Dietary Fibre, Gut Microbiome and Genetic Variability: History
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Contributor:
Guilherme Ramos Meyers
,
Hanen Samouda
,
Torsten Bohn

Dietary fibre (DF) and associated compounds are metabolized by the gut microbiota and their resulting metabolites, especially short-chain fatty acids (SCFA), were significantly associated with health beneficial effects. However, SCFA metabolic pathways are not fully understood.  As dietary patterns do not affect all individuals equally, the host genetic makeup may play a role in the metabolic fate of these metabolites, in addition to other factors that might influence the microbiota. 

  • nutrigenetics
  • nutrigenomics
  • dietary fibre
  • short chain fatty acids
  • holobiont
  • personalized nutrition

1. Introduction

The human organism is composed of eukaryotic cells, as well as of an assembly of microbes collectively termed the microbiota, including archaea, bacteria, fungi and eukaryota. These may outnumber human cells, although a 1:1 ratio seems more likely, according to more recent estimates [1]. Regardless of the quantity of genes within individual microbial cells, the microbiome (the whole genome of the microbiota) encompasses over 1000 microbial species. Thus, the microbiome complements the human genome in functionality, such as enhancing digestion or protecting from pathogenic invasion [2][3]. The largest fraction of microbiota is found in the colon, and is termed, together with a smaller fraction residing in the stomach and small intestine, the gut microbiota [4]. Indeed, evolutionary biology proposes an analogous eukaryon-mitochondrion symbiosis that occurred between multicellular eukaryotes and prokaryotes millions of years ago, the so-called holobiont theory [2].
Evidence is mounting that the gut microbiota (GM) plays a fundamental role in regulating metabolic, immune and endocrine functions, as well as priming the immune response against pathogens. Indeed, GM alterations such as total abundance of or ratios between different species or families have been associated with many different health issues [5], specifically those of non-communicable chronic diseases (NCDs) such as obesity [6], cardiovascular disease and atherosclerosis [7], type 2 diabetes (T2D) [6][8], autoimmune disorders such as rheumatoid arthritis [9], ageing conditions, e.g., osteoporosis and sarcopenia [10], neurodegenerative diseases [11][12] including Parkinson’s [13] and Alzheimer’s disease [14], as well as several types of cancer [15][16]. In addition to GM changes, the majority of these conditions is characterized by a low-grade chronic inflammation [17][18][19][20], concurring with increased levels of oxidative stress [21][22].
Research has highlighted the significant and strong relationship between dietary patterns and the development of NCDs, such as CVD, depression, cognitive decline, multiple sclerosis, Parkinson’s disease, osteoarthritis and gastrointestinal conditions such as irritable bowel syndrome (IBD) [7][23][24][25][26][27][28][29][30][31][32][33][34], with much attention being dedicated to dietary fibre (DF) [35]. Overall, a higher DF intake has been associated with reduced all-cause mortality, e.g., in the Asian population [27], and hypotheses on its role as a health protective factor have been existing for several decades [36]. Studies have demonstrated improved health outcomes with higher fiber intake in conditions ranging from C. difficile infection [37] to paediatric kidney disease [38], showing its wide applicability in health maintenance. Regrettably, in most countries, it appears that DF intake has been on the decline. In Japan, where data are available since the 1950s, a 30% drop in DF intake was observed between the 1950s and 1970s, and then stabilized—though this may be subject to change, as younger generations report far less DF intake than their elders [39]. A review by the Nutrition Society [40], as assessed by national surveys in the UK, revealed a DF intake of approximately 14.8 g/d in adults, men and women, in 1999 [41], and about 13.6 g/d in 2009–2012 [42]. In the USA, DF intakes remained stable from 1999 to 2008, but well below recommendations, at around 15 g/d [43]. Concurrently, the highest consumption of DF in Europe was found in Germany (25 g/d for males and 23 g/d for females), based on a telephone-survey performed in 2005–2006 [40], being in line with EFSA recommendations.
DF may be at the centre of the symbiotic relationship between the GM and the human host [35][44][45][46][47][48][49]. DF is not absorbed or broken down to a significant degree by human digestive enzymes, and can, at least in part, be used as an energy substrate by the GM. Depending on the nature of DF, it is predominantly metabolized into short chain fatty acids (SCFA), including butyrate, acetate, and propionate [44]. Butyrate, acetate and propionate cross the enterocyte layer and are absorbed, while lactate and succinate appear to be intermediate products of DF fermentation [50]. Immediately, butyrate acts as the main energy source for colonocytes and controls maturation of mucosa associated lymphoid tissue (MALT) [51][52][53][54][55][56][57][58][59][60][61][62][63], characterized by a high presence of immune cells such as macrophages, B and T cells and that plays an important role in antigen sensing. Only a fraction of the produced SCFA enter the host’s systemic circulation, with acetate corresponding to around 75% of total peripheral SCFA [64][65]. However, these values have shown a high degree of inter-individual variation, as well as intra-individual variation such as dose–response, time-course and circadian variance [66]. SCFA may act as pleiotropic immunomodulators, i.e., having different functions in different tissues [35][51][67]. SCFA appear to be strong influencers of immune regulation, as seen in studies regarding asthma and atopy in infants, as well as in mice models [68][69][70][71][72], or gastrointestinal health in adults [35][48][51][52][73][74][75]. As described in the following chapters, SCFA production and concentrations were associated with disease risk. In addition to SCFA, DF acts as a vehicle for antioxidants in the upper gastrointestinal tract [76][77], as it is associated with a large number of phenolic compounds [44][78][79][80][81] and other secondary plant metabolites such as carotenoids [44][80]. Especially phenolic compounds may likewise be turned into bioactive metabolites by the GM [77][82], and synergies between these food derived compounds may exist, further highlighting their importance [83][84][85][86][87].
Apart from drugs, age, delivery method, medication intake, alcohol and tobacco consumption, pathogen exposure, besides diet in general, and dietary secondary plant metabolites in particular, are known to be significant modulators of the GM [44][88][89][90][91][92][93][94]. Dietary antioxidants can alter GM composition and thus its products [95]. However, the genetic background also modulates bacterial colonization [3][96]. In particular, genetic variants such as single nucleotide polymorphisms (SNPs), may further explain some of the inter-personal variability observed following fibre intake, such as circulating levels of SCFA [53][72][97][98]. Variations in genes such as GPR41, GPR43 or GPR109A (G-protein coupled receptors for SCFA) [99] could have substantial impact on the immunometabolism of certain tissues in particular, and the organism in general. Furthermore, transporter genes of the SLC16A family (monocarbohydrate transporters), effector genes such as MUC2 (for mucus layer production in the colon) or regulatory genes such as NRF2 (regulating the expression of proteins involved in the bodies’ antioxidant defence mechanism such as superoxide dismutase (SOD)), could have important downstream effects on health outcomes (Figure 1) due to impaired absorption of SCFA or by impacting their functions intracellularly [100].
Nutrients 14 05361 g001
Figure 1. Host-driven variability in SCFA metabolism and distribution may lead to different disease outcomes. ADME (sub-) steps may explain the variability in SCFA effects. The enterotype influences the amount of SCFA produced, while human digestive enzymatic activity may regulate microbial communities; (1) Absorption: SNPs in mucin, MCTs or tight junction function could impair SCFA bioavailability. Butyrate is the main energy source for colonocytes. (2) In the portal circulation SCFA undergo first-pass effects, where a majority of propionate is metabolized via GPR109A, GPR43 and GPR41, having gluconeogenic or lipogenic effects. Distribution In the systemic circulation: although at present at low concentrations, butyrate and propionate are still detectable; acetate is now the most abundant SCFA. (3) Acetate inhibits lipolysis at the adipose tissue level. (4) Acetate can cross the “blood-brain-barrier” (BBB). Metabolism: SCFA have showed to be effective against microglial oxidative stress responses. SCFA may also have cellular signalling properties, as evidenced by its control of centrally released insulin (6) or its impact on the hypothalamic-pituitary-adrenal axis in leptin and cortisol responses, which may ultimately lead into maladaptive health conditions across the body (7). Finally, gluconeogenic, lipogenic and insulinogenic signals impact ghrelin, leptin and peptide YY release, leading to appetite suppression and satiety (8), improved insulin sensitivity and glucose metabolism, as well as reduction of serum lipids. (9) Excretion: in the kidney, SCFA can be re-absorbed by MCT1. Note: the intracellular effect of SCFA e.g., on HDAC or NF-κB are not displayed. Created with BioRender.com.

2. Dietary Fibre and Short Chain Fatty Acids

2.1. Dietary Fibre (DF)

Westernized types of diet are characterized by a relatively low intake in DF, despite attempts to increase its intake since the 1970s. Most European countries have established recommendations on daily intake for DF, e.g., 25–35 g for adults. Concretely, 25–32 g/d for adult women and 30–35 g/d for adult men, while recommendations for children and older adults depend on age, being approximately 3–4 g/MJ [40]. The Physicians Committee for Responsible Medicine (PCRM) of the US recommends even a considerably higher intake of 40 g/d for an optimal health [101].
The European Food Security Authority (EFSA) has recommended an adequate intake (AI) of 25 g/d for DF, mostly based on its association with improved bowel function (as per defecation frequency and transit time), and the reduction of gastro-intestinal symptoms such as constipation [102]. DF refers to total fibre occurring naturally in foods such as fruits, vegetables, pulses and cereal grains [40][102]. Grain products are at present the largest source for DF intake worldwide, providing approx. 32% of total dietary fibre intake in the USA and 48% in the Netherlands. Other sources vary widely in European countries, e.g., vegetables (12–21%), potatoes (6–19%) and fruits (8–23%) [40]. Lack of DF intake has been emphasized as one of the major dietary factors associated with the increased incidence of NCDs [103][104][105][106]. A recent systematic review and meta-analysis suggested that high DF consumption was associated with a 15–30% decrease in cardiovascular-related mortality, T2D and colorectal cancer, when compared with low-fibre consumption [107]. Concurring dietary factors such as increased sugar consumption, increased saturated fat consumption and low nutrient density, among others, and their possible relationship to metabolic and neurophysiological disorders, may be present and are expected to play a role [40][108]. However, as human lifespan has expanded during the past decades [109][110], researchers expect to face an increase of NCDs, as these are rather associated with age-related chronic inflammation (i.e., inflammageing [18]). Therefore, it is paramount to fully understand the pathophysiology of NCDs, and how to counteract them with affordable and efficient strategies, including improved dietary patterns and healthy food items [18][110][111][112][113][114][115][116][117]. In this respect, fiber intake could be increased both within a low-fat diet a low-carbohydrate diet. A randomized controlled trial aiming at weight reduction over a period of 12 months assessed sources of DF in a balanced low-fat diet vs. a balanced low-carbohydrate diet. A large proportion of DF for both diets was from non-starchy vegetables. While the low-fat group mainly increased DF intake from whole grains and fruits, the low-carbohydrate one obtained DF rather from vegetables and plant protein sources. This was further reflected in gut microbiota alterations throughout the intervention, and such dietary adaptations may constitute an important factor for precision nutrition [118].
A variety of definitions has been proposed to classify DF; most were dependent on the methods used to extract DF. This led to difficulties in defining the term, as most non-starch polysaccharides (NSP) were retrieved by such methods, which often did not include resistant (i.e., non-digestible) starches (RS). DF can further be categorized based on its solubility, fermentability or viscosity, which often caused distinctions within the group. While soluble fibres can be fermented to different degrees, and are the main substrate for colonic fermenters (e.g., β-glucans), insoluble fibres mainly serve a stool bulking function (e.g., cellulose). Both types of DF have beneficial health properties, and as such, the dichotomy of soluble-insoluble may no longer play a main role in terms of public health.
To date, definitions have reached a certain consensus [119][120]. DF is composed of carbohydrate polymers with three or more monomeric units (MU), which are neither hydrolysed by human digestive enzymes nor absorbed in the human intestine, and include NSPs from fruits, vegetables, grains and tubers, whether intrinsic or extracted, either chemically, enzymatically, or in physically modified forms. Polymers with more than 10 MU, e.g., cellulose, hemicelluloses, pectins, hydrocolloids (i.e., gums, β-glucans, mucilages); resistant oligosaccharides, e.g., fructo-oligosaccharides (FOS), galacto-saccharides (GOS) with 3–9 MU; and RS with 10 or more MU [40] are included. Furthermore, some constituents produced by micro-organisms (e.g., xanthan) and polysaccharide constituents of crustaceans and fungi (e.g., chitin, chitosan, chondroitin sulphate), are resistant to digestion and are included in the DF definition, according to some national agencies [40]. Furthermore, it has been proposed that proteins resistant to digestion exist, and may reproduce similar effects as DF, namely improved bowel function and improved immunity [121][122][123], but these are typically not included in the DF definition.
Thus, DF is any polymeric carbohydrate not digested in the small intestine. DF generally also includes substances associated with, or linked to plant cell walls, but that are not carbohydrates, such as lignin or polyphenols. Often, these distinctions are not reported in food tables, where only the sum of DF is given. In 2002, the French Agency for Food Security (ANSES), included in its definition all of the above polymeric carbohydrates (MU ≥ 3) as DF, while excluding animal-based sources and lactulose, a non-absorbable sugar, to prevent its incorporation into foods (as it is a strong laxative) as a fibre source [124].
Within this manuscript, DF is considered as any polymeric compound, which is not digestible by human enzymes and which mainly travels through the gut to reach the colonic milieu, where it is either fermented by colonic bacteria (i.e., broadly, soluble fibres) into smaller molecules such SCFA, or can act as a bulking agent during stool production (i.e., generally insoluble fibres). This broader definition would thus also include non-carbohydrate compounds such as lignin and resistant proteins, as well as compounds associated with plant-based carbohydrates, such as polyphenols. These compounds may also be substrates for bacteria, such as Akkermansia, Lactobacillus and Bifidobacterium, which produce metabolites such as SCFA, which in turn induce various beneficial effects on the host, including reduction in: appetite, insulin resistance, lipid accumulation, and inflammation [100]. However, the effects of phytochemicals are likely to vary according to the composition of the gut microbiota and host genetic polymorphisms, which affect absorption, detoxification, and overall bioactivities [125]. One such example is equol, produced form the isoflavone daidzein, which may bind to β-oestrogen receptors, and has been associated with the incidence of various types of hormone-associated cancers [126]. This is in line with the definition proposed by Jones [127], and may overcome the matter of “functionality” often discussed regarding DF, as previously pointed out [128].
Fibre fermentation relies on its chemical and physical structure, as well as the composition of the colonic microflora. Digestion of DF by the GM may vary or fluctuate depending on which fibres are consumed, and thus the amounts of SCFA produced too. For example, lignin and cellulose are rather lost through the stool, being insoluble bulking fibres; polysaccharides from extremely hard plant tissue areas are also less well digestible because physical encrustation and chemical bonding to lignin can occur [46]. Oligosaccharides, RS and pectins are the DF compounds thought to contribute the most to SCFA production in the colon [35].

2.2. Short Chain Fatty Acids (SCFA)

Recent studies on DF, GM and probiotics have emphasized the role of SCFA. Indeed, SCFA may be a good example of microbiota-derived modulator molecules, i.e., a nutrient that can modulate the host, acting as communicating molecules between the GM and the host [66]. Provided that SCFA metabolism may have a broad range of implications for human health, many studies are being conducted to understand their effects (Table 1). Sakata [66] recently pointed out relevant pitfalls in the study of these molecules. SCFA are defined as volatile fatty acids with a skeleton of six or less carbons in straight (C1, formate; C2, acetate; C3, propionate; C4, butyrate; C5, valerate; C6, caproate), or branched-chain conformation (C4, isobutyrate; C5, isovalerate and 2-methyl-butanoate). Acetate (C2), propionate (C3) and butyrate (C4) amount for 90–95% of total GM SCFA output and are derived from carbohydrate fermentation [129][130]. Until recently, caproate [131] and valerate [132] were considered dietary food components. However, recent studies have demonstrated that these may also be GM products, with caproate being significantly increased in faecal samples of volunteers with severe obesity (BMI ≥ 40) [131].
Branched-chain SCFA (BCFA), mainly isobutyrate, isovalerate and 2-methylbutanoate, contribute to as much as 5% of total SCFA production, and arise from the metabolism of the amino acids valine, leucine, and isoleucine, respectively [129][131]. BCFA levels in faecal samples show an inverse correlation with fibre consumption, especially insoluble fibre [131][133]. BCFA levels in stool have also been related to depression [32][34] and other psychiatric conditions [134], possibly through vagal afferent nerve signalling [135]. Furthermore, BCFA were found to be increased in subjects with hypercholesterolemia compared to normocholesterolemic individuals, with isobutyrate being associated with worse serum lipid profiles [136]. It is likely that such elevated BCFA correspond to high protein intake, such as from meat-based diet and a reduced DF intake, which are likewise associated with negative health outcomes and ageing related health complications [131].
Recently, products of DF fermentation have been termed post-biotics [137]. In human adults, the principal products of DF fermentation are SCFA together with certain gases (CO2, CH4, and H2), which may be taken up by the host, or excreted [50]. Production of SCFA in the colon accompanies the bacterial consumption of ammonia, H2S and BCFA in the synthesis of protein components for the microbial cell. Therefore, the reduction of these metabolites may also be, at least in part, responsible for the health benefits attributed to SCFA [66], as in addition to BCFA also ammonia [138] has been related to negative health outcomes such as neurotoxicity and hepatotoxicity, as well as increased intestinal permeability, loss of tight junction proteins and increase in pro-inflammatory cytokines as found in animal studies [139]. H2S, hydrogen disulphide, may be associated with neurological, cardiovascular and metabolic diseases, when abnormally produced [140].
In this research, SCFA describes, “saturated unbranched alkyl group monocarboxylic acids of 2 to 4 carbon atoms”, referring to acetate (C2), propionate (C3) and butyrate (C4). Researchers will briefly mention valerate (C5) and caproate (C6). It excludes BCFA, as well as succinate and lactate, which are rather intermediate products in GM metabolism, and therefore their concentrations in human serum are related rather to human metabolism, and not influenced considerably by GM or intestinal absorption.
Table 1. Identified effects of SCFA in human interventional, observational, and animal studies.
SCFA Study (Sample) Study Design Tissues Investigated End-Point Measured Observed Effects Reference
Human interventional studies
C2 H (n =32) Case-control Peripheral blood Immunopharmacological effects of Ringer’s acetate Increased polyclonal antibody production and NK cell activity in healthy and cancer subjects [141]
C3 H (n = 6) Cross-over Serum and stool Blood lipids and glucose, stool bulk and microbiota C3 supplementation lowers blood glucose. Lipid changes not significant; increase in stool bulk and Bifidobacteria after 1 week intervention [142]
C4 H (n = 16) Cross-over Sigmoid colon biopsies and plasma Oxidative stress markers in colon; CRP, calprotectin; histological inflammation Rectal administration significantly reduced uric acid and increased GSH. No significant changes in other parameters [143]
Human Observational studies
C2-C6 H (n = 232) Observation Stool Levels of faecal SCFA and BCFA association with BMI and age BCFA strongly correlated with age, but not with BMI;
BCFA negatively associated with fibre consumption;
BMI ≥ 40 showed significantly higher production of SCFA, total BCFA, isobutyrate, isovalerate and caproate
SCFA production decreases with age		 [131]
Animal (interventional) studies
C2, C3 M (n = 15) Knock-out Adipose tissue Effects of GPCR43 activation Reduction of lipolysis, reduced plasma free fatty acids levels without flushing associated with GPCR109A [144]
C2, C3 M (n = 12) Case-control Adipose, gut, vascular and mesenchymal tissues GPCR41 and GPCR43 mRNA expression GPCR43 activation promoted adipose differentiation via PPARγ2. No effects on GPCR41 [145]
C2, C3, C4 S (n = 10) Case-control Portal and peripheral blood, liver Food intake following SCFA infusions Dose-dependent depression in food intake, explained by C3 content in portal vein, which resolved with portal plexus denervation [146]
C3 R (n = 20)
P (n = 12, 60)		 Case-control Portal blood and liver Cholesterol synthesis and distribution Supplemented C3 likely absorbed in the stomach
Dose-dependent hypocholesterolemic effect likely due to redistribution of cholesterol from plasma to liver, as opposed to synthesis inhibition		 [147][148]
C3 R (n = 74, 114) Case-control Brain, intracerebral ventricles Behavioural, electrophysiological, neuropathological, and biochemical effects C3 intraventricular infusion impaired social behaviours, similar to those seen in human ASD; induced neuroinflammation and oxidative stress; Alteration of brain phospholipid and acylcarnitine1 profiles [149][150]
C4 R (n = 22) Case-control Duodenum, jejunum, cecum and distal colon PYY and proglucagon gene expression in gut epithelial cells Up-regulation of local peptide YY and proglucagon expression via colonocyte sensing following a RS diet in vivo, proved by in vitro incubation with butyrate [151]
C4 M (n = 16–20) Case-control Whole-body autopsy Insulin sensitivity and energy metabolism, mitochondrial function C4 supplementation prevented diet-induced insulin resistance and reduced adiposity in high-fat model, without reducing food intake. Attributed to enhanced mitochondrial activity and thermogenesis [152]
In Vitro Studies
C2-C6 M (n = 18) N/A mouse adipocyte cell line and adipose primary culture Leptin expression C2-C6 stimulate leptin expression via GPCR41
Acute administration of C3 increased leptin levels		 [153]
C2, C4 R, B N/A Anterior pituitary, fat and liver aspirates Leptin and leptin-receptor protein expression C2 and C4 enhanced leptin expression in bovine pituitary and fat cells, however C4 inhibited leptin expression in rat anterior pituitary cells; while C4 suppressed leptin receptor expression in both rat and bovine pituitaries; probable species specific nutrient sensing [154]
C2, C3, C4 R, H N/A Colonic stimulation Effects on colon functions, inc. motility C3 and C4 induced phasic and tonic contractions of circular muscle via GPCR41 and GPCR43 in mucosae, C2 did not [155]
C2, C3, C4 M (n= 4)
H (n= 3)		 N/A Human blood samples, colon cultures (colo320DM) and mice with colitis Anti-inflammatory properties of SCFA All SCFA decreased neutrophil TNF-α release without affecting IL-8; all decreased IL-6 release; all inhibited NF-κB activity in colon cells; C4 > C3 > C2 [156]
C3 H (n = 5–9) N/A Human umbilical vein endothelial cells (HUVEC) Expression of endothelial leukocyte adhesion molecules and leukocyte recruitment by cytokine-stimulation Significant inhibition of TNF-α and NF-κB, reducing expression of VCAM-1 and ICAM-1 in a time- and dose-dependent manner; significantly increased PPARα expression [157]
C3 H (n = 28) N/A Omental and subcutaneous adipose tissue Adipokine expression Significant leptin induction and secretion; no effect on adiponectin; Reduction of resistin mRNA expression [158]
C3 R, H (n = 1) N/A Human blood and rat mesenteric lymph nodes T and B lymphocyte proliferation and metabolism Inhibition of lipid synthesis as a possible mechanism leading to reduction of lymphocyte proliferation [159]
C3 R (n = 9) N/A Isolated hepatocytes Hepatic lipidogenesis Inhibits hepatic cholesterol and fatty acid synthesis in a dose-dependent manner, possibly by competition with C2 [160]
ASD, autism spectrum disorder; B, bovine; H, human,; M, mice; P, pigs; R, rat; S, sheep; C2, acetate; C3, propionate; C4, butyrate; C5, valerate; C6, caproate; HUVEC, human umbilical vein endothelial cells; TNF-α, tumour necrosis factor alpha; VCAM-1, vascular cell adhesion molecule-1; ICAM-1, intracellular adhesion molecule-1; RS, resistant starch; GSH, glutathione peroxidase; PYY, peptide YY; SCFA, short chain fatty acids; BCFA, branched-chain fatty acids; BMI, body mass index; GPCR, G-protein coupled receptor; TNF-α, tumour necrosis factor alpha; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells N/A, not applicable.

This entry is adapted from the peer-reviewed paper 10.3390/nu14245361

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