Intestinal Barrier and Permeability in Health, Obesity and NAFLD

Piero Portincasa, Leonilde Bonfrate, Mohamad Khalil, Maria De Angelis, Francesco Maria Calabrese, Mauro D'Amato, David Q-H Wang, Agostino Di Ciaula, Piero Portincasa, Leonilde Bonfrate, Mohamad Khalil, Maria De Angelis, Francesco Maria Calabrese, Mauro D'Amato, David Q-H Wang, Agostino Di Ciaula

Abstract

The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors. Disrupted gut permeability (leaky gut syndrome) can represent a predisposing or aggravating condition in obesity and the metabolically associated liver steatosis (nonalcoholic fatty liver disease, NAFLD). In what follows, we describe the morphological-functional features of the intestinal barrier, the role of major modifiers of the intestinal barrier, and discuss the recent evidence pointing to the key role of intestinal permeability in obesity/NAFLD.

Keywords: intestine; metabolic syndrome; metabolome; microbiota.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The integrated components of the intestinal barrier in physiological conditions: (1) the gut microbiota (i.e., microbial barrier); (2) the gut mucus, accumulating at the interface between the intestinal lumen and the brush border of enterocytes; (3) the interplay between gastrointestinal motility and secretions (i.e., the functional barrier); (4) the epithelial barrier and the tight junctions; (5) the immune-competent cells and their products (i.e., the immunological barrier); (6) the gut–vascular interface; (7) the hepatic filter (i.e., the liver barrier). Adapted from Di Ciaula et al. [11].
Figure 2
Figure 2
Potential progression of changes in the gut and the liver with ongoing nonalcoholic fatty liver disease. (1) In health, the gut microbiota has high diversity of microbial species to guarantee all physiological tasks. Both bile secretion and pancreatic juice contribute to shaping the gut microbiota. The ratio of primary (green color) to secondary bile acids (red color) is under the control of the healthy gut microbial population (see text for details). (2) With the accumulation of triglycerides, long-chain fatty acids and their metabolites in the liver (simple steatosis, nonalcoholic fatty liver, NAFL), gut microbiota can be reshaped by decreased microbial diversity, small gut overgrowth, disrupted intestinal barrier and circulating bacteria in the portal tract. (3) A further step includes the progressive necro-inflammatory and fibrotic form nonalcoholic steatohepatitis (NASH). This evolution is often associated with the rise in pro-inflammatory and pro-steatotic bacterial products in the portal circuit. Changes of the bile acid pool (a shift to increased cytotoxic secondary bile acids, deoxycholic acid, lithocholic acid by bacterial deconjugation especially in the colon) will increase the delivery of these bile acids via the portal vein to the liver, driving a further damage. The intestinal barrier will further increase the permeability, and mechanisms of damage will be perpetuated. (4) If the sequence NASH-Cirrhosis (and even hepatocellular carcinoma, HCC) develops, the intestinal barrier will be further disrupted and, culturable bacteria can translocate via the portal vein to the systemic circulation. The role of bacterial-gut-derived metabolites with systemic effects is shown with trimethylamine (TMA) produced by bacteria out of dietary compounds, is metabolized in the liver to trimethylamine N-oxide (TMAO) which has pro-atherogenic effects and increases the risk of cardiovascular events.
Figure 3
Figure 3
Relationships between foods, gut microbiota and intestinal barrier, as main contributors to obesity and nonalcoholic fatty liver disease (NAFLD). SCFA, short-chain fatty acids, LPS, lipopolysaccharides; TMA, trimetylamine.

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