Molecular Impact of Dietary Fibre Metabolites on Intestinal Immunity of Host

Abstract

Food contains several components that are essential for health. Dietary fibres are nondigestible foods that play an important role in the maintenance of health. Nondigestible carbohydrates are an important constituent of the diet. Intestinal immunity is the bedrock of host health and holistic health maintained by nutrition and the existence of the host supported by immunity. The gastrointestinal immune barrier is exposed to the environment or food, and immunity is maintained by several factors. Dietary fibres exert molecular effects through the production of short-chain fatty acids (SCFAs) and gut microbiota. Dietary fibres and microbial communities secrete metabolites that have the potential to regulate intestinal immunity. The gastrointestinal immune barrier is a primary target for dietary fibre metabolites, and these molecules exert a signalling effect on immune cells in the intestine. In the proposed chapter, we will discuss the molecular impact of dietary fibers on intestinal immunity and how innate immune response and gut microbiota are regulated by metabolites.

1. Introduction

In addition to maintaining human growth, fertility, and health, the diet is also essential to modulating and supporting the symbiotic microbiota and the microbial communities that inhabit the digestive tract. Our gut harbors trillions of microbes that play a significant role in datary fiber metabolism. The gut microbiome modulates maturation of the immune system [1], glucose and lipid metabolism [2], and juvenile growth [3]. The microbial diversity in the gut depends on the intake of dietary fibers [4] and any alteration of dietary intake of fibres may result in dysfunction of the gut and the development of chronic inflammatory diseases like intestinal bowel disease (IBD), autoimmune diseases, colorectal cancer (CRC), and allergies. The gut microbiome is affected by diet, which in turn affects the immune system. We wondered whether the results of the high-fiber diet intervention may have coincidentally impacted participants’ immune systems because the microbiota of the group differed. Here we will discuss how dietary fiber impacts gut microbial ecology, host physiology, and health by specifically focusing on the molecular impact of dietary fiber metabolites on intestinal immunity

Here, we specifically discuss the effects of the gut microbiota on immunometabolism, and more precisely, on the intracellular metabolism of immune cells, in health and the potential consequences in diseases. In this chapter, emphasis is placed on the effects of dietary fiber metabolites as prime signaling molecules, through different signaling pathways and their link between gut microbiota and host health.

2. Dietary fibers and their metabolites in molecular function

Dietary habits, dietary patterns, and lifestyles determine the presence of different microbial species [5]. In addition to modulating the gut microbiota composition, dietary fibers directly influence biological processes and homeostasis via the metabolites that are a result of microbial fermentation of nutrients, such as short-chain unsaturated fats (SCFAs) [6]. The gut microbiota is vital for the metabolization of DFs, such as nondigestible carbohydrates (NDCs), proteins, and peptides, which have escaped digestion by host enzymes in the upper gut and have been absorbed in the lower digestive tract [7], which are known to have beneficial effects by behaving as signaling molecules via different pathways. Acetate is the most abundant SCFA produced, and it is used by many gut commensals to produce propionate and butyrate in a growth-promoting cross-feeding process. In addition, SCFA has been shown to regulate metabolic activity. Acetate affects the metabolic pathway via the G protein-coupled receptor (GPCR) and free fatty acid receptor 2 (FFAR2/GPR43), while butyrate and propionate transactivate peroxisome proliferator-activated receptors (PPAR/NR1C3) and regulate Angptl4 in colonic cells. FFAR2 regulates insulin-induced lipid accumulation in adipocytes and inflammation, while peptide tyrosine-tyrosine and glucagon-like peptide 1 control appetite. Microbiota-dependent NDCs regulate glucose homeostasis, gut integrity, and hormones via GPCR, NF-kB, and AMPK.

Dietary fibers are metabolized by the microbiota in the cecum and colon resulting in the formation of major products, such as acetate (C2), propionate (C3), and butyrate (C4) SCFAs. Acetate is a major SCFA metabolite produced from pyruvate. Propionate (C3) is created when succinate is converted to methylmalonyl-CoA through the succinate pathway. Through the classical pathway, butyrate is produced by the condensation of two molecules of acetyl-CoA and their subsequent reduction to butyryl-CoA. Butyrate is then converted to butyrate by phosphorus butyrylase and butyrate kinase [8].

3. Intestinal immunity

The SCFAs activate different G-protein-coupled receptors (GPCR) e.g. propionate (C2), which is an activator of GPR43. The expression of GPR43 has been reported in the entire gastrointestinal tract including the cells of both the nervous and immune systems. In the GI tract, GPR43 is significantly expressed in endocrine L-cells of the ileum and colon of intestinal, PYY, and GLP-1 producing cells, as well as on colonocytes and enterocytes [9], that maintains the immunity and function of the intestine [10].

4. Immunity and fiber in the diet

The share of CD4+ and CD8+ T-cells in GALT, as well as their in vitro responsiveness to mitogens, were considerably affected by the diet’s fiber intake. There was a bigger proportion of CD8+ T-cells in the IEL, lamina propria, and Peyer’s patches after consuming the high fermentable fiber diet, as well as a higher proportion of CD4+ T-cells in the mesenteric lymph nodes and peripheral blood except for a higher CD4:CD8 ratio [11, 12].

In the upper gastrointestinal system, prebiotic fiber is neither hydrolyzed nor absorbed, but instead assists as a selective substrate for one or a small number of beneficial colonic bacteria, modifying the gut microbiota. There is significant proof that prebiotic fibers (inulin and oligofructose) boost the percentage of good lactic acid bacteria in the human colon [13].

To yet, the mechanism(s) through which probiotics in the diet alter immune function has primarily been hypothetical. Immune activation via uninterrupted contact of the intestinal microbiota with GALT is one logical method. Small amounts of bacteria can pass through the intestinal epithelial barrier and into Peyer’s patches, affecting or contributing to the activation of other immune cells [14]. The production of TNF-α and IL-6 by macrophages, as well as the production of IL-2 and IL-5 by stimulated CD4+ cells, was dramatically boosted by coculture with bifidobacteria [15].

5. Short-chain fatty acids (SCFAs) are produced by fermentation of fiber

Through the fermentation of food fibers to SCFA, the gut microbiota may influence immune cells. Increased natural killer cell activity is an outcome of SCFA. SCFA has also been presented to have anti-inflammatory properties in other investigations. In the colonic cell line HT-29, butyrate was found to decrease both constitutive and cytokine-induced production of the transcription factor NFkB [13].

Finally, SCFA generation in the colon, particularly butyrate, may lessen the glutamine need of epithelial cells, freeing it up for other cells such as immune system cells. The fact that lactulose injection can raise serum glutamine levels, and glutamine is a vital energy source for immune cells, which supports this notion [16].

The addition of fermentable fibers to the diet has been shown to boost mucin synthesis. The reduced incidence of bacterial translocation across the intestinal barrier observed in studies feeding dietary fibers could be due to increased mucin synthesis. The increased mucin formation may be due to the lower pH associated with SCFA production.

6. The effect of dietary fiber on the immune system of the gut

Carbohydrate polymers naturally occur in edible plants and are used up as vegetables, fruits, seeds, cereals, and tubers. Dietary fibers travel from the small to the large intestine, where they perform a physiological role. Fibers consist of two types soluble and insoluble. Soluble fibers undergo total fermentation in the colon whereas insoluble fiber undergoes fermentation to some extent. Dietary fiber consists of a range of organic polymers, each of which contains various monomers coupled by different glycosidic linkages, resulting in a complex and heterogeneous structure. Many methods of classifying dietary fiber, such as solubility, viscosity, and fermentability, have been formulated to aid in the correlation of physicochemical features of dietary fiber with their physiological roles. Although particular nutrients are known to play a role in the immune system’s development and function, little is known about the impression of dietary fibers on immunological function. Dietary fiber is essential for good health. Higher dietary fiber consumption is linked to a lower risk of disease and mortality, according to several meta-analyses. Dietary fiber consumption is linked to a higher risk of Western diseases with immune system abnormalities, implying that dietary fiber is vital for immunological homeostasis. The preservation of the gut immune barrier is one direction through which fibers may protect against disease development⁴. The innate immune system that includes physical barriers such as the skin and mucous membranes, cell-mediated barriers such as phagocytic cells, inflammatory cells, dendritic cells, and natural killer cells, and soluble mediators such as cytokines, complement, and acute-phase proteins, delivering immunity to invading organisms without the need for prior exposure to these antigens. During the 4–5 days it takes lymphocytes to become activated, this arm of the immune system supplies the early steps of host defense that safeguard the organism. Macrophages and their precursor monocytes, as well as polymorphonuclear leukocytes (neutrophils), frame the innate immune system’s core cellular component.

The human body’s janitor is the gastrointestinal immunological barrier. It is made up of a mucus layer and an epithelial cell layer that keeps luminal molecules out of the immune-cell-filled lamina propria beneath. Improving intestinal barrier function by increasing dietary fiber intake could thus be a useful therapy for preventing or delaying Western immune-related illnesses. Moreover, Dietary fibers may interact directly with immunological barrier cells in the small intestine before being destroyed by microbial enzymes in the colon. The small intestine has a thin and loose mucus layer that boosts nutrient absorption while also allowing food compounds like fibers to interact directly with intestinal epithelium and immune cells. The ramifications of these interactions are that the mucus layer is strengthened, epithelial cell barrier function is improved, and intestinal immune responses are modulated as a result of these direct interactions with intestinal immune barrier cells. Dietary fibers’ direct contact with the gut immune system could be one of the processes by which they improve health and prevent disease. Dietary fiber can also have an indirect positive effect on the gastrointestinal immunological barrier by stimulating the proliferation and metabolic activities of gut microbiota communities.

The large intestine holds the place of most populated in terms of microbiota and immune cells. As a result of this research, it is becoming increasingly clear that intestinal metabolism has a significant impact on human physiology. Together with a mucus layer, the vast intestinal layer of specialized epithelial cells joined by tight junction proteins serves as a barrier that separates the host’s mucosa from the luminal environment. Enterocytes, which are in control of nutritional absorption, and goblet cells, which create, store, and exude mucin glycoproteins, are two key cells of the intestinal epithelium. The maximum density of goblet cells can be found here, which in turn leads to a wide range of microbiota and their subsequent conversions into products, and hence, these products lead to a large no. of consequences. SCFAs (short-chain fatty acids) are made mostly by the fermentation of non-digested carbohydrates. This fermentation produces not only the primary SCFAs of acetate, propionate, and butyrate but also lactate, a crucial intermediary in the synthesis of SCFA.

Pectin, a soluble dietary fiber with recognized modulatory effects on the gastrointestinal immunological barrier, is an essential dietary fiber. Because pectins have a positive influence on microbial communities, they may indirectly look after the intestinal barrier by increasing the growth and diversity of microbiota communities. The chemical structure of pectins has an immense impact on these actions. The well-studied prebiotics include inulin, oligofructose, and fructo-oligosaccharide (FOS). All β (2–1) linear fructans with varying degrees of polymerization are referred to as inulin. Inulin is not digestible by digestive enzymes in the small intestine due to the existence of β (2–1) bonds it enters the colon intact, where it is fermented to SCFA and gases by colonic bacteria. The well-studied prebiotics include inulin, oligofructose, and fructo-oligosaccharide (FOS). Moreover, commensal communities stimulated by dietary fiber are important taking into account, intestinal immunity. The microbial community secretes metabolites such as secondary bile acids and tryptophan, which together limit the growth of pathogens.

7. How does gut interaction affect health?

There is a substantial relationship between the intestinal barrier, the gut microbiota, and immune system cells. Increased epithelial permeability, often known as “leaky gut,” permits bacteria, antigens, and toxins from the lumen to the lamina propria to enter the bloodstream, which triggers both local and systemic immune responses. The symbiotic relationship between the gut microbiota and the immune system may be disrupted by an impaired intestinal barrier function, which has been linked to the advancement of illnesses and disorders such as inflammatory bowel disease and irritability. Based on their potential effects, gut bacteria can be categorized into three categories: Lactobacilli and bifidobacteria; potentially dangerous bacteria, such as some clostridia species and other commensal bacteria, such as Bacteroides, which can have both positive and negative characteristics (Figure 1) [18].

Figure 1.

Anatomical structure and composition of the gut barrier. In order of importance, there are four types of barriers: Microbiota barrier, chemical barrier, physical barrier, and immune barrier. Microorganisms, IgA, and antibacterial peptides make up the chemical barrier. It consists of IECs, goblet cells (synthesis of mucins), Paneth cells (synthesis of AMPs), and intestinal stem cells. There are T cells, B cells, macrophages, dendritic cells, and mast cells that form the immune barrier. In this image, the real arrow indicates the route by which SCFAs affect immune cells, whereas the dotted arrow indicates a possible route not described [17].

8. Getting enough fiber diet and how it affects immunity

The share of CD4+ and CD8+ T-cells in GALT, as well as their in vitro responsiveness to mitogens, were considerably affected by the diet’s fiber intake. There was a bigger proportion of CD8+ T-cells in the IEL, lamina propria, and Peyer’s patches after consuming the high fermentable fiber diet, as well as a higher proportion of CD4+ T-cells in the mesenteric lymph nodes and peripheral blood except for a higher CD4:CD8 ratio.

In the upper gastrointestinal system, prebiotic fiber is neither hydrolyzed nor absorbed, but instead assists as a selective substrate for one or a small number of beneficial colonic bacteria, modifying the gut microbiota. There is significant proof that prebiotic fibers (inulin and oligofructose) boost the percentage of good lactic acid bacteria in the human colon (Figure 2).

Figure 2.

The immune barrier of the small intestine consists of colonocytes and goblets [19].

9. Dietary fiber strengthens the gut immune barrier

Pectin is a soluble dietary fiber with known modulatory effects on the gastrointestinal immunological barrier and is a noteworthy dietary fiber. Many fruits and vegetables, together with citrus fruits, apples, sugar beets, and potatoes, have had pectins separated from their primary and secondary cell walls. There are Linear 1,4-Dgalacturonan (homogalacturonan) segments and branching rhamnogalacturonan segments, which make up the majority. The degree of methyl-esterification, molecular weight, and neutral side chain topologies are all features that influence pectin’s functional capabilities [20]. The β-glucan and inulin metabolites also improved intestinal immunity.

10. Integrity of epithelium is preserved by SCFAs

SCFA is produced from fermented dietary fiber either through stimulation of gut microbiota which by pattern recognition receptors such as TLR2. There is no evidence that it enhances epithelial integrity under healthy conditions, but it does maintain epithelial integrity in disease states. By maintaining tight junction structures, it protects the epithelial integrity from agents that disrupt the barrier [21].

11. Conclusion

It has long been known that dietary fiber and its gut microbial metabolite like SCFAs improved metabolism of the host body. Dietary fiber via SCFA increases plasma SCFA levels and improves hepatic metabolic health. Dietary fiber intake produces SCFAs via fermentation in the gut microbiota, mainly in colon L-cells, which produce GLP-1 and PYY located mainly in the distal ileum and colon. Fiber intake suppressed the HFD-induced liver weight gain and hepatic TG accumulation along with a change in hepatic lipid metabolism, while dietary SCFA intake improved hepatic metabolic conditions by activating FFAR3. A shift in gut microbiome production of butanoate accompanied by up-regulation of microbiota and AMP-activated protein kinase (AMPK)-dependent gene expression contributes to intestinal integrity and homeostasis by influencing metabolism and transporter expression.

Conflict of interest

The authors declare no competing interest.

Notes/thanks/other declarations

We would like to acknowledge the Director, ICAR-National Dairy Research Institute, Karnal-132,001, Haryana, India.