Lactulose improves cognition, quality of life, and gut microbiota in minimal hepatic encephalopathy: A multicenter, randomized controlled trial
Corresponding Author
Ji Yao Wang
Department of Gastroenterology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
Center of Evidence-based Medicine, Fudan University, Shanghai, China
Correspondence
Ji Yao Wang, Department of Gastroenterology, Zhongshan Hospital Affiliated to Fudan University, 180 Fenglin Road, Shanghai 200032, China.
Email: [email protected]
Search for more papers by this authorJasmohan S. Bajaj
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
Search for more papers by this authorJiang Bin Wang
Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
Search for more papers by this authorJia Shang
Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou, Henan Province, China
Search for more papers by this authorXin Min Zhou
Department of Gastroenterology, Xijing Hospital Affiliated to Air Force Medical University, Xi'an, Shaanxi Province, China
Search for more papers by this authorXiao Lin Guo
Department of Gastroenterology, First Hospital of Jilin University, Changchun, Jilin Province, China
Search for more papers by this authorXuan Zhu
Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
Search for more papers by this authorLi Na Meng
Department of Gastroenterology, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang Province, China
Search for more papers by this authorHai Xing Jiang
Department of Gastroenterology, First Affiliated Hospital of Guangxi Medical University, Guilin, Guangxi Zhuang Autonomous Region, China
Search for more papers by this authorYu Qiang Mi
Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
Search for more papers by this authorJian Ming Xu
Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
Search for more papers by this authorJin Hui Yang
Department of Hepatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
Search for more papers by this authorBai Song Wang
Department of Pharmacology and Biostatistics, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, China
Search for more papers by this authorNing Ping Zhang
Center of Evidence-based Medicine, Fudan University, Shanghai, China
Search for more papers by this authorCorresponding Author
Ji Yao Wang
Department of Gastroenterology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
Center of Evidence-based Medicine, Fudan University, Shanghai, China
Correspondence
Ji Yao Wang, Department of Gastroenterology, Zhongshan Hospital Affiliated to Fudan University, 180 Fenglin Road, Shanghai 200032, China.
Email: [email protected]
Search for more papers by this authorJasmohan S. Bajaj
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
Search for more papers by this authorJiang Bin Wang
Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
Search for more papers by this authorJia Shang
Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou, Henan Province, China
Search for more papers by this authorXin Min Zhou
Department of Gastroenterology, Xijing Hospital Affiliated to Air Force Medical University, Xi'an, Shaanxi Province, China
Search for more papers by this authorXiao Lin Guo
Department of Gastroenterology, First Hospital of Jilin University, Changchun, Jilin Province, China
Search for more papers by this authorXuan Zhu
Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
Search for more papers by this authorLi Na Meng
Department of Gastroenterology, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang Province, China
Search for more papers by this authorHai Xing Jiang
Department of Gastroenterology, First Affiliated Hospital of Guangxi Medical University, Guilin, Guangxi Zhuang Autonomous Region, China
Search for more papers by this authorYu Qiang Mi
Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
Search for more papers by this authorJian Ming Xu
Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
Search for more papers by this authorJin Hui Yang
Department of Hepatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
Search for more papers by this authorBai Song Wang
Department of Pharmacology and Biostatistics, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, China
Search for more papers by this authorNing Ping Zhang
Center of Evidence-based Medicine, Fudan University, Shanghai, China
Search for more papers by this authorFunding information: Zhongshan Hospital Fudan University, Grant/Award Number: I-033
Abstract
Objective
Lactulose is effective in the treatment and prevention of overt hepatic encephalopathy (OHE), but there are limited data on its use on microbiota in relations to minimal hepatic encephalopathy (MHE) recovery. The present study aimed to assess the efficacy of lactulose in recovery of MHE in aspects of cognitive function, quality of life, and impact on intestinal microbiota.
Methods
This multicenter, open-label randomized controlled trial was conducted in 11 teaching hospitals in China. Participants were randomly allocated on a 2:1 basis to receive lactulose (Gp-L) or no therapy as control (Gp-NL) for 60 days. The primary endpoint was the MHE reversal rate. Gut microbiota were compared between MHE patients and healthy volunteers, as well as lactulose-responders and non-responders.
Results
A total of 98 cirrhotic patients were included in the study, with 31 patients in the Gp-NL group and 67 patients in the Gp-L group. At day 60, the MHE reversal rate in Gp-L (64.18%) was significantly higher than that in Gp-NL (22.58%) (P = .0002) with a relative risk of 0.46 (95% confidence interval 0.32-0.67). Number needed to treat was 2.4. Further, there was significantly more improvement in physical functioning in Gp-L (4.62 ± 6.16) than in Gp-NL (1.50 ± 5.34) (P = .0212). Proteobacteria was significantly higher in MHE patients compared with healthy volunteers (12.27% vs 4.65%, P < .05). Significant differences were found between lactulose responders and non-responders in Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria.
Conclusions
Treatment with lactulose significantly improves MHE recovery rate, and gut microbiota change in MHE patients can modulate the effectiveness of this therapy. Chinese Clinical Trial Register (ChiCTR) (ID: ChiCTR-TRC-12002342).
CONFLICT OF INTEREST
There are no potential conflicts of interest for any of the authors.
Supporting Information
| Filename | Description |
|---|---|
| cdd12816-sup-0001-FigureS1.tifTIFF image, 130 KB | Figure S1. Biodiversity of minimal hepatic encephalopathy (MHE) gut microbiota composition before and after lactulose treatment. Alpha-diversity was assessed by (A) the Simpson's index and (B) the inverse Simpson's index based on the abundances of operational taxonomic unit (OTU). ANOVA was performed to determine the significance among groups. Student's t-test was used to determine the significance between each two groups, with *P < .05 and **P < .01. Baseline is defined as total patients with MHE before treatment. Gp-L, lactulose; Gp-NL, no treatment; HC, health control. |
| cdd12816-sup-0002-FigureS2.tifTIFF image, 131.5 KB | Figure S2 The alterations of gut microbiota in minimal hepatic encephalopathy patients with (Gp-L) and without lactulose treatment (Gp-NL). ANOVA was performed to determine the significance at the (A) phylum and (B) family levels, with *P < .05, **P < .01, and ***P < .001. Relative abundance of bacteria was given in cumulative sum scaling (CSS) of the total-sum normalization (TSS).Baseline is defined as total patients with MHE before treatment. HC, healthy control |
| cdd12816-sup-0003-FigureS3.tifTIFF image, 92.2 KB | Figure S3 The abundances of gut microbial taxa were significantly different between the minimal hepatic encephalopathy (MHC) patients and healthy control (HC). ANOVA was performed to determine the significance at the (A) phylum and (B) family levels, with *P < .05, **P < .01, and ***P < .001. Relative abundance of bacteria was given in cumulative sum scaling (CSS) of the total-sum normalization (TSS). |
| cdd12816-sup-0004-FigureS4.tifTIFF image, 131.3 KB | Figure S4 The alpha-diversity of responders is higher than non-responders. Alpha-diversity was assessed by (A) the inverse Simpson's index and (B) the Simpson's index based on the abundances of operational taxonomic unit (OTU). NR-AT, non-responders after treatment; NR-BT, non-responders before treatment; R-AT, responders after treatment; R-BT, responders before treatment. |
| cdd12816-sup-0005-FigureS5.tifTIFF image, 655.2 KB | Figure S5 The gut microbiota composition of responders shifted after lactulose treatment. Discriminant analysis of principal components (DAPC) was used to calculate the beta-diversity of the responders (R) and non-responders (NR) before (BT) and after (AT) lactulose treatment. OTU, operational taxonomic unit. |
| cdd12816-sup-0006-FigureS6.tifTIFF image, 410.5 KB | Figure S6 Beta-diversity was calculated by using principal coordinates analysis (PCoA) at the operational taxonomic unit (OTU) level.Gp-L, group received lactulose; Gp-NL, group did notreceive lactulose; HC, healthy control. |
| cdd12816-sup-0007-FigureS7.tifTIFF image, 241 KB | Figure S7 Alpha-diversity was assessed by (A) the Shannon index and the alterations of gut microbiota was performed to determine the significance at the (B) phylum and (C) family levels in minimal hepatic encephalopathy patients and healthy control (HC). NR-AT, nonresponders after treatment; NR-BT, non-responders before treatment; R-AT, responders after treatment; R-BT, responders before treatment. |
| cdd12816-sup-0008-DataS1.docxWord 2007 document , 15.6 KB | Data S1. Detailed exclusion criteria. |
| cdd12816-sup-0009-DataS2.docxWord 2007 document , 13 KB | Data S2. Quality of life questionnaire for cirrhotic patients with minimal hepatic encephalopathy. |
| cdd12816-sup-0010-DataS3.docxWord 2007 document , 19.8 KB | Data S3. KEGG database. |
| cdd12816-sup-0011-TableS1.docxWord 2007 document , 13.7 KB | Table 1. Baseline characteristics between lactulose respondersand non-responders. |
| cdd12816-sup-0012-TableS2.docxWord 2007 document , 12.1 KB | Table 2. Comparison between minimal hepatic encephalopathy (MHE) and healthy control (HC) in gender and age). |
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