Clinical Evidence and Potential Mechanisms in Treating Radiation Enteritis with Modified Baitouweng Decoction

Objectives To perform a meta-analysis and network analysis identification to evaluate the efficacy, safety, and potential mechanisms of modified Baitouweng decoction (mBTWD) in the treatment of radiation enteritis. Methods We searched PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang Databases, SionMed, and Chinese Scientific Journals Database to collect the randomized controlled trials (RCTs) of mBTWD treating radiation enteritis. Rev.Man 5.3 and Stata 14.0 software are employed for meta-analysis. The GRADE online tool is used to evaluate the quality of evidence. Network analysis and molecular docking approach are applied to predict the potential targets and ingredients of representative drugs in mBTWD for the treatment of radiation enteritis. Results Seventeen studies are eventually included, covering a total of 1611 patients: (1) The clinical efficacy is significantly higher in mBTWD groups than in control groups (RR = 1.24, 95% CI (1.17, 1.32), P < 0.00001). (2) mBTWD has certain advantages in improving TCM syndromes (MD = −3.41, P < 0.00001). (3) mBTWD has a certain positive effect on the improvement of intestinal signs and symptoms (RR = 1.23, P=0.0001; OR = 3.51, P < 0.00001). (4) Indexes including CRP, KPS, and OB, are better in mBTWD groups than in control groups (P < 0.00001, P=0.002, P=0.03), but the credibility is downgraded for a small sample size. Adverse events and recurrence rates require further confirmation with larger sample sizes. (5) Univariate meta-regression for clinical efficacy shows none of the coefficients are significantly associated with the estimated risk ratio. The clinical efficacy overestimates about 4.9% from publication bias. The quality of the included studies is low according to GRADE evidence. (6) Quercetin, isorhamnetin, and beta-sitosterol are the main ingredients from representative drugs in mBTWD and its key targets are MYC, TP53, and MAPK14/MAPK1. Conclusions mBTWD may be effective in the treatment of radiation enteritis, but its long-term benefits, safety, and molecular mechanisms remain unclear due to the poor quality of the evidence. Larger sample sizes, high-quality studies, and basic research are essential in the future.


Introduction
Radiation therapy is an important treatment therapy for pelvic/abdominal malignancies such as cervical cancer and rectal cancer. While efectively killing cancer cells and controlling local difusion and distant metastasis of lesions, radiation enteritis often occurs. Oxidative stress caused by the local high doses of radiation can produce a large number of reactive oxide species (ROS), which can cause DNA damage of normal intestinal epithelial cells, atrophy and ulceration of intestinal mucosa, and fnally form radioactive enteritis [1]. Approximately 90% of patients with pelvic and abdominal tumors have been reported to have irreversible changes in their defecation habits after radiation therapy, leading to a decrease in the quality of life of approximately 50% of patients [2]. Patients with radiation enteritis mainly present with diarrhea, bellyache, mucous stool, tenesmus, and anal distention, even serious conditions such as intestinal obstruction, intestinal perforation, and fstula formation. Tese intestinal symptoms lead to a signifcant reduction in the patient's willingness to continue with radiation therapy [3,4]. With the improvement of treatment methods, more and more tumor patients beneft from longer survival due to active management of side efects. Te treatment of radiation enteritis is mainly symptomatic treatment such as antidiarrheal, anti-infammatory, analgesic, and fuid rehydration. Commonly used drugs include dexamethasone, gentamicin, lidocaine, and montmorillonite powder. Moreover, the administration is mostly by reserved enema (Re) or per os (Po). Tese treatments can alleviate symptoms to some extent, but there is often a risk of incomplete treatment, aggravating infection, and high recurrence rate.
Chinese herbal formula is a long-established, complementary, and alternative medical treatment with curative efcacy, and it is now widely accepted and studied in countries around the world [5]. In recent years, traditional Chinese medicine (TCM) made some achievements in the treatment of radiation enteritis, especially the herbal retention enema refects the unique advantages of TCM. Baitouweng decoction (BTWD) is from the Treatise on Typhoid Fever, written by Zhang Zhong Jing in the Han Dynasty, and it is a representative formula for the treatment of febrile dysentery. Te base ingredients of the modifed Baitouweng decoction (mBTWD) are mainly Baitouweng decoction, which consists of four herbs: Pulsatilla (Baitouweng), Coptis chinensis (Huanglian), tractat (Huangbo), and ash bark (Qinpi). Modern pharmacological studies show that the representative drugs in mBTWD have a good efect on intestinal infammation. Tese ingredients regulate intestinal microbiota through FXR/TGR5 and IL-6/STAT3 signaling pathways, restore T17/Treg cell balance, and improve intestinal immune function and epithelial barrier in mice with enteritis [6][7][8] (Figure 1). However, the efects and benefts of mBTWD on radiation enteritis are still uncertain, and the mechanism of mBTWD in the treatment of radiation enteritis remains to be further discovered.
In this study, we conducted a meta-analysis to summarize the clinical evidence for mBTWD in the treatment of radiation enteritis. Based on the results of the meta-analysis, we employ network analysis and molecular docking techniques to preliminarily predict the active components and key targets of mBTWD at the molecular level for the treatment of radiation enteritis. Tis study aims to provide a scientifc reference for the clinical application of mBTWD in the treatment of radiation enteritis.

Materials and Methods
Tis study is registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) (https://inplasy.com) as INPLASY 202190053.

Inclusion/Exclusion
Criteria. Te inclusion criteria are constructed following the principle of PICOS. (1) Participants: all subjects are patients with abdominal/pelvic tumors complicated with radiation enteritis, regardless of age, sex or nationality. Te diagnostic criteria refer to the consensus of Chinese experts on the diagnosis and treatment of radiation enteritis in 2021 [9]. (2) Interventions: the experimental groups are treated with mBTWD alone or combined with conventional western medicine (CWM), and the CWM is the same as the control groups. Tere are no special restrictions on the dose of herbs, and the methods of administration include retention enema and per os. Te treatment course is longer than 14 days. (3) Controls: control groups receive the CWM recommended by expert consensus or just a placebo, and the methods of administration also include retention enema and per os. For example, montmorillonite powder retention enema or oral, or montmorillonite combined with gentamicin, dexamethasone, and procaine for retention enema. (4) Outcomes: the outcome indices mainly include clinical efcacy, TCM symptom score, colonoscopy score/grade, and radiation enteritis grading, KPS score, serum infammatory factor level, fecal occult blood, adverse events, and recurrence rate. assessment. (4) Attrition bias: incomplete outcome data. (5) Reporting bias: selective reporting. (6) Other bias: each bias risk is divided into three grades: high bias risk, low bias risk, and unknown bias risk.

Statistical Analysis and GRADE Evidence.
RevMan5. 3 and Stata 14.0 software is used for data processing. Te risk ratio (RR) or odds ratio (OR) are used for dichotomous variables and the weighted mean diferences are used for continuous variables. And 95% confdence intervals (CI) are calculated for all efect sizes. Cochran's Q and χ 2 test statistics are utilized to test the heterogeneity across studies. Te fxed-efects model is adopted with low heterogeneity (P > 0.1, I 2 < 50%). If there is heterogeneity in the studies (P ≤ 0.1, I 2 ≥ 50%), the random-efects model is chosen. Sensitivity analysis, subgroup analysis, and univariate metaregression analysis are employed to deal with high heterogeneity.
A meta-regression analysis is essentially an observational study that uses regression analysis to explore the efect of certain trial or case characteristics (covariates) on the combined efect in a meta-analysis in an attempt to clarify the sources of heterogeneity across studies and to explore the efect of covariates on the combined efect. Univariate metaregression analyses are conducted to explore the cause of heterogeneity and association between factors including intervention, drug deliver, sample size, mean age, duration and publication year, and the clinical efcacy of mBTWD on radiation enteritis when there are over 10 studies included. Egger's test is a simple quantitative method for testing the symmetry of funnel plots by linear regression, developed by Matthias Egger et al. in 1997 to overcome the shortcomings of the funnel plot method. Te theoretical basis of Begg's test is based on Kendall's tau rank correlation method, which determines the existence of "publication bias" by the presence of Kendall's correlation between the standardized efect estimates and the variance of the efect estimates. Te trim and fll method aims to identify and correct funnel plot asymmetries caused by publication bias. Tis method allows both the number of missing studies to be estimated and the inclusion of missing studies to be rerun in a meta-analysis, correcting for the combined efect size of the intervention. Egger's test, Begg's test, and the funnel-plot-based trim and fll method are used to deal with the potential publication bias.
Te online Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool [11] is used to evaluate the quality of evidence (https://gdt.gradepro.org/ app/). Te GRADE standard is a grading of the body of evidence that takes into account the type of study design, methodological quality, consistency of results, and directness of evidence. It has been adopted by over 100 international organisations and associations worldwide as one of the international standards for evaluating interventional evidence. We mainly use the risk of bias, inconsistency, indirectness, imprecision, and other considerations to evaluate quality. Tere are four levels of evidence: quality of evidence-high, moderate, low, or very low.

Network Analysis and Molecular
Docking. Firstly, the chemical constituents of representative drugs, Baitouweng, Huanglian, Huangbo, and Qinpi, are collected by searching the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database (https://tcmspw.com/tcmsp.php). Te main active compounds are obtained with oral bioavailability (OBA) greater than or equal to 30% and druglike (DL) greater than or equal to 0.18 as screening conditions [12]. Ten we screen the target protein corresponding to the active ingredients and convert the target protein name into the corresponding Gene Symbol. Te UniProtKB database (https://www.uniporot.org/) is used to check the target information.
Secondly, we set the keywords to "radiation enteritis" to search for the genes related to radiation enteritis from the fve sources: GeneCards (https://www.pharmgkb.org/), OMIM (https://omim.org/) and TTD (https://db.idrblab. net/ttd/). All targets associated with radiation enteritis are obtained after repeated genes. Te R language program and Evidence-Based Complementary and Alternative Medicine Venny 2.1 software are used to predict the drug-disease common targets. Ten we use the Perl program and Cytoscape 3.8.2 software to build a compound-target-disease network.
Tirdly, common drug-disease targets are imported into the STRING database (https://string-db.org/cgi/input.pl), setting the species as "Homo Sapiens" and the Proteinprotein interaction (PPI) network is formed. We then import the PPI network into Cytoscape 3.8.2 software and simplify it according to four topology attributes (DC, Degree Centrality; BC, Between Ness Centrality; CC, Closeness Centrality; EC, Eigenvec Tor Centrality). Tus, we obtain the fnal core target PPI network.
Next, ClueGO plug-ins are used to conduct Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for the core targets to screen out the main gene items and signal pathways related to radiation enteritis. GO is divided into three parts: BP (biological process), CC (cellular component), and MF (Molecular Function) [13].
Finally, ligand fles and receptor fles for molecular docking need to be prepared. (1) Ligand fles: 2D structures of small molecule ligands of each core target are downloaded from the PubChem database (https://pubchem.ncbi.nlm. nih.gov/) and are converted from 2D to 3D structures with ChemOfce software. We then optimize them with the AutoDockTools (Version 1.5.6) and save them in PDBQT format as ligand fles. (2) Receptor fles: the PDB fles of the 3D structures of the core target are downloaded from Protein Data Bank (PDB) database (https://www.rcsb.org/). Ten we process them with Pymol software (Version 3.2.2) and AutoDockTools software (Version 1.5.6) and save them in PDBQT format as receptor fles. (3) Molecular docking: AutoGrid software is used to determine the active pocket of the docking receptor, AutoDock Vina software (Version 1.1.2) is selected for molecular docking, and Pymol software (Version 3.2.2) software is used for analysis and mapping. At the same time, dexamethasone, the commonly used drug in radiation enteritis treatment, is selected as a positive control for analysis and verifcation.

Retrieval Results and Study Characteristics.
A total of 306 related studies were preliminarily retrieved, 37 duplicate articles were removed, and 212 articles were excluded after reading titles and abstracts. Te remaining 57 papers were read in full and 17 studies selected that met the inclusion criteria ( Figure 2).
Te baseline of the 17 included studies is consistent. Te intervention groups receive mBTWD alone or in combination with conventional western medicine. Te control groups are given a placebo, gentamicin, dexamethasone, montmorillonite powder, procaine/lidocaine, or combination therapy. Te main route of administration is retention enema [9,[14][15][16][17][18][19][20][21][22]; three studies report the route of administration of retention enema combined with per os [23][24][25], and four studies report oral administration [26][27][28][29]. A total of 1611 patients are enrolled. Te baseline characteristics of included trials are shown in Table 1. Te  compositions of mBTWD from the included studies are  shown in Table 2.

Risk of Bias and Quality Assessment.
All of the included studies are randomized controlled trials (RCTs). Te risk of bias is assessed according to Cochrane Manual standards. (1) Randomization is mentioned in all included studies, and seven studies [9, 15-17, 25, 27, 29] mention the "random number table." However, none of the studies mention distribution hiding methods. (2) None of the studies is designed to mention "blindness." Although blindness is inadequate in the three studies [9,14,15], the outcomes are judged by the system evaluators to be mainly objectively detectable indicators and unlikely to be afected by the lack of blindness. (3) Only two studies [9,16] describe the missing data, and two studies [14,29] identify no cases of deletions. No absence or exclusion is reported in the remaining studies. (4) Only one study [16] publishes all prestated results, with no selective reporting. Te remaining studies could not be evaluated for too few indicators or the absence of project proposals, raising suspicions about selective reporting. (5) Two studies [21,22] are considered high-risk because of potential sources of bias associated with a particular trial design. As a result, the quality of the included studies is low (Figure 3).
Next, we read the full text of the excluded study [18] in detail and found that it lacks clear diagnostic criteria, suggesting that this is a low-quality study and should be excluded.

Total
Score of TCM Syndrome. Te main symptom (bellyache, diarrhea, tenesmus, mucosanguineous feces, burning pain in the anus, and so on) of patients is scored according to the quantitative criteria of TCM syndrome (SFDA, 2002): 0 � none, 1 � mild, 2 � moderate, 3 � severity. Moreover, Stata 14.0 software is used to combine efect sizes. A total of 7 studies describe TCM syndrome's total score regarding this standard, one study [16] is excluded from describing the discrete variables. Te remaining 6 studies [9,14,15,21,22,29] include a total of 476 patients. Te results of the meta-analysis show a moderate heterogeneous in the total score of the TCM syndrome (Chi 2 � 10.02, P � 0.07, I 2 � 50%) (Figure 6(a)). It can be seen from the forest plots that the study [14] has the least overlap with other studies; then a sensitivity analysis is conducted and heterogeneity is signifcantly reduced after this study is removed (Chi 2 � 5.11, P � 0.28, I 2 � 22%) ( Figure 6(b)). After careful reading of this study, we fnd that the score of systemic symptoms is included, while other studies are mainly based on the local symptom of the intestinal tract. Terefore, we believe that this is due to heterogeneity caused by diferences in trial design, so it is excluded.
According to the results of the meta-analysis, the difference in the TCM syndrome total score between the two groups after treatment is statistically signifcant (MD � −3.41, 95% CI (−3.75, −3.06), P < 0.00001) ( Figure 6(b)). Terefore, we discover that mBTWD has certain advantages in improving bellyache, diarrhea, tenesmus, mucosanguineous feces, and burning pain in anus syndromes.
Overall results show that mBTWD can signifcantly improve intestinal mucosal injury and reduce the degree of intestinal reaction after radiotherapy.

Safety.
No serious adverse events occur in nearly all of the studies, and there is no signifcant diference in the incidence of adverse events between the intervention groups and the control group.

Univariate Meta Regression.
Since more than 10 studies are included in the analysis of clinical efcacy, we conduct a univariate meta regression here to explore the association between the clinical efcacy indicator and the diference in intervention, drug delivery, sample size, publication year, or other characteristics of the studies including the mean age and duration of treatment. Both dichotomous and continuous covariates are employed in the regression models; the results of the univariate meta-regression analyses are presented in Table 3 and Figure 14. It is found that the association with the efect size of the intervention (mBTWD with CWM) on the clinical efcacy of mBTWD in the treatment of radiation enteritis is not statistically signifcant (metaregression coefcient 1.014, CI 0.859, 1.198, P � 0.852, I 2 � 39.730%, Tau 2 � 0.328%), suggesting that the diference in the intervention is unlikely to increase clinical efcacy with the baseline levels. Ten none of the coefcients of other covariates are signifcantly associated with the estimated risk ratio, and for this specifc reason, multivariate analyses are not performed.   Furthermore, we accurately perform publication bias using Egger's test (Figure 15(b)) and Begg's test (Figure 15(c)). All analyses are performed with Stata 14.0 software and results are shown with 95% confdence intervals. Both Egger's test and Begg's test detect the existence of publication bias (coefcient � 2.175, P � 0.006), indicating that the validity and generalization of our conclusions would be limited and afected due to possible publication bias.

Evidence-Based Complementary and Alternative Medicine
Tus, we try to employ another Funnel-plot-based trim and fll method to deal with the potential impact of publication bias, as shown in Figure 15(d). In the trim and fll method, we can re-estimate the actual efect size by flling in the "missing" studies and forming a new pooled estimate until the funnel plot reaches a new symmetry. After 4 iterations, the procedure identifes and trims 4 studies (4 inserted studies as their theoretical counterparts) until the distribution is symmetrical, with the overall efect size estimated as RR � 1.21 (95% CI from 1.12 to 1.31, P < 0.001). Compared with our initial pooled efect size of RR � 1.27, which is substantially larger than the bias-corrected efect size and indicates that the potential publication bias made the initial results overestimated (approximately 4.9%), the real efect when controlling for selective publication bias could be slightly lower. Tis indicates that our results are still robust even with the occurrence of publication bias.

Assessment Quality of Evidence.
Several types of evidence for mBTWD in the treatment of radiation enteritis are included in our meta-analysis; the GRADE evidence rating levels performed with the online tool are shown in Table 4. Te evidence quality for clinical efcacy and recurrence rate is rated as very low due to serious clinical or statistical heterogeneity problems in risk of bias, inconsistency, imprecision, or publication bias. Te quality of the evidence for KPS is rated low with other conditions rated moderate. Te criteria and reasons for upgrading or lowering the quality of evidence for each outcome are as follows. (1) Study design: all studies included in this paper are randomized controlled trials that satisfed our inclusion criteria. (2) Risk of bias: although sensitivity analysis that excludes trials with a high risk of bias does not change the main results, all of these studies are downgraded due to a lack of blinding. (3) Inconsistency: high statistical heterogeneity (I 2 > 50%) occurrence will downgrade the evidence quality to a lower level; three outcomes are marked as serious inconsistency. (4) Indirectness: mBTWD is implemented in the treatment of radiation enteritis and is directly related to those clinical outcomes in our study, so there is no downgrade of evidence. (5) Imprecision: the evidence will be downgraded if the 95% CI crosses no treatment efect or if the estimated efect size is signifcantly diferent (P > 0.05). (6) Other Considerations: downgrades if serious publication bias is detected to be signifcant (P < 0.05%), which occurs in the clinical efcacy analysis.

Sensitivity Analysis.
With evidence of the publication bias, we also propose sensitivity analyses to investigate the potential causes of heterogeneity and identify unbalanced or disproportionate contributions to the observed bias from these trials. Sensitivity analyzes are performed using metainf command with Stata 14.0, by repeating the baseline metaanalysis by excluding assumed "biased" trials one-by-one to   Note. * Statistics including Tau 2 , I 2 , and P values are derived from meta-regression models conducted with Stata 14.0, estimated risk ratio is obtained using the conventional fxed-efects model with 95% confdence interval (CI). Both dichotomous and continuous covariates are employed in the regression models. ▲ Ye and Wang [28] report related data without mean age. ■ Ye and Wang [28], Wang [21], and Wang et al. [29] report related data without duration time.
14 Evidence-Based Complementary and Alternative Medicine assess their impact on the overall estimate; relevant results are shown in Figure 16(a). It is shown that dropping out trials one by one may have little impact on the overall estimated efect size while expanding the confdential levels from (1.18, 1.36) to (1.17, 1.38). Among those excluded studies, dropping Xia [18] and Ye and Wang [28] may lead to a lower efect size while excluding Lei [17] and Lei [16] could cause a higher efect size. For better visual inspection, we also introduce the Galbraith plot to identify possible outlier studies that have an excessive infuence on the overall estimate (Figure 16(b)). From the Galbraith plot, we could draw a similar conclusion that these four studies [16][17][18]28] are the main possible outliers with a higher risk of heterogeneity and can be correlated with publication bias.

Active Ingredients and Targets Screening Results.
According to the OB and DL characteristics of the compounds, a total of 65 active ingredients are obtained from the TCMSP database; there are 11 in Baitouweng (BTW), 37 in Huangbo (HB), 14 in Huanglian (HL), and 3 in Qinpi (QP). After removing the duplicate ingredients, a total of 51 are left (Table 5). Ten, we screen the corresponding targets of the active ingredients, and 987 human-derived target proteins are obtained after the duplicate targets are removed. Te Cytoscape 3.8.2 software is used to connect the active ingredients-targets network. Te network consists of 175 nodes and 381 edges, these nodes represent compounds and the corresponding targets, and edges represent interactions between compounds and target proteins ( Figure 17).

Prediction and Construction of Drug-Disease Networks.
Five databases (OMIM, GeneCards, PharmGkb, DrugBank, and TTD) are searched to obtain 2642 disease targets related to radiation enteritis. Using the R language program and Venny2.1 software, the intersection of mBTWD and radiation enteritis targets is selected, and fnally 139 common drug-disease targets are screened out. Finally, Cytoscape 3.8.2 software is used to build the mBTWD active ingredients-targets-radiation enteritis network ( Figure 18). Of these, quercetin (MOL000098) interacted with 114 targets, isorhamnetin (MOL000354) interacted with 21 targets, and beta-sitosterol (MOL000358) interacted with 18 targets.
Other compounds, such as stigmasterol (MOL000449) and aureusidin (MOL001978), are associated with multiple targets, suggesting that the compounds in BTWD may exert pharmacological efects against radiation enteritis by acting together on these targets.

PPI Network of Key Targets.
Tese 139 drug-disease common targets are imported into the STRING database, and the PPI network of targets for mBTWD against radiation enteritis could be obtained by removing the noncorrelated targets. Ten the PPI network is imported into Cytoscape  Evidence-Based Complementary and Alternative Medicine 3.8.2 software, and the CytoNCA plug-in is used to calculate the median value of network nodes. Finally, eleven key targets are obtained, and the PPI network of core targets is constructed. Te larger the node, the darker the color, and the higher the DC value ( Figure 19). From the network, we can see that the top four are MYC, TP53, MAPK14, and MAPK1, and their DC values are 9, 8, 8, and 8, respectively. Tese results indicate that these targets are the key targets of BTWD in the treatment of radiation enteritis.

GO and KEGG Enrichment Analysis of Key Targets.
Te ClueGO plug-in is used to perform GO functional annotation and KEGG signal pathways enrichment analysis for the key targets of BTWD in the treatment of radiation enteritis (flter criteria P < 0.05). Te GO enrichment analysis mainly refers to biological process (BP), and a total of 2183 GO items are obtained, mainly involving response to lipopolysaccharide, response to xenobiotic stimulus, and response to molecule of bacterial origin and wound healing (Figure 20(a)). A total of 172 signal pathways are identifed in the KEGG enrichment analysis, which are found in the lipid and atherosclerosis, PI3K-Akt signaling pathway, and chemical carcinogenesis-receptor activation (Figure 20(b)).
According to the results of the KEGG enrichment analysis, we select the "hsa0415" (PI3K-Akt signaling pathway) to draw a pathway map using the Pathview plugin. And the red nodes indicate that the key target genes exist in the regulatory network ( Figure 21).

Molecular Docking of Active Ingredients and Key
Targets. According to the PPI network, the key targets of mBTWD in the treatment of radiation enteritis are MYC, TP53, MAPK14, and MAPK1. Molecular coupling is performed for the 4 core targets with the active ingredients of mBTWD and the positive control drug dexamethasone. Afnity < −5.0 kJ·mol −1 indicated good binding activity between ligands and receptors [33]. Te results show that MAPK1 has the highest binding activity with quercetin (afnity = −8.5 kJ·mol −1 ), followed by TP53 with quercetin (afnity = −8.3 kJ·mol −1 ). MAPK14 with aureusidin (afnity = −7.7 kJ·mol −1 ), MAPK14 with isorhamnetin (afnity = −7.2 kJ·mol −1 ). Additionally, the binding activity of these active ingredients with the key targets is stronger than the positive control drug dexamethasone (Table 6). Te optimal molecular docking diagram is shown in Figure 22.

Summary of the Evidence and Results
. Radiation enteritis is a common side efect of radiotherapy in patients with pelvic/abdominal malignancy. Te small intestine is quite sensitive to radiation, and radiotherapy could easily cause intestinal wall damage, leading to infammatory infltration of intestinal epithelial cells. Patients present with an intolerable change in stool habits that last for a long time, causing the discontinuation of radiotherapy, which severely impair their quality of life and reduce survival [34]. Acute radiotoxicity mainly damages the intestinal mucosa, leading to a decrease in the normal intestinal villous epithelial barrier and presenting as abdominal pain. Chronic radiation toxicity primarily afects the muscular and serosal layers, causing vascular degeneration and fbrosis, and manifests itself as chronic diarrhea and malabsorption, the formation of ischemic intestinal disease, intestinal fora disorder, and chronic enteritis, followed by an intestinal mucosal ulcer, perforation or abscess, and fnally, the formation of intestinal obstruction and microbial over-propagation [35,36]. Evidence also suggests that gut microbiota dysbiosis plays an important role in the development of radiation enteritis, and it is a reminder that radiation injury can be relieved by modifying the local microecosystem [1,2]. Terefore, some formulae of Chinese medicine with an antiinfammatory efect, such as Baitouweng decoction, may be a complementary means for recurrent radiation enteritis that is difcult to control by conventional western medicine. Te results of this meta-analysis show that mBTWD alone or in combination with CWM can beneft patients with radiation enteritis with better clinical efcacy than CWM alone. Due to the moderate heterogeneity (P � 0.03, I 2 � 45%), we eliminate the study [18] for its unclear diagnostic criteria by sensitivity analysis. In addition, subgroup analysis is performed according to diferent drug deliver (Re, Po, and Re + Po) to identify possible sources of heterogeneity; we fnd that the heterogeneity of these subgroups are decreased (P � 0.38, I 2 � 7%; P � 0.11, I 2 � 51%; P � 0.69, I 2 � 0%), this indicates that there is indeed some heterogeneity in diferent drug deliver. In light of the P value results of Re and Po (P < 0.00001; P � 0.002), we believe that the diference in efcacy of retention enema seems to be more signifcant. Tis might be due to the reason the TCM decoction can be quickly absorbed into the blood through the intestinal mucosa after the enema, acting directly on the lesions and avoiding the elimination of drugs by the hepatoenteric circulation [37]. To sum up, based on the remaining 14 studies, we have reason to think that mBTWD has a good clinical efect on radiation enteritis, and the efect can be increased by about 24% compared with the control groups (RR � 1.24, P < 0.00001). A study comparing montmorillonite powder alone or combined with dexamethasone in the treatment of acute radiation enteritis reports that the clinical efcacy of the two groups is 72.09% and 97.67%, respectively [38]. While the results of the metaanalysis in this article show that the mean clinical efcacy of  Evidence-Based Complementary and Alternative Medicine mBTWD combination therapy is approximately 89.2%. Tis suggests that for the treatment of acute radiation enteritis, mBTWD combined with dexamethasone can be efective in relieving symptoms. mBTWD combination therapy can signifcantly improve the symptoms of TCM. Compared to western medicine treatment alone, mBTWD combination therapy alleviates symptoms of bellyache, diarrhea, tenesmus, and mucosanguineous feces in patients with radiation enteritis, and the total score of the TCM syndrome decreases by an average of 3.41 points (MD � −3.41, P < 0.00001). Furthermore, mBTWD could improve the local bowel symptoms in   Evidence-Based Complementary and Alternative Medicine Figure 19: PPI network of the key targets for representative drugs in mBTWD against radiation enteritis.
response to xenobiotic stimulus response to lipopolysaccharide response to molecule of bacterial origin wound healing response to nutrient levels response to oxygen levels response to radiation response to metal ion response to hypoxia response to decreased oxygen levels membrane raft membrane microdomain vesicle lumen organelle outer membrane outer membrane mitochondrial outer membrane caveola plasma membrane raft serine/threonine protein kinase complex cyclin-dependent protein kinase holoenzyme complex DNA-binding transcription factor binding RNA polymerase II-specific DNA-binding transcription factor binding ubiquitin-like protein ligase binding ubiquitin protein ligase binding nuclear receptor activity ligand-activated transcription factor activity protease binding transcription coregulator binding steroid hormone receptor activity transcription coactivator binding Evidence-Based Complementary and Alternative Medicine patients. Te intestinal mucosal improvement rate in the mBTWD groups is about 23% higher than that in the CWM groups (RR � 1.23, P � 0.0001), correspondingly, the deterioration rate decreases by nearly half compared to the control groups (RR � 0.51, P � 0.0001). Colonoscopy objective signs are reported in four studies, two of which report colonoscopic intestinal mucosa scoring and another two are grading. However, these two studies of continuous variables show great heterogeneity due to diferent scoring criteria (P � 0.02, I 2 � 81%), and sensitivity analysis are unable to be conducted due to the small sample size. Another two studies estimate the grade of colonoscopy (0-IV degree) according to the same criteria, both 0-II and III-IV have strong homogeneity (P � 0.57, I 2 � 0%; P � 0.64, I 2 � 0%). Another 6 studies also report the subjective symptoms of radiation enteritis grading (0-IV degree), in order to reduce the heterogeneity, we select the OR for statistical analysis, both 0-II and III-IV have strong homogeneity (P � 0.47, I 2 � 0%; P � 0.47, I 2 � 0%). Te improvement rate of the radiation enteritis classifcation in the mBTWD groups is 3.51 times higher than that in the CWM groups (OR � 3.51, P < 0.00001 ); correspondingly, the deterioration rate is only 0.29 times that of the CWM groups (OR � 0.29, P < 0.00001). Similarly, we compare the fndings obtained with previous studies and the data show a higher efcacy of colonoscopy after mBTWD treatment compared to montmorillonite alone (82.03 vs. 65.12%) [38]. Tese results indicate that, in general, mBTWD has a certain positive efect on the improvement of intestinal mucosal signs and symptoms and is signifcantly correlated with the reduction of the rate of deterioration.
Only two studies with a total of 161 samples report the CRP level, there is no heterogeneity in the results (P � 0.66, I 2 � 0%), and the CRP level decreases by an average of 5.28 mg/L compared with the control groups after treatment (MD � −5.28, P < 0.00001). Five studies report the KPS score, including three continuous variables and two dichotomies: for the continuous variables, a subgroup analysis is performed according to the KPS score before treatment (KPS � 40-60 and KPS > 60) and the results are fne (P � 0.29, I 2 � 12%), after treatment, the KPS score improved by an average of 15.32 points compared to the control groups (MD � 15.32, P � 0.002); for dichotomies   Evidence-Based Complementary and Alternative Medicine variables, there is also little heterogeneity (P � 0.79, I 2 � 0%) and the rate of improvement of life quality in the mBTWD groups is about 23% higher than that of the CWM groups (RR � 1.23, P � 0.03); these results indicate that mBTWD is efective in improving the quality of life of patients with radiation enteritis. Although only 2 studies report the fecal occult blood, the improvement rate is about 47% higher than the control groups (RR � 1.47, P � 0.03), suggesting that mBTWD have better hemostasis. Due to fewer included studies and small sample size, we think that the credibility of these meta-analysis results of CRP levels, KPS score, and fecal occult blood is not high.
We are also interested in safety except for efcacy. Fortunately, no serious adverse events occur in both the intervention and control groups, indicating that both mBTWD and conventional western medicine treatments are safe and reliable. However, some studies have reported a certain recurrence rate after treatment, but the diference is not statistically signifcant between the two groups (RR � 0.07, P � 0.13). As noted previously, due to the small sample size and the low quality of the evidence, adverse events and recurrence rates also need to be further confrmed. In the future, larger sample sizes and more studies are needed to reach true scientifc conclusions.
Based on Egger's test, Begg's test, and Funnel-plot-based trim and fll method, we fnd that there is indeed publication bias in the reports of clinical efcacy in existing studies; the potential publication bias makes the initial results overestimated by about 4.9%. Tis indicates that our results are still robust even with the occurrence of publication bias. According to the results of the GRADE evidence, the included overall quality of the studies is low, mainly for the reason that almost all the studies do not follow the doubleblind rule and there is publication bias. With the evidence of publication bias, we also propose sensitivity analyses to investigate the potential causes of heterogeneity. Te results show that the heterogeneity decreased signifcantly after eliminating some individual studies one by one, the evidence    Evidence-Based Complementary and Alternative Medicine quality of these studies is relatively low and most of them lacked rigorous and clear inclusion or exclusion criteria.

Potential Molecular Mechanism.
Te results of network analysis show that BTWD could act on radiation enteritis with multiple targets, components, and pathways. A total of 51 ingredients are discovered and 139 common targets are screened out, such as quercetin, isorhamnetin, and betasitosterol, which could reduce the level of infammatory factors, a powerful antioxidant, endothelial cell protection, and antitumor efects [39][40][41][42]. Tese components may be the key factors in the treatment of radiation enteritis. From the PPI network, the top four are MYC, TP53, MAPK14, and MAPK1; both TP53 and MAPK regulated many biological processes, including apoptosis, protein biosynthesis, oncogenesis, and the cell cycle [43,44], indicating that these targets are the key targets of BTWD in the treatment of radiation enteritis. GO and KEGG enrichment analysis results also mainly involve some microbial infection and antitumor biological process which are related to the incidence of radiation enteritis. Molecular docking technology further verifed the better binding activity of main active ingredients and key targets in BTWD from a quantitative perspective, even better than that of positive control drugs. However, these conclusions are only the results of network pharmacological prediction and lack of further molecular validation.

Limitations and Prospects for Future Research.
Tis study also has several limitations. (1) Te research has design faws, the quality of evidence in existing studies is generally low without involving a specifc randomized control grouping method, allocation concealment, blinding, and there is certain publication bias. (2) Te included RCT studies are conducted only in China with small sample sizes and lacking larger sample studies in other languages, resulting in lowquality evidence. (3) Te inclusion criteria and outcomes evaluation of some studies are not unifed, and the course of radiation enteritis is not clearly defned, leading to an increased risk of heterogeneity. (4) Tere are too few reports on adverse events and recurrence rate, which could not objectively present the safety problems of mBTWD, and there may be false negative results. (5) Te composition of mBTWD varies greatly and is not rigorous enough, the addition or subtraction of mBTWD contains many other herbs, and the dosage of mBTWD has not been unifed or standardized, which made it difcult to determine the relationship between its efcacy and other ingredients or doses. (6) Network analysis and molecular docking techniques can only predict the possible targets and signaling pathways of representative drugs in mBTWD treatment of radiation enteritis, lacking further molecular verifcation, and the molecular mechanism needs further demonstration.
With the limitations of current studies, future studies are expected to strictly follow the randomly assigned, blinded, allocation concealment principles or to improve the quality of studies by increasing sample sizes, uniforming inclusion criteria, or outcomes measuring standards. In future studies, it is necessary to defne the main components of mBTWD clearly and restrict the dose range to reduce heterogeneity. Based on the results of this meta-analysis, we recommend herbs like Baitouweng, Huanglian, Huangbo, Qinpi, and Diyu be chosen for the clinical application of mBTWD in the treatment of radiation enteritis, and the dosage of each drug could also be adjusted accordingly. Moreover, more detailed information, including withdrawal, adverse events, recurrence rate, and follow-up times, should be recorded and discussed adequately. In particular, the results based on the network analysis and molecular docking indicate that the most probable active ingredients or targets should be experimentally validated to clarify the potential pharmacological mechanisms.

Conclusion
Although this meta-analysis provides relatively poor quality evidence to validate the efcacy and safety of mBTWD in the treatment of radiation enteritis, the clinical signifcance of this study lies in two aspects. It provides both an option and an idea for radiation enteritis treatment. In addition, it further supports the unique advantages and usage of traditional Chinese medicine to relieve symptoms and improve the quality of life in cancer patients. However, there are still some limitations. Te risk of adverse events and recurrence rate is under-reported, and further experiments should be performed to validate the predicted ingredients and targets. Terefore, it is necessary to design scientifcally rigorous large-sample RCTs and supplement basic studies to evaluate the clinical evidence and molecular mechanism of mBTWD in the future treatment of radiation enteritis.