Previous research in mice and humans has shown that high-fat (HF) diets alter both the composition and microbial metabolic function of gut microbiota in the short term, resulting in the development of metabolic disturbances. Although these studies have focused on fecal microbiota, little is known about whether microbial communities in the small intestine affect lipid metabolism and absorption.
A new study, led by Prof. Eugene B. Chang from the Department of Medicine, Section of Gastroenterology, Hepatology and Nutrition at the University of Chicago (USA), has found that small bowel microbiota is involved in dietary fat digestion and absorption in mice.
The researchers found that germ-free (GF) mice were protected from HF diet-induced obesity and showed impaired lipid digestion and absorption within the small intestine, as demonstrated using radiolabelled lipid absorption assays. GF mice did not gain weight over the 4-week study period and exhibited higher levels of stool triglycerides compared with specific pathogen-free (SPF) mice fed a HF diet.
When evaluating the involvement in GF mice of impaired enteroendocrine signaling mediated by cholecystokinin (CCK) and secretin (SCT)—hormones produced by epithelial cells in the small intestine and released upon feeding—the researchers showed that impaired CCK signaling may be partly responsible for GF resistance to diet-induced obesity. While GF mice had elevated circulating CCK levels, the defect in CCK signaling was due to a reduced expression of the cholecystokinin A receptor (CCkar) in the pancreas, as opposed to changes in the amount of the CCK protein produced.
In addition to altered lipid digestion, GF mice also showed reduced brush border membrane transport of free oleic acid. It was also shown that another alternative mechanism for GF mice’s resistance to HF diet-induced obesity was the upregulation of genes involved in fat oxidation, such as Cd36 and Ppara, in the jejunum but not in the duodenum. This would prevent absorbed fats being incorporated into chylomicrons and being delivered to the periphery, compared with SPF mice. Taken together, these data show that GF mice became resistant to diet-induced obesity due to impaired fat digestion and absorption, along with increased fat oxidation in the gut.
To better elucidate mechanisms involved in diet-microbiota interactions, the researchers then investigated the role of HF diet-induced gut microbes in lipid absorption. In SPF mice, a HF diet increased the relative abundance of the Clostridiaceae family compared with a low-fat (LF) diet and the decreased abundance of the Bifidobacteriaceae and Bacteroidaceae families, which differed along the length of the small intestine. Besides this, GF mice conventionalized with HF diet-induced jejunal microbiota exhibited increased lipid absorption to the same degree, regardless of whether they were maintained on LF or HF diets for 4 weeks. Both groups that received HF microbes showed increased lipid absorption compared with mice receiving LF microbes.
To explore whether specific strains of bacteria can affect lipid absorption pathways, the reference strain Clostridium bifermentans‘s capacity to affect lipid absorption was assessed both in vitro and in vivo. In vitro studies found that under LF conditions, C. bifermentans increased oleic acid uptake and the expression of esterification enzyme diacylglycerol O-acyltransferase (Dgat2), which is an enzyme involved in lipid triglyceride synthesis and storage, possibly through bacterium-derived molecules or bioactive compounds. Conditioned media from C. bifermentans also increased Dgat2 messenger ribonucleic acid levels in the jejunum of LF-fed mice in vivo.
Similar to C. bifermentans, Lactobacillus rhamnosus GG increased Dgat1 in the duodenum and Dgar2 gene expression and protein levels in the jejunum under LF conditions, although their levels did not reach statistical significance. Neither C. bifermentans nor L. rhamnosus GG had a significant impact on processes related to lipid digestion, which included unchanged gallbladder weight, plasma CCK or SCT levels. Although exact mechanisms need to be explored, these findings highlight the role of specific bacterial strains and their derived bioactive components or molecules on the expression of genes related to the re-esterification of triglycerides, such as Dgat2.
In conclusion, these results show for the first time that changes in the small bowel’s microbiota may be involved in the role of the small intestine in regulating host lipid digestion and absorption, at least in mice. Further research should focus on assessing bioactive bacterial components or molecules on host physiology in order to depict a clear picture of the role of the small intestine’s microbiota in lipid digestion and absorption, and its relevance in humans.
Martinez-Guryn K, Hubert N, Frazier K, et al. Small intestine microbiota regulate host digestive and absorptive adaptive responses to dietary lipids. Cell Host Microbe. 2018; 23(4):458-69. doi: 10.1016/j.chom.2018.03.011.
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