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. 2024 Jul 3;13(13):2128.
doi: 10.3390/foods13132128.

Lactitol Alleviates Loperamide-Induced Constipation in Sprague Dawley Rats by Regulating Serotonin, Short-Chain Fatty Acids, and Gut Microbiota

Joo Hyun Jang  1   2 , Sang Min Kim  1   2 , Hyung Joo Suh  1   2 , Minchul Gim  3 , Hoyeon Shin  3 , Hyunsook Jang  3 , Hyeon-Son Choi  4 , Sung Hee Han  5 , Yeok Boo Chang  1   2
Affiliations

Lactitol Alleviates Loperamide-Induced Constipation in Sprague Dawley Rats by Regulating Serotonin, Short-Chain Fatty Acids, and Gut Microbiota

Joo Hyun Jang et al. Foods. .

Abstract

The objective of this study was to examine the impact of lactitol on constipation caused by loperamide in Sprague Dawley rats, with a particular emphasis on its underlying mechanisms and potential health advantages. The lactitol effectively improved fecal parameters, intestinal tissue structure, and the expression of constipation-related gene expression and proteins. Lactitol alleviated fecal weight and water content altered by loperamide and enhanced gastrointestinal transit. The administration also restored mucosal and muscular layer thickness. Mechanistically, lactitol upregulated the mRNA expression and/or protein levels of mucins (MUC2 and MUC4), occludin, claudin-1, and zonula occludens, indicating improved intestinal barrier function. Lactitol positively regulated the composition of cecal microbiota, leading to an increased relative abundance of Bifidobacterium, Lactobacillus, and Romboutsia. Conversely, lactitol decreased the relative abundance of Prevotella, Aerococcus, Muribaculum, Blautia, and Ruminococcus. This study demonstrated the potential of lactitol to relieve constipation by modulating the gut microbiota. These findings suggest that lactitol is an alternative to traditional laxatives and has potential as a health-promoting food sweetener.

Keywords: animals; constipation; gastrointestinal transit; gut microbiota; lactitol; loperamide.

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Conflict of interest statement

Author Minchul Gim was employed by the company Lotte. He participated in funding acquisition, writing-review and editing, validation, and software in the study. The role of the company was sample provision. Author Hoyeon Shin was employed by the company Lotte. He participated in funding acquisition, writing-review and editing, validation in the study. The role of the company was sample provision. Author Hyunsook Jang was employed by the company Lotte. He participated in funding acquisition and project administration in the study. The role of the company was sample provision. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Effect of lactitol on (A) the number of fecal pellets, (B) weight of dried fecal pellets, and (C) fecal water contents in SD rats treated with loperamide. NOR: normal group; CON: loperamide-control group (5 mg/kg), PC: lactulose (2010 mg/kg) treated with loperamide; LTL: low dose of lactitol (300 mg/kg) treated with loperamide; LTM: medium dose of lactitol (500 mg/kg) treated with loperamide; LTH: high dose of lactitol (800 mg/kg) treated with loperamide. ## p < 0.01 and ### p < 0.001 vs. NOR, and * p < 0.05, ** p < 0.01, *** p < 0.001 vs. CON.
Figure 2
Figure 2
Effect of lactitol on gastrointestinal transit rate in SD rats treated with loperamide. NOR: normal group; CON: loperamide-control group (5 mg/kg), PC: lactulose (2010 mg/kg) treated with loperamide; LTL: low dose of lactitol (300 mg/kg) treated with loperamide; LTM: medium dose of lactitol (500 mg/kg) treated with loperamide; LTH: high dose of lactitol (800 mg/kg) treated with loperamide. # p < 0.05 vs. NOR, and * p < 0.05 and ** p < 0.01 vs. CON.
Figure 3
Figure 3
Effect of lactitol on (A) muscular layer and (B) mucosal layer thickness in SD rats treated with loperamide. NOR: normal group; CON: loperamide-control group (5 mg/kg), PC: lactulose (2010 mg/kg) treated with loperamide; LTL: low dose of lactitol (300 mg/kg) treated with loperamide; LTM: medium dose of lactitol (500 mg/kg) treated with loperamide; LTH: high dose of lactitol (800 mg/kg) treated with loperamide. ### p < 0.001 vs. NOR, and * p < 0.05, ** p < 0.01 and *** p < 0.001 vs. CON.
Figure 4
Figure 4
Effect of lactitol on (A) crypt cells and (B) ICC distribution in SD rats treated with loperamide. NOR: normal group; CON: loperamide-control group (5 mg/kg), PC: lactulose (2010 mg/kg) treated with loperamide; LTL: low dose of lactitol (300 mg/kg) treated with loperamide; LTM: medium dose of lactitol (500 mg/kg) treated with loperamide; LTH: high dose of lactitol (800 mg/kg) treated with loperamide. # p < 0.05 and ### p < 0.001 vs. NOR, and ** p < 0.01 and *** p < 0.001 vs. CON.
Figure 5
Figure 5
Effect of lactitol on serotonin (A) and substance P (B) content in SD rats treated with loperamide. NOR: normal group; CON: loperamide-control group (5 mg/kg), PC: lactulose (2010 mg/kg) treated with loperamide; LTL: low dose of lactitol (300 mg/kg) treated with loperamide; LTM: medium dose of lactitol (500 mg/kg) treated with loperamide; LTH: high dose of lactitol (800 mg/kg) treated with loperamide. # p < 0.05 and ### p < 0.001 vs. NOR, and * p < 0.05 and ** p < 0.01 vs. CON.
Figure 6
Figure 6
Effect of lactitol on gene expression levels of (A) Tryptophan hydroxylases (TPH)1, (B) TPH2, (C) Mucin (MUC)2, (D) MUC4, (E) Aquaporin (AQP)3, (F) AQP8, (G) Protein kinase A (PKA), (H) Occludin (OCLN), (I) Claudin (CLDN) and (J) Zonula occludens 1 (ZO1) in colon tissues of Sprague Dawley (SD) rats with loperamide-induced constipation. NOR: normal group; CON: loperamide-control group (5 mg/kg), PC: lactulose (2010 mg/kg) treated with loperamide; LTL: low dose of lactitol (300 mg/kg) treated with loperamide; LTM: medium dose of lactitol (500 mg/kg) treated with loperamide; LTH: high dose of lactitol (800 mg/kg) treated with loperamide. # p < 0.05, ## p < 0.01 and ### p < 0.001 vs. NOR, and * p < 0.05, ** p < 0.01 and *** p < 0.001 vs. CON in mRNA expression.
Figure 7
Figure 7
Effect of lactitol on protein levels of (A) c-kit, (B) Aquaporin 3 (AQP3) and (C) Occludin (OCLN) in colon tissues of SD rats treated with loperamide. NOR: normal group; CON: loperamide-control group (5 mg/kg), PC: lactulose (2010 mg/kg) treated with loperamide; LTL: low dose of lactitol (300 mg/kg) treated with loperamide; LTM: medium dose of lactitol (500 mg/kg) treated with loperamide; LTH: high dose of lactitol (800 mg/kg) treated with loperamide. # p < 0.05 and ## p < 0.01 vs. NOR, and * p < 0.05, ** p < 0.01 and *** p < 0.001 vs. CON. ns: not significant.
Figure 8
Figure 8
Effect of lactitol on content of (A) acetic acid, (B) propionic acid, (C) butyric acid, (D) valeric acid and (E) total short chain fatty acids (SCFA) in cecum of SD rats treated with loperamide. NOR: normal group; CON: loperamide-control group (5 mg/kg), PC: lactulose (2010 mg/kg) treated with loperamide; LTL: low dose of lactitol (300 mg/kg) treated with loperamide; LTM: medium dose of lactitol (500 mg/kg) treated with loperamide; LTH: high dose of lactitol (800 mg/kg) treated with loperamide. ## p < 0.01 vs. NOR, and * p < 0.05, ** p < 0.01 and *** p < 0.001 vs. CON. ns: not significant.
Figure 9
Figure 9
Effect of lactitol on the relative abundance of cecal microbiota at the phylum level in SD rats treated with loperamide. NOR, normal group, empty circle; CON, loperamide control group (5 mg/kg), filled circle; PC, lactulose (2010 mg/kg), filled triangle treated with loperamide; LTL, low-dose lactitol (300 mg/kg) treated with loperamide, upside down triangle; LTM, medium-dose lactitol (500 mg/kg) treated with loperamide, line hexagon; and LTH, high-dose lactitol (800 mg/kg), filled hexagon treated with loperamide. ### p < 0.001 vs. NOR, and *** p < 0.001 vs. CON. ns: no significant.
Figure 10
Figure 10
Effect of lactitol on the relative abundance of cecal microbiota at the genus level in SD rats treated with loperamide. NOR, normal group; CON, loperamide control group (5 mg/kg); PC, lactulose (2010 mg/kg) treated with loperamide; LTL, low-dose lactitol (300 mg/kg) treated with loperamide; LTM, medium-dose lactitol (500 mg/kg) treated with loperamide; and LTH, high-dose lactitol (800 mg/kg) treated with loperamide. ## p < 0.01 and ### p < 0.001 vs. NOR, and * p < 0.05, ** p < 0.01 and *** p < 0.001 vs. CON. ns: no significant.
Figure 11
Figure 11
Pearson correlation analysis between intestinal barrier mobility factor and gut microbiota in SD rats treated with loperamide. NOR: normal group; CON: loperamide-control group (5 mg/kg), PC: lactulose (2010 mg/kg); LTL: low dose of lactitol treated group (300 mg/kg); LTM: medium dose of lactitol treated group (500 mg/kg); LTH: high dose of lactitol treated group (800 mg/kg). A deeper shade of blue indicates a stronger positive correlation, whereas a deeper shade of red signifies a stronger negative correlation. * p < 0.05, ** p < 0.01 and *** p < 0.001 by Pearson correlation.
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