Abstract
Objective: This study is aimed at investigating the impact of mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules on intestinal mucosa barrier function and intestinal microbiota in mildly active Crohn’s disease patients.
Methods: Ninety-six Crohn’s disease patients in mild activity period were randomized into the control group (treated with mesalamine) and the observation group (treated with mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules) (n = 48). After 4 wk of treatment, the patients were evaluated for their clinical efficacy. Intestinal microbiota counts, serum inflammatory factors, T lymphocyte subsets, and mucosal barrier function indicators in both groups were assessed.
Results: After 4 wk of treatment, the total clinical effective rate of the observation group was higher than that of the control group. The number of Lactobacillus acidophilus (L. acidophilus) and Bifidobacterium Longum (B. longum) in the intestinal tract, serum IL-10 levels, and peripheral blood CD4+ and CD4+/CD8+ levels were higher, and the number of Bacteroides vulgatus (B. vulgatus), the levels of TNF-α, IL-6, CRP, CD8+, ET, D-lactate, DAO, and urine L/M ratio were lower in the observation group in comparison to those in the control group (all p < 0.05).
Conclusion: Mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules are more effective in treating mildly active Crohn’s disease.
Introduction
Crohn’s disease, initially described at the start of the last century,Citation1 is a chronic inflammatory disorder that impacts the gastrointestinal tract. It is characterized by lesions from mouth to anus and it might generate extra-intestinal complications.Citation2 It is also a bowel disease of unknown etiology related to impaired immune responses, with periods of activity and remission. Abdominal pain and diarrhea are the most frequent symptoms, severely affecting patients’ quality of life.Citation3 There are well-acknowledged risk factors for Crohn’s disease, including genetic susceptibility, environmental factors, and altered gut microbiota,Citation4 causing dysregulated innate and adaptive immune responses.Citation5 The incidence rate of Crohn’s disease is gradually elevating around the world,Citation6 which significantly impacts the economic status because of its increasing prevalence, which often affects young people.Citation7
Mesalamine, also named as 5-aminosalicylic acid (5-ASA), is a medication utilized to treat ulcerative colitis, more specifically, inducing or maintaining remission of mildly to moderately active ulcerative colitis. Besides, mesalamine may be implemented in Crohn disease after surgical resection of the affected bowel.Citation8 It is reported that mesalamine is one of the first-line drugs utilized in the treatment of inflammatory bowel diseases.Citation9 Moreover, mesalamine, as an effective anti-inflammatory drug, not only represses the production of intestinal inflammatory mediators, but also limits the abundance of Escherichia coli in the gut microbiota and reduces colibactin production.Citation10 The protection of mesalamine treatment-mediated colitis might link to microbiota and immune cell alterations.Citation11 Bifidobacterium Longum (B. longum) is a colonizing bacteria existed in the intestine, and it has been demonstrated to be able to relieve colitis and serve as an alternative or auxiliary method in inflammatory bowel disease treatment, including Crohn’s disease.Citation12 A previous study has demonstrated that mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules displays magnificent protective effects on the mucosa of ulcerative colitis patients, and curb the ulcerative colitis-related inflammation efficiently, which is a safe and reliable way that can be promoted clinically.Citation13 In our paper, the study focus was on the combined effects of mesalamine and Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules on mildly active Crohn’s disease. Consequently, this research was aimed at investigating the therapeutic effects of mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules on intestinal mucosa barrier function and intestinal microbiota in mildly active Crohn’s disease patients.
Materials and Methods
Ethics Statement
The research was under approval of the Ethic Committee of Nantong First People’s Hospital (approval number: 20180716), and the written informed consent was obtained from the participants.
Study Subjects
Ninety-six Crohn’s disease patients in mild activity period admitted to the Gastroenterology Ward of Nantong First People’s Hospital were recruited for study subjects. All cases met the clinical diagnostic criteria for Crohn’s disease in the Chinese Consensus on Diagnosis and Treatment in Inflammatory Bowel Disease (2018, Beijing) revised by the Inflammatory Bowel Disease Group, Chinese Society of Gastroenterology, Chinese Medical AssociationCitation14 and were scored as 150–220 points using the calculation method of the Best Crohn’s Disease Activity Index (CDAI).Citation15 Inclusion criteria: (1) patients met the aforementioned diagnostic criteria for mildly active Crohn’s disease; (2) patients at the age of 18–70 years; (3) patients without previous use of hormones, immunosuppressive agents, and biologics within 1 month and without use of non-steroidal anti-inflammatory drugs, antibiotics and other probiotic treatments; (4) patients voluntarily accepted treatment and signed an informed consent form. Exclusion criteria: (1) those with significant abnormalities in important organs such as heart, liver, lung, kidney and brain; (2) those with a history of drug allergy; (3) those with intestinal perforation, intestinal obstruction, internal and external fistula and gastrointestinal hemorrhage; (4) those in pregnancy or lactation; (5) patients with concomitant mental disorders.
Treatment Methods
The included 96 patients were randomized into the control group (n = 48) and the observation group (n = 48). Patients in the control group were treated with oral Mesalamine enteric-coated tablets (Jia Mu Si Luling Sunflower Pharmaceutical Group Co., Ltd., State Drug Administration: H19980148), 1 g/time, 3 times/day. Patients in the observation group were given oral Mesalamine enteric-coated tablets (Jia Mu Si Luling Sunflower Pharmaceutical Group Co., Ltd., State Drug Administration: H19980148), 1 g/day, 3 times/day. Besides, patients in the observation group were also given enteric-coated Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules (Jincheng Haisi Pharmaceutical Co., Ltd., State Drug Administration: S19993065) for treatment, 0.42 g/time, 3 times/day. The enteric-coated Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules is a compound preparation, and each gram contains B. longum ≥ 1.0 × 10[sup]6[/sup]CFU, Lactobacillus acidophilus (L. acidophilus) ≥1.0 × 10[sup]6[/sup]CFU, and Enterococcus faecalis (E. faecalis) ≥1.0 × 10[sup]6[/sup]CFU. Auxiliary materials include starch, pre-gelatinized starch, lactose, and magnesium stearate. The patients in both the control and observation groups took medication continuously for 4 wk.
Clinical Efficacy Determination
Referring to the “Chinese Consensus on Diagnosis and Treatment in Inflammatory Bowel Disease”,Citation14 patients were classified as clinically relieved (clinical symptoms disappeared, endoscopy and imaging showed improvement in ulceration and inflammation, or CDAI score <150 points); effective (clinical symptoms improved, CDAI score decreased by ≥70 points;Citation16 ineffective (clinical symptoms did not improve, endoscopy and imaging showed no improvement or aggravation of lesions, or CDAI score increased by ≥70 points.Citation16 Total effective rate = clinically relieved rate + effective rate.
Detection of Intestinal Microbiota in Feces
Polymerase chain reaction (PCR) method was utilized for the assessment of intestinal microbiota in feces. Fresh stool specimens (0.2 g) were collected from patients’ midsection before the treatment and 28 days after the treatment, respectively. The total DNA was extracted by bacterial genomic DNA extraction kit, and primers for L. acidophilus, B. longum and Bacteroides vulgatus (B. vulgatus) were synthesized by Sangon (Shanghai, China). PCR products were measured by agarose gel electrophoresis at 2% agarose gel concentration and 5 V/cm for 30 min. Based on the initial quantification results, fluorescence quantification was subsequently conducted, and finally, high-throughput sequencing was performed implementing the Illumina MiSeq platform. PCR reaction conditions: 95 °C for 3 min, 95 °C for 30 s, 55 °C for 30 s, 72 °C for 45 s, 27 cycles; 72 °C for 10 min. The data were obtained by Quanti FluorTM-ST blue fluorescence quantification system, and the PCR results are expressed as log CFU per gram of stool (log CFU/g) using the average number of copies of 16S rRNA genes in each bacterium to normalize the counts.
Detection of Serum Cytokines
Fasting peripheral venous blood was collected early in the morning before and after treatment, and the serum was isolated from the blood after it was kept at room temperature for 30 min and centrifuged at 3000 rpm for 15 min. Serum levels of albumin (ALB) and total protein (TLB) were measured by a 7600 automatic biochemical analyzer. Serum levels of diamine oxidase (DAO), D-lactate, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-10, C-reactive protein (CRP), and endotoxin (ET) were examined by using enzyme-linked immunosorbent assay (ELISA) kit (produced by milbio, Shanghai, China).
Measurement of Urinary Lactulose/Mannitol Ratio
The patients took 40 mL of lactulose-mannitol mixture (10 G of lactulose and 5 G of mannitol) orally on an empty stomach after emptying urine in the early morning and were subjected to water fasting for 30 min and food fasting for 2 h. Urine samples were collected within 6 h after the medication was taken, filtered, and then the LMR in the urine was determined using a high-performance liquid chromatograph (L/M).
T-Cell Subpopulation Testing
The subjects had venous blood collected in the morning on an empty stomach, and after anticoagulation with sodium heparin, the percentage of CD4+ and CD8+ cells in the peripheral blood was measured by a BD FACSCanto II flow cytometer and the corresponding kit ((BD Biosciences, San Diego, CA, USA). Lymphocyte Subpopulation Assay Reagent (20 μl) and mixed anticoagulated blood (50 μl) were placed to the bottom of the tube without touching the wall, which was then placed on a shaker to mix and let stand for 15 min at room temperature away from light. The sample was obtained by adding 450 μl of hemolytic reagent, mixing, and standing for 15 min devoid of light. The optical path of the flow cytometer was calibrated with the standard, and the samples were tested with the BD FACSCanto II flow cytometer, shaking and mixing again before testing. Based on the data acquired using the BD FACSCanto Clinical Software and analyzing the results, PotPlot histograms were obtained based on the forward and side scattered light of the flow cells, the lymphocyte populations were boxed out, and then the percentage of the corresponding fluorescence labeled in the lymphocyte populations was detected separately.
Statistics
SPSS 22. 0 software was employed for data analysis. Measurement data were depicted as mean ± standard deviation and the comparison was made by the t-test. Numeration data were represented as number of cases or percentages (%), and the comparison between the two groups was performed by chi-square test. p < 0.05 indicated a statistically significant difference.
Results
General Data
In the control group, the mean age of the 48 patients was 38.75 ± 7.40 years, with 28 males and 20 females. The mean duration of the disease was 3.48 ± 1.50 years, the mean value of the CDAI score was 178. 83 ± 17.16 points, and the site of the lesion was in the terminal ileum in 11 cases, the colon in 25 cases, and the ileocolon in 12 cases. In the observation group, the mean age of the 48 patients was 39.56 ± 8.16 years, with 26 males and 22 females. The mean duration of the disease was 3.65 ± 1.48 years, the mean value of CDAI score was 178. 94 ± 17.91 points, and the site of the lesion was in the terminal ileum in 10 cases, colon in 22 cases, and ileocolon in 16 cases. No statistically significant differences presented between the two groups in terms of age, gender, duration of disease, CDAI score, and lesion site (all p > 0.05) ().
Table 1. General data between the two groups.
Clinical Efficacy Between the Two Groups
The clinical efficacy of the patients in the observation and the control groups was compared after treatment. The total clinical effective rate of patients in the observation group (97.91%) was elevated in comparison with that of the control group (85.42%) (p < 0.05, ). It is suggested that mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules can effectively relieve clinical symptoms in patients with mildly active Crohn’s disease.
Table 2. Clinical efficacy between the two groups [cases (%)].
Changes in the Number of Intestinal Microbiotas Between the Two Groups
We subsequently compared the changes in the number of intestinal microbiota (L. acidophilus, B. longum and B. vulgatus) before and after the treatment of patients in the observation and control groups. It was revealed that before the treatment, no statistically significant difference presented in the number of intestinal microbiotas (L. acidophilus, B. longum and B. vulgatus) between the two groups (p > 0.05). After the treatment, the number of L. acidophilus and B. longum in the observation group was higher, and the number of B. vulgatus was lower versus those before the treatment and in the control group (both p < 0.05, ). It is summarized that mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules can regulate intestinal microbiota in patients with mildly active Crohn’s disease.
Figure 1. Changes In the number of intestinal microbiota between the control and observation groups. (A) Comparison of the number of intestinal L. acidophilus before and after treatment in the two groups. (B) Comparison of the number of intestinal B. longum before and after treatment in the two groups. (C) Comparison of the number of intestinal B. vulgatus before and after treatment in the two groups. *p < 0.05.
Changes in Nutritional Indicators Between the Two Groups
The levels of albumin (ALB) and total protein (TLB) were compared before and after the treatment of patients in the observation and control groups. We found that prior to the treatment, the differences in the levels of ALB and TLB between the two groups were not statistically significant (p > 0.05); after the treatment, elevated levels of ALB and TLB were observed in both groups in comparison to those before the treatment, and ALB and TLB levels in the observation group were raised versus those in the control group (p < 0.05, ).
Figure 2. Nutrition indicators between the control and observation groups. (A) Comparison of serum ALB levels before and after treatment in the two groups. (B) Comparison of serum TLB levels before and after treatment in the two groups. *p < 0.05.
Changes in Inflammatory Factor Levels Between the Two Groups
Comparison of serum inflammatory factors (TNF-α, IL-6, IL-10, and CRP) before and after treatment of patients in the observation and control groups revealed that prior to the treatment, there was no statistically significant difference in TNF-α, IL-6, IL-10, and CRP levels between the two groups (p > 0.05). After the treatment, TNF-α, IL-6 and CRP levels were decreased and IL-10 levels were elevated in both groups versus those prior to the treatment (p < 0.05), and TNF-α, IL-6 and CRP levels were lower and IL-10 levels were elevated in the observation group versus those in the control group (p < 0.05) (). It is summarized that mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules can reduce inflammation level in patients with mildly active Crohn’s disease.
Figure 3. Changes In the levels of inflammatory factors between the control and observation groups. (A) Comparison of serum TNF-α levels before and after treatment in the two groups. (B) Comparison of serum IL-6 levels before and after treatment in the two groups. (C) Comparison of serum IL-10 levels before and after treatment in the two groups. (D) Comparison of serum CRP levels before and after treatment in the two groups. *p < 0.05.
Changes in T Lymphocyte Subsets Between the Two Groups
The levels of T lymphocyte subsets (CD4+, CD8+, and CD4+/CD8+) were compared before and after treatment of patients in the observation and the control groups. The findings demonstrated that no significant difference was noted in the levels of CD4+, CD8+, and CD4+/CD8+ in patients of both groups before the treatment (p > 0.05). In contrast with those before the treatment, CD4+ and CD4+/CD8+ were gradually increased in the two groups, with the observation group higher versus the control group; CD8+ was gradually decreased, with the observation group lower versus the control group (p < 0.05) (). It is suggested that mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules can improve the immune capacity of the body in patients with mildly active Crohn’s disease.
Figure 4. Changes In immune function indicators between the control and observation groups. (A) Comparison of CD4+ before and after treatment in the two groups. (B) Comparison of CD8+ before and after treatment in the two groups. (C) Comparison of CD4+/CD8+ before and after treatment in the two groups. *p < 0.05.
Changes in Intestinal Mucosal Barrier Function Indicators and L/M Ratio Between Two Groups
Comparison of indicators of intestinal mucosal barrier function (ET, D-lactate, and DAO) and urinary L/M ratio levels before and after treatment of patients in the observation and control groups revealed that there was no statistically significant difference in the levels of ET, D-lactate, DAO, and urinary L/M ratio of the two groups prior to the treatment (p > 0.05), and after the treatment, the levels of ET, D-lactate, DAO, and urinary L/M ratio in the two groups were decreased versus those prior to the treatment, and these factors in the observation group were reduced versus those in the control group (p < 0.05, ). It is demonstrated that mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules can improve the intestinal mucosal barrier function in patients with mildly active Crohn’s disease.
Figure 5. Changes in intestinal mucosal barrier function indicators and lactulose/mannitol ratio between the control and observation groups. (A) Comparison of serum ET levels before and after treatment in the two groups. (B) Comparison of serum D-lactate levels before and after treatment in the two groups. (C) Comparison of serum DAO levels before and after treatment in the two groups. (D) Comparison of urine L/M before and after treatment in the two groups. *p < 0.05.
Adverse Reactions Between the Two Groups
Comparisons of the adverse effects during treatment of patients between the observation and control groups disclosed that in the control group, there was one case of dizziness, nausea, and rash, respectively. In the observation group, there was one case of dizziness, three cases of nausea, and one case of rash. The difference in the rate of adverse reactions between the two groups indicated no statistical significance (p > 0.05, ). It is implied that mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules dose not significantly increase the adverse effects in patients with mildly active Crohn’s disease.
Table 3. Adverse reactions between the two groups [cases (%)].
Discussion
Chron’s Disease evolution is regulated by a complicated alteration of inflammation featured by alterations of inner immunity of intestinal mucosa barrier along with extracellular matrix remodeling.Citation1 This study focused on the treatment effects of mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules on intestinal mucosa barrier function and intestinal microbiota in Crohn’s disease patients.
As previously reported, mesalamine is an anti-inflammatory drug that is well-established as a first-line treatment method in managing inflammatory bowel disease.Citation17 A recent study has revealed that an in-vitro mass spectrometry assay for 5-ASA acetylation validates the capability of the Firmicutes CAG:176 thiolase and the F. prausnitzii acyl-CoA NAT to acetylate 5-ASA with acetyl-CoA, achieving at a level consistent with more than 25% conversion in a physiologic timeframe. This previous paper has provided the first direct correlation between specific gut metabolic enzymes and 5-ASA treatment failure in inflammatory bowel disease, thereby yielding immediate clinical potential.Citation18 A previous study has demonstrated that the total effectiveness rate of ulcerative colitis patients treated with mesalamine and Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules is higher than that of patients treated with mesalamine,Citation13 which was consistent with our findings. In our study, it was found that the total clinical effective rate of treatment of patients in the observation group was elevated versus that of the control group. Furthermore, it is reported that the utilization of Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules is involved in improving the composition of the colonic mucosal microbiota.Citation19 Bifidobacterium triple viable capsule might give benefits, by modulating intestinal microecology balance. It can be employed in treating and preventing a variety of digestive system disorders with overall safety.Citation20 After Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules treatment, inflammatory indices count and gastrointestinal dysfunction scores are decreased and feeding dose is increased.Citation21 In patients treated with the addition of Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules, there are increased overall response rate, fecal Escherichia coli, Lactobacillus, and Bifidobacterium counts and reduced IgG and IgM. Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules plus other drugs can improve clinical symptoms and immune functions, and decrease the disease recurrence rate.Citation22 In our study, we observed that, after the treatment, the number of L. acidophilus and B. longum in the observation group was increased, and the number of B. vulgatus was lower versus those before the treatment and in the control group.
Subsequently, we observed the changes in nutritional indicators, inflammatory factor levels, and intestinal mucosal barrier function indicators and L/M ratio between the two groups, and it was found that after the treatment, ALB and TLB levels in the observation group were raised versus those prior to the treatment and those in the control group; TNF-α, IL-6, and CRP levels as well as the levels of ET, D-lactate, DAO, IL-10, and urinary L/M were decreased in both groups versus those before the treatment, and those in the observation group were decreased versus those in the control group. In a previous study, after mesalamine and Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules treatment, TNF-α and IL-8 contents are decreased evidently, and IL-10 levels are increased.Citation13 Mesalamine is effective in mild to moderate ulcerative colitis treatment. Mesalamine treatment can alleviates dextran sulfate sodium-induced colitis in piglets, which is also accompanied by attenuated mucosal damage and reduced DAO activity, D-lactate levels, and CD3+ T-cell infiltrations.Citation11 After treatment of enteric-coated Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules, the levels of CD3+, CD4+, and CD4+/CD8+ are higher, and the CD8+ levels are lower. Enteric-coated Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules in combination with enteral nutrition for chronic critical illness possesses high cure rate, which promote physiological health status, organ dysfunction, immune and coagulation function.Citation23 In our paper, we also found that after the treatment, CD4+ and CD4+/CD8+ were gradually elevated and CD8+ was gradually reduced. The difference in the rate of adverse reactions between the two groups had no statistical significance.
In our study, our research highlighted that after 4 wk of treatment, the total clinical effective rate of the observation group was higher than that of the control group. In the meantime, the number of Lactobacillus and Bifidobacterium in the intestinal tract, serum IL-10 levels, and peripheral blood CD4+ and CD4+/CD8+ levels were higher, and the levels of TNF-α, IL-6, CRP, CD8+, ET, D-lactate, DAO, and urine L/M ratio were lower than those in the control group. Most of the previous literature reported the use of mesalamine or Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules alone, or in combination of mesalamine and Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules for the treatment of intestinal-related diseases. Our article explored the treatment of mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules on mildly active Chron’s disease, involving intestinal microbiota counts, serum inflammatory factors, T lymphocyte subsets, and mucosal barrier function indicators. The synergistic use of the two drugs can play the roles of anti-inflammatory, anti-oxidative stress, regulating intestinal microecological balance, and improving intestinal mucosal repair ability from different perspectives, realizing the complementary advantages, thus enhancing the overall therapeutic efficacy and improving clinical symptoms.Citation24
In summary, this research demonstrates that mesalamine in combination with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules are more effective in treating mildly active Crohn’s disease, which improves the intestinal barrier function and intestinal microbiota of patients, and has the value of clinical promotion and application. This study lays a foundation to study the therapeutic effects of mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules in mildly active Crohn’s disease patients. Nevertheless, we will further set up a healthy control group and investigate the effects of gender on intestinal mucosal barrier function and intestinal microbiota to further validate our findings.
Disclosure statement
No potential conflict of interest was reported by the author(s).
References
- Petagna L, Antonelli A, Ganini C, et al. Pathophysiology of Crohn’s disease inflammation and recurrence. Biol Direct. 2020;15(1):1. doi:10.1186/s13062-020-00280-5.
- Veauthier B, Hornecker JR. Crohn’s disease: Diagnosis and management. American Family Physician. 2018;98(11):661–8.
- Ballester Ferre MP, Bosca-Watts MM, Minguez PM. Crohn’s disease. Medicina Clinica. 2018;151(1):26–33. doi:10.1016/j.medcli.2017.10.036.
- Cheng WX, Ren Y, Lu MM, et al. Palmitoylation in Crohn’s disease: Current status and future directions. World J Gastroenterol. 2021;27(48):8201–8215. doi:10.3748/wjg.v27.i48.8201.
- Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn’s disease. Lancet. 2017;389(10080):1741–1755. doi:10.1016/S0140-6736(16)31711-1.
- Xie J, Huang Y, Wu HG, Li J. Acupuncture and moxibustion for treatment of Crohn’s disease: A brief review. World J Gastroenterol. 2022;28(25):3001–3003. doi:10.3748/wjg.v28.i25.3001.
- Stenczel ND, Purcarea MR, Tribus LC, Oniga GH. The role of the intestinal ultrasound in Crohn’s disease diagnosis and monitoring. J Med Life. 2021;14(3):310–315. doi:10.25122/jml-2021-0067.
- Nakashima J, Preuss CV. Mesalamine (USAN). In: StatPearls; 2023.
- Xie C, Quan R, Hong F, Zou K, Yan W, Fu Y. The culprit of mesalamine intolerance: Case series and literature review. BMC Gastroenterol. 2019;19(1):138. doi:10.1186/s12876-019-1049-2.
- Tang-Fichaux M, Branchu P, Nougayrede JP, Oswald E. Tackling the threat of cancer due to pathobionts producing colibactin: Is mesalamine the magic bullet? Toxins. 2021;13(12):897. doi:10.3390/toxins13120897.
- Huang Y, Wu M, Xiao H, Liu H, Yang G. Mesalamine-mediated amelioration of experimental colitis in piglets involves gut microbiota modulation and intestinal immune cell infiltration. Front Immunol. 2022;13:883682. doi:10.3389/fimmu.2022.883682.
- Yao S, Zhao Z, Wang W, Liu X. Bifidobacterium Longum: Protection against inflammatory bowel disease. J Immunol Res. 2021;2021:8030297–8030211. doi:10.1155/2021/8030297.
- Huang M, Chen Z, Lang C, et al. Efficacy of mesalazine in combination with bifid triple viable capsules on ulcerative colitis and the resultant effect on the inflammatory factors. Pakistan J Pharma Sci. 2018;31(6(Special):2891–2895.
- Inflammatory Bowel Disease Group CSoGCMA. Chinese consensus on diagnosis and treatment in inflammatory bowel disease (2018, Beijing). J Digest Dis. 2021;22(6):298–317. doi:10.1111/1751-2980.12994.
- Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology. 1976;70(3):439–444.
- Cottone M, Papi C, Orlando A. Infliximab, azathioprine or combination therapy in the treatment of active Crohn’s disease. Expert Rev Gastroenterol Hepatol. 2010;4(6):709–712. doi:10.1586/egh.10.68.
- Vílchez A, Orts JA, Frédérique Scheirs S, Benavent G. Mesalazine renal lithiasis. Arch Esp Urol. 2020;73(6):561–564.
- Mehta RS, Mayers JR, Zhang Y, et al. Gut microbial metabolism of 5-ASA diminishes its clinical efficacy in inflammatory bowel disease. Nat Med. 2023;29(3):700–709. doi:10.1038/s41591-023-02217-7.
- Qian L, Huang J, Qin H. Probiotics and dietary intervention modulate the colonic mucosa-associated microbiota in high-fat diet populations. Turk J Gastroenterol. 2020;31(4):295–304. doi:10.5152/tjg.2020.19013.
- Fang J, Yang Y, Xie W. Chinese expert consensus on the application of live combined Bifidobacterium, Lactobacillus, and Enterococcus powder/capsule in digestive system diseases (2021). J Gastroenterol Hepatol. 2023;38(7):1089–1098. doi:10.1111/jgh.16195.
- Li HF, Hu GQ, Liu WW, Chen W. Clinical observation on the inflammatory indexes in septic gastrointestinal dysfunction treated with acupuncture at Jiaji (EX-B 2). Zhongguo Zhen Jiu. 2019;39(10):1055–1058. doi:10.13703/j.0255-2930.2019.10.006.
- Su Z, Kang Y. Influences of bifid triple viable capsules plus cetirizine on gut microbiota and immune function in children with eczema. Drug Des Devel Ther. 2022;16:2509–2515. doi:10.2147/DDDT.S363702.
- Wang W, Zhang H, Huang W. Efficacy of Bifidobacterium triple viable enteric-coated capsules combined with enteral nutrition on patients with chronic critical illness and influence on immune and coagulation function. Evid Based Complement Alternat Med. 2021;2021:3718255. doi:10.1155/2021/3718255.
- Connolly JG, Goldstone SE. Squamous cell dysplasia in the proximal rectum of three patients treated for ulcerative colitis on immunomodulators. Int J Colorectal Dis. 2017;32(5):753–756. doi:10.1007/s00384-016-2745-9.