Highlights
- Upper small intestine (USI) microbiome is crucial in nutrient absorption and digestion.
- High-fat diet greatly impacts USI microbiome diversity and composition in rodents.
- Bariatric surgery and inulin aid in the recovery of USI microbiome in HFD-fed mice
- Metagenomic richness of USI microbiome inversely correlates with insulin resistance.
- USI microbiome research in obesity is still limited and standardized methods are awaited.
Abstract
The study of the gut microbiome holds great promise for understanding and treating metabolic diseases, as its functions and derived metabolites can influence the metabolic status of the host. While research on the fecal microbiome has provided valuable insights, it tells us only part of the story. This limitation arises from the substantial variations in microorganism distribution throughout the gastrointestinal tract due to changes in physicochemical conditions. Thus, relying solely on the fecal microbiome may not be sufficient to draw comprehensive conclusions about metabolic diseases. The proximal part of the small intestine, particularly the jejunum, indeed, serves as the crucial site for digestion and absorption of nutrients, suggesting a potential role of its microbiome in metabolic regulation. Unfortunately, it remains relatively underexplored due to limited accessibility.
This review presents current evidence regarding the relationships between the microbiome in the upper small intestine and various phenotypes, focusing on obesity and type 2 diabetes, in both humans and rodents. Research on humans is still limited with variability in the population and methods used. Accordingly, to better understand the role of the whole gut microbiome in metabolic diseases, studies exploring the human microbiome in different niches are needed.
Introduction
Obesity, characterized by the chronic and progressive accumulation of excess fat mass, has now reached pandemic proportions, posing a major public health concern worldwide [1,2]. The pathophysiology of obesity is complex, driven by the interplay between lifestyle/environment factors and a multitude of biological components including genetic/epigenetic factors [3]. In this challenging context, there has been a growing interest in elucidating the role of the gut microbiome in the development of obesity and its associated complications, including type 2 diabetes (T2D), cardiovascular diseases, and cancers.
The gut microbiome encompasses all the microorganisms inhabiting the gastrointestinal tract (GIT) and plays a critical role in various physiological processes, including digestion, immunity, and metabolism [8]. Recent research underscores that changes in the composition and function of the gut microbiome can lead to metabolic dysregulation or inflammation which in turn may contribute to obesity development and progression. Therefore, targeting the fecal microbiome has emerged as a potential strategy for preventing and treating obesity and/or related comorbidities. However, the distribution of bacteria along the GIT varies significantly. Bacterial density gradually increases from the mouth to the colon, with a range of 101–103 colony-forming units (CFU)/mL in the stomach and duodenum, 104–107 CFU/mL in the jejunum and ileum, and 1011–1013 CFU/mL in the colon [15]. These changes are influenced by various physical and chemical factors that differentiate the small intestine (SI) from the colon. For instance, the SI presents a lower number of goblet cells and a thinner mucus barrier organized as a single layer compared to the colon, but it produces more antimicrobial peptides through Paneth cells, which help prevent bacterial colonization [15]. Additional factors such as increased luminal flow rate, intermittent food substrate delivery, downward peristalsis flow, and the release of bile acids (BAs) in the SI also contribute to reduced bacterial colonization. The pH of the intestine progressively increases from 6.6 in the proximal tract to 7.5 in the terminal ileum, and stabilizes at 7.0 in the distal colon, affecting the distribution of microorganisms and influencing the microbiome’s composition in each different GIT segment [16].
Furthermore, the upper small intestine (USI), which includes the duodenum and the jejunum, serves as the main site for the process of digestion and absorption of nutrients and minerals. This biological process involves a complex interplay of multiple factors including dietary signals, the hormone-secreting enteroendocrine cells (EECs), and the controlled release of bile [17]. As a result, microbial communities residing in the USI exhibit lower diversity compared to the colon in humans [18], displaying a remarkable level of dynamism that surpasses other regions of the intestine [19].
Several studies have investigated the mechanisms of lipid and glucose sensing that occur in the USI and the emerging role played by the USI microbiota in the absorption of macronutrients and in vitamin and micronutrient synthesis. Upon food consumption, the intestinal uptake of lipids, which partly occurs through the CD36 transporter, stimulates the EECs to release intestinal peptides such as cholecystokinin (CKK). Similarly, the uptake of glucose in the intestine via the sodium-glucose cotransporter-1 (SGLT1) promotes the production of glucagon-like peptide-1 (GLP-1) by the L-cells located in the ileum and its subsequent release into the bloodstream. GLP-1, in turn, plays a critical role in glucose homeostasis by enhancing insulin secretion from pancreatic beta cell [17]. Additionally, similar to CKK, GLP-1 binds receptors in the brain thereby regulating food intake and decreasing endogenous nutrient production.
Recent findings suggest that the gut microbiome may play a role in regulating the secretion and transcriptome of EECs. Surprisingly, germ-free (GF) mice exhibited higher colonic proglucagon expression compared to conventionally raised mice, leading to elevated circulating GLP-1 levels [22].
In light of these aspects, USI is an important site for neuroendocrine signaling, nutrient sensing, production of entero-hormones, and activation of different pathways that may induce energy expenditure and thermogenesis, promote satiety and lower food intake, or regulate glucose homeostasis by promoting insulin secretion or by lowering hepatic glucose production [[23], [24], [25]].
Given these considerations, it can be speculated the USI microbiome could represent a site of potential importance in the study of obesity and associated cardiometabolic diseases. However, most studies examining the gut microbiome’s interplay with host metabolism have focused on fecal or colonic luminal samples partly due to their easier accessibility [26]. This leaves major gaps in our understanding of the complex relationship between the USI microbiome and host health and disease.
The purpose of this work is to present a comprehensive overview of the current evidence regarding the impact of the USI microbiome on different metabolic phenotypes including obesity and T2D.
Date: 24 October 2023
Authors: Emilie Steinbach, Davide Masi, Agnès Ribeiro a, Patricia Serradas, Tiphaine Le Roy, Karine Clément
Link: https://www.sciencedirect.com/science/article/pii/S0026049523003165#f0015
Nutrigenomics Institute is not responsible for the comments and opinions included in this article
