Abstract
Diarrhea is one of the major abdominal symptoms in lactose-intolerant subjects. The changes in the large intestinal luminal environment and disorder of the epithelial ion transport in lactose-induced diarrhea remain unclear. The present study aimed to investigate the effect of an incremental high-lactose diet (IHLD, 30%/40%/50%) on luminal microbiota, microbiota-derived metabolite concentrations and colonic ion transport. Gut microbiota were analyzed by 16S rRNA amplicon sequencing and the concentration of SCFAs by gas chromatography, galactose, lactose and lactic acid through assay kit; Ussing chamber was performed to detect basal and stimulated ion transport; The expression and location of SCFA transporters, the Na-H exchanger 3(NHE3), cystic fibrosis transporter regulater (CFTR) and NKCC1 in the colon mucosa were analyzed by western and immunostaining. The concentrations of lactose, galactose and lactic acid of the cecal content were markedly increased (P < 0.01) and SCFA concentration was significantly decreased (P < 0.01). This was associated with depletion of the Lachnospiraceae NK4A136 group and Ruminococcaceae UCG-005 and increased relative abundance of Lactobacillus, escherichia-shigella and megamonas in the cecal microbiota. The expression of monocarboxylate transporter 1 was decreased in the colonic mucosa of the IHLD group. Low NHE3 expression and phosphorylation levels, and decreases in delta basal short circuit current after apical Na+ removal in the colonic mucosa of the IHLD group contributed to Na+ accumulation in the lumen and decrease stimulated Cl– secretion with low CFTR and NKCC1 expression would compensate for water and electrolyte loss during the diarrhea process. These results indicated that the persistence of the diarrhea state was maintained by abnormal colonic microbiota fermentation leading to high concentrations of lactose, galactose and lactic acid and low SCFAs in the lumen, and decreased Na+ absorption with the low NHE3 expression and phosphorylation levels.
Highlights
Diarrhea is a highly prevalent and bothersome disorder, in children and the elderly
The results suggested that the high concentrations of lactose, lactic acid and galactose in the colon lumen but not short-chain fatty acids (SCFAs) led to hyperosmosis in the colon, which would be the major reason for diarrhea
We established a chronic diarrhea model using lactose with a gradual increase in concentration for 3 weeks to investigate the mechanism of high lactose-induced diarrhea on organic acid production and ion transport of the colonic epithelium and NHE3, cystic fibrosis transporter regulater (CFTR) and NKCC1 expression combined with epithelial locations, which are associated with Na+ absorption and Cl− secretion
Summary
Diarrhea is a highly prevalent and bothersome disorder, in children and the elderly. Microbiota and Ion Transport in Lactose-Induced Diarrhea leads to more difficulty in treating. Lactose intolerance-induced diarrhea belongs to osmotic diarrhea, thereby resulting in colonic water and electrolyte accumulation (Hammer and Hammer, 2012). It is believed that the osmotic load is caused by undigested lactose but that the colonic fermentation capacity plays a role in lactose intolerance (He et al, 2006). Some reports have indicated that the osmolality of lactose-induced diarrhea is closely linked to the lactose content and the production of SCFAs in the colon (Binder, 2010; Alexandre et al, 2013). We speculated that the mechanism of lactose-induced diarrhea involved a change in SCFAs or lactate leading to a disturbance in colonic epithelial ion transport resulting in diarrhea. In the process of the transport of SCFAs, monocarboxylate (MCT1) and sodium MCT1 (sMCT1) transporters play an important role in mediating SCFA influx into the blood from the lumen (Ritzhaupt et al, 1998; Ganapathy et al, 2005; Sivaprakasam et al, 2017)
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