The Role of Gut Microbiota and Metabolites in Obesity-Associated Chronic Gastrointestinal Disorders

Abstract

The gut microbiota is a complex community of microorganisms that has become a new focus of attention due to its association with numerous human diseases. Research over the last few decades has shown that the gut microbiota plays a considerable role in regulating intestinal homeostasis, and disruption to the microbial community has been linked to chronic disease conditions such as inflammatory bowel disease (IBD), colorectal cancer (CRC), and obesity. Obesity has become a global pandemic, and its prevalence is increasing worldwide mostly in Western countries due to a sedentary lifestyle and consumption of high-fat/high-sugar diets. Obesity-mediated gut microbiota alterations have been associated with the development of IBD and IBD-induced CRC. This review highlights how obesity-associated dysbiosis can lead to the pathogenesis of IBD and CRC with a special focus on mechanisms of altered absorption of short-chain fatty acids (SCFAs).

Keywords: CRC; IBD; SCFAs; gut microbiota; obesity.

Figure 1

Mechanisms used by the gut bacteria in host defense. The gut microbiota modulates pathogenic bacterial overgrowth by producing antimicrobial peptides (bacteriocin), T6SS toxic protein, SCFAs, superoxide ion, and competing for food space and oxygen, which protects the host and maintains GI homeostasis. SCFAs: Short-chain fatty acids; O₂: oxygen.

Figure 2

Pathways of SCFAs production by the gut microbiota. Gut bacteria produce SCFAs mainly by the following pathways: acetate is produced from acetyl-CoA (derived from the glycolytic pathway) or and Wood–Ljungdahl pathway, butyrate is produced from acetate and acetyl-CoA, and propionate is produced from the succinate and lactate through their respective pathways.

Figure 3

An overview of SCFA transport mechanisms. SCFAs produced in the gut lumen by the gut flora exist in two forms: undissociated and dissociated SCFAs. Undissociated SCFAs can pass across the apical plasma membrane by passive diffusion while the dissociated SCFAs require the aid of transporters. MCT1–4, Monocarboxylic acid transporters (shown in light-pink, green, grey, and blue); SMCT1–2, Sodium-coupled monocarboxylate transporter (shown in yellow and red); SCFA/HCO₃⁻ exchangers (shown in magenta).

Figure 4

Schematic representation of the various layers of the GI tract. Mucus acts as a chemical barrier and separates the epithelial cells from the luminal contents while the epithelium and tight junction proteins provide a physical barrier to maintain gut integrity.

Figure 5

Schematic representation of the mechanism of SCFA butyrate on immune modulation. Butyrate binds to G-protein-coupled receptors (GPCRs), which activate various downstream signaling pathways involved in the regulation of inflammation and ROS production. SCFA, short-chain fatty acid; Foxp3, forkhead box protein P3; MAPK, mitogen-activated protein kinases; GSH, glutathione; NF-κB, nuclear factor κB; IL, interleukin; (IFN)-γ, interferon; TNF-α, tumor necrosis factor; ROS, reactive oxygen species. Upward arrow denotes increase and downward arrow denotes decrease.

Figure 6

Mechanism of LPS-mediated immune response. High-fat diet increases the population of LPS producing bacteria in the gut. LPS producing bacteria downregulates the expression of tight junction proteins, which in turn increases intestinal permeability and translocation of LPS. In the circulation, LPS binds to its receptor on immune cells and increases the release of proinflammatory cytokines causing low-grade inflammation. LPS, lipopolysaccharide. Upward arrow indicates increased; downward arrow indicates downregulation.

Figure 7

Pathomechanism of GI disorders (CD, UC) and cancer in obesity. The interplay between gut microbiota, adipose tissue, immune system, and intestinal permeability leads to the development of GI disorders and cancer. Dysbiosis increases intestinal permeability and alters SCFAs production. Defective intestinal barrier translocates bacteria into the mesenteric adipose tissue resulting in the production of proinflammatory cytokines. Defective barrier also increases circulating LPS causing inflammation. Adipocyte dysfunction alters adipokine secretion which can participate in low-grade inflammation. Thus, the complex interaction between diet, obesity and dysbiosis creates an inflammatory milieu which predisposes to GI disorders and cancer. LPS, liposaccharide; TLR, toll-like receptor; CD14, cluster of differentiation 14; NOD1, nucleotide binding oligomerization domain containing 1; NF-kB, nuclear factor kappa B; IL-6,8, interleukin; TNF-α, tumor necrosis factor alpha; SCFA, short-chain fatty acid. Upward arrow represents increase; downward arrow represents decrease; double head arrow indicates either increase or decrease.