical scenarios under which this treatment is most likely to be beneficial.

On the whole, rhubarb enemas could be perceived as a multifaceted treatment strategy instead of a simple medication approach. The outcomes can be related to the disease type, time of administration, inflammation level and state of the stomach of the patient. It could contribute to explaining why previous research did not yield consistent findings. Therefore, the next step in future research ought to be more than merely validating the occurrence of immunological changes but also establishing whether such changes may be associated with clinically significant benefits or not.

Immunological findings and their clinical implications

The most important finding of Zhong et al's study[7] is that in patients under treatment with rhubarb enemas, all the changes in the inflammation, immune response and intra-abdominal pressure were in the same direction. In particular, the level of pro-inflammatory cytokines decreased, IL-10 increased, the ratio of Th17/CD4 cells decreased, and intra-abdominal pressure was reduced.

The Th17-related pathways have been related to the severity of acute pancreatitis and the increase of systemic inflammation. Therefore, the decreases in Th17/CD4 ratio and IL-17A concentrations are biologically significant. Previous studies also suggest that enhanced Th17 responses might be associated with more severe disease and stronger systemic inflammation[19]. The simultaneous decrease in IL-17A and increase in IL-10 suggest a shift from a predominantly pro-inflammatory to a counter inflammatory immune state.

However, biologic signals should be clearly distinguished from clinical benefit. The reductions in inflammatory cytokines and the changes in the Th17/IL-17A axis indicate that rhubarb enema may influence immune pathways relevant to acute pancreatitis. However, these findings should not be regarded as a substitute for evidence of improvement in outcomes that matter directly to patients. Previous studies in acute pancreatitis have shown that improvements in inflammatory markers do not necessarily translate into persistent organ failure or reduced mortality.

The reduction in intra-abdominal pressure may also be important from a physiological point of view[20]. However, whether this improvement will lead to better clinical outcomes remains unclear. The results reported by Zhong et al[7] are better interpreted as evidence of mechanism rather than of clinical efficacy, given the lack of evidence of a mortality benefit and the small number of deaths observed. They suggest that gut-directed therapy may have systemic effects through modulation of the gut immune axis.

For now, this study should be viewed primarily as hypothesis-generating. Until changes in biomarkers are reliably consistent with improvements in patient-centered outcomes, including persistent organ failure, infected necrosis, non-ICU days, need for intervention, or mortality, rhubarb enema should be considered a promising but still unproven adjunct treatment.

Conclusion

In conclusion, the main contribution of the Zhong et al’s study[7] is not to establish the clinical efficacy of rhubarb enema, but to provide randomized evidence that it may modulate immune-inflammatory responses in acute pancreatitis, particularly through effects on the Th17/IL-17A pathway, proinflammatory cytokines, IL-10 levels, intra-abdominal pressure, and the gut-immune axis. However, due to the lack of clear evidence that it reduces mortality, unexpectedly low event rates, and the dominance of HTG-AP, these factors limit the certainty and general applicability of the study results. So, rhubarb enema should be seen as a promising but still unproven adjunct treatment, rather than a way to change clinical practice or replace standard supportive care.