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Food additives, contaminants and other minor components: effects on human

gut microbiota-a review

Article  in  Journal of physiology and biochemistry · May 2017

DOI: 10.1007/s13105-017-0564-2

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J Physiol Biochem
DOI 10.1007/s13105-017-0564-2

REVIEW ARTICLE

Food additives, contaminants and other minor components:

effects on human gut microbiota—a review
Paula Roca-Saavedra 1 & Veronica Mendez-Vilabrille 1 & Jose Manuel Miranda 1 &
Carolina Nebot 1 & Alejandra Cardelle-Cobas 1 & Carlos M. Franco 1 & Alberto Cepeda 1

Received: 25 January 2017 / Accepted: 10 April 2017

# University of Navarra 2017

Abstract Gut bacteria play an important role in several met- tract (GI) than the number of somatic cells (10 trillion cells)
abolic processes and human diseases, such as obesity and within their body [16, 28, 42]. Indeed, the gut microbiota
accompanying co-morbidities, such as fatty liver disease, in- (GM) contributes to health and disease in humans, being
sulin resistance/diabetes, and cardiovascular events. Among sometimes referred to as the Bforgotten organ^ [27].
other factors, dietary patterns, probiotics, prebiotics, The GM play an important role in a number of human
synbiotics, antibiotics, and non-dietary factors, such as stress, diseases, such as obesity [3, 51], diabetes [15, 94], [56, 74,
age, exercise, and climatic conditions, can dramatically impact 89, 114], cardiovascular diseases [38, 116], metabolic syn-
the human gut microbiota equilibrium and diversity. However, drome [27, 39, 68], non-alcoholic fatty liver disease [2, 38,
the effect of minor food constituents, including food additives 70], and in several psychiatric disorders [10, 45], which gut
and trace contaminants, on human gut microbiota has received microorganisms produce a large number of bioactive com-
less attention. Consequently, the present review aimed to pro- pounds that can influence human health [6]. Some (such as
vide an objective perspective of the current knowledge regard- vitamins) are beneficial, but other products can be harmful
ing the impacts of minor food constituents on human gut mi- [28]. Additionally, the GM interacts with the immune system,
crobiota and consequently, on human health. providing signals to promote the maturation of immune cells
and the normal development of immune functions [11, 35]. In
Keywords Antibiotics . Bacteroidetes . Dietary emulsifier . this context, GM microbes contribute to maintaining the in-
Firmicutes . Food additive . Gut microbiota . Non-nutritive tegrity of the intestinal epithelium, preserving cell-to-cell
sweetener . Proteobacteria junctions, promoting epithelial repair following injury, and
in the regulation of enterocytes turnover [103]. Thus, imbal-
ance in GM can result in a pro-inflammatory luminal environ-
Introduction ment that could contribute to the progression of low chronic
inflammation and metabolic disorders [38].
Humans have approximately 10 times as many microorgan- The association between the GM and non-transmissible
isms (approximately 100 trillion) within their gastrointestinal chronic diseases have been widely investigated [33]. Among
them, the link between the human GM and obesity has re-
ceived great attention [51]. Thus, the modulation of the GM
This article forms part of a special issue of the Journal of Physiology and
Biochemistry entitled BImpact of lifestyles patterns on human health:
can have beneficial effects to controlling obesity, and several
Integrated approach from the child to the elderly^ mechanisms that may contribute to microbiota-induced sus-
ceptibility to obesity and metabolic diseases have been pro-
* Jose Manuel Miranda posed [80]. Changes in dietary patterns, and specific function-
[email protected] al foods, prebiotics or probiotics intake, have the potential to
favorably influence host metabolism by targeting the GM and
1
Laboratorio de Higiene Inspección y Control de Alimentos. Dpto. de
may be a useful approach for the management of obesity and
Química Analítica, Nutrición y Bromatología, Universidade de other adverse metabolic conditions [80]. Various non-
Santiago de Compostela, 27002 Lugo, Spain nutritional factors, such as stress, age, exercise or climatic
 Roca-Saavedra et al.

conditions, can also dramatically affect the human GM diver- The development of the human GM is a large and complex
sity and equilibrium [28, 63, 68]. Additionally, the ability of process that begins during the fetal age [46]. Recent studies
minor food components, or additives and chemical contami- have reported that microbial contact is initiated throughout
nants, to modulate specific components of the GM has been the course of fetal development and continues thereafter in an
acknowledged. However, the attention paid to the effect of accelerated manner [31, 36, 46]. The diversity of the GM in the
these minor food constituents, food additives and trace con- infant gut is initially very low, and the GM are generally
taminants on the GM has received less attention. aerotolerant, as the gut initially contains oxygen, however, after
Consequently, the present descriptive aimed to provide an birth, they are replaced by anaerobes that are typically found in
objective perspective of the current knowledge surrounding the adult GM [27]. The GM alters considerably from birth to
the effects of these minor foods constituents on the human 6 months, when the GM appears to be relatively similar to the
GM, and, consequently, on human health. childhood-type population [36]. At this age, one of the most
important factors contributing to the formation of the GM is the
type of lactation [31, 63]. The bacterial composition begins to
Composition and evolution of human gut microbiota converge toward an adult-like GM by the end of the first year of
life and fully resembles the adult GM by 2.5–3 years of age [31,
There is a continuum increase in the number of bacterial cells 65, 125]. In terms of ecological succession, the
occurring in the human gut that ranges from 101 to 103 bac- Bifidobacterium-dominated GM of the infant changes over
teria per gram of contents in the stomach and duodenum, from time into the Bacteroidetes- and Firmicutes-dominated GM of
104 to 107 in the jejunum and ileum, culminating in 1011–1013 the adult, which can be affected by several factors [6, 49, 55,
in the colon, particularly in the distal part [2], were around 112]. Among dietary factors, it was observed that subjects con-
300–500 different species live [42]. The GM also varies in suming a diet particularly rich in animal protein and fat (such as
composition depending on the location along the GI and axial the typical Western diet) were associated with the Bacteroides
depth (mucosal versus luminal) [49]. Globally, the microbial enterotype, whereas the GM of subjects ingesting more carbo-
mass in the intestine represents about 1 kg or more body hydrates were dominated by the Prevotella enterotype [125].
weight and is essential to human metabolic functions [90]. An increase in the phylum Firmicutes and a decrease in the
Out of 53 known bacteria phyla on earth, only five to seven Bacteroidetes (mainly expressed as the Firmicutes/
phyla (predominantly Firmicutes and Bacteroidetes, compris- Bacteroidetes ratio; FBR) were associated with obesity in some
ing 90% of the total) usually colonize the human gut [107]. occasions, but this feature is still not consistent [6].
Firmicutes (the most predominant phyla in people living in Additionally, an increase of Actinobacteria in obese individuals
developed countries) encompasses mostly Gram-positive bac- was also reported [6]. These changes are probably not a mere
teria with a DNA that has a low G + C content but also include consequence of obesity but could be involved or a cause faster
Gram-negative bacteria. The Gram-negative bacteria are obesity pathogenesis [28, 68].
mainly represented by the Bacteroides genus in the human Once the GM has reached maturity, it remains mostly sta-
gut [87]. The relative proportions of these two dominant phyla ble until old age, although some differences can be found in
vary and can be influenced by a range of factors, but most the GM of the elderly from that of young adults [27].
people have similar proportions of each [28]. Lesser (but also Particularly, Bacteroidetes phyla and Clostridium genus pre-
important) contributions from members of the Cyanobacteria, dominate in the GI of elderly people compared to higher pro-
Proteobacteria, Actinobacteria, Fusobacteria and portions of Firmicutes in young adults [63]. Elderly people are
Verrumicrobia phyla comprise the rest of the microbiota [90]. also noted to have significant decreases in Bifidobacterium
Bacteroidetes, Faecalibacterium, Bifidobacterium and [63]. Young adults have variability in community composition
Eubacterium are numerically the most important genera than for old age and vary greatly among individuals, ranging
among GM and may account for more than 60% of the bac- from 3 to 92% for Bacteroidetes and 7–94% for Firmicutes
teria present in human stool, but their relative abundance is [23, 27]. These findings could be related to the greater number
highly variable across individuals [28, 101]. Clostridium, of morbidities associated with the elderly and the complex
Enterobacteriaceae and Streptococcus are also important gen- repertoire of drugs used to treat them that are likely to affect
era but less numerous [28]. the microbiota [23].
One metagenomic analysis suggested that the GM of each
human is typified by one of three enterotypes, with each
enterotype featuring distinct dominant groups of microbes Impact of the human gut microbiota on human
[6], namely Bacteroides, Prevotella and Ruminococcus. health
However, subsequent studies, including those of The Human
Microbiome Project, have been unable to provide conclusive The GM equilibrium is essential for several physiological
evidence that supports this concept [55, 57]. functions associated with impact on human health, affecting
Food additives, contaminants and other minor components

almost all organ systems that contribute to metabolic control Faecalibacterium, Roseburia or Lactobacillus and even spe-
[41]. Thus, the GM modulates appetite and food intake [42, cific species, such as Akkermansia muciniphila ,
125], absorption of nutrients from the gut, hepatic steatosis, Faecalibacterium prausnitzii or Roseburia intestinalis, have
inflammation, triglyceride accumulation in adipose tissue been shown to prevent health disorders such as obesity or
[14], and fatty acid oxidation in skeletal muscle and the liver diabetes, or to improve immunity and inflammatory status
[125] and synthesis of vitamins. However, there is still limited [49, 51, 55, 63].
knowledge on the exact mechanisms by which the GM affects
human metabolism.
The GM express the enzymatic machinery to process oth- Effect of minor food compounds on the human gut
erwise non-digestible carbohydrates, such as fructooligosac- microbiota
charides, galactooligosaccharides and inulin, and thus, release
monosaccharides that can be used by the host for metabolic Although dietary patterns have an important effect on the hu-
purposes [63]. In addition to the conversion of complex car- man GM, the individual effects of minor food compounds
bohydrates into absorbable substrates, the GM also benefits have received less attention than conventional diets, with dif-
the human host by producing SCFAs, with great impact in the ferent proportions of macronutrients. Micronutrients are piv-
colonic epithelial cells maintenance, and vitamins, like vita- otal for several health-related functions, like energy metabo-
min K, as well as some water-soluble B vitamins, such as lism, cellular growth and differentiation, and organ and im-
biotin, cobalamin, folic acid, nicotinic acid, pantothenic acid, mune function [9]. A diet low in micronutrients, but not nec-
pyridoxine, riboflavin and thiamine [2]. essarily low in energy, is frequent in populations of low-
The GM also influences the host health status through the income countries, but may also be present in poverty-
enzymatic transformation of bile acids, natural detergents with affected settings in middle- and high-income countries [9]. It
novel signaling functions including regulation of cholesterol is estimated that more than three billion people worldwide
synthesis and absorption, modulation of inflammatory re- suffer from various types of micronutrient deficiencies (pre-
sponses, and energy homeostasis [19]. Moreover, the GM dominantly vitamin A, iron and zinc), with the majority being
synthesizes amino acids, influences iron absorption, and it is women and children [9]. Vitamin A can modulate the immune
involved in the conversion of dietary polyphenolic com- response of the intestine by interactions with immune cells of
pounds and in the bile acid biotransformation process [63]. modulation of the microbiota [11]. Iron deficiency or anemia
The intestinal microbiota is able to transform potentially car- is related to a depletion of Lactobacillus in women [7].
cinogenic compounds, such as N-nitroso compounds and het- Some reports have shown that prophylactic doses of Zn in
erocyclic amines, and to activate bioactive compounds includ- various animal models increased the presence of Gram-
ing phytoestrogens [104]. negative facultative anaerobic bacterial groups, the colonic
Globally, although the healthier GM is not yet fully concentration of short chain fatty acids (SCFAs), as well as
established, it is well known that the richness and diversity overall species richness and diversity [96]. Likewise, others
of bacterial species in the human gut may be an indicator of have found a gut microbiota enriched in members of the phy-
wellbeing, and consequently, alterations in GM can affect lum Firmicutes, specifically Lactobacillus, following ZnO ad-
multiple health issues [49]. In this context, compositional ministration [101]. Moreover, even mild zinc deficiencies can
and functional alterations in the GM have been linked to mal- profoundly impact growth and development, as well as block
nutrition [109], obesity and adiposity-related diseases [68, immune differentiation and maturation [96]. Supplementation
95], cardiovascular events [12, 76], type 2 diabetes [64], in- with high levels of zinc has been shown to result in an increase
flammatory bowel disease [85], colorectal cancer [127], of Lactobacillus in the GM of weaned pigs [108]. Using
neurodevelopmental disorders [52] and aging-related distur- chicks as a model, one study recently demonstrated that zinc
bances [59, 76]. Considering the increasing global incidence deficiency results in a remarkable change in the microbiota,
of many of these conditions, changes in the lifestyle and diet with metabolic changes, such as decreased SCFAs output
in the post-industrialization/westernization era have been ar- [96].
gued to contribute to their emergence by shifting the GM Various other dietary constituents, including various com-
ecology [125]. pounds belonging to polyphenols, also nourish colonic mi-
Knowledge of the effects of specific microbial phyla is still crobes [28]. Polyphenols are secondary metabolites found
limited. However, the presence of Firmicutes, from diverse abundantly in a wide variety of foods, such as fruits, vegeta-
families, namely Clostridiales, Erysipelotrichaceae, bles, herbs, seeds and cereals, and in beverages, such as cof-
Ruminococcaceae, Eubacteriaceae, and Lachnospiraceae fee, tea, cocoa and wine [84]. The beneficial activities of poly-
have been shown to be associated with healthy populations phenols on the prevention of cancer and cardiovascular dis-
[63]. Additionally, certain bacterial genus such as Bacteroides, ease and, specifically, on the GM have been widely investi-
Bifidobacterium, Clostridium clusters XIVa/IV, Eubacterium, gated in recent years [28, 39, 84]. Most polyphenols pass
 Roca-Saavedra et al.

through the SI without being absorbed, thus encountering the to modulate the GM and consequently, impact human health.
GM, which colonizes the colon [84]. Once reached the colon Thus, Chaplin et al. [17] found that conjugated linoleic acid
the interaction polyphenols-GM results in a two-way mutual increased A. muciniphila levels, that was associated with sev-
reaction. First, polyphenols are biotransformed in vivo by eral beneficial associations with metabolism [16]. It was also
some GM bacteria, increasing their bioavailability, and thus reported that L-carnitine, present in red meats, can be metab-
increasing their effects on human wellbeing [39]. Second, olized to trimethylamine and trimethylamine oxide, and in-
polyphenols modulate the composition of the GM mostly crease atherosclerosis risk [66]. Colonic bacteria can hydro-
through the inhibition of pathogenic bacteria and the stimula- lyze choline to form dimethylamine and trimethylamine,
tion of beneficial bacteria [39, 40, 42, 84]. Several phenolic which are precursors of dimethylnitrosamine [2], a potent
compounds have been recognized as potential antimicrobial hepatotoxin, and carcinogen.
agents with bacteriostatic or bactericidal effects, and have var- Mice fed diet with 0.25% sphingomyelin showed a higher
ious effects on bacterial species or genus [42, 76, 84]. About relative phylogenetic abundance of the predominately Gram-
90% of the dietary polyphenols escape digestion and absorp- positive Firmicutes phylum and significantly lower numbers
tion in the SI [116, 118] and can have a significant influence of the Gram-negative Bacteroidetes phylum and some intesti-
on the microbial populations and their activities [69, 77, 119], nal pathogens [83]. Milk sphingomyelin supplemented mice
but our understanding of the microbial bioconversion process- had a significantly relative abundance of the beneficial bacte-
es is still limited [69]. ria Bifidobacterium, and higher relative abundance of
Flavonols [69], quercetin [37, 54], catechin and puerarin Bacteroides, one of the few microbes that synthesize and uti-
[54], anthocyanins [50, 52], ellagitannins [74], resveratrol lize sphingolipids [83]. A summary of some previously pub-
[94], trans-resveratrol [37] and pterostilbene [41] are all re- lished works regarding effects of food minor compounds in
ported to impact the GM. Quercetin supplementation resulted human GM is displayed in Table 1.
in an altered composition of the GM at different taxonomic
levels, including the FBR and inhibiting the growth of bacte-
rial species associated with diet-induced obesity, such as Effects of food additives on human gut microbiota
Erysipelotrichaceae, Bacillus, and Eubacterium cylindroides
[37]. In other recent work, it was demonstrated that different An important change in human diets since the mild-twentieth
types of flavonoids can modulate the growth of different phyla century is the increasing consumption of food additives that
and genus from GM [63]. are incorporated into almost all processed foods, often to aid
Li et al. [73] demonstrated that ellagitannins can stimulate stability, shelf-life, taste, and texture improvement, particular-
the growth of several bacterial genera with beneficial proper- ly in processed foods [19]. The primary basis for approving
ties for human health, such as Akkermansia muciniphila, the use of these agents is the notion that they do not cause
Butyrivibrio, Escherichia, Lactobacillus or Prevotella. acute toxicity at concentrations reasonably greater than their
Proanthocyanidins from grape seed can increase approved concentrations. However, only few prospective in-
Lachnospiraceae, Clostridiales, Lactobacillus and terventional human studies address the possible impact of ad-
Ruminococcacceae in female pigs [22]. In another research, ditives on the human GM, presumably due to difficulties in
Qiao et al. [94] found that resveratrol ameliorated the allocation of cohorts of healthy individuals who have not been
dysbiosis in the GM of mice induced by a high-fat diet. previously exposed to food additives, and the need for robust
Specific effects included an increase in the FBR, significant stratification of potentially confounding factors, such as ge-
inhibition of the growth of Enterococcus faecalis, and in- netics, lifestyle and dietary patterns [19]. Consequently, re-
creased growth of Lactobacillus and Bifidobacterium. searchers have turned to animal models to study the effect of
Flavonols can also increase the relative abundance of food additives on the GM. Recent studies have demonstrated
Bifidobacterium and Lactobacillus at the expense of potential- that the consumption of non-nutritive sweeteners (NNS) and
ly pathogenic bacteria, notably Clostridium histolyticum [77]. dietary emulsifiers (DEs) can alter the GM, resulting in intes-
In a recent work, it was demonstrated that pterostilbene (a tinal disturbance and inflammation, favoring the development
dimethoxy resveratrol derivative) supplementation in rats of the metabolic syndrome [19, 26] (Table 2).
exerted protective antiobesity effects, improved insulin sensi- Nowadays, most processed foods contain one or more DEs
tivity and modified GM by decreasing Firmicutes and increas- in order to seek for specific textures. Some authors have sug-
ing Verrucomicrobia. Regarding specific genus, pterostilbene gested that DEs may be a factor resulting from industrialization
supplementation increased mucin-degrading bacterial mem- that has resulted in a reduction of GM diversity, altered host-
bers, such as A. muciniphila and Odoribacter spp. [41]. microbiota interactions and, consequently, have contributed to
Besides polyphenols, other minor compounds such as con- the increased incidence of metabolic syndrome and other in-
jugated linoleic acid [17], L-carnitine [61], choline [2], flammatory diseases in industrialized societies [19, 27]. Two
sphingomyelin [76] or ellagitannins [69] have been reported DEs, namely carboxymethylcellulose and polysorbate 80, have
Table 1 Recent works regarding the effects of micronutrients on gut microbiota (GM)

Reference Models Micronutrients Supplementation dosage Main conclusion

[7] Observational study (8 anemic Iron – Fecal Lactobacillus were significantly lower
and 26 normohemic females) in anemic women
[17] Pigs Conjugated linoleic acids (CLA) 6 mg of CLA/day was given to mice consuming CLA supplementation exerted a prebiotic action on
both a normal-fat diet and a high-fat diet Bacteroidetes/Prevotella and Akkermansia muciniphila.
However, it was not able to override the negative
effects of a high-fat diet on Bifidobacterium spp.
[22] Pigs Proanthocyanidins Diet containing 1% (w/w) of grape seed extract Dramatic increase in fecal Lachnospiraceae,
daily for 6 days Clostridiales, Lactobacillus and Ruminococcacceae
[37] Rats Polyphenols Trans-resveratrol (15 mg/kg body weight/day], Quercetin attenuated the Firmicutes/Bacteroidetes
quercetin (30 mg/kg/day) or a combination ratio and inhibited the growth of Erysipelotrichaceae,
of both polyphenols at those doses Bacillus and Eubacterium cylindroides.
Trans-resveratrol supplementation alone or in
combination with quercetin scarcely modified the GM
[41] Rats Pterostilbene 15 mg/kg body weight and day for 6 weeks Pterostilbene decreased Firmicutes levels and increased
Food additives, contaminants and other minor components

Verrucomicrobia, A. muciniphila and Odoribacter spp.

[50] In vitro model of human gut Malvidin-3-glucose, gallic acid Gallic acid (150 mg/L and 1000 mg/L), All the anthocyanins tested significantly enhanced
and a mixture of anthocyanins malvidin-3-glucoside (20 mg/L and the growth of Bifidobacterium spp. and
200 mg/L), and enocianin (4850 mg/L Lactobacillus−Enterococcus spp.
and 48,500 mg/L)
[54] In vitro model of the human gut Flavonoids (quercetin, catechin, Each flavonoid at 0.15 g/L Catechin and puerarin presented different activities
puerarin) on regulating the GM, but all increased GM diversity
[66] Mice L-carnitine 250 mg L-carnitine supplementation significantly altered
cecal microbial composition, markedly
enhanced synthesis of trimethylamine/trimethylamine
oxide, and increased atherosclerosis
[72] Uncontrolled study including Ellagitannins Pomegranate extract at 1000 mg/day for 4 weeks Ellagitannins from pomegranate stimulated A. muciniphila,
22 healthy human volunteers Butyrivibrio, Enterobacter, Escherichia, Lactobacillus
and Prevotella and inhibited Collinsella
[77] Case-controlled study including Flavonols Dark chocolate at 50 g/day for 1 week Cocoa flavonols increased the relative abundance of
22 healthy human volunteers Bifidobacterium and Lactobacillus at the expense of
potentially pathogenic bacteria, notably the
C. histolyticum group
[83] Mice Sphingomyelin High-fat diet with 0.25% of milk sphingomyelin Decrease in Gram-negative bacteria, such as Bacteroidetes
added 45% Kcal as fat or Tenericutes phyla and increase in Gram-positive
bacteria, such as Firmicutes and Actinobacteria phyla
[94] Mice Resveratrol 200 mg/kg per day Resveratrol increased GM dysbiosis induced by a high-fat
diet, with an increase in the FBR, Lactobacillus and
Bifidobacterium growth and a significant decrease in
Enterococcus faecalis
[96] Chicken Zinc Zinc oxide supplementation at 42 μg/g or The zinc-deficient group had a significantly lower
2.5 μg/g cecal microbial diversity
 Roca-Saavedra et al.

demonstrated to promote bacterial overgrowth in the murine SI

and facilitate translocation of bacteria across a model gut epi-

Consuming the HCF drink for 4 weeks significantly

increased the Bifidobacterium and Lactobacillus
thelia [19]. Additionally, they reduced the mucus layer thick-
Enterobacteriaceae and the Escherichia group
as well as for Lactobacillus spp. and for three
ness and were involved in the onset of intestinal inflammation,

populations but significantly decreased the

obesity, and diabetes. These effects were also associated with
Pronounced reductions were observed for

an increased food intake, from still unknown origin [27]. A

Clostridia counts in fecal samples

of five studied Lactobacillus spp.
previous study, also carried out in mice, showed as polysorbate
80, enhances the translocation of E. coli across M-cells [35].
An increase in numbers of E coli have been found in associa-
tion with Crohn’s mucosa [99]. There are studies showing that
the E. coli translocation can increase in 59 folds. Thus, this
Main conclusion

emulsifier may contribute to the impact of dietary factors on

Crohn’s disease pathogenesis [99].
As a result of the many negative health conditions associ-
ated with the intake of excessive sugar, there has been an
upsurge in the consumption of NNS as an alternative [105,
111]. NNS are synthetic compounds that are several hundred-
flavanol and low-cocoa flavanol group received
494 mg cocoa flavonols/day), while low-cocoa

fold sweeter than sucrose. Thus, they can be used in small

amounts with negligible added caloric value. Some NNS are
High-cocoa flavonol (HCF) group received

23 mg cocoa flavonols/day, for 4 weeks

57 (low) or 2425 (high) mg/kg zinc oxide

excreted unchanged from the mammalian body, and are, there-

fore, considered metabolically Binert^ [105, 111].
Theoretically, NNS would only aid in weight loss if compen-
satory sugar intake did not occur. However, the common per-
ception that NNS may promote weight loss by reducing calo-
Supplementation dosage

ries is misguided because it was reported that consumption of

saccharin-sweetened liquids might increase overall food in-
for 5 weeks

take [1, 105]. Furthermore, positive correlations between

NNS consumption and increased body mass index in children
and adolescents have been described in several observational
studies [43, 105].
The effects of NNS on the GM could be due to the bacte-
riostatic effects of the NNS, such as saccharin, sucralose, as-
partame and stevia [1, 86, 110, 111]. Data from studies in
animals [1, 86] and from a small study in human subjects
[110] suggests that the bacteriostatic effects of NNS are not
Cocoa flavonols

limited to the microbial inhabitants of the mouth, but extend to

Micronutrients

those in the gut, thereby affecting the host metabolic pheno-

type and disease risk [89]. Pioneer work showed that 12 weeks
of exposure to Splenda significantly altered the GM compo-
Zinc

sition by decreasing beneficial bacteria and was associated

with weight gain in rats [1]. In another work, it was confirmed
22 healthy human volunteers

and extended these findings by identifying a microbe-

Case-control study including

mediated mechanism by which NNS might influence metab-

olism [110], inducing higher glucose intolerance, mediated by
alterations in the GM. Consistent with previous findings, it
was showed that 8 weeks of aspartame exposure in a dose
equivalent to human subjects consuming 2–3 diet soft drinks
Models

per day, perturbed the GM and resulted in elevated fasting

Table 1 (continued)

Pigs

glucose levels and impaired insulin tolerance in rats [1, 86].

Other additives reported to significantly alter the GM are
Reference

essential oils (EOs), which were used to prevent the growth of

pathogenic bacterial species that are generally more sensitive
[108]

[119]

to EOs than most commensal bacteria [113]. It was

Food additives, contaminants and other minor components

Table 2 Recent works regarding the effects of food additives on gut microbiota (GM)

Reference Models Additive Supplementation dosage Main conclusion

[1] Rats Splenda 100, 300, 500, or 1000 mg/kg Total anaerobes, Bifidobacterium, Lactobacillus,
for 12 weeks Bacteroides, clostridia, and total aerobic bacteria
were significantly decreased. No significant
changes were found in the Enterobacteriaceae
[19] Mice Carboxymethylcellulose 1% of each emulsifier Reduction in the microbial diversity, Bacteroidales,
and polysorbate-80 for 12 weeks Verrucomicrobia phyla (particularly Akkermansia
muciniphila) and enriched mucosa-associated
inflammation-promoting Proteobacteria
[29] Rats Aspartame Chow and high-fat feed added with Increase in total bacteria associated with aspartame
0.4 g/100 mL of aspartame in addition, and reductions in Lactobacillus
water for 8 weeks and Bacteroides
[32] Pigs Saccharin Diet supplemented with 0.015% Saccharin + neoesperidin dihydrochalcone
saccharin + neoesperidin dramatically increased the cecal population
dihydrochalcone abundance of Lactobacillus
[86] Rats Aspartame 5–7 mg/kg/day for 8 weeks Aspartame increased total bacteria,
Enterobacteriaceae and Clostridium leptum in
the feces, and attenuated the increase in
Firmicutes/Bacteroidetes ratio
[97] In vitro trial Sucralose 1.1–11 mg/kg Sucralose had little effect on E. faecalis and C.
sordellii, while there was a concentration-
dependent inhibition of the growth of Bacteroides,
B. fragilis and B. uniformis
[110] Mice Saccharin 0.1 mg/ml in water for 11 weeks Saccharin induced an increase of the Bacteroidetes
and reduction in Firmicutes
[113] In vitro model of Thymol, nerolidol, eugenol, 100–500 mg/kg Thymol and geraniol suppressed pathogens,
the human gut methyl isoeugenol such as C. difficile, with no concern for
and geraniol beneficial colonic bacteria in the distal gut

demonstrated that EOs (mainly thymol), selected for their ef- and exert potentially toxic effects to their consumers. A sum-
fectiveness against gut pathogens (C. difficile) did not have mary of previously published work, describing toxic com-
significant effects on the abundance of F. prausnitzii, which pounds produced by its metabolization by GM, is reported
plays an important anti-inflammatory role in the gut [113]. In in Table 3.
particular, EOs may have potential use as an adjunct to che- In particular, alcohol can be metabolized by bacteria to
motherapeutic agents used to treat colorectal cancers [89]. aggravate their intrinsic negative effects. Thus, oral bacteria,
Patients receiving chemotherapy for cancer treatments suffer such as Streptococcus, have the capacity to convert ethanol in
from gastrointestinal disturbances due to damage to the mu- wine to acetaldehyde, which is an in vitro and in vivo
cosal cells of the GI and disrupt the gut ecological balance. genotoxin and a recognized human carcinogen [15].
Consequently, chemotherapy increases the risk of bacterial Furthermore, the GM is suggested to play an important role
infections, such as the overgrowth of C. difficile [113] and in alcohol-induced liver injury, apparently through dysbiosis
decreases beneficial microbial populations such as of the intestinal ecosystem caused by alcohol intake [15].
B i f i d o b a c t e r i u m , L a c t o b a c i l l u s , Ve i ll o n e l l a a n d Other example was reported that the occurrence of renal
F. prausnitzii. Consequently, EOs might be exploited as pro- injury in infants and children exposed to melamine-tainted
phylactic agents and as adjuncts in chemotherapy to protect milk in China could also be attributed to the metabolism of
commensal bacteria, including Bifidobacterium spp. and the GM [60]. Certain gut bacterial species, like Klebsiella
F. prausnitzii [126]. terrigena, can convert melamine to cyanuric acid, which then
forms complex precipitates that lead to kidney stone formation
and causes renal toxicity [60].
Toxic compounds produced by gut microbiota Another group of compounds that can be metabolized by
metabolism the GM and cause harmful effects are contaminants, such as
drugs, heavy metals or environmental chemicals [25]. An in-
In addition to their action on certain populations of the GM, teresting study showed how the GM has the ability to inacti-
some compounds can be metabolized by gut microorganisms vate drugs delivered into the intestine, with the potential to
 Roca-Saavedra et al.

Table 3 Recent works regarding foods that can become toxic by the metabolism of gut microbiota (GM)

Reference Models Food/substance Dosage Main conclusion

[15] Mice Alcohol 10% v/v in drinking water for The GM plays an important role in alcohol-induced
7 days, plus an additional liver injury, apparently through dysbiosis of the
oral gavage of 5 mg/kg intestinal microbial ecosystem caused by
on day 7 alcohol intake
[20] Mice Mixture of polychlorinated 150 μmol/kg for 2 days PCBs decreased the levels of Proteobacteria
biphenyls (PCBs) congeners and induced substantial changes in the gut
microbiome, which may then influence
their systemic toxicity
[62] Rats Chlorpyrifos 1 mg for 30 days Chronic, low-dose exposure to chlorpyrifos was
found to induce dysbiosis in the microbial
community with the proliferation of Bacteroides
sp. and decreased levels of Lactobacillus and
Bifidobacterium spp.
[92] Mice Arsenic Cecal content of mice was added Thioarsenicals were found in soluble and
with 0, 200, 1000 and particulate fractions of the reaction mixtures,
2000 μg/kg arsenic suggesting interactions with anaerobic
microbiota
[106] In vitro trial Glyphosate 0.05, 0.15, 0.075, 0.3, 0.6, Reduction of beneficial bacteria, such as some
1.2 and 2.4 mg/ml Bifidobacterium spp. or Lactobacillus spp. that
for 5 days could disturb the normal gut bacterial
community, whereas limited effect was shown
on the intestinal pathogens
[120] In vitro model Polycyclic aromatic Hypothetical soil ingestion PAHs biotransformation potency of colon
of human gut hydrocarbons (PAHs) of 5 g/day microbiota suggests that the current risk
assessment may underestimate the risk from
ingested PAHs
[122] Mice Nitric oxide (NO) Daily intrarectal bolus treatment NO-producing microorganisms in the gut lumen
with an NO donor in two should be considered a modulating process
doses + 4% dextran sodium during colitis
sulfate
[124] Mice Nitrogen compounds Diet supplemented with 1.0% Mice fed diets supplemented with trimethylamine
betaine, 1.0% choline, 0.12% species (choline or trimethylamine oxide)
trimethylamine N-oxide or showed increased peritoneal macrophage
1.0% dimethylbutanol for cholesterol content and raised plasma levels of
3 weeks trimethylamine oxide
[129] Rats 2,3,7,8-tetrachlorodibenzofuran 24 μg/kg for 5 days Dietary 2,3,7,8-tetrachlorodibenzofuran altered the
GM by shifting the Firmicutes/Bacteroidetes
ratio. The cecal content was enriched with
Butyrivibrio spp. but depleted in Oscillibacter
spp. These changes in the GM were associated
with altered hepatic lipogenesis,
gluconeogenesis, and glycogenolysis
[60] Rats Melamine 0.2 mg/kg Melamine is converted to cyanuric acid in vitro by
Klebsiella terrigena cultured from normal rat
feces. Rats colonized by K. terrigena showed
exacerbated melamine-induced nephrotoxicity

generate toxic compounds, like hydrogen sulfide [104]. The the bacterial community in the gut of a terrestrial isopod
gut normally converts luminal hydrogen sulfide to thiosulfate, (Porcellio scaber) [20].
which can be further oxidized to tetrathionate. High concen- Contaminants may be poorly absorbed after ingestion, and
trations of hydrogen sulfide severely inhibit cytochrome C subsequently can reach the distal SI and caecum by peristalsis.
oxidase, blocking mitochondrial activity [104, 122]. Additionally, environmental chemicals (or their metabolites)
Regarding effects of heavy metals by the GM, Pinyayev may also be excreted in the bile [25]. There is increasing
et al. [92] reported that anaerobic microbiotas of the mouse evidence that chronic exposure to environmental chemicals
cecum convert arsenate into oxyarsenicals and thioarsenicals. through the diet, particularly persistent organic pollutants,
Additionally, it was reported that exposure to mercury altered may promote the development of obesity and type 2 diabetes
Food additives, contaminants and other minor components

in humans, even without inducing dysbiosis [25]. Of particu- [47, 67]. The effect of these drugs on the human GM, both
lar interest is the role of the aryl hydrocarbon receptor, which during and after the treatment has been widely investigated in
is bound and activated by a variety of persistent organic pol- recent years, although it is not yet fully understood [87].
lutants including coplanar polychlorinated biphenyls and ha- Interestingly, although the effects of therapeutic doses of
logenated aromatic hydrocarbons [129]. For instance, it was antibiotics employed in human medicine have been widely
recently reported that a persistent organic pollutant, 2,3,7,8- investigated in recent years, the effects on GM of antibiotics
tetrachlorodibenzofuran, can dramatically alter the GM by residues present in foods at trace concentrations, derived from
shifting the FBR, increasing Butyrivibrio spp. and decreasing veterinary medicine, have received little attention [18, 21, 82,
Oscillibacter spp. These changes in the GM were associated 98]. Only a few investigations focused on the effects of low
with altered BA metabolism and subsequent host metabolic concentrations of antibiotics on the GM [30, 34, 121]. This is
disorders as a result of an altered hepatic lipogenesis, gluco- surprising because antibiotics are the most widely used drugs
neogenesis, and glycogenolysis [25]. in the livestock industry in the world [8] and their residues can
Conversely, the GM can regulate the expression of cyto- reach humans through animal feeds, vegetables and surface
chrome P450 enzymes, which are involved in the metabolism waters [98]. Paradoxically, while humans are interested in
of a variety of environmental chemicals [24]. Polycyclic aro- modulating their microbiota to aid in weight loss, producers
matic hydrocarbons are among the most widespread organic of animal feed have used antibiotics for decades to increase
pollutants and can be transformed by the GM to estrogenic the weight gain of the animals. Antibiotics in livestock pro-
metabolites [120]. Furthermore, it has been shown that the rat duction are incorporated in animal feed either as growth pro-
and human GM could regenerate benzo(a)pyrene from its he- moters in countries where such use is allowed [30, 73, 98] or
patic conjugate, reversing the endogenous detoxification pro- as prophylactic or therapeutic agents in the European Union
cess, which is of potential toxicological relevance [24]. Choi and other countries where antibiotic use as growth promoters
et al. [20] reported that after exposure to polychlorinated bi- is banned. Importantly, these antibiotic effects are not limited
phenyls in mice, the most striking change in the intestinal to oral administration, but may also be present and, therefore,
microbial profiles was a decrease in bacterial species. have effects on microbiota when administered parenterally
Other environmental chemicals, for example, pesticides or [31] (Table 4).
herbicides, can also exert increased harmful effects on human As a general rule, it was reported that antibiotic intake in
health via the action of the GM [57, 98]. Indeed, chronic mice increased adiposity [3, 18, 30, 67, 81, 117], and thus
exposure to chlorpyrifos, an organophosphate insecticide favored the development of obesity and type II diabetes
commonly used to treat fruit and vegetable crops and [79], besides affecting normal metabolic activity, hormonal
vineyards has been shown to induce dysbiosis of the GM in and immune development. However, antibiotic treatment does
both human and rats and was associated with the proliferation not always display adverse effects on the GM of experimental
of Bacteroides sp. and decreased levels of Lactobacillus sp. animals. Indeed, in some instances, antibiotic treatment im-
and Bifidobacterium sp. [62]. Glyphosate, the most widely proved the insulin response in Bio-Breeding diabetes-prone
used herbicide worldwide, has been shown to have important rats [13].
effects in poultry GM [109]. The sensitivity to glyphosate is Antibiotics exert very different actions on the individual
dependent on the bacterial strain. Some typical pathogens, groups that constitute the GM. Overall, for a variable period
such as Salmonella or Clostridium, are highly resistant, after antibiotic treatment ceases, the microbiota usually
whereas beneficial bacteria, like Lactobacillus spp. or regains its original composition. However, some bacterial spe-
Bifidobacterium spp. are moderately or high susceptible. No cies have been reported to irreversibly disappear in certain
trials were performed using human models, but if it were individuals [27]. This can influence the health of the host,
demonstrated that glyphosate acts similarly in human GM, particularly if the bacterial group that is suppressed affects a
this would be of a toxicological relevance [106]. physiological health-related function [27].
Cho et al. [21] found a significant increase in the FBR
as a result of the administration of beta-lactams and van-
Specific effects of antibiotics on the human gut comycin. An increase in this ratio, as explained previous-
microbiota ly in this review, is associated in diverse studies with
obesity and other metabolic disorders. Other authors [30]
Several drugs can modulate the GM. Although it was reported found significant decreases in the taxa associated with
that other pharmacological treatment can alter the GM [44, beneficial health properties, such as Lactobacillus spp.
71], the drugs that primarily play the most significant action and Bifidobacterium spp. and significant increases of
on the GM are antibiotics [26, 78, 100, 102]. Antibiotics are Enterobacteriaceae family that includes many genres con-
one of the most prescribed drugs in human medicine, particu- sidered potentially pathogenic. Other authors [102] treated
larly in pediatrics and neonatal nursing in developed countries mice with antibiotics, such as amoxicillin, metronidazole,
Table 4 Effects of antibiotics and concentrations on the gut microbiota (GM)

Reference Models Antimicrobial Dosage Main conclusion

[3] Prospective trial in 28,354 mother-child Different antibiotics Several antibiotics and doses depending on Early exposure to antibiotics increased the risk of being
days for 7 years the type of disease and patient characteristics overweight in later childhood by decreasing the
diversity of the GM
[5] Prospective trial in 27 preterm infants Different antibiotics Several antibiotics and doses depending on the Prematurity and perinatal antibiotic administration caused
and 13 full-time babies type of disease and patient characteristics lower percentages of Lactobacillaceae or Bacteroidaceae
and increased Enterobacteriaceae on GM
[21] Mice Penicillin, vancomycin, tetracycline or Subtherapeutic dosages at 1 μg/g body Antibiotic treatment induced significant changes in GM,
vancomycin + penicillin weight per day increased adiposity and modified lipid metabolism and
cholesterol
[30] Mice Penicillin Subtherapeutic dosages Modified the GM and induced long-term changes in the
metabolism of the host, inducing obesity
[34] Prospective trial in 3 people before Ciprofloxacin 1 g/day for 5 days Ciprofloxacin treatment reduced the GM diversity, with
and after antibiotic treatment significant effects on 1/3 of the bacterial taxa
[48] Observational study in 74 infants Ampicillin and gentamicin Various dosages and treatment and durations Infants who received 5–7 days of antimicrobials in the first
week had an increased relative abundance of Enterobacter
and lower bacterial diversity in the second and third weeks
of life
[58] Prospective trial on 6 patients Clarithromycin + metronidazole 250 mg + clarithromycin and 400 mg Antibiotic treatment affected the GM by decreasing
metronidazole Actinobacteria and this disturbance on the GM persisted
after 4 years
[79] Prospective study in 12 males Vancomycin, gentamicin and 500 mg vancomycin, 40 mg gentamicin and Antibiotic treatment caused significant shifts in the GM.
meropenem 500 mg meropenem Nevertheless, the changes observed did not have
important effects on glucose metabolism
[81] Retrospective cohort study of 74,946 Different antimicrobials Several antibiotics and doses depending Exposure to antibiotics during the first year of life was
children with asthma and /or allergies on the type of disease and patient associated with an increase in the body mass index of
characteristics 5–8-year-old children
[87] Prospective study in patients with Different antimicrobials Several antibiotics and doses depending on the Both fluoroquinolones and beta-lactam reduced the GM
no digestive diseases type of disease and patient characteristics diversity in more than 25% of the patients
[91] In vitro model of the human gut Ampicillin + sulbactam and cefazolin Ampicillin + sulbactam on first days and Antibiotic treatment caused a marked decrease in
intravenous cefazolin during 14 days Bacteroidetes and increase in Firmicutes
[100] Mice Vancomycin 100 mg/L in drinking water Different antibiotics had specific effects on the GM
[102] Mice Vancomycin or streptomycin 200 mg/L in drinking water Vancomycin caused a loss in Bacteroidetes, which were largely
replaced by Firmicutes, Paenibacillaceae, Verrucomicrobia
(specifically Akkermansia), and Enterobacteriaceae. In
contrast, streptomycin increased the Bacteroidetes,
particularly Porphyromonadaceae and Bacteroidaceae
[115] Observational study in 96 males Vancomycin plus other antibiotics Different doses depending on the type Vancomycin plus gentamicin treatment increased the risk of
of disease and patient characteristics obesity in men. High levels of Lactobacillus were found,
possibly related to the use of vancomycin as a growth
promoter
[121] Calves Ampicillin, ceftiofur, penicillin and 0.005, 0.01 and 0.3 mg/ml and 0.1 g/ml, Antibiotic residues resulted in discriminate GM
oxytetracycline respectively from birth to weaning communities, although they did not result in
disruption of the taxonomic levels above the genus
[123] Randomized controlled trial Vancomycin 500 mg for 7 days Vancomycin reduced fecal microbial diversity with a
in 20 obese males decrease in Gram-positive bacteria (mainly
Firmicutes) and a compensatory increase in
Gram-negative bacteria (mainly Proteobacteria)
[128] Mice Tetracycline and ampicillin 50 mg/kg or 2 mg/kg (for tetracycline) Antibiotic oral administration had important effects on
and 30 mg/kg (for ampicillin) the selection and extent of antibiotic resistance genes
Roca-Saavedra et al.
Food additives, contaminants and other minor components

cefoperazone, and a combination of all three. As a result, pre-antibiotic state [47]. However, in this stage of life, the
the Proteobacteria and, in particular, the Enterobacteriaceae, GM is relatively strong and, in most instances, recovers after
become dominant in the intestinal tract of the treated mice, several weeks of ceasing the antibiotic treatment [87].
accounting for 73% of the total microbiota. Two weeks after However, other studies have shown that after cessation of
ceasing the antibiotic treatment, the microbiota of these ani- treatment, the microbiota requires several months to fully re-
mals recovered a relatively low proportion of Proteobacteria cover [34, 58, 75, 87]. However, in some cases, it has even
(5.77%), although it remained considerably more abundant demonstrated that some bacterial groups eliminated by an an-
than the percentage of the total microbiota representing this tibiotic treatment not reappear again in several years after
phylum in untreated mice (1.2%). discontinuation of treatment [27, 31, 123]. These effects can
Indeed, although Proteobacteria usually represent about be more severe in elderly people, in whose GM is less diverse
15% of the intestinal microbiota, they accumulate more compared to younger adults and a more unstable balance that
than 35% of the antibiotic resistance genes contained in can easily lead to the emergence of various pathologies [23,
the microbiome. In contrast, despite representing 31% of 93].
the total microbiota, Bacteroidetes accumulate only 6% of It has also been shown that upon contact with antibiotics,
the antibiotic resistance genes [53]. Hence, it is highly the GM is perhaps the most accessible reservoir of genes
feasible that an antibiotic treatment can cause fewer de- encoding antibiotic resistance due to their high density within
clines in the population of Proteobacteria (or even in- the gut ecosystem, which can have important consequences
crease, occupying the space left by other bacterial groups for human wellbeing [31]. The GI is also an open system,
more sensitive to the action of the antimicrobial) than which incorporates everyday bacteria from the environment
Bacteroidetes, for instance. Similarly, it is also reasonable [88]. These incoming bacteria often possess antibiotic resis-
that once the Proteobacteria reach a high proportion with- tance genes, and besides being a potential risk to the host,
in the microbiota, before gradually declining, its popula- because these resistance encoding genes can be transferred
tion will be maintained at high levels compared to prior to to the host.
the administration of the antimicrobial.
Another study developed in experimental animals showed
that after treatment with cefoperazone (a broad-spectrum an- Conclusions
tibiotic), there was a significant loss of microbial diversity,
without recovery, even at 6 weeks post therapy [4, 47]. In The vast majority of experimental evidence supporting the
another research work [102], in which mice were given van- effects of food minor components and contaminants on GM
comycin or streptomycin in their drinking water, no signifi- has been generated in animal (especially mice) models.
cant changes regarding the action of streptomycin were found, However, mice and humans differ in their microbiota compo-
while vancomycin was associated with significant variations sition, immune function, diets, and metabolism and the results
in both the bacterial load and diversity. An almost total remov- obtained in mice are not totally extrapolable and valid to
al of Bacteroidales and a marked enrichment of Lactobacillus humans. Thus, interventional studies in humans are also need-
were observed. ed, although are seriously limited by ethical concerns. In this
However, humans have a greater variation in diet and life- sense, the use of in vitro models of the human gut enables
style than experimental mice, which introduces factors affect- investigating the effects of minor compounds (even those dan-
ing the recovery of metabolic disturbances or susceptibility to gerous for humans) without health risks and ethical concerns.
weight gain [30]. Hence, the influence of antibiotics on the In view of the results explained in the present work, there are a
GM of humans, particularly children, has been studied. large variety of food minor components, additives and chem-
Children are often the most exposed to antibiotic treatments ical contaminants that can dramatically affect GM. Thus, there
within the human population and typically experience the is a profound need for more in-depth investigations into the
greatest effects [47]. Indeed, some reports suggest that expo- effects on the human GM of the cited compounds.
sure to antibiotics within the first 6 months of life predisposes
the individuals to a significant increase in body mass in later
life [3, 80, 117]. However, other authors found conflicting Acknowledgments The authors want to thank the European Regional
results, suggesting important differences according to the an- Development Funds (FEDER), grant GRC 2014/004 for covering the
costs.
tibiotic regimens, the routes of administration, the choice of
methods of statistical analysis, or other poorly controlled fac-
tors [47].
Compliance with ethical standards
Antibiotic treatments can also significantly alter the micro-
biota composition of the adult GI, causing a decrease in the Conflict of interest The authors declare that they have no conflict of
microbial diversity to between one-quarter to a third of the interest.
 Roca-Saavedra et al.

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