Exploring the effects of dietary fibre on gut microbiome and inflammatory diseases

Authors: Feng Zhang, Dejun Fan, Jian-lin Huang, Tao Zuo

Link to Research: The gut microbiome: linking dietary fiber to inflammatory diseases – ScienceDirect

Link to Media Release: Exploring the effects of dietary fiber on gut microbiome and inflammatory diseases (news-medical.net)

Abstract

Dietary fiber intake in humans is nowadays substantially decreased as compared to the communities of ancestral populations. Accompanying that, the incidences of inflammatory bowel disease (IBD), allergy, and other autoimmune diseases are steadily increasing over the past 60 years, especially in high-income countries, which is partly attributed to the changing dietary habit in modern societies. Chronic inflammation triggered by immune disorders is the central part of the pathophysiology of various non-communicable diseases. Dietary fiber intake is inexorably linked to the gut microbiome leading to the reduction of inflammation. This review explores how dietary fibers modulate the gut microbiota composition and function leading to the alteration of host physiology. High-fiber dietary regime has been consistently shown to increase the microbiome alpha diversity and short-chain fatty acids (SCFAs)-producing bacteria in the human gut. SCFAs are the main players in the interplay between diet, microbiota, and host health. In clinical settings, therapies with high fiber or SCFA supplementations are proposed for inflammatory diseases. However, due to greater variations in the dosage, type, and duration of dietary fiber intervention in different clinical trials, the effects remain controversial. Unraveling the mechanisms exerted by dietary fiber in synergy with the gut microbiome in human pathophysiology holds a promising prospect in guiding next-generation precision therapies.

1. Introduction

Diet is one of the environmental factors shaping the gut microbiome of individuals in humans [[1], [2], [3]], while exercise [4,5], age [6], smoking [7], and antibiotic use [[8], [9], [10]] also have significant effects. Dietary fiber is universally accepted as a health-promoting and nutritionally important ingredient. Due to the emergence and rise of western diets (characterized by intake of high levels of processed foods, refined sugars and carbohydrates, saturated fatty acids, animal protein, and low levels of dietary fiber) associated with the development of industrialization, modern people consume much less dietary fiber than ancient people, which is now below the recommended adults daily range of 28−35g. Western diets have inevasible effect on gut microbiome configuration and adversely impact host metabolism, immunity and physiology [11]. Dietary fiber intake can change metabolic status including reducing postprandial blood glucose, improving serum lipid levels, and preventing obesity [12,13]. Epidemiological studies have demonstrated that lower intakes of total dietary fiber are associated with increased risk of several chronic inflammatory diseases [[14], [15], [16]], and the beneficial effects of fiber vary by its type and food source.

The gut microbiome collectively regulates host metabolism and immunity homeostasis via their metabolites, secretions, and cellular components. The complexity relationship of fiber, human health and disease is gradually unveiled accompany the advances in the field of microbiome science. Various types of dietary fiber or their metabolic products such as short-chain fatty acids (SCFAs) have profound impacts on the host [17]. Given that different bacterial species have their unique capacity to produce the enzymes needed for degradation of fiber and complex carbohydrate, dietary fiber as a critical resource can influence the gut microbiota composition. The gut microbiota plays multifaceted roles in human health, including protecting against pathogens [18], promoting the development and homeostasis of the gut immune system [19], vitamin synthesis [20], metabolism of xenobiotics [21], and even regulating complex gut-brain communication [22]. The profiles of human gut microbiota are altered in inflammatory disease states such as inflammatory bowel disease (IBD) [23] and rheumatoid arthritis (RA) [24]. Studies have been made on how to modulate its composition, as well as the metabolic function of the different microbial species that colonize the gastrointestinal (GI) tract, to improve human health and potentially prevent or treat diseases.

Dietary fiber can change the composition of gut microbiome and affect the composition and activity of metabolites, which is one of the mechanisms for dietary fiber to affect inflammatory diseases. By further studying how each fiber type regulate host microbiota populations, and the well-defined mechanisms of fiber fermentation that affect immune response and gut homeostasis, it provides the possibility for targeted therapeutic dietary fiber intervention to aid in alleviating certain disease associated with the altered inflammatory state. This review aims to illustrate the effects of dietary fiber interventions on the gut microbiome, and in turn what effects these changes have on chronic inflammatory diseases.

2. Dietary fiber modulates the gut microbiota

2.1. Definition of dietary fiber

Dietary fiber which refers to the carbohydrates found in plants (such as fruits, vegetables, legumes, nuts, seeds and grains) cannot be metabolized by human genome encoded digestive enzymes. Instead, dietary fiber only can be selectively metabolized through anaerobic fermentation by the gut microbiome. In 2001, the Food and Nutrition Board, Institute of Medicine of the National Academy of Sciences defined that dietary fiber is made up of intrinsic and intact carbohydrates and lignin which can’t be digested in plants and functional fiber is made up of physiological beneficial carbohydrates which are isolated, nondigestible in humans, both of them are total fiber [25]. In 2009, the Codex Alimentarius Commission highlighted that as carbohydrate polymers consisting with 10 or more monomeric units and dietary fiber could not be hydrolyzed by the human endogenous enzymes [26]. Although there is no universally accepted definition of dietary fiber, dietary fiber is commonly referred to complex carbohydrate polymers.

2.2. The physicochemical properties of fiber on regulating the gut microbiota

Each dietary fiber, most of which is structural polysaccharide components of plant cell walls, may have different solubility, viscosity and fermentability. Fibers can be classified as different types according to their physicochemical properties. They are classified as soluble fibers (with varying degrees of solubility) or insoluble fibers according to water solubility. Fibers can also be classified as viscous or non-viscous fibers according to their gel-forming ability. Meanwhile, according to the fermentability, fibers can be classified as non-fermentable fibers, partially fermented (semi-fermented) fibers, or fully fermented fibers. For example, inulin is a water-soluble, fermentable, non-viscous fiber, while pectin is a water-soluble, fermentable, viscous fiber. The base chemical structure of dietary fiber is a carbohydrate (molecular structure is Cm(H₂O)n, polysaccharide), which is a complex mixture of macromolecular pentosan or hexane condensed by multiple monosaccharide molecules (generally more than 200) through non-α-1,4 glycosidic bonds. It can also be called non-starch polysaccharide, that is, non-α-glucan polysaccharide.

Common dietary fibers and their chemical structures are described as following: cellulose is a linear polymer composing of dehydrated glucose and linked by β-1,4-glycosidic bonds [27], hemicellulose is a branched heteropolysaccharide composing of pentose (xylose and arabinose), hexose (glucose, mannose, and galactose) and hexuronic acid (4-O-methyl-D-glucuronic acid, D-glucuronic acid and D-galacturonic acid) [28], pectin is constructed with the backbone composed of α-(1,4)-linked galacturonic acid residues and combined with monosaccharides like rhamnose, galactose, arabinose, mannose, xylose and fucose [29], resistant staresistant (RS) is a linear polymer composing of glucose and linked by α-(1,4)-glycosidic bonds and branched with α-(1,6) glucose [30] and polyfructans include inulin (composed of one glucose residue and 2–60 fructose residues linked via β-(2,1) glycosidic bonds) [31] and levan (composed of repeating five-member fructofuranosyl rings connected by β-(2,6) glycosidic bonds) [32].The physicochemical properties of dietary fiber may influence its functional properties in the GI tract through a variety of mechanisms including affecting glucose and lipid absorption, promoting fecal output, and stimulating intestinal changes [33].

The physicochemical properties of fibers, such as solubility, viscosity and fermentation, essentially determine that various fiber types have different function in regulating microbiota and diverse impact on host health and disease. Short-term consumption of 12 ​g of chicory-derived Orafti inulin in healthy adults with mild constipation resulted in increased abundances of Bifidobacterium and Anaerostipes, but a decreased abundance of Bilophila [34]. Similar effects on regulation of Bifidobacteriaceae and Lachnospiraceae were found in patients with active ulcerative colitis (UC), validating its role as a prebiotic in modulating gut microbiota composition and activity [35]. While high intake of resistant starch (RS) and nonstarch polysaccharides (NSP) in healthy adults led to an increase in Ruminococcus bromii, Faecalibacterium prausnitzii, and Eubacterium rectale [36]. In vitro studies have shown that inulin and pectin, when supplied as sole energy sources to the human colonic microbial community, promoted a very different community distribution, with inulin promoting Bacteroides uniformis and Bacteroides caccae enrich and pectin promoting Bacteroides vulgatus/dorei, Bacteroides stercoris, Bacteroides eggerthii, Bacteroides cellulosilyticus/intestinalis, Bacteroides ovatus, and Bacteroides thetaiotaomicron enrich [37].

2.3. Dietary fiber alters the gut microbiome in animals and humans

Dietary fiber is one of the key resources in the gut for microorganisms with the necessary enzymes needed to degrade these complex carbohydrates. So it can affect the composition, diversity and richness of the gut microbiome, which are mainly members of two taxa including Clostridia (phylum Firmicutes) and Bacteroidia (phylum Bacteroidetes) [13,38]. As dietary fiber influences the composition of the microbiome in murine gut, it helps maintaining the community diversity. Long-term low fiber diet led to an irreversible extinction of microbiota that depend solely on this critical resource, which cannot be recovered after the re-introduction of high fiber diet over several generations [39]. If humanized germ-free mice were given a fiber-free diet and then exposed to antibiotics, their gut microbes collapsed more severely and recovered more slowly [40].

Despite the fact that there are numerous studies on the effects of dietary fiber supplementation on gut microbiota composition in rodent models, relevant studies in humans are limited. Numerous studies outline how the consumption of different diets, in different geographical locations and socio-economic backgrounds, alters the gut microbiome in humans [[41], [42], [43], [44]]. In general, people from less developed countries or rural societies consume a higher proportion of fiber in their diets, in comparison with people in industrialized countries or cities. People whose diets are low in fiber tend to have changed fiber-consuming bacteria (particularly among microbes involved in fermentation and production of SCFAs, such as Akkermansia muciniphila, Bacteroides spp., Prevotella spp.) [45].

A study comparing the gut microbiota of residents from two non-industrialized regions Papua New Guinea with that of Americans showed that consuming more dietary fiber resulted in a higher abundance of Prevotella and a lower abundance of Bifidobacterium, Faecalibacterium, Ruminococcus, Bacteroides, Blautia, Bilophila, and Alistipes [43]. A short-term study comparing the effects of a fiber-rich, plant-based diet and a protein-rich animal-based diet on individuals in the United States found that the former increased the abundance of Prevotella, Roseburia, E. rectale and R. bromii, which metabolize dietary plant polysaccharides [42]. Another study identified that fiber-rich diet can select Prevotella copri types with enhanced potential for carbohydrate catabolism by the enrichment in genes encoding for Glycoside hydrolase (GH) and carbohydrate esterase (CE) [46]. A meta-analysis in healthy adults [47] demonstrated that dietary fiber intervention, particularly ifructans and galacto-oligosaccharides, led to a higher fecal abundance of Bifidobacterium and Lactobacillus spp. but did not affect the α-diversity of the gut microbiome.

Consumption of whole grains and vegetables was proved to increase the diversity of the microbiota on pregnant women with overweight or obesity [48]. Low-FODMAP diet (characterized by intake of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) was proved to decrease the relative abundance of Bifidobacterium adolescentis, Bifidobacterium longum, and F. prausnitzii, while no change in microbiome diversity in patients with quiescent IBD [49]. An increase in dietary fiber intake (25–30 ​g/day for females and 30–35 ​g/day for males) would lead to the change of the gut microbial composition of quiescent IBD patients, manifested by an increase in the mean relative abundance of Faecalibacterium, Bifidobacterium and a trend towards a decrease in Proteobacteria [50]. Research also found that a fiber-free diet notably induced two bacterial taxa belonging to the Clostridium clade XIVa, Ruminococcus torques and Ruminococcus gnavus [51]. Overall, these evidences suggest that dietary fiber consumption can alter the gut microbiota and lack of dietary fiber will lead to a tremendous change in microbiome.

The breakdown of complex dietary fibers is controlled by a series of carbohydrate-active enzymes (CAZymes) including GHs, CEs, Polysaccharide lyases (PLs) and enzymes showing auxiliary activities. Dietary fiber utilization ability of gut microbes depends on their gene content that encodes CAZymes. Some bacteria can utilize a large number of different carbohydrates with various structures and others can utilize only a few carbohydrates [52]. The polysaccharide utilization loci (PULs) are the gene clusters located in specific regions and encoded a series of enzymes necessary to utilize fiber structure. Bacteroidetes is one genus of the most common dietary fiber degraders in the gut encoding 269 ​GHs, 18 CEs and 17 ​PLs [53].

The Bacteroides genus (such as B. thetaiotaomicron) degrades complex carbohydrates (such as pectin) through the cooperation of multiple PULs [54]. Polysaccharides bound to the cell surface by the surface glycan-binding proteins on bacteria, and subsequently are hydrolyzed by surface GHs generating the small oligosaccharides to transport through the SusC-like protein [55]. PLs and GHs process oligosaccharides into smaller units or monosaccharides in the periplasm. Three inner membrane-spanning regulators sense the existent of oligosaccharide degradation products and then drive the transcription of genes involved in the transport and degradation of the target polysaccharide [55].

Disaccharides or monosaccharides are then shuttled into the cytoplasm for fermentation via a specific transporter. On the other hand, Campylobacter hominis encodes only 6 ​GHs and 3 CEs, suggesting that the dietary fiber utilization ability of this bacteria is more limited [32]. While the phylum Firmicutes possess different strategies for glycan degradation. Polysaccharides bound to carbohydrate-binding modules or solute-binding proteins which are subsequently broken down by GHs, and then transport oligosaccharides and monosaccharides into the cytoplasm via the ATP-binding cassette. Finally, these oligosaccharides are decomposed into monosaccharides by intracellular GHs or CEs [56]. In vitro studies have also shown that different bacterial species (such as B. ovatus and B. thetaiotaomicron) had different preferences for the same dietary fiber, and specific bacteria can use different fibers [57]. Therefore, different types of fiber diets are beneficial to different bacteria or bacterial groups in the gut, thereby differentially regulating the intestinal ecology.

3. The effect of dietary fiber on inflammatory diseases

Data from both epidemiological and clinical studies have consistently suggested that higher dietary fiber intake have been linked to a reduced risk for several chronic inflammatory diseases [14,58]. Wenjie Ma et al. found that dietary fiber intake was associated with significantly lower plasma levels of C-reactive protein (CRP) in a cohort of 307 generally healthy men [58]. Two large prospective cohort studies in Sweden showed that people who adhered to Mediterranean diet (characterized by a high intake of fruits and vegetables, whole grains and proteins from fish, legumes and nuts, seafood) had a lower risk of late-onset Crohn’s disease (CD, a subtype of IBD) and poor adherence to a Mediterranean diet conferred a population attributable risk of 12% for later-onset CD [59]. The benefits of dietary fiber intake on inflammatory diseases include supporting the immune system, preventing or ameliorating inflammatory diseases such as diabetes, inflammatory arthritis, inflammatory gastrointestinal disorders and so on [60].

Dietary fiber can provide protection to the intestinal barrier mediated by SCFAs, since butyrate provides energy to enterocytes to contribute to the integrity of the gut epithelium and acetate promotes intestinal barrier integrity by activating the interleukin-18 receptor [61]. In murine model, high fiber (including soluble fibers such as psyllium, pectin, and insoluble fiber such as cellulose) diet was protective against dextran sodium sulfate (DSS)-induced colitis [[62], [63], [64]]. Possible preventive protection rather than treatment was provided by a high-fiber diet in acute and chronic DSS-induced colitis in mice [65]. Fiber-free diet sensitized mice to low-dose (0.5%) DSS-induced colitis, while acetate supplementation modulated neutrophils recruitment and attenuated inflammatory damage of the host colon [66].

Dietary fiber deprivation in mice led to mucus layer depletion, disruption of intestinal barrier due to the alteration of mucus-eroding microbes (such as B. caccae and A. muciniphila) [67], which might increasing intestinal permeability induced by DSS [68]. Diets containing low amounts of fruits and vegetables and high amounts of red meat might be associated with an increased risk of IBD and diverticulitis [[69], [70], [71], [72]]. Meanwhile, high-fiber diet is considered to lower the disease-specific outcomes in patients with IBD [73]. The Mediterranean diet is widely thought to decrease the risk of IBD [69], improve symptoms [74,75] and reduce mortality in patients with established IBD [76].

Meanwhile, dietary fiber has been linked to beneficial effects in inflammation beyond the GI tract. A high-fiber dietary intervention resulted in decreased secretion of the pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) and pro-inflammatory cytokines interleukin-18 and interleukin-33 in RA patients [77]. In collagen-induced arthritis (CIA) mice butyrate supplementation showed anti-inflammatory benefits by promoting T regulatory cell (Tregs), while suppressing T follicular helper (Tfh) cells and Th17 ​cells [78].

Another study showed a high fiber diet rich in resistant starch significantly reduced CIA and bone damage and altered gut microbial composition with concomitant increase in circulating propionate (another end-products of fiber fermentation in vivo) [79]. Earlier clinical studies showed that vegan diet was associated with clinical improvements in RA patients. Compared to the control group, the vegan diet group had significantly less tender and swollen joints, pain, erythrocyte sedimentation rate (ESR), and CRP [80,81]. Consistently, after RA patients consuming the Mediterranean diet for 7 days, the mean Disease Activity Score (DAS-28) was significantly decreased [82]. Another study found that Mediterranean diet improved clinical outcomes without affecting the intestinal microbiota in patients with RA [83].

Moreover, low-fiber diet exacerbated the inflammatory state in mice with allergic airway inflammation and lupus-prone NZB/WF1 mice, leading to worse disease outcomes [84,85]. Feeding high-fiber or acetate led to suppression of allergic airways disease since acetate could enhance Treg cell numbers by increasing acetylation at the forkhead box P3 (Foxp3) promoter [86]. Feeding high-fiber or butyrate could alleviate inflammation of autoimmune hepatitis through regulation of Treg/Th17 ratio and intestinal barrier function [87].

4. The mechanism of dietary fiber interventions on inflammatory diseases in relation to the microbiome

Microbiota-accessible carbohydrates existing in dietary fiber play an important role in maintaining the diversity of gut microbiota and its production SCFAs play an active role in maintaining the gut barrier function and reducing inflammation [33]. The SCFAs including acetate, propionate, and butyrate are the primary metabolic products derived from the colonic fermentation of dietary fiber by gut microbes and is estimated to be produced in a molar ratio of 60:20:20 [88]. SCFAs play important roles in mammalian physiology, particularly butyrate serving as an energy source for intestinal epithelial cells and Treg generation [89]. SCFAs can also regulate immune responses through their effects on various immune cells such as neutrophils, macrophages, dendritic cells, T cells and B cells [[90], [91], [92]]. SCFAs exert their functions through several different mechanisms, including activation of epithelial cell and immune cell surface G-protein-coupled receptors (GPCRs) and histone acetylase (HDAC) and histone deacetylase enzymes inhibition inducing epigenetic changes in the genome (Fig. 1) [93].

SCFAs act as signaling molecules that recognize three well characterized GPCRs including GPCR41 (also known as FFAR3), GPCR43 (also known as FFAR2) and GPCR109A (also known as HCAR2), thus promoting immune homeostasis [94]. Mice with GPCR43 deficiency would lead to immune cell recruitment, increased inflammatory mediators and aggravated inflammation, whether in experimentally mouse models of colitis, arthritis or asthma [95]. GPCR43 deficiency also affects acetate-induced IgA secretion from B cells, resulting in lower IgA secretion [96].

In another study, propionate attenuated allergic airway inflammation allergic airway inflammation by reducing eosinophil infiltration in the lung in a GPR41-dependent manner [84]. GPR109A is necessary for protection against colitis, since butyrate binding to it in the colon promotes the expression of anti-inflammatory molecules by macrophages and dendritic cells (DCs) and enables them to support the differentiation of Tregs and interleukin-10-producing T cells [97].SCFAs activates the pyrin domain-containing 3 (NLRP3) inflammasome in colon epithelial cell through G-protein-coupled receptors GPR43 and GPR109a, promoting interleukin-18 production and contributing to relieve colitis [68].

SCFAs could regulate gene expression by acting as inhibitors of histone deacetylases (mainly refers to butyrate) and affect energy metabolism [93,98]. SCFAs can promote T-cell differentiation into effector and regulatory T cells and increase the expression of interleukin-10, interferon-γ (IFN-γ) and interleukin-17 by inhibiting HDACs and regulating P70 S6 kinase-RS6 [99]. Butyrate regulates Treg cell differentiation by enhancing histone H3 acetylation of the conserved non-coding sequence region and the Foxp3 gene promoter [100].

Colonic Tregs exposure to propionate significantly increased Foxp3 and interleukin-10 expression and reduced HDAC6 and HDAC9 expression [101]. Butyrate exposure enhances acetylation of the Foxp3 locus and Foxp3 protein and HDAC-inhibitory activity of butyrate decreases pro-inflammatory cytokine expression within DCs to promote Treg induction [102]. Butyrate could also modulate the intestinal macrophages by inhibiting histone deacetylase to down-regulate nitric oxide, interleukin-6, and interleukin-12 proinflammatory mediators, thereby contributing to the maintenance of symbiotic tolerance [92]. Propionate could directly act on to intestinal γδ T cells by inhibiting histone deacetylases, reducing the production of interleukin-17 and interleukin-22 [103].

Nowadays, there is growing interest in the role of the microbiota in the inter-connected gut-brain axis and evidence showed that high fiber diets will improve the health of our brains [104]. The potential mechanism relating dietary fiber to the brain-gut-microbiota axis (BGMA) is mainly mediated by SCFAs and lactic acid [12]. SCFAs entering blood vessels can be transported across the blood-brain barrier into the brain and cerebrospinal fluid, and then affect immune function in brain tissue via GPCR-dependent signaling [105].

Dietary fiber deficiency activated microglia and induced phagocytosis of hippocampal synapses, whereas SCFAs restored microglial cell (the resident macrophages of the brain and spinal cord) morphology and reversed microglial immaturity by reducing pro-inflammatory cytokines, increasing anti-inflammatory cytokines and Treg cells [106]. Recent studies showed that acetate was the key short-chain fatty acid driving microglial maturation and regulated homeostasis, and that it regulated microglial phagocytosis and neurodegeneration disease progression [107]. Further studies are warranted to link fiber-induced microbiota shifts with changes in specific host physiological pathways regulating host metabolic and immune health.

Utilization of dietary fiber in Bacteroides is mediated by PULs, which consist of sets of co-regulated genes and gene clusters for sensing nutrient availability, glycan capture, uptake, and digestion. However, a subset of SCFAs-producing bacteria (including the phylum Firmicutes) has a narrower range of glycan-degrading capability. Anaerostipes caccae, one of the butyrate-producers, was not able to utilize lactose and human milk oligosaccharides. It could cross-feed on B. thetaiotaomicron-derived monosaccharides, acetate, and d-lactate for growth and concomitant butyrate production [108,109].

 Eubacterium ramulus can degrade quercetin in the presence of glucose but is unable to use starch for growth or quercetin degradation. When starch was the only energy source available, B. thetaiotaomicron would stimulate E. ramulus to produce butyrate via cross-feeding of glucose and maltose molecules released from starch [110]. Recent study showed that PULs are major drivers of inter-species interactions with butyrate producers and PUL-dependent glycan utilization by B. uniformis impacts butyrate production by modulating the growth of the butyrate producers [109]. In conclusion, the unselfish release of polysaccharide breakdown products and metabolic byproducts from Bacteroides could establish new metabolic niches that could be exploited by butyrate producers.

5. Clinical applications of dietary fiber on inflammatory diseases

Gut microbiota is an important factor influencing host metabolic homeostasis and immune system. It is a site of remarkable interaction between microorganisms and human body. The application dietary fiber (or prebiotics) [111] is one of the beneficial dietary intervention approaches to modulate the dysbiosis of the gut microbiota linking to a disease or mortality. Based on fiber intake, dietary interventions were classified as low fiber (such as specific carbohydrate diet, FODMAP diet, and low-carb diet), high fiber (such as Mediterranean diet, vegetarian, vegan, high-fiber diet), or supplemental fiber (such as inulin, galacto-ogliosaccharide, fructo-ogliosaccharides, psyllium, synbiotic, high-fiber functional food). Wagenaar et al. stated that when comparing to supplemental fiber dietary interventions, high fiber dietary interventions led to a larger increase in the diversity of the gut microbiome [73]. A challenge in most diet-feeding studies is the inability to isolate the effect of a single dietary component. Therapies with exogenous SCFAs have been proposed to reduce inflammation in several diseases, but more human RCTs are needed to confirm the therapeutic and protective effects of SCFAs in animal studies. One issue is that these findings cannot be directly translated into human interventional studies due to the huge quantities of dietary fiber used in mice.

5.1. Inflammatory bowel disease

Marlow et al. showed that Mediterranean-inspired diet reduced markers of inflammation and normalized the microbiota in patients with CD [112]. One study in UC patients showed that, when comparing to an improved Standard American Diet the high-fiber intervention group had a lower Partial Mayo score, fecal calprotectin, and CRP and a higher relative abundance of F. prausnitzii and Prevotella [113]. Kanauchi et al. showed in a 4-week open-label study that supplementation with 20–30 ​g/day of germinated barley foodstuff (6.66–10 ​g/day fiber) reduced clinical activity index (CAI) scores compared with the control group and increased fecal concentrations of Bifidobacterium and Eubacterium limosum [114]. In another study, butyrate-producing dietary fiber additives might aid in maintenance of remission or be non-inferior to 5-aminosalicylates in maintaining remission in UC [115,116]. E Furrie et al. reported that a symbiotic supplement (B. longum with 12 ​g/day inulin-oligofructose) in UC reduced the CAI and CRP levels at the end of the 4-week study and increased the amount of Bifidobacteria [117]. However, Benjamin et al. reported no significant differences in disease-specific or microbiome outcomes after the 15 ​g/day FOS supplementation in CD patients [118]. The guidance from International Organization for Study of Inflammatory Bowel Diseases (IOIBD) recommends that it is necessary to increase the intake of fruits and vegetables in patients with CD [119]. Results from dietary intervention studies in CD and UC have been promising, additional published studies are listed in Table 1, but high-quality randomized trials are needed to assess efficacy.

5.2. Diverticulitis

Among the existing studies which have explored the dietary management strategy of diverticulitis, only one study measured the effect of dietary fiber on diverticulitis incidence [120]. Recommendation of dietary fiber intake is not mentioned in the consensus of acute diverticulitis management. A systematic review recommended that patients with uncomplicated diverticulitis should be placed on a liberalized diet, as opposed to dietary restrictions, and a high-fiber diet that meets individualized nutrient requirements, with or without fiber supplementation [121]. Some guidelines which based on clinical practice, rather than robust clinical trials suggest a low-fiber diet to ‘minimize irritation’12 and a gradual increase to 20–30 ​g per day through diet or as fiber supplements once inflammation is resolved [122]. Overall, there is limited evidence for the benefits of fiber in preventing acute diverticulitis.

5.3. Rheumatoid arthritis

In the last century, studies in RA patients showed that vegetarian and Mediterranean-based dietary interventions led to attenuation of disease activity in RA patients with significant improvements in the number of tender joints and swollen joints, pain, and duration of morning stiffness [80,81,[123], [124], [125]]. Recently, a single-arm study observed that RA patients receiving high-fiber bars or cereals for 28 days led to increasing circulating Treg cell numbers and decreasing markers of bone erosion [126]. In some studies, Mediterranean diet is thought to reduce inflammation and improve symptoms in RA patients by modulating intestinal microbiota and intestinal barrier function [127]. While most studies on anti-inflammatory protective properties of the Mediterranean diet focused on n-3 polyunsaturated fatty acids rather than fiber [[128], [129], [130]]. On the contrary, some studies showed no association between the consumption of a Mediterranean diet and later development of RA. A systematic review concluded that there is currently insufficient evidence to support the Mediterranean diet to prevent RA, but it may provide a secondary benefit, of lessening future complications of the disease [131].

6. Conclusions and perspectives

The results of epidemiological and experimental studies on high-fiber dietary intervention both indicated beneficial improvements of clinical and microbiome outcomes. Gut microbial ecology is largely regulated by the human diet, especially available component, and high fiber intake has been associated with elevated levels of Prevotella [132]. Dietary interventions are therefore a potential tool for regulating the gut microbiome and dietary therapies may be conducted as microbiota-based precision therapies, and large, randomized placebo-controlled clinical trials, should be considered, especially in patients with active inflammatory diseases. Given the vital effects of dietary fiber on the composition and function of the gut microbiome, diet intervention may be a feasible microbiome regulation approach. In future, to determine the efficacy of personalized diets in treating immune diseases and to investigate how these diets affect the host immune response may be effective and promising. Yet, due to a large heterogeneity of recent studies, it’s still difficult to draw concrete conclusions.

Current dietary fiber recommendations fail to provide detail types and doses in the treatment of disease [33] due to the limited and conflicting research results. High-fiber, whole-diet interventions were more effective than fiber supplements in reducing inflammation or improving disease-specific outcomes [73]. The inconsistent research results may be due to greater variations of dietary fiber pattern, impact from other dietary components, the limited number and quality of studies as well as the variations in the fiber interventions (including fiber type, source, dose and duration of treatment). Moreover, as the field of microbiome science is relatively young and the technology applicable is growing rapidly, there are still various limitations in previous microbiome studies.

Despite recommendation suggests that individual adult intakes of total dietary fiber should be no less than 25–29 ​g per day and higher intakes likely bring additional benefits [14], the average amount of dietary fiber consumed by adults worldwide is still far below the recommended amount (under 20 ​g per day). Increased public awareness of the benefits of dietary fiber has prompted food manufacturers to use refined dietary fiber to fortify processed foods. However, recent studies showed that refined dietary fiber s are not universally beneficial and inappropriate consumption of refined dietary fibers may risk both gastrointestinal and liver health [133].

Therefore, we recommend the use of natural dietary fiber rather than refined dietary fiber. Given the diversity of fiber available in the human diet and the variety of physiological effects, the functionality and benefits they offer differ. Considering the large diversity of the gut microbiome in addition to fiber types and quantity, one should be cautious in choosing fibers paired with the individualized gut microbiome.

By understanding the processes that link dietary fiber and the gut microbiome with broad health benefits, we may be able to develop targeted pharmacologic therapies that mimic the effects of dietary fiber. Use of novel fibers and/or the co-administration of fibers is an additional therapeutic approach yet to be extensively investigated. With each new gut microbial-derived metabolite identified to reveal a mechanistic association with disease, there may be many additional therapeutic modalities. Future research may focus on selective small-molecule therapies targeting specific microbial pathways or host participants for precision medicine, based upon the discovered causal metabolic pathways of the gut microbes as well as the human host in response to dietary fiber.