Interindividual Variability in Gut Microbiota and Host Response To Dietary Interventions

Emerging Science
Interindividual variability in gut microbiota and host response

to dietary interventions
Genelle R. Healey, Rinki Murphy, Louise Brough, Christine A. Butts, and Jane Coad
Dysbiosis is linked to human disease; therefore, gut microbiota modulation strategies

provide an attractive means of correcting microbial imbalance to enhance human
health. Because diet has a major influence on the composition, diversity, and metabolic
capacity of the gut microbiota, numerous dietary intervention studies have been con-
ducted to manipulate the gut microbiota to improve host outcomes and reduce disease
risk. Emerging evidence suggests that interindividual variability in gut microbiota and
host responsiveness exists, making it difficult to predict gut microbiota and host re-
sponse to a given dietary intervention. This may, in turn, have implications on the con-
sistency of results among studies and the perceived success or true efficacy of a dietary
intervention in eliciting beneficial changes to the gut microbiota and human health.
INTRODUCTION are detected in feces are Bacteroidetes and Firmicutes.7

The key genera within the Bacteroidetes phyla include
Noncommunicable diseases, such as cardiovascular disease, Alistipes, Bacteroides, and Prevotella, and key genera
type II diabetes mellitus (T2DM), chronic respiratory dis- within the Firmicutes phyla include Enterococcus,
eases, and cancer, contribute to more than half of all deaths Lactobacillus, Coprococcus, Dorea, Blautia, Roseburia,
worldwide.1 Major modifiable noncommunicable disease Ruminococcus, and Faecalibacterium. Other lower abun-
risk factors include smoking, unhealthy dietary intakes (ie, dance phyla that reside in the human GI tract include
high saturated fat, trans fat, salt, and sugar intakes and low Actinobacteria (Bifidobacterium), Verrucomicrobia
whole-grain, fruit, and vegetable intakes), physical inactiv- (Akkermansia), and Proteobacteria (Escherichia). The
ity, and excessive alcohol consumption.2 It has been postu- predominant intestinal bacteria appear to be relatively
lated that the commensal microbes that reside within the stable over time in adults.8 However, observational
gastrointestinal (GI) tract are implicated in human disease. studies have demonstrated inter- and intra-individual
Dysbiotic gut microbiota has been associated with obesity,3 variability in gut microbiota composition, which may
inflammatory bowel disease (IBD),4 T2DM,5 and colon occur secondarily to external factors such as age,9–11
cancers.6 It is difficult to disentangle whether a dysbiotic sex,12,13 antibiotics,14,15 disease,3–6 and diet.16
gut microbiota is causally linked to these diseases or is the Numerous human studies have established that diet
result of these diseases or the dietary patterns and medica- has a major influence on the structural and functional
tions associated with certain disease states. capacity of the gut microbiota,16–20 but emerging re-
High-throughput sequencing technology has revo- search suggests that gut microbiota response to dietary
lutionized the way in which microbes that colonize the interventions is highly variable among individuals.21–23
GI tract are analyzed. The main bacterial phylum that It has been established that individuals harbor microbial
Affiliation: G.R. Healey, L. Brough, and J. Coad are with the Massey Institute of Food Science and Technology, School of Food and Nutrition,
Massey University, Palmerston North, New Zealand. G.R. Healey and C.A. Butts are with the Food, Nutrition & Health Group, New Zealand
Institute for Plant & Food Research Limited, Palmerston North, New Zealand. R. Murphy is with the Faculty of Medical and Health Sciences,
University of Auckland, Auckland, New Zealand
Correspondence: G. Healey, New Zealand Institute for Plant & Food Research Limited, Private Bag 11 600, Palmerston North, New Zealand.
E-mail: [email protected].
Key words: gut microbiota, habitual dietary intake, host outcomes, interindividual variability, responsiveness.
C The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute.
V
All rights reserved. For Permissions, please e-mail: [email protected].
doi: 10.1093/nutrit/nux062
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taxa that are either responsive or resilient to dietary but higher Bifidobacterium spp. concentrations37,38 com-
change, making it very difficult to predict how an indi- pared with formula-fed infants. Jimenez and colleagues33
vidual’s gut microbiota may respond to a given dietary used a murine model to investigate whether the maternal
intervention and ultimately how the individual will ben- gut microbiota transfers to the fetus in utero. Pregnant
efit from the dietary intervention. Previous research mice were given milk that contained genetically labeled
suggests that baseline gut microbiota composition20,24,25 Enterococcus faecium. After sterile Cesarean section,
and habitual dietary intake26,27 may influence gut microbes within the pups’ meconium were analyzed.
microbiota and host response. However, a large propor- Genetically labeled E. faecium was able to be cultured
tion of dietary intervention studies that aim to modu- from the meconium of pups born to mothers that con-
late the gut microbiota do not currently take baseline sumed the genetically labeled milk but not from the con-
gut microbiota composition and habitual dietary intake trol pups. This result suggests that maternal microbiota
into consideration. A greater understanding of the fac- transmission does occur in mammals. Human studies
tors implicated in gut microbiota and host responsive- have suggested that maternal microbiota transmission
ness is needed to establish successful gut microbiota may occur,39 but to date the most convincing evidence
and host outcome modulation strategies. comes from animal studies. Antibiotic use in the first
This review examines the evidence for the link be- month of life has been shown to reduce the concentrations
tween gut microbiota and human disease. This review of bifidobacteria and Bacteroides fragilis group. However,
also explores the role diet plays in modulating the gut antibiotic use by the mother during pregnancy did not ap-
microbiota and highlights whether heterogeneous gut pear to have an influence on the gut microbiota composi-
microbiota and host response to a given dietary inter- tion of the offspring.35 Early life exposure to antibiotics is
vention could be influenced by differing baseline gut also associated with childhood overweight and obesity,
microbiota composition and habitual dietary intake. which suggests that antibiotic-driven perturbation of the
microbial balance at this critical time may have implica-
GUT MICROBIOTA AND HUMAN DISEASE tions on host metabolic functionality.40,41 In one study,
the negative association between antibiotic exposure in in-
The human GI tract harbors a complex ecosystem of bac- fancy and childhood overweight was only observed in
teria, commonly referred to as gut microbiota. A symbi- children born to normal weight mothers. Children born
otic host–microbe relationship is believed to benefit to overweight mothers experienced a slight reduction in
human health because the commensal gut microbiota pro- childhood overweight if exposed to antibiotics in in-
tects its human host against enteropathogenic organism fancy.40 This is an interesting finding because it suggests
colonization,28,29 modulates the innate and adaptive im- that early life antibiotic exposure in offspring of over-
mune system,29 extracts nutrients from undigested dietary weight women may reduce the abundance of potentially
components,29,30 and synthesizes essential vitamins.31 In obesogenic microbiota that may have been passed on via
contrast, intestinal dysbiosis has been suggested to pro- maternal microbiota transmission.
mote or aggravate certain disease states.
Obesity
Gut microbiota development in early life
Gnotobiotic mouse models have demonstrated that
Development of the gut microbiota during a critical pe- germ-free mice have reduced adiposity; lower circulat-
riod in early life is thought to play a substantial role in the ing leptin, insulin, and glucose levels; and enhanced
maturation of the immune system and may have an glucose tolerance compared with conventional mice
influence on the incidence of atopic, autoimmune, and that harbor gut microbiota.42 The discovery that germ-
inflammatory diseases. Modern medical interventions free mice fed a Western-style diet did not develop
implemented to reduce infant mortality, such as Cesarean diet-related obesity provided further evidence for an as-
sections, infant formula feeding, and antibiotic treatment, sociation between gut microbiota and metabolic dis-
may contribute to the rise in immune-mediated diseases ease.43 Additionally, greater body fat accretion occurred
observed in economically developed countries. It has been in germ-free mice that received fecal microbiota trans-
suggested that gut microbiota development is influenced fer from obese human donors than in germ-free mice
by mode of delivery,32 maternal microbe transfer during colonized with the microbiota of lean human donors,
gestation,33 environmental microbe exposure,34 use of further suggesting that the gut microbiota is linked to
antibiotics,35 breast or infant formula feeding,36 and com- host metabolism.44 Several mechanisms have been pro-
plementary feeding practices.35 Breastfed infants have posed to explain the association between the gut micro-
been shown to have lower concentrations of opportunistic biota and host metabolism, including 1) increased
bacteria such as Escherichia coli and Clostridium difficile36 energy extraction from fermentable substrates due to
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the production of short-chain fatty acids (SCFAs)45; 2) with T2DM, with a depletion in the abundance of
altered sensory perception of nutrients such as dietary several butyrate-producing bacteria (ie, Roseburia
fat46 and sucrose47; and (3) high-fat dietary intakes lead- spp., Clostridium spp., Eubacterium rectale, and
ing to an increased production of bacterial lipopolysac- Faecalibacterium prausnitzii) observed in individuals
charide (LPS) and, therefore, high concentrations of with T2DM.55–58 Multiple bacterial groups have been
circulating LPS leading to insulin resistance, endotoxe- shown to be positively correlated with plasma glucose
mia, and chronic low-grade inflammation.48,49 The concentrations, including the ratio of Bacteroidetes to
mechanisms that underlie the link between gut micro- Firmicutes and the ratio of Bacteroides-Prevotella to
biota and host metabolism are incompletely understood Clostridium coccoide-E. rectale.55 Gut microbiota shown
and need to be explored in greater detail. In humans, to be higher in abundance in individuals with T2DM
obese individuals have a gut microbiota profile that is include Betaproteobacteria, Desulfovibrio, and a
distinct from the gut microbiota profile of normal- number of Lactobacillus spp.55,56,58 In a study of 123
weight individuals. Some studies have demonstrated nonobese and 169 obese individuals, a phenotype char-
that obese individuals have a decreased abundance of acterized by metabolic disturbance (ie, increased serum
Bacteroidetes and an increased abundance of leptin, decreased high-density lipoprotein cholesterol,
Firmicutes.3,50 A study conducted in 98 individuals marked inflammation, insulin resistance, and hyperin-
(30 lean [body mass index (BMI), 18.5–25 kg/m2], 35 sulinemia) was observed in individuals with lower mi-
overweight [BMI, 25.1–30 kg/m2], and 33 obese crobial gene richness.53 Therefore, reduced microbial
[BMI > 30 kg/m2]) demonstrated contrary results.51 diversity could be a result of insulin resistance and
Obese and overweight individuals had Firmicutes/ chronic low-grade inflammation, leading to an in-
Bacteroidetes ratios that favored Bacteroidetes, creased metabolic disease risk. It has been suggested
highlighting the controversy surrounding obesity and that LPS produced by bacteria stimulates Toll-like
the Firmicutes/Bacteroidetes ratio.51 The same study receptors, resulting in a proinflammatory response. In
demonstrated that total SCFAs and propionate concen- mice, increasing the circulating levels of LPS (also
trations in overweight and obese individuals were known as metabolic endotoxemia) through continuous
> 20% higher than that in lean individuals. A number subcutaneous infusion led to an increase in glycemia,
of known propionate producers belong to the phylum insulinemia, and weight gain comparable in degree to
Bacteroidetes (ie, Bacteroides and Prevotella), and the that observed in mice fed a high-fat diet.48 In humans,
joint concentrations of these propionate producers were metabolic endotoxemia has been observed to increase
shown to be significantly (p ¼ 0.001) higher in over- inflammatory markers and insulin resistance.59 The
weight individuals.51 Another study demonstrated that metabolic functionality of gut bacteria may also be im-
overweight and obese individuals (n ¼ 37) produced plicated in glucose tolerance. De Mello and colleagues60
higher amounts of total SCFAs, propionate, butyrate, recruited individuals with impaired glucose tolerance
and acetate compared with lean individuals (n ¼ 52). and followed them over a 15-year period to determine
The Firmicutes/Bacteroidetes ratio did not differ be- whether they developed T2DM. In participants that did
tween the 2 groups, but the ratio was shown to signifi- not develop T2DM, serum metabolite profiles, particu-
cantly (p < 0.0001) correlate with total SCFA larly 3-indolepropionic acid (a neuroprotective antioxi-
concentrations, suggesting that they may be interre- dant) and lipid metabolites, were positively linked to
lated.52 Microbial diversity also appears to be lower in improved insulin production and sensitivity and nega-
obese individuals than in lean individuals,50 with lower tively linked to low-grade inflammation. The research-
microbial diversity being shown to be associated with ers suggested that 3-indolepropionic acid could be used
disease risk.53 Even though fairly convincing evidence as a biomarker of T2DM risk. It has been proposed that
exists to link dysbiosis with an obese state, uncertainty SCFAs produced by gut microbiota also affect insulin
remains around whether dysbiosis is a cause or conse- sensitivity and glucose homeostasis.61 A number of
quence of obesity. mechanisms of action have been suggested, including
activation of intestinal gluconeogenesis by butyrate and
Type 2 diabetes mellitus propionate62 and an increased secretion of gut hor-
mones from intestinal enteroendocrine cells, such as
Paralleling obesity, rates of T2DM continue to rise glucagon-like peptide-1 and peptide YY, which enhance
worldwide. It is predicted that the number of individu- satiety and glucose control.61
als with T2DM will rise from 382 million (prevalence in Recent research has highlighted that gut microbiota
2013) to 592 million by 2035.54 Emerging evidence sug- analysis of patients with T2DM may be confounded by
gests that microbiota residing within the GI tract influ- antidiabetic drugs such as metformin.63 Metformin
ence T2DM risk. It appears that dysbiosis is associated treatment has been shown to be associated with an

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increase in Escherichia spp. and a reduction in to current medical treatments, such as immune-
Intestinibacter abundance. Therefore, it is important to modulating therapies. Because the gut microbiota is im-
separate the influence a specific disease has on the gut plicated in IBD pathogenesis, novel microbiota-based
microbiota from the effect a drug taken to help control therapeutic strategies (ie, prebiotics and probiotics)
a specific disease has.63 have the potential to reduce disease incidence and
severity.
Inflammatory bowel disease
The incidence and prevalence of IBD in economically Colorectal cancer

developed countries, such as the United States, the
United Kingdom, Canada, and New Zealand, continue The gut microbiota has been recognized as an impor-
to rise.64 Inflammatory bowel disease pathogenesis is tant component of colon carcinogenesis; therefore, it
not fully understood; however, genetic and environ- has been hypothesized that colorectal cancer can be pre-
mental factors are believed to be involved. Recent work vented through modulation of the gut microbiota.
has indicated that interactions between the gut micro- Studies have shown that individuals with colorectal can-
biota and host may be involved in the development and cer have a dysbiotic gut microbiota profile compared
exacerbation of IBD.65 It has been hypothesized that with healthy individuals.6 Butyrate-producing species
IBD may develop due to a dysfunctional immune re- have been shown to be under-represented in patients
sponse that targets the commensal gut microbiota in with colorectal cancer.74 Ohigashi and colleagues6
hosts with genetic susceptibility. In healthy individuals, established that colorectal cancer patients (n ¼ 93) also
the interactions between the gut microbiota, mucosal had lower total bacteria, C. coccoides group, Clostridium
barrier, and immune system are thought to be in equi- leptum subgroup, B. fragilis group, Bifidobacterium,
librium. In individuals with IBD, this balance is dis- Atopobium cluster, total SCFAs, acetate, butyrate, and
turbed, leading to dysbiosis, a leaky gut (ie, increased propionate concentrations compared with healthy indi-
intestinal permeability), and inflammation. Ulcerative viduals (n ¼ 49). Fecal pH was also higher in patients
colitis (UC) and Crohn’s disease (CD) are the 2 major with colorectal cancer compared with healthy individu-
types of IBD. In individuals with UC, the disease is iso- als with no adenoma.6 Another study provided evidence
lated to the colon, whereas Crohn’s disease can occur to suggest that colorectal cancer risk may be mediated
anywhere along the GI tract. Microbial dysbiosis is reg- by health-promoting (ie, butyrate) and potentially carci-
ularly reported in individuals suffering from IBD, nogenic (ie, secondary bile acids) bacterial fermentation
particularly in individuals with CD.65 It is, however, metabolites. The microbiota composition and metabolic
unclear whether the changes in gut microbiota are a activity of African Americans with high risk for colorec-
cause or consequence of the disease. Crohn’s disease tal cancer (n ¼ 12) were compared with those of
is characterized by lower microbial diversity; a reduc- matched native Africans with low risk for colorectal
tion in F. prausnitzii, Ruminococcus gnavus, and cancer (n ¼ 12). The high-risk group was found to have
Bifidobacterium adolescentis; and an increase in E. a higher abundance of Bacteroides and potentially path-
coli.66 Ulcerative colitis has been associated with lower ogenic Proteobacteria and a lower abundance of
microbial diversity,67 but gut microbiota profiles in Prevotella, Faecalibacterium, Succinivibrio, and
individuals with UC tend to be more similar to those in Oscillospira. The high-risk group had fecal primary and
healthy individuals than to those in individuals with secondary bile acid concentrations that were signifi-
CD.68 A number of studies have demonstrated that bac- cantly (p < 0.05) higher compared with the low-risk
terial species from the butyrate-producing Clostridium group. There were also distinctions in production of
cluster IV and XIVa (ie, F. prausnitzii and Roseburia SCFAs between the 2 groups, with the high-risk group
hominis) are reduced in abundance in individuals with having lower concentrations of acetate, propionate, and
IBD.66,69,70 A number of bacterial genera shown to be butyrate.75 The mechanisms implicated in the carcino-
in low abundance in individuals with IBD (ie, genic potential of a dysbiotic gut microbiota are
Bifidobacterium, Lactobacillus, and Faecalibacterium) thought to be linked to the metabolic byproducts the
are known to enhance immune system tolerance and bacteria produce. Gut microbiota provide their human
reduce GI inflammation by stimulating CD4þ regula- host with a supply of folate, biotin, and butyrate. Folate
tory T-cell activity,71 downregulating inflammatory is involved in DNA repair, replication, and methylation;
cytokines (such as tumor necrosis factor alpha),72 and biotin is involved in gene repression and DNA repair;
upregulating anti-inflammatory cytokines (such as in- and butyrate has potent anti-inflammatory and antineo-
terleukin 10).73 It has been reported that a large propor- plastic properties. These bacterial metabolites are
tion of individuals with IBD do not respond adequately known to regulate epithelial proliferation; therefore,

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they have the potential to moderate colorectal cancer (NAs; n ¼ 12). The dietary differences between the AA
risk.76 and NA groups were similar to what was observed in
Because compositional diversity and functional dis- the de Filippo study, with AAs consuming more animal
tinctions in gut microbiota exist between healthy indi- protein and fat and less dietary fiber than NAs. The
viduals and individuals with disease, microbial most prominent difference in gut microbiota observed
modulation strategies are an attractive option for en- was a higher abundance of Prevotella in the NA group
hancing human health and well-being. and a higher abundance of Bacteroides in the AA
group.75 These results correspond with the pioneering
DIETARY MODULATION OF THE GUT MICROBIOTA enterotype study, which established that individuals
could be classified based on 3 predominant bacterial
Dietary intake has been shown to have a major influ- groups—Prevotella, Bacteroides, and Ruminococcus.80 A
ence on the structural and functional capacity of the gut study published in the same year observed that entero-
microbiota. In mice, dietary change (to a high-fat diet) types were strongly linked with habitual dietary intakes,
explains 57% of the variability in gut microbiota com- with dietary differences being the primary reason for
position, with genetics being much less influential.77 It the distinction in enterotypes. High intakes of animal
has been hypothesized that the shifts that occur in gut protein and saturated fat were correlated with a
microbiota composition due to dietary change occur Bacteroides enterotype, whereas high intakes of carbo-
because the saccharolytic capacity of the bacterial hydrates and simple sugars were correlated with a
species that reside within the GI tract varies depending Prevotella enterotype.16
on the genetic capacity of the bacterial communitiy. Other distinctive habitual dietary patterns (ie,
Additionally, the GI environment (ie, pH, substrate omnivorous vs vegetarian/vegan diets) are also charac-
availability, bile salt concentrations) influences the sur- terized by differing bacterial profiles and metabo-
vival of bacterial species. Because the gut microbiota lomes.18,81–83 Matijasic and colleagues18 showed there
plays a profound role in human health and disease, nu- were a number of compositional differences in the gut
trition and health strategies should aim to target modu- microbiota of lacto-vegetarians/vegans (n ¼ 31) and
lation of the gut microbiota. omnivores (n ¼ 29) living in Slovenia. Lacto-
vegetarians/vegans had a higher relative quantity of
Human observational studies Bacteroides-Prevotella, Bacteroides thetaiotaomicron,
Clostridium clostridioforme, and F. prausnitzii and a re-
Traditional populations have been studied to investigate duced relative quantity of Clostridium cluster XIVa
the influence of modern lifestyles in economically de- compared with omnivores. The large variance in micro-
veloped countries on the structural and functional ca- bial composition was suggested to be related to the con-
pacity of the gut microbiota.12,17,75,78,79 De Filippo and sumption of differing dietary components. Another
colleagues17 demonstrated that, in comparison with study, conducted in the United States, found very few
each other, European children (EC; n ¼ 15) had a gut microbiota composition differences between vegans
higher abundance of Firmicutes and Proteobacteria, (n ¼ 15) and omnivores (n ¼ 16), but the investigators
whereas children from a rural African village (AC; did demonstrate that plasma metabolome differences
n ¼ 14) had a higher abundance of Actinobacteria and existed, with 25% of the metabolites tested differing be-
Bacteroidetes. Xylanibacter, Prevotella, Butyrivibrio, and tween vegans and omnivores. Interestingly, diet
Treponema are capable of fermenting indigestible car- appeared to be more predictive of metabolome produc-
bohydrates and were found exclusively in the AC. Large tion than gut microbiota composition in this cohort.83
distinctions in dietary patterns were observed between As previously noted, commensal microbes that re-
the AC and EC, which led the researchers to hypothe- side within the GI tract are implicated in human dis-
size that the microbiota of the AC were adapted to the ease. Therefore, because habitual dietary intakes have a
high indigestible carbohydrate content of their diet, major impact on the composition of the gut microbiota,
leading to the higher abundance of saccharolytic bacte- it is plausible that dietary interventions could be used to
ria. The gut microbiota of EC were also shown to be modulate the gut microbiota to reduce disease risk.
lower in microbial diversity and were less functionally
active compared with those of the AC. It is possible that Human dietary intervention studies
the lower intake of indigestible carbohydrates led to the
lower SCFA concentrations observed in EC.17 Similar Dietary interventions that aim to elicit changes in the
results were found when structural and functional dis- gut microbiota provide an exciting prospect for disease
tinctions in gut microbiota were analyzed in African prevention and management. Extensive research has
Americans (AAs; n ¼ 12) and rural native Africans demonstrated that dietary interventions can elicit

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changes in gut microbiota composition and function. FODMAP content of the diet is believed to reduce the
Pronounced short-term changes in macronutrient in- production of microbial fermentation byproducts, such
take have been shown to result in dramatic shifts in gut as gas, helping to alleviate common IBS symptoms (ie,
microbiota composition within 24 hours. David and flatulence and bloating). Microbial production of
colleagues19 initiated a 5-day dietary intervention con- SCFAs is thought to help reduce diarrhea, another com-
sisting of either a plant-based diet of grains, legumes, mon symptom of IBS, because SCFAs help stimulate
fruits and vegetables or an animal-based diet of meat, fluid absorption in the colon.89 A number of low
eggs, and cheese in 10 healthy individuals. The animal- FODMAP dietary intervention studies in individuals
based diet had the most pronounced impact on the bac- with IBS have been conducted to demonstrate whether
terial taxa, particularly for bile-tolerant bacterial groups the reduction in symptoms is associated with changes
(ie, Bilophila wadsworthia, Alistipes putredinis, and in gut microbiota. Considerable changes in gut micro-
Bacteroides spp.) and amino-acid fermentation-specific biota have been shown after a low FODMAP diet.90–92
SCFA production (ie, isovalerate and isobutyrate). A Halmos and colleagues90 observed lower total bacteria
positive correlation between saccharolytic bacteria (ie, concentrations and Clostridium cluster XIVa and
Roseburia spp., E. rectale, and F. prausnitzii) and Akkermansia muciniphila abundance in individuals
carbohydrate fermentation byproducts (ie, acetate and consuming a low FODMAP diet compared with a typi-
butyrate) was demonstrated in those assigned to the cal Australian diet. Stool pH was higher after the low
plant-based diet. FODMAP diet, but there were no differences in stool
Dietary fibers are nondigestible plant oligo- and SCFA concentrations between the 2 diet types. The low
polysaccharides, such as nonstarch polysaccharides, re- FODMAP diet reduced GI symptoms irrespective of
sistant starch, beta-glucan, and inulin-type fructans, changes in stool SCFA concentrations.93 Conversely,
that are found in whole grains, legumes, nuts and seeds, increases in dietary fiber intake in healthy individuals
fruits, and vegetables. A diet that is high in fiber has have led to changes in the intestinal microbiota. Five-
been shown to have a number of health benefits.84 The day supplementation with 10 or 40 g/day of dietary fiber
exact mechanisms are not fully understood; however, in a group of 19 healthy individuals led to modest dif-
research suggests that the benefits of dietary fiber on ferences in gut microbiota composition between the
human pathophysiology may be mediated by the gut low and high dietary fiber supplemented groups.20
microbiota.85,86 In germ-free mice inoculated with hu- Over-representation of microbial genes associated with
man microbiota, dietary fiber deficiency led to micro- glycan and lipid metabolism and a downregulation of
bial utilization of host-secreted mucin as a source of genes associated with mucin degradation were seen
energy because diet-derived fermentable substrates in individuals whose diets were supplemented with
were unavailable. Colonic mucin degradation led to in- 40 g/day of dietary fiber.20 These results suggest that di-
testinal barrier dysfunction, which promoted microbial- etary fiber–associated changes in the functional capacity
induced colitis.87 Long-term low fiber consumption in of the microbiota may occur irrespective of changes in
mice has also been shown to lead to intergenerational microbiota community structure.
loss of certain bacterial species that are not restored by A prebiotic is “a substrate that is selectively utilized
increasing the fiber content of the diet in future genera- by host microorganisms conferring a health benefit”.94
tions. This suggests that “extinction” of potentially ben- Prebiotics have the potential to be used to increase ben-
eficial microbes may occur when the GI environment is eficial bacteria that are low in abundance in individuals
depleted of fermentable carbohydrates.88 A study con- with increased disease risk. Established prebiotics in-
ducted in 82 individuals demonstrated that in women clude inulin-type fructans (eg, inulin, oligofructose, and
total fiber and fiber from fruit, vegetables, and grains fructo-oligosaccharides), galacto-oligosaccharides, and
were associated with overall gut microbiota composi- lactulose. Targeting specific bacterial taxa requires an
tion, whereas in men the only association was for bean understanding of what constitutes a beneficial bacterial
fiber and gut microbiota composition. Additionally, profile as well as a broad appreciation of the substrates
intakes of fiber from fruit and vegetables was shown to used by beneficial bacteria. A number of prebiotic inter-
cluster with the class Clostridia, whereas intakes of fiber vention studies in humans have been conducted to
from beans clustered with members of the phyla demonstrate the influence of a given fermentable sub-
Actinobacteria.85 strate (ie, prebiotic) on gut microbiota composition and
Diets low in indigestible short-chain carbohydrates, host outcomes. A large proportion of prebiotic inter-
also known as low fermentable oligosaccharides, disac- vention studies have focused on eliciting changes in
charides, monosaccharides, and polyols (FODMAP) bifidobacteria because high levels of these bacteria are
diets, have been used as a dietary therapy for individuals considered to represent a healthy microbial consor-
with irritable bowel syndrome (IBS). A reduction in the tium.95–98 Other bacterial groups have also been shown

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to increase as a result of prebiotic interventions, includ- mass and led to a reduction in post–oral glucose toler-
ing Lactobacillus97 and Faecalibacterium,99 but very few ance test glycemia compared with the placebo.102
studies have demonstrated what influence prebiotics
have on the entire community. Holscher and col- INTERINDIVIDUAL VARIABILITY IN GUT MICROBIOTA
leagues100 used high-throughput sequencing technology AND HOST RESPONSIVENESS TO DIETARY
to determine the impact of 5 or 7.5 g/day of agave inulin INTERVENTIONS
on the entire microbial community of 29 healthy adults.
In addition to a significant increase in Bifidobacterium Even though various dietary intervention studies have
relative abundance (p < 0.01), a reduction in elicited changes in both host outcomes and the gut
Ruminococcus (p < 0.01) and Desulfovibrio relative microbiota, mounting evidence suggests that individu-
abundances (p ¼ 0.01) were demonstrated, providing a als are heterogeneous when it comes to gut microbiota
clearer picture of the response of the entire microbial and host responsiveness to a given dietary intervention.
community to agave inulin. It is possible that gut microbiota and host resilience to
A number of studies that have demonstrated that a dietary change may be related to interindividual vari-
given dietary intervention elicits changes in the struc- ability in baseline gut microbiota composition and ha-
ture and functional capacity of the gut microbiota have bitual dietary intake. Individualized gut microbiota
also shown that gut microbiota changes are associated resilience may actually play a more pronounced role in
with improvements in host health outcomes. A study gut microbiota response than dietary change itself.21 It
conducted in 81 metabolically healthy individuals aged appears that the responsive bacterial taxa differ among
between 40 and 65 years determined whether a diet rich individuals.23,103–105 Presently, it is very difficult to pre-
in whole grains was able to change the gut microbiota dict how the gut microbiota and host will respond to a
and improve host immune response.101 Participants given dietary intervention. Individualized gut micro-
were instructed to consume a Western-style diet high in biota and host responsiveness have the potential to in-
refined grains for 2 weeks to help minimize the influ- fluence study results and impact reproducibility among
ence of their habitual diet on the results. For the follow- studies. Identification and a greater understanding of
ing 6 weeks, half of the participants continued on the the factors that influence individualized responsiveness
diet high in refined grains (8 g of dietary fiber per may help ensure that the true efficacy of a given dietary
1000 kcal), and the other half commenced a diet rich in intervention is established.
whole grains (16 g of dietary fiber per 1000 kcal). The
calorie content of the diets was personalized to ensure Response of gut microbiota to dietary interventions
each participant’s weight was stable throughout the
trial. Individuals consuming the diet high in whole Influence of baseline gut microbiota composition. The
grains experienced an increase in stool weight and fre- emerging concept of individualized gut microbiota re-
quency. A small but significant increase in total SCFAs sponsiveness indicates a link between baseline gut
(p ¼ 0.05) and acetate (p ¼ 0.02) were observed in the microbiota composition and response to a dietary
group that consumed a diet high in whole grains com- intervention. Certain baseline gut microbiota profiles
pared with the group that consumed a diet high in re- may express an inherent resistance to change and in-
fined grains. A modest increase in the acetate- crease their resilience toward dietary modification.
producing genera Lachnospira and a reduction in the Table 120–27,96,100,103–111,122 summarizes a sample of hu-
proinflammatory genera Enterobacteriaceae were also man intervention studies that have observed varying
observed. The diet high in whole grains also had an in- gut microbiota responses based on differing baseline
fluence on effector memory T cells and acute innate im- gut microbiota profiles or habitual dietary intakes. The
mune response.101 Dewulf and colleagues102 first studies to observe individualized gut microbiota
demonstrated that a 3-month inulin-type fructan prebi- responses established that baseline bifidobacteria con-
otic intervention in 30 obese women led to significant centrations affected the magnitude of change that
(p < 0.05) increases in bifidobacteria and F. prausnitzii occurs in bifidobacteria after a prebiotic intervention.
concentrations. The increases in these bacterial groups Tuohy and colleagues106 were the first researchers to
were shown to be negatively associated with changes in demonstrate that individuals with lower baseline bifido-
LPS, a proinflammatory byproduct of bacterial fermen- bacteria concentrations experience a more pronounced
tation. This result is interesting because high plasma increase in bifidobacteria after an inulin intervention.
concentrations of LPS are thought to be associated with This result has been replicated in a number of prebiotic
the chronic low-grade inflammation characteristic of intervention studies.96,107–109 One study conducted in
obesity.48 The prebiotic also appeared to reduce fat 31 healthy individuals demonstrated that biscuits

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Table 1 Observed differences in baseline gut microbiota composition and function and/or dietary intake and host characteristics between responders and nonresponders
on 09 January 2018
1066
in studies that demonstrated differing gut microbiota responses to a dietary intervention
Gut microbiota responsiveness Reference
Study information Responsiveness Observed baseline differences Observed differences in gut
definition microbiota response
Participants Intervention Analysis method Gut microbiota composi- Dietary intake
tion and function and host
characteristics
10 healthy 100 g of cracker con- 454 pyrosequencing, Magnitude of Not investigated Not investigated The magnitude of change var- Martınez et al.
taining 33 g of RS DGGE, and qPCR change in gut ied considerably among indi- (2010)104
for 3 wk: either microbiota viduals. None of the
RS2 Hi-Maize or composition community shifts were ob-
RS4 Fibersym served in all participants
18 healthy 4 wk of each of the 454 pyrosequencing Change in major No baseline differences Not investigated R: Significant change in at least Davis et al.
following: chews bacterial groups in gut microbiota 1 of the major bacterial (2011)23
with 0 g, 2.5 g, 5 g, analyzed: composition between groups analyzed after the 5 g
and 10 g/d of GOS Bifidobacterium R and NR and/or 10 g/d GOS
and Bacteroides NR: Bacterial groups analyzed
were unaffected by 5 g and
10 g/d GOS
14 over- 1 wk M diet, 3 wk Pyrosequencing, Distance between Differing baseline gut Not investigated R: Postintervention samples a Walker et al.
weight high RS, 3 wk high DGGE, and qPCR baseline and microbiota composi- distance away from the base- (2011)105
mena NSP and 3 wk postintervention tion between R and line sample on a PCoA
weight loss diet samples on a NR; did not elaborate NR: Postintervention and base-
(high protein, low PCoA line samples cluster on a
CHO) PCoA

31 healthy Biscuits containing FISH Change in Lower baseline bifido- Not investigated R: Increase in bifidobacteria Tuohy et al.
6.6 g/d FOS and bifidobacteria bacteria levels in R NR: No change in bifidobacteria (2001)24
3.4 g/d guar gum compared with NR. NR
for 21 d had a baseline bifido-
bacteria 9.3 log10
cells/g
9 healthy 8 g/d of IN for 2 wk FISH Change in Lower baseline bifido- Not investigated R: Higher response in Tuohy et al.
bifidobacteria bacteria levels in R bifidobacteria (2001)106
compared with NR NR: Lower response in
bifidobacteria
8 healthy Consumed either 2.5 Culture based Change in Lower baseline bifido- Not investigated R: Higher response in Bouhnik et al.
per group g, 5 g, 7.5 g, or 10 bifidobacteria bacteria levels in R bifidobacteria (2004)107
R
g/d of SC-FOS, compared with NR NR: Lower response in
SBOS, GOS, or RS bifidobacteria
for 7 d (16 groups)
30 healthy 2 wk 5 g/d of IN, 1 FISH Change in Significantly lower base- Not investigated R: Increase in bifidobacteria Kolida et al.
wk washout and 2 bifidobacteria line bifidobacteria lev- NR: No change in bifidobacteria (2007)108
wk of 8 g/d of IN els in R compared
with NR for 5 and
8 g/d of IN

(continued)
Table 1 Continued
on 09 January 2018
R
characteristics
39 healthy 5 g/d IN for 4 wk Culture based Change in Lower baseline bifido- Not investigated R: Higher response in Bouhnik et al.
bifidobacteria bacteria levels in R bifidobacteria (2007)96
compared with NR NR: Lower response in
bifidobacteria

19 healthy For 4 wk of Lactulose qPCR and DGGE Change in Lower baseline bifido- Not investigated R: Higher response in de Preter et al.
10 g twice a day bifidobacteria bacteria levels in R bifidobacteria (2007)109
OR Synergy 1 (FOS: compared with NR NR: Lower response in
IN) 10 g twice a bifidobacteria
day
12 healthy 5 g Synergy 1 (FOS: qPCR Change in No significant difference Not investigated R: Higher response in Fuller et al.
IN) twice a day for bifidobacteria in baseline bifidobac- bifidobacteria (2007)110
3 wk teria between R and NR: Lower response in
NR bifidobacteria
19 healthy 10 g/d or 40 g/d of 454 pyrosequencing Microbial stability R: Low microbial NR had a higher R: Higher microbial change Tap et al.
dietary fiber (cross- and qPCR diversity diversity of NR: Higher microbial stability (2015)20
over design) with a (OTU numbers) vegetable in-
2 wk washout NR: High microbial take compared
phase diversity with R
(OTU numbers)

45 over- 6 wk of calorie-re- SOLiD sequencing Microbial gene R: LGR R fewer fruit, veg- R: Significant increase in gene Cotillard et al.
weight striction, high pro- richness stability NR: HGR etables, and richness; however gene rich- (2013)111
and tein, low glycemic fish products ness was still significantly
obeseb index diet followed and there was lower than in NR
by a 6 wk M diet a trend toward NR: No change in gene richness
lower dietary fi-
ber intakes
compared with
NR
14 over- 1 wk M diet, 3 wk HITChip and qPCR Distance between R had significantly lower No difference in R: Postintervention samples a Salonen et al.
weight high RS, and 3 wk baseline and microbial diversity (in- habitual diets distance away from the base- (2014)21
mena high NSP and 3 wk postintervention verse Simpson index) between R and line sample on a PCoA
weight loss diet samples on than NR NR. NR: Postintervention and base-
(high protein, low PCoA NSP intake corre- line samples cluster on a
CHO) lated with mi- PCoA
crobial diversity
in R but not NR
(continued)
1067
Table 1 Continued
on 09 January 2018
1068
characteristics
45 over- 6 wk of calorie-re- SOLiD sequencing Change in gut Baseline differences Not investigated R: Increase in Bacteroides the- Shoaie et al.
weight striction, high pro- microbiota in Bifidobacterium taiotaomicron and a decrease (2015)103
and tein, low glycemic composition adolescentis, in Lactobacillus reuteri and
obeseb index diet followed Faecalibacterium F. prausnitzii
by a 6 wk M diet prausnitzii, and NR: Decrease in L. reuteri
Eubacterium rectale
between R and NR
groups
46 healthy 4 wks 25 g/d NSP, 2 SCFA only: Gas Increase in buty- Baseline butyrate con- NR (highest quar- R: Increase in butyrate McOrist et al.
wk washout, and 4 chromatography rate centratio differences; tile) had higher concentration (2011)22
wk 25 g/d NSP þ concentration grouped into quartiles BMI, energy, NR: Decrease or no change in
22 g/d RS diet and protein butyrate concentration
intakes com-
pared with R
(lowest quar-
tile). Fiber in-
take did not
differ
14 healthy 7 wk of FMP; 16S rRNA bacterial Persistence of R:Lactococcus carrier Not investigated R: Persistence of L. lactis (probi- Zhang et al.

women 2 4 oz./d gene sequencing Lactococcus lac- Higher abundance of otic within FMP) after FMP (2016)25
tis strains after Barnesiellaceae, stopped (n ¼ 5)
FMP stopped Odoribacteraceae, and NR: No L. lactis persistence after
Clostridiaceae FMP stopped (n ¼ 9)
NR: Lactococcus noncar- Significantly higher weighted
rier. Lower abundance UniFrac distance after 1 wk of
of Barnesiellaceae, FMP in R compared with NR
Odoribacteraceae, and
Clostridiaceae
29 healthy 3 3 wk interven- 16S rRNA Illumina Change in Not investigated Higher dietary fi- R: Significant increase in Holscher et al.
tions with a 1 wk sequencing Bifidobacterium ber intakes Bifidobacterium relative (2015)100
washout phase be- relative were associated abundance
tween each inter- abundance with increased NR: No significant increase in
R
vention phase. butyrate pro- Bifidobacterium relative
Chocolate chews duction and a abundance
with 0, 5, or 7.5 g trend toward
of agave IN higher
Bifidobacterium
(continued)

Table 1 Continued
on 09 January 2018
R
characteristics
10 healthy Fecal samples from 5 16S rRNA bacterial Shift in dietary R: Higher abundance of CRON donors R: CRON-inoculated mice had a Griffin et al.
donors þ CRON individuals gene sequencing pattern associ- Bacteroides species consumed shift toward the CRON or (2017)26
30 gnoto- and 5 AMER indi- ated bacteria (cellulosilyticus, thetaio- 42.1% less calo- AMER dietary pattern associ-
biotic viduals. Inoculated taomicron), ries, 48.6% less ated bacterial profile to match

mice gnotobiotic mice Parabacteroides gold- fat, 33.5% less the diet (CRON or AMER)
were fed a repre- steinii, and Allstipes carbohydrates, consumed
sentative CRON or putredinis 37.6% less total NR: AMER-inoculated mice had
AMER diet NR: Higher abundance of protein, and a weaker shift toward a
Dorea longicatena, 60.8% less pro- CRON-associated bacterial
Blautia, Coporoccus tein from ani- profile on the CRON diet
comes, and Clostridium mal sources
clostridioforme compared with
AMER donors
22 healthy 50 g/d palm date for FISH Change in gut R: Lower baseline R had a higher di- R: Significant increase in total Eid et al.
3 wk and 3.9 g microbiota Bacteroides etary fiber in- bacteria, Bacteroides, (2015)27
maltodextrin and composition concentration take (18.5 g/d) Lactobacillus/Enterococcus,
33.19g dextrose NR: Higher baseline then NR (6 g/d) C.coccoides-E. rectale,
per day for 3 wk Bacteroides Ruminococcus bromii þ
with a 2 wk wash- concentration flavefaciens, and Roseburia þ

out period be- E. rectale groups
tween NR: No change in gut
interventions microbiota
34 healthy 16 g/d of inulin-type 16S rRNA Illumina Change in gut R: Lower abundance of R had higher die- R: Increase in Bifidobacterium Healey et al.
fructan prebiotic sequencing microbiota unknown genus of tary fiber, en- and Faecalibacterium, de- (2017) (in
for 3 wk composition Lachnospiraceae ergy, fat, PUFA, crease in Coprococcus, Dorea, press)122
NR: Higher abundance of MUFA, CHO, fi- and Ruminococcus
unknown genus of ber per 1000 NR: Increase in Bifidobacterium
Lachnospiraceae kJ, vegetable, only
fruit, nut, and
seed intakes
than NR
Abbreviations: AMER, American diet with no calorie-restriction; BMI, body mass index; CHO, carbohydrate; CRON, calorie-restricted adequate nutrition diet; DGGE, denaturing gradient gel
electrophoresis; FOS, fructo-oligosaccharide; FISH, fluorescence in situ hybridization; FMP, fermented milk product; GOS, galacto-oligosaccharide; HGR, high bacterial gene richness; HITChip,
human intestinal tract chip; IN, inulin; LGR, low bacterial gene richness; M, maintenance; MUFA, monounsaturated fatty acids; NR, nonresponder; NSP, nonstarch polysaccharide; OUT, opera-
tional taxonomic unit; PCoA, principal coordinate analysis; PUFA, polyunsaturated fatty acids; qPCR, quantitative polymerase chain reaction; R, responder; RS, resistant starch; rRNA, ribosomal
RNA; SCFA, short-chain fatty acid, SC-FOS, short-chain fructo-oligosaccharide; SBOS, soybean oligosaccharide; SOLiD, sequencing of oligonucleotides by ligation.
a
Same study cohort.
b
Same study cohort.
1069
containing fructo-oligosaccharides (6.6 g/d) and guar The HGR group experienced a significant (p < 0.05) in-
gum (3.4 g/d) stimulated bifidobacteria growth only in crease in B. thetaiotaomicron and a decrease in
individuals with a baseline bifidobacteria concentration Lactobacillus reuteri and F. prausnitzii, whereas the
of < 9.3 log10 cells/g.24 However, one study demon- LGR group only experienced a significant (p < 0.05) de-
strated that baseline bifidobacteria populations among crease in L. reuteri in response to the calorie-restriction
individuals varied considerably (ie, below detectable diet. These studies highlight that greater microbial
levels to 4.6% of total bacterial genes) but no correlation diversity and gene richness may lead to a gut micro-
existed between baseline bifidobacteria and change in biota profile that is more resilient to dietary change.
bifidobacteria after an inulin-type fructan prebiotic in- Additionally, individuals with differing bacterial gene
tervention.110 The heterogeneity in results seen between richness appear to have differing baseline gut micro-
this study and the studies previously noted may be re- biota communities that respond distinctively to a given
lated to the small sample size used (n ¼ 12) or the dietary intervention.
reporting of the relative proportion of bifidobacteria (ie, Interindividual variability in gut microbiota re-
percentage of total bacterial genes) rather than absolute sponse may also be evident in probiotic intervention
bifidobacteria concentrations. studies. Zhang and colleagues25 conducted a study to
As well as being associated with metabolic and determine whether any of the probiotic strains found in
immune-mediated inflammatory disease risk,53 a fermented milk product (FMP) persisted after the pro-
microbial diversity and gene richness also appear to be biotic intervention was stopped. It was reported that
associated with individualized gut microbiota re- persistence of Lactococcus lactis (probiotic strain found
sponse.20,21,103 A study conducted in 14 overweight in the FMP) was reliant upon whether a participant was
men classified participants as responders and nonres- a Lactococcus carrier or noncarrier during the washout
ponders based on microbial community stability during phase. Lactococcus noncarriers appeared to shed
3 dietary interventions: resistant starch, nonstarch poly- L. lactis, whereas Lactococcus carriers appeared to re-
saccharide, and weight loss interventions. Principal co- tain L. lactis after FMP administration. Baseline differ-
ordinate analysis data identified responders as having ences in gut microbiota composition existed between
gut microbiota communities that were unstable and carriers and noncarriers, with carriers having a higher
nonresponders as having gut microbiota communities abundance of Barnesiellaceae, Odoribacteraceae, and
that were more stable in response to the dietary inter- Clostridiaceae than noncarriers. Carriers also experi-
ventions. It was demonstrated that responders had sig- enced a greater change in beta diversity (bacterial diver-
nificantly (p < 0.05) lower baseline alpha diversity sity between samples; weighted UniFrac distances) due
scores (bacterial diversity within a sample; inverse to the probiotic intervention compared with noncar-
Simpson index) than nonresponders.21 Tap and col- riers, which suggests that the gut microbiota of
leagues demonstrated in 19 healthy individuals who Lactococcus carriers were more responsive to the probi-
consumed a low (10 g/d) vs high (40 g/d) dietary fiber otic intervention. It is, therefore, possible that
intervention, that individuals with higher alpha diver- Lactococcus carriers harbored endogenous bacteria that
sity (species richness) at baseline had gut microbiota were unable to successfully compete with L. lactis and/
that were more resilient to change (Jensen Shannon or had a colonic environment that allowed L. lactis to
Distances metrics) during the high dietary fiber inter- thrive (ie, optimal pH and substrate availability) after
vention phase.20 Microbial gene richness has also been the FMP intervention was ceased.
shown to influence gut microbiota responsiveness. A number of preliminary studies have demon-
Cotillard and colleagues111 conducted a calorie- strated that baseline gut microbiota differences exist be-
restriction study in 45 overweight and obese partici- tween individuals who have gut microbiota that are
pants and identified that individuals with high bacterial responsive and individuals who have gut microbiota
gene richness (HGR) were less likely to experience a that are resilient to a given dietary intervention. Very
change in gene richness but individuals with low bacte- few studies have, however, been conducted with the pri-
rial gene richness (LGR) had a significant (p < 0.01) in- mary aim of determining what constitutes a resilient
crease in gene richness in response to the dietary gut microbiota profile. It is highly likely that gut micro-
intervention. Shoaie and colleagues103 demonstrated, biota resilience will differ depending on the dietary in-
using the same participant cohort as Cotillard and col- tervention being studied and host characteristics, such
leagues,111 that significant (p < 0.05) baseline differen- as age, sex, and habitual dietary intakes, of the study
ces in B. adolescentis, F. prausnitzii, and E. rectale cohort.
existed between the HGR and LGR groups. Moreover,
different bacterial taxa responded to the dietary inter- Influence of habitual dietary intakes. The type and
vention in the HGR group versus the LGR group. amount of fermentable substrates (ie, indigestible

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Figure 1 Hypothetical response in relative abundance of a number of gut microbiota genera (represented by vertical bars) to differ-
ences in habitual dietary fiber intake (A, C) and the addition of a prebiotic in the presence of the differing habitual dietary fiber
intakes (B, D). This figure depicts that the abundance of certain bacterial genera will markedly differ between individuals with low vs high
habitual dietary fiber intakes (the cross-hatched bars indicate a significant [p < 0.05] difference in bacterial relative abundance between low
and high habitual dietary fiber consumers) (A, C). The figure also illustrates that certain bacterial genera may respond in a distinctive manner
to a prebiotic as a result of differing baseline gut microbiota profiles and habitual dietary fiber intakes (B, D). Hypothetically individuals with
low habitual dietary fiber intakes (B) may have a higher proportion of gut microbiota genera, which significantly change in relative abun-
dance in response to a prebiotic (the striped bars indicate a significant [p < 0.05] increase in relative abundance from baseline and the dotted
bars indicate a significant [p < 0.05] decrease from baseline) when compared with individuals with high habitual dietary fiber intakes (D).
Adapted from Flint et al. (2007).112
carbohydrates or fiber) normally presented to colonic fiber are expected to have more responsive gut micro-
microbiota will vary considerably depending on the biota because the prebiotic supplement increases the
host’s habitual dietary intake. Individuals consuming a amount of fermentable substrates available, leading to a
high-fiber diet will present their gut microbiota with a proliferation of previously low abundance bacterial taxa
large range of fermentable substrates available for use as that are well equipped to use fermentable substrates but
key energy sources. A low-fiber diet deficient in fer- had been deprived of them. An alternative scenario may
mentable substrates will deprive the gut microbiota of be that bacterial taxa metabolically capable of using fer-
external energy sources, resulting in reliance on endog- mentable substrates are lost in individuals with low ha-
enous fermentable substrates such as mucin. Variability bitual dietary fiber intakes due to chronic fermentable
in the types and amounts of available fermentable carbohydrate deficiency. Therefore, individuals with
substrates has a major impact on gut microbiota com- higher habitual dietary fiber intakes may harbor gut
position and functional capacity. Gut microbiota dis- microbiota that are better equipped to use the addi-
tinctions exist among individuals with differing tional fermentable substrates, leading to a greater mi-
habitual dietary intakes.16 It is, therefore, plausible that crobial response.
the responsiveness of the gut microbiota to an increase Very little is known about the influence of habitual
in fermentable substrates (ie, prebiotic supplementa- dietary intake on gut microbiota response. Preliminary
tion) may be influenced by an individual’s habitual die- research has shown that habitual diet may influence gut
tary intake. Figure 1 provides a hypothetical example of microbiota responsiveness (Table 1). A recent study
the influence of differing habitual dietary fiber intakes conducted using germ-free mice colonized with human
on gut microbiota response to a prebiotic intervention. gut microbiota from donors with 2 varying dietary pat-
In this example, individuals with low habitual intakes of terns (typical American style dietary pattern [AMER] or

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a plant-rich, calorie-restricted diet with optimal nutri- the gut microbiota to an inulin-type fructan prebiotic
ent composition [CRON]) demonstrated that mice in- (n ¼ 34) (Healey et al. 2017 [in press]122)). It was estab-
oculated with AMER microbiota were less responsive to lished that the LDF group had bacterial taxa that were
the plant-based diet compared with mice inoculated less responsive to dietary change than the HDF group.
with CRON microbiota. When AMER-colonized mice The only bacterial genus that significantly changed due
were cohoused with CRON-colonized mice, it appeared to the inulin-type fructan prebiotic in the LDF group
that CRON-associated bacteria were exchanged (ie, via was Bifidobacterium (p < 0.01), but in the HDF group
coprophagia) between the 2 mouse types because the significant prebiotic-driven changes in Bifidobacterium
AMER microbiota had an improved response to the (p < 0.01), Faecalibacterium (p < 0.05), Coprococcus
plant-based diet.26 In humans, a 21-day palm date inter- (p < 0.05), Dorea (p < 0.05), and Ruminococcus
vention in 22 healthy individuals did not lead to (p < 0.05) were observed. These results differ from
changes in select bacterial taxa.27 Secondary analysis those of the palm date intervention study previously
demonstrated that participants with LDF intakes had a noted.27 In the case of the palm date intervention study,
significant change in a number of bacterial taxa, includ- the LDF group rather than the HDF group appeared to
ing total bacteria (p < 0.01), Lactobacillus/Enterococcus have gut microbiota that were more responsive to the
(p < 0.05), and Roseburia þ E. rectale (p < 0.01), palm date. The dietary fiber intake criteria used to clas-
whereas participants with HDF intakes had no change sify participants as LDF or HDF consumers did differ
in bacterial taxa. These results suggest that participants markedly between studies. The average dietary fiber in-
with HDF intakes harbored gut microbiota that were take of the LDF (6 g/d vs 18 g/d) and HDF (18.5 g/d vs
more resilient and participants with LDF intakes har- 38.6 g/d) groups were much lower in the palm date in-
bored gut microbiota that were more responsive to the tervention study. The discrepancy in responsiveness be-
palm date intervention.27 Holscher and colleagues dem- tween the 2 studies may also be related to the different
onstrated that an agave inulin supplement (7.5 g/d) led dietary interventions studied. This suggests that a palm
to a > 1% increase in Bifidobacterium relative abun- date intervention may have more of an influence on the
dance in only 15 of the 29 participants. A trend toward gut microbiota of LDF consumers and an inulin-type
a positive correlation between Bifidobacterium relative fructan intervention may have more of an influence on
abundance and grams of dietary fiber consumed per ki- the gut microbiota of HDF consumers. Additional
localorie was observed. Additionally, a positive correla- research is required to further clarify the influence of
tion between butyrate production and total dietary fiber habitual dietary fiber intake on gut microbiota respon-
intakes was established. These results suggest that habit- siveness to certain dietary interventions.
ual dietary fiber intakes influence butyrate production
and bifidogenic response.100 Some studies have shown Host response to dietary interventions
that individuals with gut microbiota that are more resil-
ient to dietary change have a higher diversity of vegeta- Dietary interventions have been shown to elicit differen-
ble intake20 and higher vegetable, fruit, and fish tial gut microbiota responses among individuals. A given
intakes.111 Other studies have found no differences in dietary intervention leads to variable host responses.
habitual dietary intake21 or dietary fiber intakes22 Although dietary interventions affect host metabolic out-
between individuals with responsive gut microbiota comes in an individualized way, host parameters such as
and individuals with permissive gut microbiota, indicat- interindividual variability in gut microbiota composition
ing that inconsistencies in study results exist. and habitual dietary intakes may prove useful in predict-
Heterogeneous results may exist due to considerable ing host responses.
differences in the dietary interventions and dietary as-
sessment methods used and in participant characteris- Influence of baseline gut microbiota composition.
tics between studies. Additionally, in these studies only Because gut microbiota structure and function are im-
post hoc analysis was conducted to determine whether plicated in disease risk, it is imperative to investigate
dietary differences existed between responders and whether gut microbiota composition is linked to inter-
nonresponders. Until recently no studies had been con- individual variability in host responses. Emerging re-
ducted with the primary aim of determining whether search suggests that an association between baseline gut
habitual dietary intakes influence the responsiveness of microbiota composition and host responses does exist
the gut microbiota to dietary interventions. (Table 291,111,113–120). A study conducted in 800 healthy
To help fill this knowledge gap, a study was con- individuals demonstrated that glycemic response to a
ducted that recruited participants with distinctive habit- given food is highly variable among individuals.
ual dietary fiber intakes to determine whether low vs Researchers were able to use baseline gut microbiota
high habitual dietary fiber influenced the response of composition, blood parameters, anthropometric

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Table 2 Observed differences in baseline gut microbiota composition and function and/or dietary intake and host characteristics between responders and nonresponders
in studies that demonstrated differing host responses to a dietary intervention
Host responsiveness Reference
Study information Responsiveness Observed baseline differences Observed differences in response
R
definition
Participants Intervention Analysis method Gut microbiota composi- Dietary intake and Host clinical outcome Gut microbiota
tion and function host characteristics
12 healthy Algorithm-de- 16S rRNA bacterial PPGR Used as a factor to Dietary patterns R: Significantly higher Interindividual vari- Zeevi et al.
rived personal- gene help predict used as a factor to PPGR during the ability in gut (2015)113
ized diet sequencing glycemic response: help predict gly- “bad” diet phase com- microbiota
Enterobacteriaceae, cemic response pared to with “good” responses; did not

Proteobacteria, and diet phase analyze R and NR
Actinobacteria NR: No difference in separately
PPGR between the
“good” and “bad” diet
phases
20 healthy 3 d BKB followed 454 Improved glucose R: Higher Prevotella Not investigated R: Incremental blood R: Increase in the Kovatcheva-
by 3 d of WWB pyrosequencing metabolism abundance glucose area de- Prevotella/ Datchary
NR: Lower Prevotella creased by at least Bacteroidetes ratio et al.
abundance 25%, total AUC de- NR: No change in (2015)114
creased, and insulin Prevotella/
AUC decreased by at Bacteroidetes ratio
least 15%
NR: No difference in
glucose and/or insulin
response

7 healthy 1 wk saccharin 16S rRNA bacterial Glycemic PCoA differences Not investigated R: Poor glycemic re- R: Pronounced Suez et al.
intervention— gene response between R and NR sponse to saccharin change in gut (2014)115
15 mg/kg sequencing NR: No glycemic re- microbiota
body weight sponse to saccharin composition
NR: No change
PCoA differences af-
ter the interven-
tion between R
and NR
49 overweight 6 wk calorie-re- SOLiD high- Metabolic R: High Akkermansia R: More metaboli- R: Higher Disse index, R: Reduction in A. Dao et al.
and obesea striction diet throughput se- improvements muciniphilia cally healthy greater improvement muciniphilia (abun- (2016)117
followed by a quencing and NR: Low A. muciniphilia NR: Less metaboli- in LDL cholesterol and dance still higher
6 wk M diet qPCR cally healthy a continued decrease than NR group)
No difference in diet in waist circumference NR: Minimal change
quality between R NR: Less benefit from in A. muciniphilia
and NR intervention
(continued)
1073
Table 2 Continued
on 09 January 2018
1074
definition
78 overweight Cohort 1 HITChip Change in R: High or low abun- Not investigated R: Decrease (39%) or no R: Microbial stability Korpela
and obese (n ¼ 52): high cholesterol dance of Eubacterium change (62%) in <0.87. et al.
fiber rye and ruminantium and cholesterol Higher response in (2014)118
WG diet and a Clostridium felsineum. NR: Decrease (24%) or bifidobacteria
low fiber re- Lower bifidobacteria an increase (23%) in NR: Microbial stabil-
fined grain diet. NR: Average abundance cholesterol ity >0.92
Cohort 2 (n ¼ 13): of E. ruminantium and Lower response in
8 g of IN and C. felsineum. Higher bifidobacteria
8 g of FOS. bifidobacteria
Cohort 3 (n ¼ 13):
3 wk WL diet
(high protein,
low CHO)
49 overweight 6 wk of calorie- qPCR Intervention- R: Higher concentration NR had a higher R: 7.6% WL at 6 wk and Not investigated Kong et al.
and obesea restriction diet driven WL and of Lactobacillus/ starch and oil in- 10% at 12 wk (2013)116
followed by a M Leuconostoc/ take and a lower NR: 4.4% WL at 6 wk
6 wk M diet Pediococcus group intake of protein and 2.9% weight
NR: Lower concentration compared with R regain at 12 wk (only
of Lactobacillus/ a 1.5% WL over the
Leuconostoc/ 12 wk)

Pediococcus group
28 healthy Three 4-wk 454 Immunological Higher abundance of Not investigated R: Highest tertile Not investigated Martınez
whole-grain pyrosequencing response IL-6 Dialister and a lower change in IL-6 due to et al.
flake interven- abundance of the BR þ WGB (2013)119
tions: WGB, Coriobacteriaceae in R intervention
BR þ WGB, compared with NR NR: Lowest tertile
and BR change in IL-6 due to
the BR þ WGB
intervention
45 overweight 6 wk of calorie- SOLiD sequencing Change in inflam- R: HGR NR less fruit, vegeta- R: More marked im- R: No change in Cotillard
and obesea restriction diet matory NR: LGR bles, fish products, provement in inflam- gene richness et al.
followed by a markers and trend toward mation markers NR: Significant in- (2013)111
6 wk M diet lower dietary fiber NR: Less pronounced crease in gene
R
compared with R. improvements in in- richness; however
NR had higher insu- flammatory markers gene richness was
lin resistance and still significantly
fasting serum lower than in R
TAGs compared
with to R

(continued)
Table 2 Continued
on 09 January 2018
definition
R
8 children with 1 wk of LFSD 454 Reduction in pain R: Higher abundance of No difference in die- R: 50% reduction in R: Increased abun- Chumpitazi
IBS pyrosequencing frequency an OTU from tary intake be- abdominal pain fre- dance of et al.
Ruminococcaceae (spe- tween R and NR quency and lower hy- Prevotellaceae and (2014)120
cifically Sporobacter and drogen production unclassified
Subdoligranulum) NR: <50% reduction in Coriobacteriaceae

NR: Higher abundance of abdominal pain fre- and a reduction in
Bacteroidales and an quency and higher hy- Dialister
OTU from drogen production NR: Increased abun-
Ruminococcaceae dance of
Actetivibrio cellulo-
lyticus, Bacteroides,
and Dialister
33 children with 48 h low 454 Reduction in pain R: Higher abundance of No differences in R: Significant improve- Not investigated Chumpitazi
pediatric FODMAP or pyrosequencing frequency Bacteroides, baseline dietary ment in pain episodes et al.
Rome III– typical Ruminococcaceae, intake (1 3-d during low FODMAP (2015)91
defined IBS American Dorea, Faecalibacterium diet record) be- diet phase
childhood diet prausnitzii, and cc_115 tween R and NR NR: No improvement in
(crossover de- (family Erysipilotrichaceae). pain episodes during
sign) with a Three enriched CHO low FODMAP diet
5 d washout metabolism-specific phase

phase KEGG orthologs at
baseline
NR: Higher abundance of
Turicibacter from the
family
Turicibacteraceae. No
enriched KEGG
orthologs
(continued)
1075
measurements, and self-reported lifestyle behavior (ie,
tional taxonomic unit; PCoA, principal co-ordinate analysis; PPGR, postprandial glycemic response; PUFA, polyunsaturated fatty acids; qPCR, quantitative polymerase chain reaction; R, responder; rRNA,
Reference
press)122
dietary habits and physical activity levels) data to iden-
et al. (in
Genomes; LDL, low-density lipoprotein; LFSD, low fermentable substrate diet; LGR, low bacterial gene richness; M, maintenance; MUFA, monounsaturated fatty acids; NR, nonresponder; OTU, opera-
Abbreviations: AUC, area under curve; BR, brown rice; BKB, barley kernel–based bread; CHO, carbohydrate; FODMAP, fermentable oligosaccharides disaccharides monosaccharides and polyols; FOS,
tify factors associated with individual variability in gly-
Healey
fructo-oligosaccharide; HITChip, human intestinal tract chip; HGR, high bacterial gene richness; IBS, irritable bowel syndrome; IL-6, interleukin 6; IN, inulin; KEGG, Kyoto Encyclopedia of Genes and
cemic response.113 A machine-learning algorithm was
devised, based on the factors associated with individual
Bifidobacterium and
Coprococcus, Dorea,
and Ruminococcus
variability, to accurately predict glycemic responses.
Faecalibacterium,
Gut microbiota
Bifidobacterium
ribosomal RNA; SOLiD, sequencing of oligonucleotides by ligation; TAG, triacylglycerol; WL, weight loss; WG, whole grain; WWB, white wheat flour bread; WGB, whole-grain barley.
The algorithm was used in a human intervention study
NR: Increase in
Observed differences in response
decrease in
R had higher dietary R: Significant reduction R: Increase in (n ¼ 26) to generate personalized dietary interventions.
The algorithm-derived personalized dietary interven-
only
tions were shown to significantly (p < 0.05) lower glyce-
mic responses and alter gut microbiota composition.113
This study highlights the potential in using host out-
Host clinical outcome
lunch and hunger af-

ter dinner, and a sig-
in satisfaction before
fullness and satisfac-
change in appetite
nificant increase in
NR: No significant come parameters and baseline gut microbiota data to

tion after lunch
better predict dietary intervention success. A number of

other studies have also demonstrated a link between
glycemic response and baseline gut microbiota compo-
ratings
sition. Individuals with higher baseline Prevotella abun-

dance experienced an incremental decrease in blood
glucose and insulin area under the curve after 3 days of
ble, fruit, nut, and
host characteristics
seed intakes than

Dietary intake and
fiber, energy, fat,
1000 kJ, vegeta-
consuming barley kernel–based bread.114 The improve-

CHO, fiber per
PUFA, MUFA,
ment in glycemic response was also associated with an

Observed baseline differences
increase in Prevotella/Bacteroides ratio. Individuals with

lower baseline Prevotella abundance did not experience
NR
a host or gut microbiota response after the dietary inter-

vention, suggesting a more resilient host phenotype and
Gut microbiota composi-
NR: Higher abundance of
gut microbiota profile.114

R: Lower abundance of
tion and function
unknown genus of
unknown genus of
Recent research suggests that artificial sweeteners

Host responsiveness
Lachnospiraceae
Lachnospiraceae
may be detrimental to health. Suez and colleagues115

demonstrated that saccharin led to glucose intolerance
in a subset of their participant cohort. Baseline principal
coordinate analysis data demonstrated that individuals
who had no saccharin-related change in glycemic re-
sponse (nonresponders) had gut microbiota profiles
Responsiveness
Improvement in
that clustered together. Individuals who experienced a

definition
appetite
glycemic response (responders) had gut microbiota pro-

ratings
files that clustered separately from nonresponders,

demonstrating that responders and nonresponders had
differing gut microbiota compositions at baseline.
16S rRNA Illumina
Analysis method
Saccharin responders also experienced a more pro-

sequencing
nounced change in gut microbiota composition due to

the saccharin intervention compared with nonrespond-
ers, suggesting that dysbiosis may have led to the ob-
served saccharin-related glucose intolerance.
Study information
Other host metabolic outcomes, such as cholesterol

16 g/d of inulin-
Intervention
prebiotic for
type fructan
and weight reduction, have been associated with base-

line gut microbiota composition differences.116–118
3 wk
Individuals with low baseline A. muciniphila abundance

were shown to be less metabolically healthy but more
Same study cohort.
Table 2 Continued
metabolically resilient to a 6-week calorie-restriction

diet than individuals with high baseline A. muciniphila
abundance.117 In individuals with high baseline A.
Participants
34 healthy
muciniphila abundance, the calorie-restriction interven-

tion led to a higher Disse index (assesses insulin sensi-
a
tivity), greater improvements in low-density lipoprotein

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on 09 January 2018
cholesterol, a continued reduction in waist circumfer- levels of the inflammatory marker sCD14, higher levels
ence, and a reduction in A. muciniphila abundance, of anti-inflammatory adipose tissue macrophage
even after the calorie-restriction diet was discontinued CD163, and the highest microbial gene richness com-
and participants began a weight maintenance diet.117 pared with clusters 1 and 2.121 In the same participant
Using the same participant cohort, Kong and col- cohort, Cotillard and colleagues111 demonstrated that a
leagues116 demonstrated that weight loss success after calorie-restriction diet led to more pronounced
the calorie-restriction diet was dependent on baseline improvements in inflammatory markers in participants
concentrations of the Lactobacillus/Leuconostoc/ with the healthiest dietary pattern. Other research has
Pediococcus group. Individuals with lower concentra- confirmed that individuals with healthier dietary pat-
tions of Lactobacillus/Leuconostoc/Pediococcus experi- terns have higher microbial gene richness.17 Therefore,
enced a 4.4% reduction in total body weight during the individuals with higher microbial gene richness may
calorie-restriction diet phase but regained 2.9% of their harbor gut microbiota with a larger repertoire of bacte-
total body weight during the 6-week weight mainte- rial genes that are metabolically capable of coping with
nance diet phase. Conversely, individuals with higher extreme changes in macronutrient intake, leading to a
concentrations of Lactobacillus/Leuconostoc/Pediococcus greater potential to influence host outcomes.
at baseline had a 7.6% reduction in total body weight A number of studies have been unable to demon-
during the calorie-restriction diet phase, and by the end strate dietary intake differences between individuals that
of the weight maintenance diet phase had lost an have and individuals that have not experienced changes
additional 2.4% of their total body weight. Korpela and in host outcomes after a given dietary interven-
colleagues118 used 3 previously published dietary inter- tion.91,117,120 In these studies, participants were not ac-
vention cohorts to determine whether a baseline gut tively recruited based on distinctions in dietary intakes,
microbiota signature was associated with more pro- and dietary assessment methods that assessed only cur-
nounced host-specific metabolic changes. A very high rent rather than habitual dietary intakes were used. As
or very low abundance of Eubacterium ruminantium previously noted, the study conducted by the authors of
and Clostridium felsineum was shown to be associated this article recruited individuals with distinctive habitual
with a more responsive gut microbiota. Interestingly, dietary fiber intakes and demonstrated that habitual die-
individuals with more responsive gut microbiota also tary fiber intakes influence the response of the gut micro-
had greater changes in cholesterol, demonstrating the biota to an inulin-type prebiotic intervention (Healey et
prognostic value of baseline gut microbiota. A number al. 2017 [in press]). In the same participant cohort, an as-
of studies have revealed that inflammatory responses to sociation between habitual dietary fiber intake and host
dietary change111,119 and low FODMAP diet-related appetite ratings was also demonstrated. In the HDF
reductions in IBS-associated pain91,120 are also linked to group, the inulin-type fructan prebiotic led to a signifi-
baseline gut microbiota composition, providing further cant reduction in satisfaction before lunch (p < 0.05) and
evidence of the role of baseline gut microbiota composi- in hunger after dinner (p < 0.01) and a significant in-
tion in host response. crease in fullness (p < 0.01) and satisfaction after lunch
At present, the efficacy of a dietary intervention in (p < 0.05). Changes in appetite ratings were not associ-
changing gut microbiota composition and host health ated with a change in weight or a reduction in caloric in-
outcomes is highly individualized and unpredictable. take, but the 3-week prebiotic intervention may not have
Mounting evidence suggests that microbial-specific been long enough to initiate changes in these host out-
biomarkers could be used to predict the individualized comes. Conversely, the LDF group did not experience
success a given dietary intervention may have on host any changes in appetite ratings, weight, or caloric intake
responses. after the prebiotic intervention. The HDF group also had
gut microbiota that were more responsive to the inulin-
Influence of habitual dietary intake. Recent research has type fructan prebiotic than the LDF group. This is the
suggested that habitual dietary intake may also be asso- only study in humans that has been conducted with the
ciated with variability in host responses (Table 2). One primary aim of determining whether differing habitual
study in 45 overweight and obese individuals demon- dietary intakes influence the gut microbiota and host re-
strated that 3 distinctive dietary pattern clusters were sponse to a dietary intervention. Therefore, it is essential
linked with distinctions in metabolic and inflammatory that additional studies be conducted in this area.
variables and microbial gene richness. Cluster 1 was as-
sociated with the least healthy dietary pattern, cluster 3 CONCLUSION
had the healthiest dietary pattern, and cluster 2 had a
dietary pattern between clusters 1 and 3. Individuals Dietary modulation of the gut microbiota to improve
with the healthiest dietary pattern cluster had lower human health is an attractive strategy for reducing the

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increasing prevalence of metabolic and inflammatory- parameters, as introduced by Zeevi and colleagues,113
related disease. The multifaceted interactions that exist have promise in ensuring dietary interventions are tai-
within a gut microbiota community make it difficult to lored to the individual to improve their success.
predict how a specific dietary intervention may influ- Continuing advancements in -omics technologies and a
ence gut microbiota composition and host outcomes. In deeper understanding of gut microbiota and host physi-
addition, the complexity and individuality of gut micro- ology resilience may help facilitate the advancement of
biota and host responsiveness make any progress in this more robust personalized microbiota-targeted dietary
area challenging. Therefore, gaining a better under- approaches in the future.
standing of the factors implicated in interindividual var-
iability in gut microbiota and host responsiveness may
Acknowledgments
help improve dietary intervention success and subse-
quently enhance human health outcomes.
Author contributions. GRH compiled the literature and
The majority of studies reviewed suggest that base-
wrote the manuscript. RM, CAB, LB and JC were in-
line gut microbiota composition and habitual dietary
volved in the development and editing of the
intakes are factors implicated in gut microbiota and
manuscript.
host responsiveness. A limited number of studies have
found no link between responsiveness and baseline gut
microbiota composition23,110 or dietary intake.91,117,120 Funding. GRH received a PhD stipend as part of the
The discrepancies in results among studies may be re- Foods for Health fund awarded to The New Zealand
lated to heterogeneity in participant characteristics (ie, Institute for Plant & Food Research Limited and other
age, sex, ethnicity, BMI) and the differing dietary assess- collaborating New Zealand organizations by the
ment methods, dietary interventions, and gut microbial Ministry of Business, Innovation, and Employment,
analysis methods used. Larger, less heterogeneous New Zealand Government (C11X1312).
cohorts and analytical methods should be used in the
future to provide further insight into the influence of Declaration of interest. The authors have no relevant
baseline gut microbiota composition and habitual die- interests to declare.
tary intake on gut microbiota and host response to die-
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Interindividual Variability in Gut Microbiota and Host Response To Dietary Interventions

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Emerging Science

Interindividual variability in gut microbiota and host response

Dysbiosis is linked to human disease; therefore, gut microbiota modulation strategies

INTRODUCTION are detected in feces are Bacteroidetes and Firmicutes.7

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The incidence and prevalence of IBD in economically Colorectal cancer

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lunch and hunger af-

fullness and satisfac-

NR: No significant come parameters and baseline gut microbiota data to

better predict dietary intervention success. A number of

sition. Individuals with higher baseline Prevotella abun-

seed intakes than

fiber, energy, fat,

1000 kJ, vegeta-

consuming barley kernel–based bread.114 The improve-

ment in glycemic response was also associated with an

increase in Prevotella/Bacteroides ratio. Individuals with

a host or gut microbiota response after the dietary inter-

NR: Higher abundance of

gut microbiota profile.114

Recent research suggests that artificial sweeteners

may be detrimental to health. Suez and colleagues115

that clustered together. Individuals who experienced a

glycemic response (responders) had gut microbiota pro-

files that clustered separately from nonresponders,

Saccharin responders also experienced a more pro-

nounced change in gut microbiota composition due to