Causality of small and large intestinal microbiota in weight regulation and insulin resistance.
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.
Department of Vascular Medicine, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands; Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR), VU University Medical Center, Amsterdam, The Netherlands.
Torsten P M
TP
Scheithauer
Department of Vascular Medicine, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.
Geesje M
GM
Dallinga-Thie
WU Agrotechnology and Food Sciences, Wagening University, Wageningen, The Netherlands.
Willem M
WM
de Vos
Department of Vascular Medicine, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands; Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR), VU University Medical Center, Amsterdam, The Netherlands.
Max
M
Nieuwdorp
Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR), VU University Medical Center, Amsterdam, The Netherlands.
Daniël H
DH
van Raalte
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