Causality of small and large intestinal microbiota in weight regulation and insulin resistance

Abstract

Objective: The twin pandemics of obesity and Type 2 diabetes (T2D) are a global challenge for health care systems. Changes in the environment, behavior, diet, and lifestyle during the last decades are considered the major causes. A Western diet, which is rich in saturated fat and simple sugars, may lead to changes in gut microbial composition and physiology, which have recently been linked to the development of metabolic diseases.

Methods: We will discuss evidence that demonstrates the influence of the small and large intestinal microbiota on weight regulation and the development of insulin resistance, based on literature search.

Results: Altered large intestinal microbial composition may promote obesity by increasing energy harvest through specialized gut microbes. In both large and small intestine, microbial alterations may increase gut permeability that facilitates the translocation of whole bacteria or endotoxic bacterial components into metabolic active tissues. Moreover, changed microbial communities may affect the production of satiety-inducing signals. Finally, bacterial metabolic products, such as short chain fatty acids (SCFAs) and their relative ratios, may be causal in disturbed immune and metabolic signaling, notably in the small intestine where the surface is large. The function of these organs (adipose tissue, brain, liver, muscle, pancreas) may be disturbed by the induction of low-grade inflammation, contributing to insulin resistance.

Conclusions: Interventions aimed to restoring gut microbial homeostasis, such as ingestion of specific fibers or therapeutic microbes, are promising strategies to reduce insulin resistance and the related metabolic abnormalities in obesity, metabolic syndrome, and type 2 diabetes. This article is part of a special issue on microbiota.

Keywords: 16s rRNA, 16S ribosomal RNA (30S small subunit of prokaryotic ribosomes); AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; AS160, Akt substrate of 160 kDa; Angptl4, Angiopoietin-like 4; CB1R, cannabinoid receptor type 1; CCL2, Chemokine (C–C motif) ligand 2; DIO, diet-induced obesity; Diabetes; GF, germ-free; GLP, glucagon-like peptide; Gpr, G-protein coupled receptor; Gut microbiota; HFD, high fat diet; IL, interleukin; IRS-1, insulin receptor substrate 1; Insulin resistance; JNK, C-Jun N-terminal kinase; LBP, LPS-binding protein; LPL, lipoprotein lipase; LPS, lipopolysaccharide; MCP-1, monocyte chemotactic protein 1; NOD1, nucleotide-binding oligomerization domain-containing protein 1; Obesity; PKB, protein kinase B (also known as Akt); PYY, peptide YY (for tyrosine–tyrosine); RYGB, Roux-en-Y gastric bypass; SCFA, short-chain fatty acid; T2D, Type 2 diabetes mellitus; TLR, toll-like receptor; TNF-α, tumor necrosis factor alpha; VLDL, very low density lipoprotein; WHO, World Health Organization; Weight regulation; ZO, zonula occludens.

Figure 1

Function, dominant bacteria, microbial density and oxygen pressure in the different segments of the human intestine. The pH of the intestine increases from the stomach (1.5–5) to the large intestine (5–7). Similarly, the bacterial density increases from 10² to 10¹¹ cells/mL. The small intestine consists of duodenum, jejunum and ileum. Each segment shows different functions, which are mainly responsible for nutrient digestion and absorption. The colon (large intestine) is responsible for absorption of water and fermentation products such as short chain fatty acids (SCFAs). A decrease in oxygen concentration and antimicrobial compounds along the intestine leads to an increasing diversity in the large intestine with several obligate anaerobic bacteria. In upper parts reside more facultative aerobic bacteria, which can tolerate oxygen. Abbreviations: FFA, free fatty acids.

Figure 2

Involvement of the gut microbiota in weight regulation and insulin resistance. The gut microbiota is able to ferment polysaccharides into monosaccharides and short-chain-fatty-acids (SCFAs). These products are taken up by the epithelium and transported to the liver. An obese type of microbiota shows higher levels of Firmicutes than Bacteroidetes, which is associated with a higher SCFA production leading to more energy extraction from the diet. Further, the altered microbiota leads to a lower expression of Angiopoietin-like 4 (Angptl4), which inhibits Lipoprotein lipase (LPL) activity. This enzyme facilitates the hydrolysis of triglycerides (TG) in very low-density lipoprotein (VLDL) and chylomicrons resulting in the uptake of fatty acids in skeletal muscle, heart, and adipose tissue. An obese-type microbiota shows higher TG storage in adipocytes. Similarly, obese subjects show lower activities of phosphorylated adenosine monophosphate protein kinase (pAMPK), which is necessary for the activation of fatty acid oxidation. Lastly, an altered microbiota is associated with lower expression of satiety inducing gut hormones such as peptide YY (PYY), glucagon-like peptide (GLP) 1 and 2.

Figure 3

Different degrees of potential causal relationships between human disease and altered microbiota composition. The human gut microbiota is a stable ecosystem, which is dependent on environmental and genetic factors. Under healthy conditions, gut microbiota lives in symbiosis with its host. Different human disease states have been associated with altered fecal microbial composition; however, at this moment, it not known whether this is merely a reflection of the underlying disease. Moreover, it is very likely that the intestinal microbiota are not equally important in all human disease states; thus, their role in the pathophysiology may vary from disease modifiers to causal drivers. Abbreviations: ESBL, extended-spectrum beta-lactamase producing Enterobacteriaceae; VRE, vancomycin-resistant enterococci; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; T1D, Type 1 diabetes mellitus; T2D, Type 2 diabetes mellitus.