Journal Pre-proofs

Review

Health promoting microbial metabolites produced by gut microbiota after pre-

biotics metabolism

A. Peredo-Lovillo, H.E. Romero-Luna, M. Jiménez-Fernández

PII: S0963-9969(20)30498-1
DOI: https://doi.org/10.1016/j.foodres.2020.109473
Reference: FRIN 109473

To appear in: Food Research International

Received Date: 24 April 2020

Revised Date: 10 June 2020
Accepted Date: 21 June 2020

Please cite this article as: Peredo-Lovillo, A., Romero-Luna, H.E., Jiménez-Fernández, M., Health promoting
microbial metabolites produced by gut microbiota after prebiotics metabolism, Food Research International
(2020), doi: https://doi.org/10.1016/j.foodres.2020.109473

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 Health promoting microbial metabolites produced by gut microbiota after prebiotics

metabolism

Peredo-Lovillo, A.1, Romero-Luna, H.E.1, Jiménez-Fernández, M.2*

1 Instituto Tecnológico Superior de Xalapa, Tecnológico Nacional de México, Reserva

Territorial s/n, Sección 5, Santa Bárbara, CP 91096, Xalapa Enríquez, Veracruz, México.
2Centro de Investigación y Desarrollo en Alimentos, Universidad Veracruzana, Av. Doctor

Luis Castelazo, Industrial Ánimas, Xalapa Enríquez, CP 91190, Veracruz, México.

*Corresponding author. E-mail address: maribjimenez@uv.mx (M. Jiménez-Fernández).

Declarations of interest: None.

ABSTRACT

Human gut microbiota (HGM) is a microbial complex where dynamic mutualistic

interactions related to digestion and absorption of dietary components take place. The

consumption of specific food ingredients, such as prebiotics and dietary fibers, constituted

mainly by carbohydrates polymers, can modulate the HGM composition and metabolism

serving as a fermentable substrate to produce bacterial metabolites with beneficial effects on

host health. Especially, bacterial short-chain fatty acids, tryptophan and organic acids have

shown positive effects on pathogenic bacteria control, mineral absorption, weight control and

obesity, immune response homeostasis, gut barrier improvement, brain modulation and

anticancer activity. Despite the fact that these effects vary between individuals due to

personal HGM richness, the information presented in this review contributes to

1
understanding the effects of prebiotics and dietary fibers consumption on the generation of

HGM metabolites and the mechanisms by which these metabolites interact with host cells

improving host health.

Keywords: Dietary fiber; gut microbiota; health; metabolites; prebiotics; probiotics.

CONTENTS

1. INTRODUCTION

2. DIETARY FIBERS

2.1 Classification of dietary fibers

3. PREBIOTICS

3.1 Classification of prebiotics

4. METABOLISM OF DIETARY FIBERS AND PREBIOTICS

5. HUMAN GUT MICROBIOTA AND HOST HEALTH

6. BENEFICIAL EFFECTS OF METABOLITES PRODUCED BY HUMAN GUT

MICROBIOTA FROM DIETARY FIBERS AND PREBIOTICS METABOLISM

6.1 Defense against pathogenic bacteria

6.2 Appetite control and anti-obesity effect

6.3 Improvement of minerals absorption

6.4 Intestinal barrier reinforcement

6.5 Immune response improvement

6.6 Anticancer effects

6.7 Brain function modulation

7. CONCLUDING REMARKS
2
Abbreviations: AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase;

ATP, adenosine triphosphate; BBB, blood brain barrier; BDNF, brain-derived neurotrophic

factor; CNS, central nervous system; CRC, colon rectal cancer; EC, enterochromaffin cells;

ENS, enteric nervous system; FOS, fructooligosaccharides; GOS, galactooligosaccharides;

GPL1, glucagon-like peptide 1; GPR, G protein-coupled receptor; HbA1c, glycosylated

hemoglobin; HGM, human gut microbiota; 5-HT, 5-hydroxytryptamine; IBD, inflammatory

bowel disease; IL, interleukin; ISAPP, International Scientific Association for Probiotics and

Prebiotics; LPS, lipopolysaccharide; NK cells, natural killer cells; PDX, polydextrose; PYY,

tyrosine-tyrosine peptide; SCFA’s, short chain fatty acids; TEER, transepithelial electrical

resistance; TLR, Toll-like receptors; TNF-α, tumor necrosis factor alpha; Treg, regulatory T

cells; XOS, xylooligosaccharides.

1. INTRODUCTION

The human gut microbiota (HGM) can be considered as a highly active metabolic organ due

to the activity of the microbial complexes that comprise it, which provide metabolic,

immunologic and protective functions as result of dynamic mutualistic relationships between

the microbial species and the host (Holscher, 2017). Therefore, alterations in the composition

of HGM can affect aspects of human health (Danneskiold-Samsøe et al., 2019).

The HGM composition can be modulated by internal and external factors such as genetics,

host physiology (age, diseases, stress conditions) and environmental factors (lifestyle, use of

medications, pesticides, pollutants, diet) (Jin, Wu, Zeng, & Fu, 2017; Velmurugan,

Ramprasath, Gilles, Swaminathan, & Ramasamy, 2017; Korcz, Kerényi, & Varga, 2018).
3
Diet has been one of the most studied and determining factors, since the beneficial health

effects depend on the metabolism of dietary ingredients by HGM (Carlson, Erickson, Lloyd,

& Slavin, 2018). Among those dietary ingredients, studies have reported that the

consumption of prebiotics may positively affect the HGM composition and metabolic

functions at the level of small intestine and colon (Prado, Parada, Pandey, & Soccol, 2008;

Carlson & Slavin, 2016; Sanders, Merenstein, Reid, Gibson, & Rastall, 2019; Nogacka et al.,

2020).

In 2010, the International Scientific Association for Probiotics and Prebiotics (ISAPP),

defined prebiotics as “selectively fermented ingredients that result in specific changes in the

composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon

host health” (Gibson et al., 2017). Some of the health benefits of prebiotics metabolism by

HGM include the improvement of gastrointestinal function and barrier homeostasis, increase

in mineral absorption, modulation of energy metabolism and satiety, and reduction of the risk

of intestinal infections (Sanders et al., 2019).

On the contrary, aside from to the quality of the diet, the absence in consumption of dietary

fibers and prebiotics in Western diets leads to a depletion of HGM diversity, and the

consequent increase of chronic non-communicable diseases such as obesity, cardiovascular

diseases, type 2 diabetes and colon cancer. (Deehan & Walter, 2016; Holscher, 2017; Loo,

Howell, Chan, Zhang, & Ng, 2020). Meanwhile, the consumption of diets rich in prebiotics,

increases the HGM diversity, influencing both microbial metabolic activities and the

formation of determined fermentative end products (Healey et al., 2018; Korcz et al., 2018;

Birkeland et al., 2020); for example short-chain fatty acids (SCFA’s), branched-chain fatty
4
acids, organic acids, peptides, ammonia, amines, phenolic compounds and gases (Verbeke et

al., 2015; Aguilar-Toalá et al., 2018). Specific bacterial metabolites show local and systemic

benefits to the host, including antimicrobial, antioxidant, and immunomodulatory properties.

These metabolites are mainly produced by beneficial bacteria present in the HGM (Aguilar-

Toalá et al., 2018, 2019).

Bifidobacteria and lactobacilli are considered the majority beneficial genera within HGM

and hence the principal bacteria recognized as probiotics; and in turn, they have been used

as markers for the effect of prebiotic supplementation analysis (Markowiak & Śliżwewska,

2017). However, recent evidence has shown that other genera such as Bacteroides,

Eubacterium, Faecalibacterium, Roseburia and some species of Clostridia, and recently

Akkermansia muciniphila, are involved in the fermentation of prebiotics and dietary fiber

with similar beneficial effects to those offered by probiotics (Critteden et al., 2002; Verbeke

et al., 2015). This suggests that the beneficial effects may be due to the ability to metabolize

prebiotics/dietary fibers and the subsequent synthesis of specific metabolites with functional

properties beneficial to the host.

In this sense, the generation of bacterial metabolites as a result of the metabolism of dietary

components like prebiotics or dietary fibers by HGM seems to be a promising way by which

the host health improvement can be achieved (Verbeke et al., 2015; Korcz et al., 2018).

Therefore, future studies on human health related to the effect of consumption of fibers could

be focused on the analysis of the metabolic activity of HGM and the metabolites produced

from the fermentation of prebiotics and dietary fibers. Hence, this review discusses the

impact of dietary fibers and prebiotics consumption on the HGM, including the effects on
5
the bacterial composition of gut tract and the production of specific fermentative end

products; highlighting the healthy benefits derived from the mechanisms of interaction of

these metabolites with the host cells, for their potential applicability as markers for improving

gut/host health.

2. DIETARY FIBERS

Most countries have adopted the definition of dietary fiber as proposed by the Codex

Alimentarius, which includes those edible carbohydrates polymers with three or more

monomeric units resistant to the endogenous digestive enzymes, being neither hydrolyzed

nor absorbed in the small intestine (Holscher, 2017). According to this definition, the dietary

fibers could be considered as edible carbohydrate polymers from natural sources as fruits,

vegetables and cereals; as well as edible carbohydrate polymers obtained from food raw

materials by physical, enzymatic and chemical mechanisms that have shown physiological

benefits and synthetic carbohydrates polymers with proven physiological benefits (Makki,

Deehan, Walter, & Bäckhed, 2018).

The dietary fiber is classified according its solubility; the soluble fiber shows benefits on

serum lipids; on the contrary, the insoluble fiber is linked to laxation benefits (Dong, Chen,

Gutin, & Zhu, 2019). However, scientific evidence supporting that dietary fiber beneficial

effects is inconsistent, some soluble fibers such as oat bran or psyllium increase stool weight,

meanwhile resistant starch and inulin (considered as prebiotics) do not show a decrease in

blood cholesterol level (Hoving et al., 2018; Mistry, Gu, Schols, Verkade, & Tietge, 2018;

Jalanka et al., 2019; Jane, McKay, & Pal, 2019; Snelson et al., 2019).

6
Additionally, the viscosity and fermentability may be considered as the secondary

physiological benefits of fibers. The viscosity contributes to the gel formation into the

intestinal tract, and fermentable fibers are those that can be metabolized by the HGM

(Soliman, 2019). Generally, soluble fibers are more completely fermentable and have higher

viscosity than insoluble, but not all soluble fibers are viscous, and some insoluble fiber may

be completely fermented (Slavin, 2013). This fermentation may be possible due to the

presence or lack of keystone species strains that possess the enzymatic capacity to metabolize

specific prebiotics or dietary fibers (Makki et al., 2018).

It has been observed that the dietary fiber fermentation generates shifts in the HGM diversity,

observed during the substrate consumption. Nevertheless, the ability to modify the HGM

composition depends on the nature of the dietary fiber. Since the bacterial metabolites

produced depend on it, which alter the intestinal environment and the interactions between

bacteria from the HGM (Reichardt et al., 2018; Wang et al., 2019).

3. PREBIOTICS

Some authors include dietary fibers as prebiotics, although they are not accepted. Since the

difference between the prebiotics and dietary fiber definitions is that the first are selectively

metabolized by specific genus or kinds of indigenous microorganisms; meanwhile, the

dietary fibers are metabolized by the majority of colonic microorganisms, and this difference

should not be used interchangeably (Al-Sheraji et al., 2013; Markowiak & Śliżwewska,

2017).

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The prebiotics concept was first introduced by Gibson and Roberfroid (1995) but has been

modified according to new knowledge generated. Roberfroid et al. (2010), defined prebiotics

as non-digestible food ingredients that beneficially affect the host by selectively stimulating

the growth or activity of limited number of bacteria in the colon, improving host health. Since

then, the definition has been adjusted to include indigestible short-chain carbohydrates,

which pass intact into intestinal tract and selectively stimulate the growth, composition and

activity of intestinal microbiota, improving health status on the host (Al-Sheraji et al., 2013;

Anandharaj, Balayogan, & Rani, 2014; Hamasalim, 2016).

Most well recognized prebiotics are carbohydrates, available in various structures and

consumed naturally in the human and animal diets (Markowiak & Śliżwewska, 2017).

Prebiotics are obtained either by extraction from plants (chicory inulin), followed by an

enzymatic hydrolysis (oligofructose from inulin), or synthesis (trans-glycosylation) from

mono- or disaccharides such as sucrose (fructooligosacchadires) or lactose

(galactooligosacchadires) (Wang, 2009). Microorganisms are other sources of carbohydrates

with prebiotic potential that have been poorly studied. Some bacteria have the ability to

generate an external capsule composed of exopolysaccharides (oligosaccharides). Many of

them, such as curdlan, have received interest from researchers due to their potential

applications as a prebiotic and as an additive in the food industry (Verma et al., 2020).

Oligosaccharides are the most common prebiotics in the diet and in the nutritional

supplements designed for clinical management of disease states (Danneskiold-Samsøe et al.,

2019). The oligosaccharides from breast milk are considered as the original prebiotic,

however, other dietary sources include soybeans, inulin (Jerusalem artichoke, jicama, chicory

root and agave), raw oats, unrefined wheat, unrefined barley and yacon. Banana also contains
8
inulin, which has shown prebiotic activity and probiotic/microbe-stimulating capacity

(Whisner & Castillo, 2018). The main probiotic bacteria that serve as target for prebiotics are

commonly Bifidobacterium and Lactobacillus, species with the capacity to aid digestion,

reduce constipation, resist infections, prevent traveler’s diarrhea and ameliorate intestinal

bowel disease (IBD) (Danneskiold-Samsøe et al., 2019). In fact, bifidobacteria is stimulated

by the presence of oligosaccharides contained in breast milk, this effect is known as “bifidus

factor” (Al-Sheraji et al., 2013). Therefore, the presence of prebiotics in diet can affect the

composition of the HGM, its metabolic activity and thus to increase and maintain the healthy

status of host (Ranadheera, Baines, & Adams, 2010). An example of this is reported by

Azcarate-Peril et al. (2017) who founded an increase in the relative abundance of

Bifidobacterium, Faecalibacterium and Lactobacillus after high purified (>95%)

galactooligosaccharides (GOS) administration in humans with dairy intolerance. Regarding

the metabolic activity of HGM; Daguet, Pinheiro, Verhelst, Possemiers, and Marzoratti

(2016), reported an increase in the production of SCFA’s in different colon areas, after

fructooligosaccharides (FOS) and arabinogalactan administration in a Simulator Intestinal

Microbial Ecosystem inoculated with fecal material from IBD patient. Thus, the

administration of both prebiotics induced the synthesis of SCFA’s which exerted positive

effects against gut barrier inflammation. These results suggest that the prebiotics not only are

used for the growth and development of specific colonic bacteria, but also promote the

production of bacterial metabolites with potential health benefits.

3.1 Classification of prebiotics

Prebiotics are classified according to their metabolic characteristics. The definition of

prebiotics added three criteria for their recognition: resistant to gastric digestion, tolerance to
9
hydrolysis for gastric enzymes and gastrointestinal absorption. Once observed these three

criteria, the prebiotics should be fermented by HGM and stimulate the growth or metabolic

activity of beneficial microorganisms (Holscher, 2017). So, the prebiotics should not be

digested (or partially digested) and then absorbed in the small intestine, must be poorly

fermented by oral cavity bacteria, fermented by beneficial gut bacterial and poorly or not

fermented by pathogenic bacteria (Markowiak & Śliżwewska, 2018).

Another classification of prebiotics depends on the number of constituting monomers bound

together. Prebiotics may be classified as disaccharides (i.e. lactose), oligosaccharides (3-10

monomers) (i.e. sialylactose, fucosyllactose) and polysaccharides (>10 monomers), from

which the FOS, GOS, isomaltooligosaccharides, xylooligosaccharides (XOS),

trasgalactooligosaccharides and soybean oligosaccharides, are the most representative

prebiotics (Patterson & Burkholder, 2003; Al-Sheraji et al., 2013; Wu et al., 2017a).

Carbohydrates, including dietary fiber, are the principal source of potential prebiotics.

Currently, the FOS, oligofructose, lactulose, GOS and inulin are the most common and the

most used prebiotics. The GOS are derived from lactose and consist of chains of galactose

monomers, while inulin is constituted of fructans which have shown several beneficial effects

on fermentation profile of HGM (Anandharaj et al., 2014).

4. METABOLISM OF DIETARY FIBERS AND PREBIOTICS BY HUMAN GUT

MICROBIOTA

To understand the role of the dietary fiber and prebiotics inside the HGM, must be understood

that the colon comprises a complex functional ecosystem. Within this ecosystem the

microorganisms have several functions including the conversion of incoming dietary

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carbohydrates, proteins and fats into metabolites that can show positive or negative effects

on host health (Sanders et al., 2019). The human digestive system lacks enzymes to digest

higher polysaccharides such as cellulose, xylan and pectin, that reach the distal colon intact,

while short-chain prebiotics can reach the proximal colon and long-chain prebiotics can reach

more distally or along an extended portion of the intestine; place where are fermented by the

HGM bacteria lying there (Carlson, Erickson, Hess, Gould, & Slavin, 2017; Whisner &

Castillo, 2018).

The HGM provide 130 glycoside hydrolase, 22 polysaccharide lyase and 16 carbohydrates

esterase families, which allow to improve the fermentation of dietary fibers and provide the

microbiome flexibility to adapt to different energy sources of fiber depending on the

availability (Makki et al., 2018). Thus, the consumption of dietary fibers or prebiotics

modifies the diversity of HGM providing substrates used by specific microbial species in

order to expand their population. The enzymatic capacity favors the ability of microbes to

degrade complex substrate as dietary fibers, however, the microorganisms also must possess

the ability to adhere to the substrate, tolerate the changing environmental conditions as result

of fiber metabolism (i.e. acidity increase through fermentation), and benefit from

carbohydrate breakdown products (secondary fiber degraders) and metabolites (through

cross-feeding) (Deehan et al., 2017). Firmicutes and Actinobacteria species are the main

responders of dietary fibers, however they contain minimal fiber-metabolizing enzymes per

organism, thus they participate in the initiation of substrate degradation. For example,

resistant starch administration enriches Bifidobacterium adolescentis, Ruminococcus bromii,

Eubacterium rectale and Parabacteroides distasonis, meanwhile the consumption of GOS

11
induces Bifidobacterium species that possess the enzymatic machinery to utilize this

substrate (Monteagudo-Mera et al., 2016; Alfa et al., 2018).

The dietary fibers that escape digestion in the upper gastrointestinal tract such as resistant

starch, non-starch polysaccharides, non-digestible oligosaccharides and sugar alcohols reach

the colon and become of an important carbon source for HGM, which generate large amounts

of pyruvate, lactate and SCFA’s, mainly acetate, propionate and butyrate (Sander et al.,

2019). An example of this is reported by Carlson et al. (2017), who evaluated the effect of

five fibers supplementation on the SCFA’s production in healthy individuals. These authors

observed a higher colonic production of propionate and a significant increase in the genus

Bifidobacterium when commercial oatwell and XOS were administrated; also, an increase of

the beneficial genus Collinsella was reported after inulin and chicory whole fiber

consumption. The rapid assimilation of dietary fibers depends on the range of extra-cellular

glycosidases and transport systems present in each of the bacterial species of HGM. For

instance, bifidobacteria can metabolize low-molecular-weight carbohydrates, while the

Lactobacillus species such as Lactobacillus acidophilus can metabolize both high and low

molecular fructans, may be due to the production of fructan-β-fructusidases. Conversely,

Bifidobacterium longum subsp. infantis prefer short-chain FOS, which may result from the

lack of extracellular β-fructofuranosidase (Martínez-Gutiérrez et al., 2017). So, anaerobic

bacteria under specific intestinal conditions can metabolize complex carbohydrates and thus

carry out the generation of metabolites (Makki et al., 2018). These metabolites can be

classified into primary and secondary. The primary metabolites are those products of

metabolism that are essential for growth or that are by-products of energy-yielding

12
metabolism such as SCFA’s. Meanwhile, the secondary metabolites do not have an obvious

role in the cell metabolism (Verbeke et al., 2015).

As mentioned above, SCFA’s are produced from the fermentation process by colonic bacteria

along with hydrogen, methane, carbon dioxide and lactate, which at the same time serve as

energy source for certain colonic bacteria (Rowland et al., 2018). Particularly, Bacteroides

are the dominating genus that digests the polysaccharides and releases simple sugars useful

for the glycolysis metabolism. In addition to adenosine triphosphate (ATP) formation, the

further hydrolysis of these biomolecules leads generation of more ATP, simple carbon

molecules and SCFA’s derived from colonic bacterial metabolism, which possess an integral

role since the colonocytes use more butyrate as an energy source than more available

compounds such as glucose or glutamine (Slavin, 2013; Carlson et al., 2017).

Through the different stages in life, the pattern and amount of SCFA’s change as the diet and

HGM: in early infancy acetate predominates and by the age of two years butyrate production

increases and becomes more similar to that observed in adults (Verbeke et al., 2015). The

majority of SCFA’s producing bacteria belong to distinct families of the Firmicutes, but

members of other nine families such as Actinobacteria, Fusobacteria, Proteobacteria,

Spirochaetes and Thermotogue, have been identified as potential butyrate producers bacteria.

Likewise, other bacteria belonging to Eubacterium, Roseburia and Faecalibacterium genus

can produce butyrate from bacterial lactate and acetate metabolism. This cross-feeding

process allows to explain the differences between the results obtained from a single bacterial

culture and those obtained from a bacterial co-culture in vitro and in vivo assays (Holscher,

2017; Thongaram, Hoelflinger, Chow & Miller, 2017). The main probiotic fermentative end
13
products inside the gastrointestinal tract are the SCFA’s. However, the concentration of

SCFA’s varies through the intestinal tract, the highest concentration is found in the proximal

colon and decreases in the distal colon, this last region is where great number of microbes

exist (Holscher, 2017). The principal beneficial effects of SCFA’s are their influence on

gastrointestinal tract cell integrity, glucose homeostasis and immune function modulation

(Koh, de Vadder, Kovatcheva-Datchary, & Bäckhed, 2016).

From all SCFA’s produced from prebiotic fermentation by HGM, the butyrate is considered

as one of the most important colon metabolites because it serves as a source of energy for the

colonocytes, has anti-inflammatory properties and regulated gene expression (Sanders et al.,

2019). Although the production of these functional metabolites depends on the fermenting

species and the fermented substrate, the information presented above indicates that the

consumption of prebiotics is a viable strategy for generation of this type of metabolites via

modulation of the HGM.

5. HUMAN GUT MICROBIOTA AND HOST HEALTH

The HGM is a dynamic community of millions of microorganisms, dominated by bacteria

with Firmicutes and Bacteroidetes as the most abundant phyla, and usually separated from

the host by a single layer of epithelial cells (Nogacka et al., 2019; Wan, Ling, El-Nezami, &

Wang, 2019). The localization and spatial organization of the HGM are not uniform along

the gut tract. The highest density of microorganisms is present in the colon, with an estimated

concentration of 1013 bacteria cells per gram of contents, associated with a broad range of

enzymes for dietary ingredients biotransformation (Verbeke et al., 2015; Clarke et al., 2019).

After digestion, the direct microbial biotransformation of dietary ingredients occurs in the
14
intestinal lumen determined by the fermentation patterns and the gut tract times. In this

context, carbohydrates fermentation promotes the production of specific bacterial

metabolites such as vitamins and SCFA’s, some of them with health benefits (Verbeke et al.,

2015). For example, SCFA’s production inhibits the growth of pathogenic bacteria by

reducing the luminal and fecal pH; as well as reduces the formation of toxic nitrogen

(ammonia, ammines) and phenolic compounds, and decreases the activity of undesirable

bacterial enzymes (Slavin, 2013).

The HGM composition, and thus, the production of microbial metabolites varies among the

individuals and within them throughout life. However, studies have shown the presence of a

“core microbiome” shared between healthy humans constituted by specific and stable

microbial gene families, metabolic modules and regulatory pathways with positive effects on

the host physiology homeostasis (Nogacka et al., 2019; Wan et al., 2019). Nevertheless, host

extrinsic and intrinsic factors such as diet, age, medications, illness, stress and lifestyle

conditions can modify the composition and functionality of HGM. The principal effect of

these modifications is the disequilibrium in microbiota, also known as dysbiosis, related to a

decrease in intestinal bacterial richness, variation in abundance of microbial genes and

functions, inflammatory bowel disease, autism, colon rectal cancer, among others (Nogacka

et al., 2019). Usually, the gastrointestinal diseases are treated by using drugs, although in

some cases may produce harmful side effects such as antibiotic-associated diarrhea. Because

of this, the dietary modulation has opened an opportunity for the employment of functional

foods as drug alternatives for human gut health improvement (Wan et al., 2019). Functional

foods are part of the human diet, provide health benefits and decrease the risk of chronic

diseases beyond their nutritional contributions. This concept encompasses the dietary fiber,
15
prebiotics and probiotics as beneficial modulators of the HGM composition and metabolism

(Al-Sheraji et al., 2013). The probiotic genera present in the gut tract are used as makers of

healthy HGM and are consider targets for the dietary stimulation (Carlson & Slavin, 2016).

This selective stimulation guarantees the presence of bacteria with health beneficial

properties for the host; however, currently is has been observed that the beneficial effects not

only depend of viable bacteria, but on the metabolites produced by them as a result of the

specific dietary component metabolism (Dahiya et al., 2017; Peng et al., 2020).

Because to this, is necessary to determine the relationships between the consumption of

dietary components, specifically dietary fiber and prebiotics, and the improvement of HGM

and host health by microbial stimulation. Therefore, in the following lines the effect of

dietary fiber and prebiotics on the HGM metabolism will be revised and focused on the

synthesis of specific microbial metabolites with host health benefits.

6. BENEFICIAL EFFECTS OF METABOLITES PRODUCED BY HUMAN GUT

MICROBIOTA FROM DIETARY FIBERS AND PREBIOTICS METABOLISM

As mentioned above, the HGM is a complex microbial ecosystem that produce a wide range

of metabolites as result of dietary fibers and prebiotics fermentation. Such metabolites may

be absorbed and then, influence in the improvement or decrease health status of host. Many

of the proposed health effects derivatives of the addition of prebiotics and dietary fibers are

based on the eventual production of bacterial metabolites obtained from carbohydrates

fermentation (Fig. 1) (Verbeke et al., 2015; Wegh, Geerlings, Knol, Roeselers, & Belzer,

2019). In addition, is important to mention that the same as the HGM, the production of

bacterial metabolites with health effects inside the gastrointestinal tract varies between
16
individual; being then dependent of the specie and strain of the fermenting microorganism

and the type of dietary component administered (Peng et al., 2020). In this sense, it has been

reported that the Western diets, reduced in dietary fibers are related to the long-term

incidence of a number of gut tract diseases (Danneskiold-Samsøe et al., 2019). Thus, in the

following lines are listed the benefits of some metabolites produced by the HGM as result of

the addition and metabolism of a specific prebiotics or dietary fibers.

6.1 Defense against pathogenic bacteria

Probiotics can produce organic acids as result of their metabolism, resulting in reduction of

the luminal pH, inhibiting the growth of pathogens (Sanders et al., 2019). Vulevic et al.

(2015), observed a notably enhanced the lactic acid production, phagocytic activity and

activity of natural killer cells against pathogenic bacteria in the lumen of elderly individuals

(age 65-80 years), after administration of 5.5 g/day of GOS for 10 weeks. Moreover, the

prebiotics consumption has been related to anti-adherence effect, as shown by inulin and

short-chain FOS in presence of Escherichia coli O157:H7. This effect does not promote the

generation of HGM metabolites, however, improve the maintenance of epithelial barrier

function and protect from injury caused by non-invasive pathogens trough the induction of

select tight junction proteins (Wu et al., 2017a). Animal studies showed that the intake of

dietary fibers can prevent pathogenic infection by acidification of the colonic lumen (Jasso-

Padilla et al., 2016; Metzler-Zebeli et al., 2019); this effect could be associated to the

production of SCFA’s after dietary fiber fermentation, which are effective in lowering the

levels of pH-sensitive pathogens in the gut (Verspreet et al., 2016). Therefore, the

consumption of prebiotics seems to be key issue to improve the function of the intestinal

17
barrier, avoiding the adhesion, proliferation and translocation of pathogenic bacteria,

maintaining the homeostatic state of the host.

6.2 Appetite control and anti-obesity effect

The presence of obesity is associated to the activation of low grade inflammatory signaling

molecules from adipose tissue such as TNF-α, IL-1 and IL-6, which disrupt the correct

metabolism and can generate insulin resistance (Ouchi, Parker, Lugus, & Walsh, 2011). Once

consumed, the colonic fermentable carbohydrates are metabolized into SCFA’s, which

crosses the blood-brain barrier and suppresses appetite by central hypothalamic mechanisms

(Verbeke et al., 2015). Propionic acid reduces lipogenesis and cholesterol synthesis and

activates G protein-coupled receptor (GPR) 41 and GPR43, releasing satiety hormones that

exercises anti-inflammatory effects (Verbeke et al., 2015; Honda & Littman, 2016; Rogers

et al., 2016). About 10% of daily energy requirement by the host epithelial cells and more

than 70% of energy for cellular respiration are obtained from SCFA’s derived from prebiotics

or dietary fibers fermentation. However, periodic acquisition of energy from SCFA’s allows

fat deposition which triggers obesity development (Dahiya et al., 2017). Besides, significant

reduction in concentration of butyrate producing bacteria such as Roseburia and

Eubacterium, was also observed in obese human. This finding suggests that there is a relation

between the HGM composition, and the obesity development based on SCFA’s production

(Louis & Flint, 2009). In this sense, van der Beek et al. (2018), found that the SCFA’s

obtained from inulin fermentation regulate the balance between fatty acid synthesis,

oxidation and breakdown in vitro. Fatty acid oxidation is activated in the liver and muscle

tissue, while fatty acid synthesis and lipolysis are inhibited in the liver and adipose tissue

(Hong et al., 2005; Gao et al., 2009; Yamashita et al., 2009). These effects are based on the
18
capacity of bacterial SCFA’s to be converted into acetyl-CoA, which enters the citric cycle

in mitochondria and is used for oxidation in the liver and muscle after activating the

adenosine monophosphate (AMP)-activated protein kinase (AMPK) (van der Beek et al.,

2018).

The production of SCFA’s not only depends of HGM richness, but other factors such as

availability of substrate, mucosal absorption, interactions between different HGM species

and transit time of food (Dahiya et al., 2017). Regarding the time of gastrointestinal transit,

fibers slowdown gastric emptying and decrease the glucose absorption in the gut tract, also,

the insulin response may be blunted. The slow transit of food, generated by dietary fiber

consumption, increases the release of gut satiety hormones which regulate food intake and

energy balance to finally send satiation signals to the brain (Slavin, 2013).

In the case of prebiotics, it has been reported that inulin fructans increase intestinal pro-

glucagon and glucagon-like peptide 1 (GLP1), and simultaneous decrease the ghrelin in

treated Wistar rats in comparison to the control (Dahiya et al., 2017). These hormones are

involved in the regulation of appetite and body weight in human and animal models. GLP1

is an incretin hormone responsible for the liberation of insulin and has been linked to the

presence of SCFA’s in the intestinal lumen. Butyrate seems to be the principal potently of

GLP1 release, followed by propionate and acetate (Danneskiold-Samsøe et al., 2019).

Similarly, an obesity amelioration effect was observed in Wistar rats administered with FOS;

due to the modulation of expression of gut situated peptides as GLP1. The effect of prebiotics

consumption on the generation of these hormone could be elucidated as a modulation of

HGM composition, of SCFA’s producer bifidobacteria and lactobacilli present in HGM

19
(Dahiya et al., 2017). For example, colonic propionate production may attenuate the reward-

based eating behavior in humans, via striatal pathways independent of PYY and GLP1

changes in plasma (Byrne et al., 2016). According to de Vadder et al. (2016), the

consumption of FOS enriched diets can induce to Prevotella to produce other type of

metabolites such as succinate, and organic acid that improve glycemic control and energy

metabolism positively affecting the hepatic glucose production and body weight in C57BL/6J

mice.

da Silva, dos Santos, and Bressan (2013), found that bifidobacteria promotes its growth in

presence of prebiotics and ameliorates obesity. Nevertheless, the stimulating effect of

prebiotics is not only restricted to a specific bacteria genus, but also influences other bacteria

taxa that play an important role in obesity. Prebiotic feeding in obese mice generates a

decrease in Firmicutes, while an increase in Bacteroidetes was observed. This change in

microbial proportion was also observed for more than 100 distinct taxa. This leads to

identification of new genus present in HGM, such as Akkermansia; whose presence in the

gut tract is negatively correlated with obesity development and its supplementation shows

weight lowering effects (Dao et al., 2016; Remely et al., 2016). Likewise, Schneeberger et

al. (2015), observed a positive role of Akkermansia in obesity treatment, which was validated

by an alleviation of pathophysiological parameters and reduction in body weight in high fat

diet mice. In obesity, the prebiotics administration stimulates growth of Akkermansia that

concomitant increases the intestinal levels of endocannabinoid, regulating intestinal

inflammation, gut permeability, and anorexigenic peptide release (Dahiya et al., 2017).

Additionally, Akkermansia spp. has shown host protection against insulin resistance and was

found to thicken the mucin layer (Burokas et al., 2017).

20
In humans, the obesity has been associated to phylum-level changes in HGM, reducing

diversity and altering metabolic pathways genes (Dahiya et al., 2017). FOS treatment

increased hydrogen excretion in the breath by 3-fold as a result of HGM fermentation and

reduced hunger rates. Furthermore, the prebiotic increases satiety hormones in plasma, while

decreasing postprandial plasma glucose after the normal diet (Slavin, 2013). Regarding to

glucose control, a recent study by Zhao et al. (2018), demonstrated positive effects of dietary

fiber metabolism by HGM in type 2 diabetic individuals, linked to GLP1 secretion

enhancement and improvement of glycosylated hemoglobin (HbA1c), which is not affected

by the sudden changes in blood glucose concentration. Meanwhile in type 1 diabetes, the

SCFA’s acetate and butyrate exhibited a reduction of diabetes in non-obese diabetic mice by

boosting colonic regulatory T (Treg) cells function, minimizing the number of autoreactive

T cells and improving the gut barrier (Mariño et al., 2017). After their production by HGM,

SCFA’s are absorbed and used in different host biosynthetic routes. Propionate is

incorporated in gluconeogenesis, whilst acetate and butyrate are introduced in lipid

biosynthesis, showing a potential role in the control of metabolic syndrome. This protective

effect of SCFA’s seems to be dependent of down-regulation of the peroxisome proliferator-

activated receptor gamma, changing lipid synthesis and oxidation (Ríos-Covián et al., 2016).

During the last decade, an association between obesity and HGM composition has been

demonstrated in animal and human studies, highlighting the higher Firmicutes:Bacteroidetes

ratio in obese subjects (Zou et al., 2020). This condition promotes a more effective

fermentation capacity in obese animals and humans compared with normal-weight subjects,

which would explain the increased concentration of caecal and faecal SCFA’s. However,
21
later studies observed that the HGM composition and obesity in human subjects is less clear

and may be associated to more subtle changes in the HGM composition (Magne et al., 2020).

6.3 Improvement of minerals absorption

Inulin, oligofructose, FOS, GOS, soybean oligosaccharides, resistant starch, sugar alcohols

and di-fructose anhydride improve the absorption of vitamins, antioxidant compounds and

mineral micronutrients (calcium, magnesium, zinc, iron and copper), that collaborate to

amelioration of cancer risk (Scholz-Ahrens et al., 2016; Rivera-Huerta et al., 2017). There is

an increase of the solubility and absorption of minerals due to production of SCFA’s through

prebiotic fermentation. These SCFA’s stimulate the expression of calcium-binding proteins,

help in the degradation of phytic acid-mineral complex, augmented the absorption area,

stabilize the HGM richness and improve intestinal mucus (Scholz-Ahrens, Schaafsma, van

den Heuvel, & Schrezenmeir, 2001; Raman et al., 2013). Once liberated or solubilized, most

of the minerals serve as cofactors in the biochemical processes present in bacterial cells of

HGM. Accordingly, zinc can improve metabolic activity of HGM resulting in an increase of

health parameters such as synthesis of SCFA’s. Additionally, some of these minerals possess

antimicrobial properties under specific conditions, helping in the prevention of gut infections

(Makki et al., 2018). Nevertheless, these effects seem to be specific to the type of fermentable

carbohydrate and depend of the ingested dose (Scholz-Ahrens et al., 2001).

As organic acids produced by the fermentation of prebiotics, the production of SCFA’s

reduces the pH luminal, increasing calcium solubility and facilitate the passive uptake

(Sanders et al., 2019). It has been shown that the consumption of a mixture of inulin-type

fructans (8 g/day), by young adolescents increases the calcium absorption in 32 of 48

22
individuals, comparable to a daily calcium intake by at least 250 mg (Abrams, Griffin, &

Hawthorne, 2007). Another study tested the effect of GOS uptake (by smoothie drinks with

2.5 or 5 g of GOS, twice daily for three weeks), in healthy adolescent girls. Significant

improvements in calcium absorption were observed with both doses of GOS, reaching an

increase in the population of bifidobacteria which is responsible for lowering the pH due the

production of SCFA’s (Whisner et al., 2013). These same results have been reported in

animal studies, using different prebiotics such as inulin-type fructans, lactulose and GOS,

concluding that minerals absorption such as calcium, magnesium or phosphorus are related

to the acidification of lumen by lactic acid or SCFA’s produced and excreted for probiotic

bacteria as result of prebiotic fermentation (Pérez-Conesa, López, Abellán, & Ros, 2006;

Whisner et al., 2013).

Weaver, Martin, Story, Hutchinson, and Sanders (2010), have proposed different

mechanisms by which the prebiotics, such as inulin and FOS, and soluble corn and dextrin

fibers stimulate mineral absorption. The authors suggested that the osmotic effect of

prebiotics promotes paracellular transport trough increased mineral solubilization in a large

fluid volume in the lower bowel. Another proposed mechanism agrees with the one

mentioned previously, which involves an increase in surface area in response to colonic cell

proliferation with SCFA’s generation (acetate and n-butyrate). Possibly, fermentable fibers

also increase hypertrophy or permeability of gut epithelial cells and increase water-holding

capacity which promote a nutrient reservoir and HGM alteration, increasing mineral

absorption (Weaver et al., 2010; Skrypnik & Suliburska, 2017).

6.4 Intestinal barrier reinforcement

23
In the gut tract, the epithelium is covered by a mucus layer keeping bacteria separated from

the mucosa. This structure may be disrupted by an altered gut microbiota resulting from a

low fiber diet, which enhances the susceptibility to infections and development of chronic

inflammatory diseases (Desai et al., 2016: Makki et al., 2018; Schroeder et al., 2018). The

fiber induces the production and secretion of mucus by butyrate and acetate interaction.

These SCFA’s produced by specific bacteria such as Bacteroides thetaiotaomicron, also

contribute to goblet cells differentiation and expression of mucin-related genes (Makki et al.,

2018). Likewise, bacterial butyrate influences mucin synthesis, improving both bacterial

transport across the epithelium and increase the thigh junction assembly, enhancing the

permeability of gut barrier (Peng, Li, Green, Holzman & Lin, 2009). These beneficial effects

are obtained after butyrate oxidation by colonocytes, which consume oxygen and turn the gut

into an anaerobic milieu. This environment is optimal for growth of butyrate producing

bacteria from prebiotics metabolism. However, if the concentration of this type of anaerobic

bacteria decreases, the intestinal lumen would become in an oxygenated environment which

may lead Escherichia coli and Salmonella enterica serovar Typhimurium to growth (Makki

et al., 2018). Therefore, the adequate consumption of prebiotics and dietary fibers could

guarantee the integrity of intestinal barrier and its reinforcement (derived from the

metabolism of the bacterial SCFA’s by the colonocytes), avoiding infections by pathogenic

bacteria. Regardless of the antimicrobial effect generated by the decrease in intestinal pH due

to the production of SCFA’s and lactic acid by the HGM.

6.5 Immune response improvement

The immunomodulatory effect of prebiotics is influenced by the existing HGM diversity.

Anaerobic fermentation of prebiotics produces mainly SCFA’s which can modulate the
24
expression of genes responsible for production of anti-inflammatory cytokines in epithelial

tissue (Pretorius, Prescott, & Palmer, 2018). The levels of SCFA’s are related to the presence

of diseases like IBD, atherosclerosis, diabetes and cancer (Yahfoufi, Mallet, Graham, &

Matar, 2018). In this sense, both plant- and human breast milk-oligosaccharides are

metabolized by select groups of bacteria producers of SCFA’s and lipopolysaccharides

(LPS). However, the immune effect is specifically related to the subtype of metabolite

produced by the bacteria genera. For example, Bacteroides-derived LPS lacks

immunogenicity and thus, do not reduce the development of type 1 diabetes (Wu, Jeffrey,

Johnson-Henry, Green-Johnson, & Sherman, 2017b).

Regarding to SCFA’s, these compounds can promote the generation of colonic Treg cells by

binding to GPR41, GPR43 and GPR109A (dependent of butyrate interaction) on dendritic

cells, as well as by inducing histone H3 acetylation and expression of aldehyde

dehydrogenase, resulting in suppression of the pro-inflammatory cytokine secretion (Honda

& Littman, 2016). In the pregnancy and lactation, a high-fiber feeding increases butyrate

levels in the blood of the offspring and contributes to the enhancement of peripheral and

thymic Treg counts of the animals in a GPR41-dependent manner. In the same way, the

butyrate production may mediate the secretion of IL-18 via intestinal epithelial cells, by

interaction with GPR109A, which is reported to be involved in the suppression of colonic

inflammation (Danneskiold-Samsøe et al., 2019). In animal models of IBD, the reduced

levels of SCFA’s in faeces are associated with disease severity, while in human models, the

lack of potentially SCFA’s producer bacteria is indicative of Crohn’s disease patients (He et

al., 2017). So, the production and presence of SCFA’s in colon is a critical factor for the

25
regulation and maintenance of normal function of the innate and adaptive immune system

(Makki et al., 2018).

In addition to the gut tract, the immunomodulatory effect of SCFA’s produced by HGM may

influence the lung immune system related to asthma development. A low fiber diet increases

the production of asthma markers such as: IL-4, IL-5, IL-13, IL-17, goblet cell hyperplasia,

IgE antibodies and production of mucus in lung tissue. Conversely, the presence of these

makers was diminished in mice subjected to pectin-rich diet, a readily fermentable dietary

fiber (Trompette et al., 2014; Wood, 2017; McLoughlin et al., 2019).

6.6 Anticancer effects

It is widely known that the cancer incidence and susceptibility is determined by the gene-

environment interactions and microbial communities of HGM (Sharma & Shukla, 2016). The

cancer incidence, specifically the colon rectal cancer (CRC), which is the third most common

cancer in both women and men and the second leading of cancer-associated mortality; is

influenced by the balance of microbial production metabolites (Makki et al., 2018). Femia et

al. (2002), evaluated the protective effect of symbiotic (inulin separately mixed with

Bifidobacterium lactis Bb12 and Lactobacillus rhamnosus GG), against azoxymethane-

induced colon cancer in rats, observing an increase in bacterial butyrate production, lower

proliferative activity and a variation in the expression of enzymes involved in the

pathogenesis of CRC. Similar results are reported in rodent models, in which long-chain

inulin-type fructans and short-chain FOS showed inhibitory effects on reduction of

azoxymethane-induced colonic pre-neoplastic aberrant crypt foci, by lowering pH and

modulating the immune response (Verghese, Rao, Chawan, Williams, & Shackelford, 2002;
26
Raman et al., 2013). Respect to SCFA’s generation, butyrate promotes colon motility,

reduces inflammation, increases visceral irrigation, induces apoptosis of cancerous

colonocytes and inhibits cell progression (Zitvogel, Daillère, Roberti, Routy, & Kroemer,

2017). On the other hand, propionate induces the differentiation of Treg cells, contributing

to control of intestinal inflammation via histone deacetylation (Kolida & Gibson, 2011; Ríos-

Covián et al., 2016).

Prebiotics show anti-carcinogenic activity through functional properties such as: stimulation

of beneficial indigenous bacteria, production of SCFA’s and lactic acid as fermentation

products (Wen et al., 2020). Modifications of gene expression in the cecum, colon and feces,

increase the absorption of micronutrients in the colon, modulate the activity of xenobiotic

metabolizing enzymes and the immune response (Raman et al., 2013). On the contrary, a

low-carbohydrate diet does not only reduce the SCFA’s production, but also increases the

potentially detrimental metabolites derived from amino acids fermentation including

branched-chain fatty acids, ammonia, amines, N-nitroso compounds, p-cresol, sulphides,

indolic compounds and hydrogen sulfide. These compounds show a cytotoxic and pro-

inflammatory nature that contribute to the development of chronic diseases, particularly CRC

(Makki et al., 2018).

Lactic acid, SCFA’s, linoleic acid, some glycoproteins/peptides and potentially carcinogenic

metabolites such as amines and secondary bile acids, are extra-cellular microbial metabolites

that affect the host-specific physiological functions connected with the activity of host

indigenous microbiota (Shenderov, 2013). However, the metabolites produced by the HGM

help to maintain the homeostatic state in the gut, enhancing the growth of beneficial bacteria
27
that can inhibit the conversion of pro-carcinogens into carcinogens, mainly inactivating

enzyme levels of nitro-reductase, β-glucoronidase and β-glucosidase (Verma & Shukla,

2015). In this sense, it has been reported that supernatants of Lactobacillus casei and

Lactobacillus paracasei, isolated from human breast milks, showed cytotoxicity against

cervical cancer cells, potentiating their use as natural antitumor drugs (Chuah et al., 2019).

Furthermore, lactobacilli and bifidobacteria have shown the ability to bind and eliminate

carcinogens from the intestinal system; as reported by Serrano-Niño et al. (2014), who

evidenced in an in vitro study that Lactobacillus strains can bind to two dietary carcinogens:

aflatoxin B1 and acrylamide, by interactions with their teichoic acids of the cell wall.

The production of SCFA’s from prebiotic fermentation by HGM, is the key for the

maintaining gut health, intestinal morphology, and function (Raman et al., 2013). SCFA’s,

mainly acetic, propionic and butyric, generate an increase in levels of glutathione-S-

transferase and glutathione-transferase-pi which contribute to the stability of colon cells

(Sharma & Shukla, 2016). As for the effect of dietary prebiotics/fibers on the anticancer

effect of bacterial metabolites, it has been demonstrated that the butyrate production by

fermentation of starch amylose reduces the oxidative stress in gut and may also activate pro-

carcinogen metabolizing enzymes that contribute in colon cancer prevention (Treptow-van

Lishaut, Rechkemmer, Rowland, Dolara, & Pool-Zobel, 1999). Meantime, in diets of

Western countries, relation between the low fiber content and lower HGM diversity has been

observed, especially a reduction of butyrate-producing bacteria (Cantu-Jungles, Rasmussen,

& Hamaker, 2019). The combination of these factors has been suggested to contribute to

increase IBD and Crohn’s disease development and prevalence. Indeed, the chronic

prevalence of IBD can lead CRC development, so for a potential reduction in the incidence
28
of some type of cancers, the consumption of a diet low in fats and high in fiber-containing

grain products, vegetables and fruits is recommended (Makki et al., 2018).

Similarly, butyrate has a key role related to cell differentiation, apoptosis by inhibition of

histone deacetylase, angiogenesis in cancer cells, regulation of the proliferation of normal

cells, promotion colon healing in colitis, and improvement of the function of the intestinal

barrier (Verbeke et al., 2015; Sharma, Chandel, & Shukla, 2019). Whilst, lactate improves

the gut health, immune defense and increases the absorption area in the intestinal barrier.

Meanwhile, propionate and acetate induce apoptosis in human colorectal cancer cell lines

(Raman et al., 2013).

On the other hand, the effect of prebiotic addition to probiotic cultures has been reported by

in vitro study of Le, Ngoc, and Yang (2020), who observed an inhibition in the proliferation

of Caco-2 and HCT116 cell lines when XOS were added to a fermented soymilk by bacteria

cultures of Weissella cibaria FB069 and L. rhamnosus GG. In other study it was observed

that colon cells treated with the supernatant of inulin fermentation by lactic acid bacteria

elevated the levels of glutathione S-transferase-pi, enzyme chemopreventive against

mutagens (Scharlau, Borowicki, & Habermann, 2009). However, the anti-mutagenic activity

depends upon the growth phase, cell number of bacterial strains and mutagen type (Raman

et al., 2013). Furthermore, new investigations are necessary to confirm the use of prebiotics

and dietary fiber as microbiome modulators, and the potentially beneficial effects obtained

from this modulation, on cancer treatment.

6.7 Brain function modulation

29
The HGM can modulate indirectly the brain function through the innate immune response by

alterations in pro- and anti-inflammatory cytokines levels in blood (Rogers et al., 2016). The

HGM can also affect the immune system directly via activation of vagus nerve and triggering

bidirectional communication with the central nervous system (CNS) (Rogers et al., 2016).

The HGM-metabolites generated from prebiotics or dietary fibers metabolism: bacterial LPS,

polysaccharide A or surface-exopolysaccharyde, SCFA’s, glutamate; access the lamina

propria after cross or bypass the epithelium to act directly on CNS. Once translocated, the

bacterial metabolites interact with specific receptors such as Toll-like receptors and G-

protein coupled receptors (Liu, Cao, & Zhang, 2015). The SCFA’s produced can interact

with nerve cells by the sympathetic and autonomic nervous system via GPR41 and GPR43,

showing a regulatory function in microglia homeostasis necessary for the correct brain

development (Fig. 2). Also, the SCFA’s can regulate the synthesis of gut-derived 5-

hydroxytryptamine (5-HT) serotonin from enterochromaffin cells (EC), which is linked to

psychiatric disorders such as depression (Rogers et al., 2016; Pusceddu, Murray, & Gareau,

2018). The 5-HT from EC has intrinsic roles within gut tract, mainly in the metabolic control

by activating afferent nerve endings in order to send signals to the CNS. Moreover, is unclear

whether the alteration on tryptophan levels reflects increased bacterial utilization or is a

product derived from bacterial metabolism which impact on tryptophan to serotonin

metabolism of the host (Burokas et al., 2017). In addition to SCFA’s and tryptophan

byproducts, the HGM is capable to produce other neuroactive and immunomodulatory

compounds including dopamine, γ-aminobutyric acid (GABA), histamine and acetylcholine

in the lumen of gut tract; however, these neurotransmitters may have an indirect influence on

brain function acting on the enteric nervous system, instead of crossing the blood brain barrier

(BBB) (Rogers et al., 2016; Pusceddu et al., 2018).

30
These findings suggest that the prebiotics metabolism by HGM impacts on brain chemistry,

increasing brain-derived neurotrophic factor (BDNF) expression, involved in learning and

memory process, probably through the liberation of gut hormones, which function as

neurotransmitters to CNS (McVey et al., 2017).

Animal study by McVey et al. (2017), showed that supplementation of probiotic LGG (L.

rhamnosus GG), prebiotics PDX (polydextrose) and GOS, or both in combination, generated

a reduction in the expression of glucocorticoid receptor, mineralocorticoid receptor and

BDNF in the hippocampus of rodents early-life stressed due to maternal separation. The

supplementation of the probiotic and prebiotics in rodent diet resulted in a normalization of

deleterious effects of stress conditions, without altering the body weight gain or food and

fluid intake. Thus, the effects produced by the supplementation of prebiotics on the HGM,

can be useful to treat the state of stress without affecting normal eating patterns. Although

the effects obtained in brain modulation are due to the metabolites produced by probiotics or

by the bacteria present in HGM, it is the consumption of prebiotics that stimulates the

metabolism of different species of beneficial bacteria simultaneously, offering a synergistic

effect (Liu et al., 2015).

Bacterial metabolites are considered another pathway of communication between the gut

tract and brain. SCFA’s such as butyric, propionic and acetic acids have shown an influencing

effect on memory and learning processes through histone deacetylase modulation in rodents

(Pusceddu et al., 2018). In this context, Burokas et al. (2017), observed that the chronic

administration of FOS, GOS and combination of both, modified behavior, and brain
31
chemistry relevant for the anxiety and depression in mice. The authors reported changes in

microbial community, coupled with an increase of caecal weight and higher levels of SCFA’s

in the cecum.

The complex network of communication between the HGM and the brain comprises the

CNS, both sympathetic and parasympathetic branches of the autonomic nervous system,

bacterial metabolites such as SCFA’s and serotonin metabolism (Burokas et al., 2017). In

this sense, the availability of tryptophan is influenced by the HGM. The gut tract bacteria can

metabolize tryptophan, obtained from proteins or peptides denaturalization, and use it for

growth and subsequently produce indole, indole-3-aldehyde, and tryptamine with different

ligand properties (Rogers et al., 2016; Danneskiold-Samsøe et al., 2019). The tryptophan is

an essential diet-derived amino acid required for serotonin synthesis in the CNS once it has

crossed the BBB. However, the availability of tryptophan in the intestinal lumen is highly

influenced by the HGM, altering the serotonergic neurotransmission in the gut-brain axis

(Fig. 2) (Rogers et al., 2016). It is unclear whether the alteration of tryptophan availability

reflects an increase of bacterial utilization of this serotonin precursor or the bacterial

metabolites affect the local host tryptophan metabolism for serotonin obtaining (Burokas et

al., 2017). Therefore, the use of selective dietary microbial growth substrates, such as

prebiotics, may be appropriate for broad-scale alteration of HGM in order to relate different

species with the ability to produce metabolites with immunomodulatory functions that

directly affect the brain activity (Rogers et al., 2016).

7. CONCLUDING REMARKS

32
Currently, there is enough knowledge about the impact of dietary components on the

diversity of the intestinal microbiota and its effect on the generation of metabolites with

benefits to the host health (Table 1). At present, the SCFA’s produced from dietary

components fermentation, seem to be the principal bacterial metabolites produced by HGM

responsible of several healthy effects and modulation of the intestinal microbiota of the host.

However, it has been shown that the modulation of HGM does not depend only on diet or the

components present in it, but also on the diversity and mutualistic interactions of HGM, the

diet components and the presence or absence of specific bacterial genera. This review

addresses the knowledge related to the interaction mechanisms of the microbial metabolites,

obtained after the metabolism of prebiotics and dietary fibers by HGM, and their effects on

the health of the host; in order to demonstrate the importance of incorporating these health-

promoting dietary components into the diet.

Nonetheless, future research requires a more in-depth study related to individualized analysis

of HGM richness and the interplay with food components such as dietary fibers, prebiotics,

proteins, or phytochemicals, always focused on their role in human health homeostatic

modulation. Furthermore, the evidence base is still limited since there is a lack of in vivo

studies as well as the use of these bacterial species and metabolites separately in clinical trials

and the employment of these findings as possible therapeutic use in a concomitant state.

Therefore, the information from such analysis would be the starting point for the prevention

of lifestyle-associated diseases through a personalized functional diet.

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Table 1. Healthy bacterial metabolites produced by HGM from prebiotics fermentation.

Bacterial
Health effect Prebiotic/HGM specie Proposed mechanism Reference
metabolite
Antipathogenic GOS/Bifidobacterium Lactic acid Improvement of NK* cells activity Vulevic et al. (2015)
spp.
Dietary fiber/ B. SCFA’s* Decrease luminal pH from 6.7-6.5 to Verspreet et al.
thetaiotaomicron 5.5 (2016), Dahiya et al.
(2017)

FOS/No No metabolite Anti-adherence effect on E. coli Wu et al. (2017a)

microorganisms O157:H7

Appetite control Dietary fiber/P. copri SCFA’s, succinate Improve glucose tolerance and Kovatcheva-Datchary
and anti-obesity promotion of glycogen storage. et al. (2015); de
effect Employment of succinate as Vadder et al. (2016)
intestinal gluconeogenesis
Dietary fiber/Gut Acetate and Anti-inflammatory effect by Verbeke et al. (2015);
bacteria propionate reduction of lipogenesis and Honda and Littman
cholesterol synthesis; and GPR* (2016)
activation
Inulin fructans, Butyrate, Regulation of appetite and body Dahiya et al. (2017);
FOS/Bifidobacteria, propionate and weight trough induction of GLP1* Danneskiold-Samsøe
Lactobacilli acetate release et al. (2019)

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Mineral Inulin, FOS, GOS, SCFA’s, lactic acid Mineral solubility and absorption Scholz-Ahrens et al.
absorption Resistant Starch/Gut improvement (2001)
bacteria
GOS/Bifidobacteria SCFA’s Higher mineral absorption by Whisner et al. (2013)
lowering pH
Oligofructose, Acacia SCFA’s Increase absorptive surface and Scholz-Arhens et al.
gum/L. acidophilus solubilization of calcium and (2016)
NCC90 phosphorus in the intestinal lumen;
stimulation phytic acid-mineral
complex degradation and improve
intestinal mucus
Lactose/Gut bacteria SCFA’s, organic Increase of mineral paracellular and Areco et al. (2015);
acids transcellular transport; increase of Scholz-Arhens et al.
caecal mucosa and soluble Ca (2016)
concentration

Intestinal barrier Dietary fiber, GOS, Butyrate, acetate, Enhancement of intestinal integrity Peng, He, Chen,
reinforcement FOS/Gut bacteria propionate by augmenting TEER* of a Caco-2 Holzman, and Lin
cell monolayer. Facilitation of tight (2007); Peng et al.
junction assembly via modulation of (2009); Elamin,
AMP*-activated protein kinase and Masclee, Dekker,
restore of barrier dysfunction via Pieters, and Jonkers
AMPK* signaling pathway (2013)
Dietary fiber/B. Butyrate, acetate Secretion of mucus, goblet cells Makki et al. (2018)
thetaiotaomicron differentiation and mucin-related
genes expression

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 Inulin/Gur bacteria SCFA’s Energy source for colonocytes and Wan et al. (2019)
regulation of intestinal permeability
Undigested Butyrate Maintenance of intestinal Liu et al. (2020)
carbohydrates/Gut homeostasis by production to IL-18*
bacteria after histone deacetylase inhibition

Immune response Inulin-oligofructose/B. SCFA’s Levels of mRNA human defensins, Childs, Röytiö,
improvement longum TNF-α* and IL*-1α diminished to Alhoniemi, and
concentration found in healthy Fekete (2014);
tissues Derikx, Dieleman,
and Hoentjen (2016);
GOS/Bifidobacteria Lactic acid, acetate Anti-inflammatory effect by higher Vulevic et al. (2015)
production of IL-10 and NK cells
activity
Dietary fiber/Gut SCFA’s Generation of colonic Treg* cells by Honda and Littman
bacteria binding to GPR on dendritic cells, (2016)
and expression of aldehyde
dehydrogenase suppressing pro-
inflammatory cytokines secretion
Oligosaccharides, GOS, SCFA’s Mucin gene expression, alteration of Barnett, Roy,
lactose/L. rhamnosus inflammatory response, epithelial Cookson, and
GG, L. plantarum 299v, cell adhesion and differentiation of McNabb (2018)
L. rhamnosus HN001 epithelial cells
and L. casei Shirota
Brain function Dietary fiber/L. Ferulic acid Stimulation of neurogenesis in Tomaro-Duchesneau
modulation fermentum NCIMB corticosterone-treated mice related to et al. (2012); Mori,
5221 prevention of Alzheimer disease Koyama, Guillot-

59
 Sestier, Tan, and
Town (2013)
FOS, GOS/Gut bacteria SCFA’s, LPS and Regulation of ENS* integrity by Brun et al. (2013)
EPS TLR*-2 signaling and increase of
enteric neurons and glial cells
Protein/Gur bacteria Tryptophan Translocation of the serotonin Rogers et al. (2016)
precursor and alteration of the
serontonergic neurotransmission in
the gut-brain axis
FOS, GOS/Gut bacteria SCFA’s Chronic administration of prebiotics Burokas et al. (2017)
controlled anxiety and depression in
mice modifying behavior and brain
chemistry
PDX, GOS/L. GABA Reduction of anxiety by reduced McVey et al. (2017)
rhamnosus GG expression of glucocorticoid,
mineralcorticoid receptors and
BDNF* expression

Anticancer Inulin/B. longum Not specified Decrease of β-glucuronidase activity Rowland, Rumney,
and ammonia concentration in the Coutts, and Lievense
caecal contents; both factors linked (1998)
to carcinogenesis in colon
Corn starch/Gut n-butyrate Induction of colonic glutathione-S- Treptow-van Lishaut
bacteria transferase preventing genotoxic et al. (1999)
impact of carcinogenic factors
Inulin/L. rhamnosus SCFA’s, secondary Reduction of colorectal proliferation, Rafter et al. (2007)
GG, B. lactis Bb12 bile salts induction of necrosis in colonic cells

60
 and improve epithelial barrier
function
Dietary fiber/L. Ferulic acid Antioxidant and anti-inflammatory Sadar, Vyawahare,
fermentum NCIMB properties by upregulation of IL-10 and Bodhankar
5221 (2016)
Dietary fiber/Gut Butyrate Protective effect against CRC* by Wei, Sun, Yu, Yang,
bacteria inhibition of histone deacetylase and Ai (2016)
*AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; BDNF: brain-derived neurotrophic factor; CRC: colon rectal cancer; GLP1: glucagon-
like peptide 1; ENS: enteric nervous system; GPR: G protein-coupled receptor; IL: interleukin; NK cells: natural killer cells; SCFA’s: short chain fatty acids; TEER:
transepithelial electrical resistance: TLR: Toll-like receptor; TNF-α: tumor necrosis factor alpha. Treg: regulatory T cells.

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Figure Captions:

Fig. 1. Interactions between human gut microbiota, bacterial metabolites from

prebiotics and dietary fiber fermentation and host health.
IN LAMINA PROPRIA: Bacterial short chain fatty acids (SCFA’s) propionate (PROP),
butyrate (BUT) and acetate (ACET), obtained from prebiotics and dietary fibers metabolism
cross the epithelium promoting T-regulatory cells (Treg) differentiation via histone H3
deacetylation (HDA), increasing anti-inflammatory cytokines (AIF-CYTK’s) liberation.
Concomitantly, the SFCA’s enter to portal vein stream and reach the liver tissue where
contribute to fatty acid oxidation in liver by oxaloacetate conversion and adenosine
monophosphate-activated protein kinase (AMPK) activation. Furthermore, differentiated
dendritic cells (DC) induce mucin generation genes (MGG) in enterocyte. BUT is the
principal energy source for the enterocytes, however, also participates with GPR49 in the
immune response of epithelium due the interaction with DC and the increase of anti-
inflammatory interleukins (AIF-IL’s) release, generating an anti-inflammatory effect and an
improvement of gut epithelium. IN INTESTINAL LUMEN: The bacterial production of
SCFA’s reduce luminal pH that avoid pathogens colonization and increase the Ca+2 solubility
and both paracellular and intracellular transport through enterocyte to lamina propria.
Finally, SCFA’s can decrease colon-rectal cancer (CRC) incidence by oxidative stress (OS)
reduction and irritable bowel disease (IBD) amelioration through activation of pro-
carcinogen metabolizing enzymes such as glutathione-S-transferase (GST). HGM: human
gut microbiota; BMT’s: bacterial metabolites; GOS: galactooligosaccharides; FOS:
fructooligosaccharides.

Fig. 2. Brain function modulation by bacterial metabolites from prebiotics and dietary
fibers metabolism.
Tryptophan (TRYPT), obtained from bacterial protein denaturalization, cross the intestinal
epithelium and then exerts vagus nerve signalization. After signalization, TRYPT interacts
with the hypothalamus (HYP) after being transported by the blood stream and modifies both
mood and cognitive process. Likewise, bacterial neurotransmitters (NT’s, such as GABA,
histamine, acetylcholine, indole and tryptamine) and serotonin (5-HT), interact with the
vagus nerve and simulate the central nervous system (CNS). Both HYP, NT’s and 5-HT
modulate the brain behavior improving the stomach satiety and the memory and learning
processes; at the same time that control the anxiety, depression episodes and obesity
development. Bacterial lipopolysaccharides (LPS) excites dendritic cells (DC) increasing
anti-inflammatory cytokines (AIF-CYTK’s) liberation and vagus nerve signalization.
Bacterial short chain fatty acids (SCFA’s) can enter blood stream and control the adrenal
liberation of cortisol, mediated by HYP, for stress amelioration into lamina propria and gut
epithelium. The SCFA’s stimulate both G-protein-coupled (GPR’s) and Toll-like (TLR’s)
receptors in the enterocytes improving the liberation of peptide YY and glucagon-like peptide
1 (GLP1), determinants for the satiety signaling and depletion of obesity development.

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HGM: human gut microbiota; BMT’s: bacterial metabolites; GOS:
galactooligosaccharides; FOS: fructooligosaccharides.

Chemical compounds studied in this review:

Butyric acid (PubChem CID: 264).
Propionic acid (PubChem CID: 1032).
Acetic acid (PubChem CID: 176).
Tryptophan (PubChem CID: 6305).
Lactic acid (PubChem CID: 612).
Gamma-Aminobutyric acid (PubChem CID: 119).
Dopamine (PubChem CID: 681).
Cortisol (PubChem CID: 5754).
Serotonin (PubChem CID: 5202).
Inulin (PubChem CID: 24763).

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64
65
Graphical abstract

66
Highlights
 Prebiotics and dietary fibers modulate HGM diversity after ingestion.

 Prebiotics and dietary fibers fermentations by HGM produce bioactive metabolites.

 Bacterial SCFA’s participate in specific mechanisms related to host health benefits.

 The intake of prebiotics and dietary fibers generates health benefits

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