Elsevier

Biochimie

Volume 141, October 2017, Pages 97-106
Biochimie

Review
Impact of high-fat diet on the intestinal microbiota and small intestinal physiology before and after the onset of obesity

https://doi.org/10.1016/j.biochi.2017.05.019Get rights and content

Highlights

  • High-fat diet (HFD) impacts immunological and metabolic functions of the host.

  • Gut dysbiosis, inflammation and leakage are induced by HFD consumption.

  • These changes seem to be associated the development of obesity and its complications.

  • Some prebiotics, probiotics and antidiabetics attenuate this HFD-induced phenotype.

Abstract

The modulation of the intestinal microbiota by high-fat diet (HFD) has a major impact on both immunological and metabolic functions of the host. Taking this into consideration, the aim of this contribution is to review the impact of HFD on microbiota profile and small intestinal physiology before and after the onset of obesity and its metabolic complications. Evidence from animal studies suggest that before the onset of obesity and its metabolic complications, HFD induces intestinal dysbiosis - encompassing changes in composition balance and massive redistribution with bacteria occupying intervillous spaces and crypts - associated with early physiopathological changes, predominantly in the ileum, such as low-grade inflammation, decreased antimicrobial peptides expression, impaired mucus production, secretion and layer's thickness, and decreased expression of tight junction proteins. With time, major inflammatory signals (e.g. toll-like receptor-4 dependent) become activated, thereby stimulating proinflammatory cytokines secretion in the small intestine. This inflammatory state might subsequently exacerbate disruption of the mucus layer barrier and increase epithelial permeability of the small intestine, thereby creating an environment that facilitates the passage of bacterial components (e.g. lipopolysaccharide, peptidoglycan and flagellin) and metabolites from the intestinal lumen (e.g. secondary bile acids) to the circulation and peripheral tissues (i.e. leaky gut), eventually promoting the development of systemic inflammation, obesity, adiposity, insulin resistance and glucose intolerance preceding hyperglycemia. Although the mechanisms are still not completely understood, prebiotics, probiotics, polyphenols, peroxisome proliferator-activated receptor-γ agonists (such as rosiglitazone) and exercise have been shown to reverse HFD-induced intestinal phenotype and to attenuate the severity of obesity and its associated metabolic complications.

Introduction

The epithelium of the small intestine is composed of a single layer of cells that affects extensive folding, thereby forming several crypt-villus units [1]. Villi are finger-like invaginations that project into the intestinal lumen to maximize the absorptive surface area of the small intestine [2], while crypts are epithelial invaginations found at the base of these villi [1] (Fig. 1). At the bottom of the crypts, intestinal stem cells continuously divide, leading to progenitors that differentiate into specialized epithelial cells (ECs) as they migrate upward the crypt-villus unit [2], [3]. These intestinal ECs include: a) enterocytes, the most numerous, mainly involved in the absorption of nutrients, electrolytes and water [2], [3]; b) goblet cells, which secrete mucin glycoproteins and peptides such as trefoil factor 3 (TFF3) into the intestinal lumen [2], [3]; c) Paneth cells, which remain at the bottom of the crypts and are involved in antimicrobial peptides secretion [2], [3] and nurture of adjacent stem cells [4]; and d) enteroendocrine cells, which secrete hormones regulating digestive functions [2] (Fig. 1). Adhesion and communication between adjacent intestinal ECs is ensured by membrane tight-junction proteins (such as occludin, claudins and junctional adhesion molecules) and junctional complex proteins (such as zonula occludens (ZO)) (Fig. 1). As a consequence, these proteins play a critical role in the maintenance of both integrity and permeability of the intestinal epithelium [2], [5]. The luminal mucus layer is the first physical and biochemical barrier that prevents contact of microbes with the intestinal epithelium. This layer is mainly composed of mucins (the most abundant being MUC2), and also mucin interacting-peptides (e.g. TFF3) and antimicrobial peptides such as lysozyme and defensins [1], [3], [6]. B and T lymphocytes, microfold cells and macrophages residing in close proximity to the mucosal surface coordinate, together with the mucus layer, the intestinal immune response [7]. The development of an appropriate immune response - which results in tolerance against beneficial microbes or elimination of pathogenic microbes - also depends on the ability of intestinal ECs to express a variety of pattern-recognition receptors (PRRs) such as membrane toll-like receptors (TLR) and cytosolic nucleotide-binding oligomerization domain (NOD)-like receptors [2] (Fig. 1). These PRRs recognize microbial-associated components (e.g. TLR4 recognize bacterial lipopolysaccharides (LPS) while NOD1 and NOD2 recognize peptidoglycans [8], [9], [10], [11]) thereby activating inflammatory pathways that alert the host to infection [12]. Not completely understood, however, is how intestinal ECs discriminate between beneficial and pathogenic microbial components in order to orchestrate an appropriate response, i.e. activation of physiological inflammatory responses that keep beneficial microbes at bay or activation of pathological inflammatory responses (e.g. that culminates in nuclear factor-kappa B (NF-κB) activation) that eliminate pathogenic microbes [2]. One hypothesis is the polarized expression of PRRs by intestinal ECs at either apical or basolateral membrane [9], [13], [14], [15].

The gut microbiota is a complex microbial community inhabiting the gastrointestinal tract that includes 100 trillion bacteria and archaea distributed over more than 1000 species [8]. The majority of those bacteria are non-pathogenic and co-habit with intestinal ECs in a symbiotic commensal manner [16]. In fact, it has been demonstrated that the intestinal microbiota has a vast positive impact on host intestinal physiology by: 1) stimulating innate immune response [17]; 2) inducing proliferation and renewal of intestinal ECs [18], [19]; 3) preventing the overgrowth of pathogenic microorganisms [20]; 4) metabolizing non-digestible carbohydrates leading to the production of short-chain fatty acids such as butyrate (which can be used as an energy source by the host) [21]; 5) synthesizing vitamins [22]; and 6) metabolizing xenobiotics [23]. The human intestinal microbiota is dominated by two bacterial phyla: Firmicutes (60–80%) and Bacteroidetes (20–40%) [24]. Small proportions (≤1%) of other bacterial phyla are also present including Actinobacteria, Proteobacteria and Verrucomicrobia and one Archaea phylum (Euryarchaeota) [8], [24], [25], [26], [27]. Although there is considerable similarity between both human and rodent intestinal microbiota at the phylum level, at lower taxonomic ranks there are significant differences e.g. many bacterial genera and species found in mice are not seen in humans [24].

Each segment of the human intestine has specific physiological functions [27]. As a consequence, parameters like pH, oxygen and nutrient levels and also distribution of intestinal ECs differ between each of those segments. For this reason, both diversity and abundance of microbiota is different along the length of the intestine, and even along the length of the crypt-villus unit, going from 103 bacteria/g in the duodenum, to 104 bacteria/g in the jejunum, to 107 bacteria/g in the ileum and to 1012 bacteria/g in the colon [25]. Concerning diversity, the duodenum, jejunum and ileum are mainly enriched in Firmicutes (Lactobacillaceae family), Proteobacteria (Enterobacteriaceae family) and Actinobacteria (Bifidobacterium and Collinsella genus) whereas the colon is mainly enriched in Bacteroidetes (Bacteroidaceae, Prevotellaceae and Rikenellaceae families), Firmicutes (Lachnospiraceae and Ruminococcaceae families and Clostridium genus) and Verrucomicrobia [25], [27]. Interestingly, the top of the intestinal crypt-villus units is usually dominated by Firmicutes whereas the bottom is dominated by Proteobacteria [25].

Consumption of HFD, particularly when strongly enriched in saturated fatty acids, is one of the main factors contributing to the development of obesity [28], [29]. Human and animal studies have shown that both HFD and obesity are associated with changes in intestinal microbiota and that this community has a major impact on both immunological and metabolic functions of the host [30], [31], [32], [33]. HFD have been reported to reduce the levels of gram-positive and gram-negative bacteria and to increase LPS concentrations in colonic epithelia. This latter event was found to be associated with impairments in colonic epithelial integrity and barrier function, e.g. an increase in permeability, a decrease in mucus layer thickness and an increase in pro-inflammatory cytokines secretion, with subsequent development of systemic inflammation, obesity, insulin resistance and type 2 diabetes [9], [31], [32], [33]. Since the effect of HFD on intestinal microbiota and their impact on the colon physiology have already been well described, we aimed to review the current knowledge about HFD-induced changes on microbiota profile before and after the onset of obesity and its metabolic complications, and how this impacts small intestinal physiology (where both digestion and absorption of fats occur [25]).

Section snippets

Changes in intestinal microbiota associated with HFD and obesity

Studies in mice and humans have shown that obesity is associated with changes in microbiota's diversity and abundance (obesity-associated dysbiosis) at intestinal level (reviewed by Refs. [25], [26]). In fact, a 50% reduction in the abundance of Bacteroidetes and a proportional increase in the abundance of Firmicutes was observed in the colonic microbiota of obese mice [24] and humans [34], [35], [36], these changes being restored following weight loss [35]. One potential explanation for this

Effect of high fat diet on microbiota profile and small intestinal physiology before the onset of obesity and its metabolic complications

Very few studies have described the impact of HFD on microbiota profile and small intestinal physiology before the onset of HFD-induced obesity and associated metabolic complications (i.e. insulin resistance and glucose intolerance) (Table 1). Feeding high or low aerobic fitness rats with HFD (45% kcal from fat) for 3 days was associated with changes in colonic microbiota profile marked by an increase in abundance of Porphyromonadaceae family, specifically Parabacteroides genus, and a decrease

Effect of high fat diet on microbiota profile and small intestinal physiology after the onset of obesity and its metabolic complications

The majority of studies describing the impact of HFD on microbiota profile and small intestinal physiology were performed after the onset of obesity and its metabolic complications: insulin resistance, hyperglycemia, systemic inflammation and/or dyslipidemia (Table 2, Table 3). Cani et al. [31] observed that mice given HFD (72% kcal from fat) during 4 weeks, developed obesity, insulin resistance and adipose tissue inflammation. These changes were associated with: 1) a reduction in colonic

Conclusions and perspectives

Modulation of the intestinal microbiota by HFD has a major impact on both immunological and metabolic functions of the host. Before the onset of obesity, HFD induces intestinal dysbiosis - encompassing changes in composition balance and massive redistribution with bacteria occupying intervillous spaces and crypts - associated with early physiopathological alterations such as low-grade inflammation, impaired mucus production and secretion, and decreased expression of tight junction proteins.

Conflict of interests

The authors declare that they have no conflict of interest.

Acknowledgments

This work was supported by the European Union Seventh Framework Programme [FP7-2007-2013] under grant agreement n° HEALTH-F2-2013-602222 “Targeting novel lipid pathways for treatment of cardiovascular disease” (Athero-Flux) and Assu 2000/Euro-Assurance.

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