nutrients

Review
Impact of Exercise on Gut Microbiota in Obesity
Jerónimo Aragón-Vela 1,2, * , Patricio Solis-Urra 3,4 , Francisco Javier Ruiz-Ojeda 2,5,6,7 ,
Ana Isabel Álvarez-Mercado 2,5,6 , Jorge Olivares-Arancibia 8,9 and Julio Plaza-Diaz 5,6,10, *

1 Department of Physiology, School of Pharmacy, University of Granada, Campus de Cartuja s/n,

18071 Granada, Spain
2 Institute of Nutrition and Food Technology “José Mataix”, Center of Biomedical Research, University of
Granada, Avda. del Conocimiento s/n, 18016 Granada, Spain; fjrojeda@gmail.com (F.J.R.-O.);
alvarezmercado@ugr.es (A.I.Á.-M.)
3 PROFITH “PROmoting FITness and Health through Physical Activity” Research Group, Department of
Physical Education and Sports, Faculty of Sports Science, University of Granada, 18071 Granada, Spain;
patricio.solis.u@gmail.com
4 Faculty of Education and Social Sciences, Universidad Andres Bello, Viña del Mar 2531015, Chile
5 Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada,
18071 Granada, Spain
6 Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada,
18014 Granada, Spain
7 RG Adipocytes and Metabolism, Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz
Center Munich, Neuherberg, 85764 Munich, Germany
8 Grupo AFySE, Investigación en Actividad Física y Salud Escolar, Escuela de Pedagogía en Educación Física,
Facultad de Educación, Universidad de las Américas, Santiago 8370035, Chile; jorge.olivares.ar@gmail.com
9 IRyS Research Group, School of Physical Education, Pontificia Universidad Católica de Valparaíso,



Valparaíso 2374631, Chile

 10 Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
Citation: Aragón-Vela, J.; Solis-Urra,
* Correspondence: jeroav@ugr.es (J.A.-V.); jrplaza@ugr.es (J.P.-D.); Tel.: +34-958220319 (J.A.-V.);
+34-958241599 (J.P.-D.)
P.; Ruiz-Ojeda, F.J.; Álvarez-Mercado,
A.I.; Olivares-Arancibia, J.;
Plaza-Diaz, J. Impact of Exercise on Abstract: Physical activity, exercise, or physical fitness are being studied as helpful nonpharmaco-
Gut Microbiota in Obesity. Nutrients logical therapies to reduce signaling pathways related to inflammation. Studies describing changes
2021, 13, 3999. https://doi.org/ in intestinal microbiota have stated that physical activity could increase the microbial variance
10.3390/nu13113999 and enhance the ratio of Firmicutes/Bacteroidetes, and both actions could neutralize the obesity
progression and diminish body weight. The aim of this review is to provide an overview of the
Academic Editors: Nathalie Boisseau literature describing the relationship between physical activity profiles and gut microbiota and in
and Nicolas Barnich obesity and some associated comorbidities. Promoting physical activity could support as a treatment
to maintain the gut microbiota composition or to restore the balance toward an improvement of
Received: 15 October 2021
dysbiosis in obesity; however, these mechanisms need to be studied in more detail. The opportunity
Accepted: 8 November 2021
to control the microbiota by physical activity to improve health results and decrease obesity and
Published: 10 November 2021
related comorbidities is very attractive. Nevertheless, several incompletely answered questions need
to be addressed before this strategy can be implemented.
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
Keywords: gut microbiota; physical activity; health; obesity; children; humans; non-communicable
iations. diseases

1. Introduction
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
A positive energy balance causes excessive lipid accumulation in adipose tissue that
This article is an open access article
influences the affected individual in regards to other diseases such as insulin resistance, car-
distributed under the terms and diovascular diseases that can culminate in certain types of cancers and type 2 diabetes [1].
conditions of the Creative Commons Indeed, visceral fat rather than total fat is the main driver of insulin resistance and other
Attribution (CC BY) license (https:// comorbidities such as dyslipidemia and chronic low-grade inflammation status in individ-
creativecommons.org/licenses/by/ uals [2]. At the cellular level, adipocyte hypertrophy results in compromised blood supply
4.0/).

Nutrients 2021, 13, 3999. https://doi.org/10.3390/nu13113999 https://www.mdpi.com/journal/nutrients

Nutrients 2021, 13, 3999 2 of 15

to adipose tissue, higher fibrosis, hypoxia, systemic and local inflammation, and insulin
resistance in the adipocytes [3,4].
Although scientists continue making substantial progress in understanding adipose
tissue function, prevention, and treatment of obesity, the pandemic continues to spread and
is one of the main health complications in industrialized and developing countries [5]. In
Europe, the overweight prevalence is expected to be near 50%, and the obesity prevalence
to be approximately 24% of the population [6], increasing from 11% in 2000 to 24% in 2018,
on typical through European member states [6,7]. It is noteworthy that high-calorie diets
and the absence of physical activity, which is strongly affected by a variety of factors such
as lifestyle and socioeconomic status, play a part in the advance of metabolic diseases [8].
Despite the multiple factors that interact in the progress of obesity, the gut microbiota
seems to be a critical role as a bodyweight regulator [9]. In fact, Liu et al. have reported
elevated body mass index (BMI) and adiposity, dyslipidemia, insulin resistance, and a more
marked inflammatory status in individuals who have also exhibited significantly lesser
diversity in gut bacteria [10]. Numerous mechanisms have been suggested to elucidate the
potential role of gut microbiota in obesity progress.
The term microbiota includes the full collection of microbes (bacteria, fungi, and
viruses, among others) that naturally subsist within a particular biological niche, around
500–1000 species, and their impact on human health [11]. Several endogenous and exoge-
nous factors are involved in the gut microbiota such as the delivery method of a neonate,
host immune response, diet, antibiotics, host genetic features, other drugs, infections,
diurnal rhythm, and environmental microbial exposures [12,13].
With regards to obesity, a high-fat diet causes systemic insulin resistance and metabolic
dysfunction in mice, which drives a functional and structural dysbiosis of the gut micro-
biota, defined as “a reduction in microbial diversity and a combination of the loss of
beneficial bacteria such as Bacteroides strains and butyrate-producing bacteria” [12,14,15],
increasing Lactococcus and lowering Turicibacter, which confer an enhanced inflammatory
response [16]. The systemic inflammation in obesity is related to augmented intestinal per-
meability, which is linked with “leaky gut” and gut dysbiosis, which is a new objective for
therapy and disease prevention [17]. Indeed, disturbances of gut microbiota composition
may upsurge the leakage of the mucosa, increasing the seepage of bacteria and bacteria
components such as lipopolysaccharide (LPS) across the intestinal mucosa [18]. In addition,
it is well-known that obesity causes a reduction in the ratio of Bacteroidetes/Firmicutes and
greater levels of Prevotella [19]. Thus, maintaining and restoring a healthy gut microbiota
can help prevent the initial start and progress of metabolic diseases, including obesity.
Microbial dysbiosis could be determined using bioinformatic analysis with ecological
variables, such as diversity (alpha or beta), species richness [20], microbial abundances
such as Bacteroidetes/Firmicutes ratio [21], and clinical measures such as organic acid
test [22] and hydrogen breath test [23].
Numerous metabolites are created by gut microbiota from the dietary metabolism
such as short-chain fatty acids (SCFAs), trimethylamine, and trimethylamine N-oxide,
among others, which are linked to metabolic disorders pathogenesis [24]. In this context,
new treatments (including pre and probiotics) such as fecal microbiota transplantation [25],
personalized nutrition, dietary education, and physical activity [26] may help to reestablish
and/or preserve the composition of gut microbiota, changing the brain–gut axis and
decreasing pathology risk [27]. In particular, physical exercise induces changes in microbial
diversity, cardiorespiratory fitness, and insulin resistance among others [28].
The composition of gut microbiota is directly linked to systemic metabolic homeostasis
and adiposity, which influences the progress of obesity. Though several mechanisms be-
tween microbial diversity and metabolic health have been described, the causal relationship
is not completely understood [29–31].
Exercise is recognized to stabilize the progression of obesity and modify the gut
microbiota composition by increasing the microbial diversity [32,33], improving the Fir-
micutes/Bacteroidetes ratio that could potentially contribute to decreasing body weight,
Nutrients 2021, 13, 3999 3 of 15

obesity-associated pathologies, and gastrointestinal disorders [32]. In addition, exercise

is considered an efficient non-pharmacological therapy by decreasing inflammatory sig-
naling pathways [34]. Overall, promoting exercise could help as a treatment to maintain
the composition of gut microbiota or to restore the balance toward an improvement of
dysbiosis in obesity; however, these mechanisms need to be studied in more detail. In the
present work, we review the literature describing the association between exercise and gut
microbiota in obesity and its associated comorbidities.

2. Physical Activity, Exercise, and Physical Fitness and Their Relationship with
Obesity and Health Maintenance
Physical activity, exercise, and physical fitness are terms that define distinct concepts.
Physical activity is well described as every physical movement using skeletal muscles
that produce an energy expenditure in daily life that can be categorized into occupational,
household, sports, conditioning, or other activities [35]. Exercise is a subsection of physical
activity that is structured, premeditated, and cyclic and has as a final or an intermediate
objective the progress or physical fitness maintenance, that is, a group of aspects that are
both skills- or health-related [36].
The most in-depth and straightforward consequence associated with exercise benefits
is weight loss, with the probable to mitigate or reverse the course of obesity and co-
morbidities even with no dietary intervention [37–39]. Physical activity importance for
weight loss evaluated by BMI is debated, but it is well established the effect of exercise on
adiposity and several chronic diseases. Instead, there is robust evidence describing how
physical activity levels and exercise intervention are important to avoid weight regain after
weight loss [40–45].
According to anthropometry, there are other measures instead BMI that might be
related to the gut microbiota, waist circumference, hip circumference, and waist-to-hip
ratio, which have become important indicators of adiposity, disease risk, and mortality
risk [46,47]. Recently, Osborne et al. have reported the associations between some of the
aforementioned variables with the composition of gut microbiota. Participants with high
values of BMI, mid-upper arm circumference, waist circumference, and waist-to-hip ratio
were related to a diminished alpha diversity. Oscillospira and the family S24-7 relative
abundances were inversely associated with anthropometric measures. BMI and waist and
hip circumferences were related positively to Acidaminococcus, especially more in women
than in men [47].
One of the proposed mechanisms is that physical activity raises energy expenditure
activating lipolysis, so the fat mass is diminished if the energy consumed is not reimbursed
for with a rise in caloric intake, maintaining a negative energy balance [48]. On the contrary,
physical inactivity in contemporary obesogenic circumstances originates maladaptation,
characterized by a positive energy balance, causing long-lasting disease and becoming a
main public health problem [49]. Nevertheless, regular physical activity has a deep expres-
sion effect on our genome [50], which has been preferred for enhancing aerobic metabolism
to maintain energy in a situation of food insufficiency [51,52], occasioning numerous favor-
able adaptations and reduced risk of chronic diseases [53]. The identification of adaptations
of exercise is advancing our knowledge of the pathophysiology of long-lasting diseases
and varying old views, which might benefit new therapeutic approaches and targets [53].

3. Physical Activity and Gut Microbiota in Obesity

Lifestyle changes are still the most widely used and recommended strategies to achieve
weight reduction in obesity, particularly using different dietary strategies and promoting
physical activity and exercise [54]. Recent authors conclude that there seems to be an
intimate association between the gut microbiota and lifestyle proposing that an active
lifestyle may improve the quality of the microbiota [55]. In this sense, obesity is related to
minor diversity and richness of the intestinal microbiota, with a lower ratio of Bacteroidetes-
to-Firmicutes [29]. Indeed, exercise training improves obesity status by increasing insulin
sensitivity, reducing systemic inflammation, and improving VO2max [56]. Thus, according
Nutrients 2021, 13, 3999 4 of 15

to data from recent epidemiological, physiological, and omics-based studies, completed

through studies in animals and cells studies, it seems plausible that microbial communities
might be directly or indirectly influenced, among other environmental factors, by physical
activity or exercise [57,58].
Maintaining or restoring microbial diversity is essential to avoid perturbed intestinal
homeostasis, which is related to dysbiosis. The excessive production of SCFA, due to
fermentation of non-digestible food polysaccharides by intestinal bacteria, may induce
lipogenesis in the liver and accumulation of triglycerides in host adipocytes [5]. Indeed,
these SCFAs may also be implicated in alterations associated with insulin resistance, given
that one of the objectives for these SCFA induced signals is glucose homeostasis [59].
This is possible due to glucagon-like peptide 1 (GLP-1), a recognized mediator related to
glucose homeostasis. In general terms, GLP-1 is produced in the intestine and has a critical
protagonist in adjusting the plasma glucose concentration [59]. Interestingly, a recent study
reveals that rectal administration of SCFAs increases the GLP-1 secretion, confirming a
close association between GLP-1 and SCFAs [60]. Therefore, a fecal bacteria reduction may
produce glucose intolerance through a reduction in the secretion of GLP-1 [61]. Another
mechanism suggested clarifying the connection between obesity and the gut microbiota is
the role of the activation of adenosine monophosphate kinase (AMPK). One of the main
functions of AMPK is the oxidation of fatty acids [62]. Therefore, its inhibition could cause
an increased fat accumulation [63].

4. Physical Activity and Microbiota: Some Underlying Mechanisms

Physical activity can stimulate variations in the gut microbiota by numerous mecha-
nisms such as myokines release, increased intestinal transit, or the secretion of neurotrans-
mitters and hormones [64]. However, the inter-individual variation and gut microbiota
plasticity have hampered efforts to identify a “healthy” intestinal microbiota. Indeed, in ad-
dition to physical activity, many factors lead to instability of the gut microbiota, such as diet,
sleep pattern, antibiotic exposure, and various comorbidities [65]. Importantly, a healthy
microbiota is involved in the immune system development, with an anti-inflammatory
role through reducing histone deacetylases in regulatory T cells by G protein-coupled
receptors [65].
Recent studies by Castellanos et al. reported that active individuals who meet the rec-
ommendations for physical activity and diet from the World Health Organization (WHO)
exhibit different relative abundances of three species of the Bacteroides genus: B. uniformis,
B. ovatus, and an unclassified species [66]. Indeed, changes in the composition of the
microbiota following an active lifestyle are associated with increases in SCFA, such as
n-butyrate, which can modulate host energy balance and lead to increased nutrient avail-
ability [67]. On the other hand, a sedentary lifestyle is related to a significantly diminished
diversity and a less dense microbial network structure [66]. In this context, gut microbiota
diversity has developed as a candidate indicator of overall host health, the gut microbiota
network of active people being more robust than that of sedentary people [64]. Thus, active
people, who display a more diverse microbial community, appear to be more stable, resist
pathogenic invasions, exhibit greater resilience, and show functional redundancy leading
to more efficient resource utilization than sedentary individuals [68]. Furthermore, this
phenomenon of increased bacterial diversity could help to restore and avoid dysbiosis,
especially in severe situations such as the use of antibiotics, which this treatment per se
drives a decrease of some bacterial species [66]. In concordance with these results, Bressa
et al. showed that physical activity executed at short doses but continuously may rise
the health-promoting bacteria abundance (Bifidobacterium spp., Akkermansia muciniphila,
Roseburia hominis, and Faecalibacterium prausnitzii) in the gut microbiota [55]. However, a
sedentary lifestyle is inversely associated with intestinal microbiota richness [55]. Kern et al.
demonstrated that exercise increases alpha diversity and disturbs the general microbiota
composition in individuals with overweight and obesity after 6 months of intervention in a
randomized clinical trial (RCT) [69]. Similarly, another trial revealed that both moderate-
Nutrients 2021, 13, 3999 5 of 15

intensity exercise and resistance training for 8 weeks trigger shifts in microbial diversity, in
particular, alpha bacteria [70]. Mahdieh et al. reported an improvement of Bifidobacterium
counts in 18 women with obesity who were training aerobic exercise (3 sessions per week,
lasting 30–45 min) for 10 weeks [71]. In addition, they showed how exercise decreases in-
testinal inflammation and modifies gut microbiota profile in insulin-resistant subjects [72].
Therefore, physical activity is suggested as a useful non-pharmacologic instrument to
counteract pathological alterations of the gut microbiota in order to prevent metabolic
disturbances, especially in obesity. In addition, a sedentary lifestyle has materialized as a
new risk variable for health, which is related to a high incidence of chronic diseases such
as cancer cardiovascular diseases and type 2 diabetes [64,67], with obesity being the main
contributor to the development of these pathologies [5].
Some proposal mechanisms of the intestinal microbiota and obesity are related to
primary bile acids safely converted by gut microbiota to secondary bile acids that perform
throughout the TGR5 receptor to stimulate GLP-1 release improving thermogenesis in
adipose tissue [57,73] and also by the nuclear farnesoid X receptor related to carbohydrate
metabolism [74].
The dietary fiber fermentation by microbes, belonging especially to Firmicutes and
Bacteroidetes, creates SCFAs (propionate, butyrate, and acetate) that impact the host
metabolism in several ways by performing on G protein-coupled receptors expressed by
enteroendocrine cells [75,76]. SCFAs could stimulate GLP-1 and peptide YY liberation
affecting the brain and pancreas, and acetate may improve fat storage through the action of
ghrelin secretion [76,77].
LPS, compounds found in Gram-negative bacteria, are related to inflammation pro-
cesses [77]. In addition, succinate, a microbial-derived, could have pro-inflammatory
actions on LPS-derived macrophages and might therefore cause inflammation and insulin
resistance in adipose tissue [78]. Other studies support that succinate could activate the
uncoupling protein 1 expression that affects the adipose tissue thermogenesis [79,80]
Gut bacterial-derived branched-chain amino acids related, in cases of high fat intake,
to insulin resistance in both rodents and humans [57,81]. Secreted proteins through gut
bacteria also regulate endocrine or paracrine action (e.g., G protein-coupled receptor
119) [82].
Finally, physical activity could be a tentative treatment to produce different actions in
specific levels, changing the microbiota composition and activating over specific proteins,
such as uncoupled protein 1, or stimulating the liberation of SCFAs.

5. Obesity, Diet Interventions, Physical Activity/Exercise, and Their Impact on Gut

Microbiota
Although scientists continue to make substantial progress in improving lifestyles in
order to decrease the epidemic of obesity and its related to comorbidities, of course, lack of
physical activity (strongly affected by a variety of factors, primarily socioeconomic and
lifestyle status) and high-calorie diets act as an important part in the progress of metabolic
diseases. The first recommended treatment for obesity is a low-calorie diet and regular
physical activity. However, these lifestyle interventions have low overall compliance and
limited effectiveness in people with obesity. In adults, Muralidharan et al. [31] revealed that
energy restriction and Mediterranean diet with physical activity, and behavioral support
could provoke a reduction in numerous Firmicutes members, especially belonging to
Lachnospiraceae after 1-year of intervention in individuals with obesity and overweight.
In addition, they observed a selective rise in some SCFA producers [31]. This type of
intervention may have a beneficial effect on cardiovascular diseases, potentially modulated
by gut microbiota [31]. Furthermore, Allen et al. showed that exercise-induced modulation
of intestinal microbiota and SCFAs were related to changes in VO2max after 6 weeks of
aerobic exercise in individuals with obesity [56]. In addition, they observed that the
return to the sedentary state was inversely associated with the changes that happened in
response to exercise training [56]. Overall, these findings confirm that physical activity and
dietary control contribute significantly to improving the composition of the gut microbiota.
Nutrients 2021, 13, 3999 6 of 15

Moreover, it appears that exercise on fecal SCFAs levels is positively correlated with body
composition [83]. One of the possible mechanisms that could explain this theory could
be that SCFAs may improve skeletal muscle insulin sensitivity and regulate satiety [84],
with an impact on body composition. In addition, SCFAs are also energy substrates
for several tissue types, such as adipose tissue, colon, and muscle [56], suggesting that
SCFAs may improve energy intake from the diet, ultimately leading to increased tissue
development, including skeletal muscle [67]. Another mechanism that could explain the
benefits of physical activity on the intestinal microbiota is the shift in gut pH during
physical activity [83]. These changes might produce an environmental setting allowing
for richer community diversity. Moreover, resistance training may cause changes in the
gastrointestinal tract, as low tissue hypoxia and blood flow, driving to increased absorption
capacity and transit [85].

5.1. Children and Adolescent Population

Interesting target population studies are children and adolescents with obesity. In
this line, a recent systematic review evaluated the composition of gut microbiota related to
adiposity in children and adolescents, concluding that there is an absence of consensus for
the composition of intestinal microbiota associations with adiposity. Moreover, the healthy
gut microbiota are related to a diet rich in fruits and vegetables with moderate consumption
of animal fat and protein [86]. Of note, even the maternal gut microbiota alterations
during important phases of embryonic, fetal, and early postnatal development could have
consequences on the gut microbiota offspring, with lifelong effects for susceptibility to
disease [87]. A recent study indicated that the diversity and abundance of gut microbiota in
children with obesity were significantly minor than those in normal-weight children [88].
An exercise program combined with dietary restrictions may improve gut microbiota
health in children with obesity. Nevertheless, the most effective training program is not
still well established, though it seems that the combined training program of resistance and
aerobic exercise could be able to decrease body fat and increase gut diversity [34,54]. Huang
et al. reported that a six-week exercise training (aerobic and resistance exercises) with
dietary restriction not only decreased bodyweight but also increased central hemodynamic
measures (peripheral arteriolar resistance and microvascular coronary perfusion) that were
related to modifying gut microbiota in adolescents with obesity [89]. In addition, a recent
study has reported that six weeks of exercise and the dietary program are useful tools in
order to increase autonomic function and central hemodynamics with reduced arterial
stiffness in adolescents with obesity [90]. Moreover, Cho et al., with a weight reduction
program that involved dietary alteration, augmented behavioral modification and physical
activity during 2 months in children with obesity, observed significant modifications in the
gut microbiota composition, and expected functional profiles of the gut microbiota and
richness with weight loss after lifestyle changes [91]. On the other hand, Quiroga et al.,
without nutritional intervention, show through aerobic and resistance combined training
during 12 weeks in thirty-nine children with obesity that the existence of a detrimental
microbiota profile in obesity is altered by exercise intervention, emphasizing the value of
exercise routine as an effective non-pharmacological therapy in early obesity [34]. Finally,
in children with overweight and obesity, it is described that oligofructose-enriched inulin
prebiotics modify the gut microbiota composition and moderately decrease inflammatory
biomarkers, adiposity, and body weight [92].

5.2. Physical Activity, Diet, Microbiota, and Treatment

Physical activity significantly decreases the Gammaproteobacteria and Proteobacteria.
Moreover, it tended to rise Dialister, Blautia, and Roseburia, creating a microbiota profile
similar to that of healthy children. Training protocol significantly repressed the triggering of
the obesity-associated NLRP3 signaling pathway [34]. However, there are limited findings
of the gut microbiota composition in obese children, denoting that additional analysis
established on the function of the intestinal microbiota in childhood obesity is necessary.
Nutrients 2021, 13, 3999 7 of 15

A systematic review of the outcomes of nine cross-sectional studies and six interven-
tions reporting the outcomes of dietary fat on intestinal microbiota in humans [93] showed
that diets with excessive saturated or monounsaturated fats harmfully predisposed the gut
microbiota while diets high in polyunsaturated fat seemed to be neutral with respect to
the gut microbiota. Similarly, high-polysaccharide diet interventions have caused different
gut microbiota connected with serum, increased fecal, or urine concentrations of SCFAs,
improvements of cytokine and metabolome profiles, and weight loss [94–97]. Likewise,
interventions with augmented physical activity have exhibited adaptive and transmissible
variations of the intestinal microbiota connected with an augmented capacity for the break-
down of branched-chain amino acids and lactate, an augmented potential for synthesis of
SCFAs, and improvements in insulin sensitivity and cardiorespiratory fitness.
Lactobacillus, Bifidobacterium, and Saccharomyces spp. are generally recognized as safe
(GRAS) probiotics [98–100], and in the past years, new members have been included
such as F. prausnitzii [101], A. muciniphila [102], and numerous Clostridia spp. [103]. New
data have reported that it is possible that some probiotics, A. muciniphila strains, do not
even require colonizing the intestine to obtain helpful metabolic effects in the host related
to health [104,105]. RCTs assessment of prebiotics (non-digestible polysaccharides) has
reported that inulin-type fructans transformed the gut microbiota composition in adult
women with obesity, leading to modest changes in host metabolism [106]. Finally, the
new integrant of the “biotics” family, postbiotics, means or relates with the pasteurized
version of probiotics or portions of microbial strains holding health-promoting effects [107].
A pilot trial of pasteurized A. muciniphila and its membrane protein Amuc_1100 showed
positive effects on human metabolism indicators [102,108]. This protein recovers gut barrier
functions with augmented goblet cell density by toll-like receptor 2 and moderately repeats
the beneficial effect of live bacterium A. muciniphila on insulin sensitivity and energy
metabolism [102,108].

6. Performance: Gut Microbiota Profile in Athletes

Professional athletes are a specific population with evident differences in microbiota
composition when compared with the non-athlete population [109]. Several studies have
demonstrated the association between gut microbiota and both physical activity and ex-
ercise [110]. Differences are marked also according to different athletes characteristics as
well as their body composition [111]. Athlete gut microbiota shows the highest alpha di-
versity in comparison with obesity patients being associated with several risk factors [112].
Importantly, cardiorespiratory fitness (a powerful indicator of athletic performance and
health) has been associated to Firmicutes/Bacteroidetes ratio in healthy young adults,
and these associations were independent of diet composition, demonstrating that gut
microbiota diversity depends on the level of physical fitness of the population [113]. On
the other hand, athletes’ characteristics are also a factor related to their microbiota com-
position [109]. Specifically, differences are evident in rugby athletes that show a higher
proportion Akkermansia genus than a group with an elevated BMI [33]. Moreover, the Bac-
teroides to Prevotella ratio is different between endurance (cardiovascular exercise performed
for an extended period) training elderly subjects and healthy controls [114]. Interestingly,
bacterial genus Veillonella was related to exercise changes in athletes after running the
Boston Marathon [115], suggesting that exercise changes related to microbiota include
enzymatic processes related to lactate production. Moreover, a professional cyclist shows a
higher abundance in taxa related to exercise loads, such as Prevotella and Methanobrevibacter
smithii, which could be related to positive consequences of exercise to performance and
athletic health [45].
Finally, Donovan et al. [116] studied the microbiota composition according to different
groups of sports and found differences in relative abundance across five species, namely,
Polynucleobacter necessaries, Eubacterium rectale, B. vulgatus, F. prausnitzii, and Gordonibacter
massiliensis. Interestingly, the classification was based on dynamic (more related to aug-
mented cardiac output) and inactive components (more associated with increasing the
Nutrients 2021, 13, 3999 8 of 15

maximal voluntary contraction) [116,117]. They found that those participating in high
dynamic sport have a bigger abundance of Lactobacillus acidophilus, Bifidobacterium animalis,
F. prausnitzii, and Prevotella intermedia, while athletes with both static components and
high dynamic were related to a greater Bacteroides caccae abundance. Thus, the authors
have indicated that the differences in abundance across groups may be a result of the
specific characteristics of sports, principally related to the production of creatine, lactate,
and substantial muscle turnover [118].

7. Further Perspectives
The WHO ranked physical inactivity as the fourth principal risk element for global
mortality. In contrast, regular and adequate physical activity levels drop the mortality
rate produced by some chronic diseases. For instance, physical exercise benefits the
prevention of several obesity-related disorders such as dyslipidemia, insulin resistance,
and hypertension, reducing intrahepatic lipid [119].
Additionally, exercise may positively control gut microbiota in immune-based and
chronic diseases. In fact, exercise can provoke qualitative and quantitative changes in
microbial composition in humans [120]. In addition, a deteriorated microbiota profile
may contribute to the etiopathogenesis of obesity [121]. Accordingly, there is a conceptual
framework in which studies on exercise in the reversion of hypercaloric diets effects and
obesity by modulating microbiota are gaining momentum within the scientific commu-
nity. However, unsolved questions remain open concerning the complex nexus between
microbiota, health maintenance, and obesity, and even more, the exercise intensity, type,
duration, or doses remains a controversial issue. For example, it is likely the impact of
exercise on the microbiota would not be the same if it is practiced as a habit to maintain
weight and health, intensively as a high-level athlete, or as a weight-loss strategy with or
without caloric restriction. In consequence, the exercise effects on the microbiota cannot be
considered globally as there are many variables to consider in this equation depending on
the ultimate purpose of the exercise. Moreover, it is also necessary to consider that exercise
provokes unique microbiota profiles according to the host characteristics. Furthermore,
the target exercise population should be considered, not only the baseline physical fitness
and the presence or absence of underlying diseases but also the age, sex, and metabolic
and hormonal status of the individual. At this point, it should be noted whether women
are post- or pre-menopausal since it is one of the main controllers of circulating estrogens
in the gut microbiota [122]. In consequence, the implied metabolic pathways could not
be the same and therefore neither could be their impact on the microbiota. Further, the
close connection between the brain and the gut microbiota (the “gut–brain axis”) should
also be considered. In this regard, some pieces of evidence show that there is an elevated
relationship between emotional and physical stress throughout exercise and modifications
in gastrointestinal microbiota composition [123], but it is yet unsolved whether exercise
modifies mental health, which is suggested by modifications in the gut–brain axis or the
observed improvement in mental health due to exercise-induced changes in the microbiota.
Figure 1 summarizes the main information described in the present manuscript.
Nutrients 2021, 13, x FOR PEER REVIEW 9 of 15

Nutrients 2021, 13, 3999 9 of 15

in the microbiota. Figure 1 summarizes the main information described in the present
manuscript.

Figure 1. Impact of exercise on gut microbiota in obesity. Abbreviations: BCAA, branched-chain amino acids; FXR, far-
Figure 1. Impact of exercise on gut microbiota in obesity. Abbreviations: BCAA, branched-chain amino acids; FXR, farnesoid
nesoid X receptor; LPS, lipopolysaccharide; GLP-1, Glucagon-like peptide 1; GPCRs, G-protein-coupled receptors;
X receptor; LPS, lipopolysaccharide; GLP-1, Glucagon-like peptide 1; GPCRs, G-protein-coupled receptors; GPR119, G
GPR119, G protein-coupled receptor 119; PYY, Peptide YY; UCP-1, Uncoupling protein 1; TGR5, G-protein-coupled bile
protein-coupled receptor
acid receptor, TLR2, 119;receptor
toll-like PYY, Peptide
2. YY; UCP-1, Uncoupling protein 1; TGR5, G-protein-coupled bile acid receptor,
TLR2, toll-like receptor 2.
8. Conclusions
8. Conclusions
Intestinal microbiota act as a significant player in obesity progression. Physical activ-
Intestinal microbiota act as a significant player in obesity progression. Physical activ-
ity potentially benefits obesity through changes in microbiota composition. Microbiota,
ity potentially benefits obesity through changes in microbiota composition. Microbiota,
exercise, and dietary habits have a complex relationship. Accordingly, it is mandatory to
exercise, and dietary habits have a complex relationship. Accordingly, it is mandatory
evaluate the possible influence of exercise and specific diets, foods, nutrients, or supple-
to evaluate the possible influence of exercise and specific diets, foods, nutrients, or sup-
ments on microbial diversity in the gut. The changes of gut microbiota stimulated by
plements on microbial diversity in the gut. The changes of gut microbiota stimulated
physical exercise depend on the basal physiological state and maybe conditioned by pa-
by physical exercise depend on the basal physiological state and maybe conditioned by
rameters, such
parameters, asas
such age ororBMI.
age BMI.Further
Furtherinvestigation
investigationisisneeded
neededto
to elucidate
elucidate the
the underlying
underlying
mechanisms.
mechanisms.
Author Contributions:
Author Contributions: J.A.-V., P.S.-U., F.J.R.-O.,
J.A.-V., P.S.-U., F.J.R.-O., A.I.Á.-M.,
A.I.Á.-M., J.O.-A.
J.O.-A. and
and J.P.-D.
J.P.-D. participated
participated in
in the
the
bibliographic search, discussion, and writing of the manuscript. All authors have read and agreed
bibliographic search, discussion, and writing of the manuscript. All authors have read and agreed to
to the published version of the manuscript.
the published version of the manuscript.
Funding: This research received no external funding.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Nutrients 2021, 13, 3999 10 of 15

Acknowledgments: Julio Plaza-Diaz is part of the “UGR Plan Propio de Investigación 2016” and the
“Excellence actions: Unit of Excellence on Exercise and Health (UCEES), University of Granada”.
Patricio Solis-Urra was supported by a fellowship from the National Agency for Research and Devel-
opment (ANID) BECAS Chile/72180543. Julio Plaza-Diaz is supported by a fellowship awarded to
postdoctoral researchers at foreign universities and research centers from the “Fundación Ramón
Areces”, Madrid, Spain. Jerónimo Aragón-Vela was funded by a Postdoctoral fellowship from the
‘Fundación Alfonso Martín Escudero’ (Spain). Francisco Javier Ruiz-Ojeda is supported by a fellow-
ship from Spanish Government “Agencia Estatal de Investigación-Juan de la Cierva-Incorporación”
program (IJC2020-042739-I). We are grateful to Belén Vázquez-González for her assistance with the
illustration service.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Longo, M.; Zatterale, F.; Naderi, J.; Parrillo, L.; Formisano, P.; Raciti, G.A.; Beguinot, F.; Miele, C. Adipose tissue dysfunction as
determinant of obesity-associated metabolic complications. Int. J. Mol. Sci. 2019, 20, 2358. [CrossRef]
2. Ellulu, M.S.; Patimah, I.; Khaza’ai, H.; Rahmat, A.; Abed, Y. Obesity and inflammation: The linking mechanism and the
complications. Arch. Med. Sci. AMS 2017, 13, 851. [CrossRef]
3. Corvera, S.; Gealekman, O. Adipose tissue angiogenesis: Impact on obesity and type-2 diabetes. Biochim. Biophys. Acta (BBA)-Mol.
Basis Dis. 2014, 1842, 463–472. [CrossRef]
4. Luo, L.; Liu, M. Adipose tissue in control of metabolism. J. Endocrinol. 2016, 231, R77–R99. [CrossRef] [PubMed]
5. Palmas, V.; Pisanu, S.; Madau, V.; Casula, E.; Deledda, A.; Cusano, R.; Uva, P.; Vascellari, S.; Loviselli, A.; Manzin, A. Gut
microbiota markers associated with obesity and overweight in Italian adults. Sci. Rep. 2021, 11, 5532. [CrossRef]
6. Gromek, N. Overweight and obesity–the scale of the phenomenon and risk factors. Wiadomości Stat. Pol. Stat. 2020, 65, 9–29.
[CrossRef]
7. Marques, A.; Peralta, M.; Naia, A.; Loureiro, N.; de Matos, M.G. Prevalence of adult overweight and obesity in 20 European
countries, 2014. Eur. J. Public Health 2018, 28, 295–300. [CrossRef] [PubMed]
8. Heymsfield, S.B.; Wadden, T.A. Mechanisms, pathophysiology, and management of obesity. N. Engl. J. Med. 2017, 376, 254–266.
[CrossRef] [PubMed]
9. Lane, M.; Howland, G.; West, M.; Hockey, M.; Marx, W.; Loughman, A.; O’Hely, M.; Jacka, F.; Rocks, T. The effect of ultra-
processed very low-energy diets on gut microbiota and metabolic outcomes in individuals with obesity: A systematic literature
review. Obes. Res. Clin. Pract. 2020, 14, 197–204. [CrossRef] [PubMed]
10. Liu, R.; Hong, J.; Xu, X.; Feng, Q.; Zhang, D.; Gu, Y.; Shi, J.; Zhao, S.; Liu, W.; Wang, X. Gut microbiome and serum metabolome
alterations in obesity and after weight-loss intervention. Nat. Med. 2017, 23, 859–868. [CrossRef]
11. Gilbert, J.A.; Krajmalnik-Brown, R.; Porazinska, D.L.; Weiss, S.J.; Knight, R. Toward effective probiotics for autism and other
neurodevelopmental disorders. Cell 2013, 155, 1446–1448. [CrossRef]
12. Álvarez-Mercado, A.I.; Navarro-Oliveros, M.; Robles-Sánchez, C.; Plaza-Díaz, J.; Sáez-Lara, M.J.; Muñoz-Quezada, S.; Fontana, L.;
Abadía-Molina, F. Microbial population changes and their relationship with human health and disease. Microorganisms 2019, 7,
68. [CrossRef] [PubMed]
13. Zhernakova, A.; Kurilshikov, A.; Bonder, M.J.; Tigchelaar, E.F.; Schirmer, M.; Vatanen, T.; Mujagic, Z.; Vila, A.V.; Falony, G.;
Vieira-Silva, S. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science
2016, 352, 565–569. [CrossRef] [PubMed]
14. Humphreys, C. Intestinal Permeability. In Textbook of Natural Medicine; Elsevier: Amsterdam, The Netherlands, 2020;
pp. 166–177.e164.
15. Plaza-Díaz, J.; Gómez-Fernández, A.; Chueca, N.; Torre-Aguilar, M.J.D.L.; Gil, Á.; Perez-Navero, J.L.; Flores-Rojas, K.; Martín-
Borreguero, P.; Solis-Urra, P.; Ruiz-Ojeda, F.J. Autism spectrum disorder (ASD) with and without mental regression is associated
with changes in the fecal microbiota. Nutrients 2019, 11, 337. [CrossRef] [PubMed]
16. Jiao, N.; Baker, S.S.; Nugent, C.A.; Tsompana, M.; Cai, L.; Wang, Y.; Buck, M.J.; Genco, R.J.; Baker, R.D.; Zhu, R. Gut microbiome
may contribute to insulin resistance and systemic inflammation in obese rodents: A meta-analysis. Physiol. Genomics 2018, 50,
244–254. [CrossRef]
17. Fukui, H. Increased intestinal permeability and decreased barrier function: Does it really influence the risk of inflammation?
Inflamm. Intest. Dis. 2016, 1, 135–145. [CrossRef] [PubMed]
18. Amar, J.; Chabo, C.; Waget, A.; Klopp, P.; Vachoux, C.; Bermúdez-Humarán, L.G.; Smirnova, N.; Bergé, M.; Sulpice, T.; Lahtinen, S.
Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: Molecular mechanisms
and probiotic treatment. EMBO Mol. Med. 2011, 3, 559–572. [CrossRef] [PubMed]
19. Hermes, G.; Zoetendal, E.; Smidt, H. Molecular ecological tools to decipher the role of our microbial mass in obesity. Benef.
Microbes 2015, 6, 61–81. [CrossRef]
20. Plaza-Diaz, J.; Bernal, M.J.; Schutte, S.; Chenoll, E.; Genovés, S.; Codoñer, F.M.; Gil, A.; Sanchez-Siles, L.M. Effects of Whole-Grain
and Sugar Content in Infant Cereals on Gut Microbiota at Weaning: A Randomized Trial. Nutrients 2021, 13, 1496. [CrossRef]
Nutrients 2021, 13, 3999 11 of 15

21. Magne, F.; Gotteland, M.; Gauthier, L.; Zazueta, A.; Pesoa, S.; Navarrete, P.; Balamurugan, R. The Firmicutes/Bacteroidetes Ratio:
A Relevant Marker of Gut Dysbiosis in Obese Patients? Nutrients 2020, 12, 1474. [CrossRef] [PubMed]
22. Lord, R.S.; Bralley, J.A. Clinical applications of urinary organic acids. Part 2. Dysbiosis markers. Altern. Med. Rev. 2008, 13,
292–306.
23. Erdrich, S.; Tan, E.C.K.; Hawrelak, J.A.; Myers, S.P.; Harnett, J.E. Hydrogen-methane breath testing results influenced by oral
hygiene. Sci. Rep. 2021, 11, 26. [CrossRef] [PubMed]
24. Agus, A.; Clément, K.; Sokol, H. Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut 2021, 70,
1174–1182. [CrossRef] [PubMed]
25. Koszewiczz, M.; Jaroch, J.; Brzecka, A.; Ejma, M.; Budrewicz, S.; Mikhaleva, L.M.; Muresanu, C.; Schield, P.; Somasundaram,
S.G.; Kirkland, C.E. Dysbiosis is one of the risk factor for stroke and cognitive impairment and potential target for treatment.
Pharmacol. Res. 2020, 164, 105277. [CrossRef] [PubMed]
26. Bai, J.; Hu, Y.; Bruner, D. Composition of gut microbiota and its association with body mass index and lifestyle factors in a cohort
of 7–18 years old children from the American Gut Project. Pediatric Obes. 2019, 14, e12480. [CrossRef]
27. Singh, R.K.; Chang, H.W.; Yan, D.; Lee, K.M.; Ucmak, D.; Wong, K.; Abrouk, M.; Farahnik, B.; Nakamura, M.; Zhu, T.H.; et al.
Influence of diet on the gut microbiome and implications for human health. J. Transl. Med. 2017, 15, 73. [CrossRef]
28. Sohail, M.U.; Yassine, H.M.; Sohail, A.; Al Thani, A.A. Impact of physical exercise on gut microbiome, inflammation, and the
pathobiology of metabolic disorders. Rev. Diabet. Stud. RDS 2019, 15, 35. [CrossRef]
29. Crovesy, L.; Masterson, D.; Rosado, E.L. Profile of the gut microbiota of adults with obesity: A systematic review. Eur. J. Clin.
Nutr. 2020, 74, 1251–1262. [CrossRef]
30. Baothman, O.A.; Zamzami, M.A.; Taher, I.; Abubaker, J.; Abu-Farha, M. The role of gut microbiota in the development of obesity
and diabetes. Lipids Health Dis. 2016, 15, 108. [CrossRef]
31. Muralidharan, J.; Moreno-Indias, I.; Bulló, M.; Lopez, J.V.; Corella, D.; Castañer, O.; Vidal, J.; Atzeni, A.; Fernandez-García, J.C.;
Torres-Collado, L. Effect on gut microbiota of a 1-y lifestyle intervention with Mediterranean diet compared with energy-reduced
Mediterranean diet and physical activity promotion: PREDIMED-Plus Study. Am. J. Clin. Nutr. 2021, 114, 1148–1158. [CrossRef]
32. Monda, V.; Villano, I.; Messina, A.; Valenzano, A.; Esposito, T.; Moscatelli, F.; Viggiano, A.; Cibelli, G.; Chieffi, S.; Monda, M.;
et al. Exercise Modifies the Gut Microbiota with Positive Health Effects. Oxid. Med. Cell. Longev. 2017, 2017, 3831972. [CrossRef]
[PubMed]
33. Clarke, S.F.; Murphy, E.F.; O’Sullivan, O.; Lucey, A.J.; Humphreys, M.; Hogan, A.; Hayes, P.; O’Reilly, M.; Jeffery, I.B.; Wood-
Martin, R.; et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut 2014, 63, 1913–1920. [CrossRef]
[PubMed]
34. Quiroga, R.; Nistal, E.; Estebanez, B.; Porras, D.; Juarez-Fernandez, M.; Martinez-Florez, S.; Garcia-Mediavilla, M.V.; de Paz, J.A.;
Gonzalez-Gallego, J.; Sanchez-Campos, S.; et al. Exercise training modulates the gut microbiota profile and impairs inflammatory
signaling pathways in obese children. Exp. Mol. Med. 2020, 52, 1048–1061. [CrossRef]
35. Latorre-Roman, P.A.; Guzman-Guzman, I.P.; Delgado-Floody, P.; Herrador Sanchez, J.; Aragon-Vela, J.; Garcia Pinillos, F.; Parraga
Montilla, J.A. Protective role of physical activity patterns prior to COVID-19 confinement with the severity/duration of respiratory
pathologies consistent with COVID-19 symptoms in Spanish populations. Res. Sports Med. 2021, 1–12, in press. [CrossRef]
36. Caspersen, C.J.; Powell, K.E.; Christenson, G.M. Physical activity, exercise, and physical fitness: Definitions and distinctions for
health-related research. Public Health Rep. 1985, 100, 126–131.
37. Goisser, S.; Kiesswetter, E.; Schoene, D.; Torbahn, G.; Bauer, J.M. Dietary weight-loss interventions for the management of obesity
in older adults. Rev. Endocr. Metab. Disord. 2020, 21, 355–368. [CrossRef]
38. D’Souza, A.C.; Lau, K.J.; Phillips, S.M. Exercise in the maintenance of weight loss: Health benefits beyond lost weight on the
scale. Br. J. Sports Med. 2021, in press. [CrossRef]
39. Jovanovic, Z.; Crncevic-Orlic, Z.; Stimac, D.; Kokic, S.; Persic, V.; Ruzic, T.; Goll-Baric, S. Effects of obesity reduction on
cardiovascular risk factors: Comparison of individual and group treatment—Substudy of the Croatian Healthy Weight Loss
Programme. Coll. Antropol. 2009, 33, 751–757.
40. Barefoot, J.; Heitmann, B.; Helms, M.; Williams, R.; Surwit, R.; Siegler, I. Symptoms of depression and changes in body weight
from adolescence to mid-life. Int. J. Obes. 1998, 22, 688–694. [CrossRef]
41. Donnelly, J.E.; Smith, B.; Jacobsen, D.J.; Kirk, E.; DuBose, K.; Hyder, M.; Bailey, B.; Washburn, R. The role of exercise for weight
loss and maintenance. Best Pract. Res. Clin. Gastroenterol. 2004, 18, 1009–1029. [CrossRef]
42. Haapanen, N.; Miilunpalo, S.; Vuori, I.; Oja, P.; Pasanen, M. Association of leisure time physical activity with the risk of coronary
heart disease, hypertension and diabetes in middle-aged men and women. Int. J. Epidemiol. 1997, 26, 739–747. [CrossRef]
[PubMed]
43. Williamson, D.; Madans, J.; Anda, R.; Kleinman, J.; Kahn, H.; Byers, T. Recreational physical activity and ten-year weight change
in a US national cohort. Int. J. Obes. Relat. Metab. Disord. J. Int. Assoc. Study Obes. 1993, 17, 279–286.
44. Rissanen, A.; Heliövaara, M.; Knekt, P.; Reunanen, A.; Aromaa, A. Determinants of weight gain and overweight in adult Finns.
Eur. J. Clin. Nutr. 1991, 45, 419–430.
45. Petersen, L.M.; Bautista, E.J.; Nguyen, H.; Hanson, B.M.; Chen, L.; Lek, S.H.; Sodergren, E.; Weinstock, G.M. Community
characteristics of the gut microbiomes of competitive cyclists. Microbiome 2017, 5, 98. [CrossRef] [PubMed]
Nutrients 2021, 13, 3999 12 of 15

46. Czernichow, S.; Kengne, A.-P.; Huxley, R.R.; Batty, G.D.; De Galan, B.; Grobbee, D.; Pillai, A.; Zoungas, S.; Marre, M.; Woodward,
M. Comparison of waist-to-hip ratio and other obesity indices as predictors of cardiovascular disease risk in people with type-2
diabetes: A prospective cohort study from ADVANCE. Eur. J. Prev. Cardiol. 2011, 18, 312–319. [CrossRef] [PubMed]
47. Osborne, G.; Wu, F.; Yang, L.; Kelly, D.; Hu, J.; Li, H.; Jasmine, F.; Kibriya, M.G.; Parvez, F.; Shaheen, I.; et al. The association
between gut microbiome and anthropometric measurements in Bangladesh. Gut Microbes 2020, 11, 63–76. [CrossRef]
48. Pedersen, B.K.; Saltin, B. Exercise as medicine—Evidence for prescribing exercise as therapy in 26 different chronic diseases.
Scand. J. Med. Sci. Sports 2015, 25, 1–72. [CrossRef]
49. Blair, S.N. Physical inactivity: The biggest public health problem of the 21st century. Br. J. Sports Med. 2009, 43, 1–2.
50. Timmons, J.A.; Knudsen, S.; Rankinen, T.; Koch, L.G.; Sarzynski, M.; Jensen, T.; Keller, P.; Scheele, C.; Vollaard, N.B.; Nielsen, S.
Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans. J.
Appl. Physiol. 2010, 108, 1487–1496. [CrossRef]
51. Booth, F.W.; Laye, M.J.; Lees, S.J.; Rector, R.S.; Thyfault, J.P. Reduced physical activity and risk of chronic disease: The biology
behind the consequences. Eur. J. Appl. Physiol. 2008, 102, 381–390. [CrossRef]
52. Booth, F.W.; Lees, S.J. Fundamental questions about genes, inactivity, and chronic diseases. Physiol. Genomics 2007, 28, 146–157.
[CrossRef]
53. Fiuza-Luces, C.; Garatachea, N.; Berger, N.A.; Lucia, A. Exercise is the real polypill. Physiology 2013, 28, 330–358. [CrossRef]
[PubMed]
54. Mitchell, C.M.; Davy, B.M.; Hulver, M.W.; Neilson, A.P.; Bennett, B.J.; Davy, K.P. Does exercise alter gut microbial composition? A
systematic review. Med. Sci. Sports Exerc. 2019, 51, 160–167. [CrossRef] [PubMed]
55. Bressa, C.; Bailén-Andrino, M.; Pérez-Santiago, J.; González-Soltero, R.; Pérez, M.; Montalvo-Lominchar, M.G.; Maté-Muñoz, J.L.;
Domínguez, R.; Moreno, D.; Larrosa, M. Differences in gut microbiota profile between women with active lifestyle and sedentary
women. PLoS ONE 2017, 12, e0171352.
56. Allen, J.M.; Mailing, L.J.; Niemiro, G.M.; Moore, R.; Cook, M.D.; White, B.A.; Holscher, H.D.; Woods, J.A. Exercise alters gut
microbiota composition and function in lean and obese humans. Med. Sci. Sports Exerc. 2018, 50, 747–757. [CrossRef]
57. Fan, Y.; Pedersen, O. Gut microbiota in human metabolic health and disease. Nat. Rev. Microbiol. 2021, 19, 55–71. [CrossRef]
58. Lynch, S.V.; Pedersen, O. The Human Intestinal Microbiome in Health and Disease. N. Engl. J. Med. 2016, 375, 2369–2379.
[CrossRef]
59. Mokkala, K.; Houttu, N.; Cansev, T.; Laitinen, K. Interactions of dietary fat with the gut microbiota: Evaluation of mechanisms
and metabolic consequences. Clin. Nutr. 2020, 39, 994–1018. [CrossRef]
60. Perry, R.J.; Peng, L.; Barry, N.A.; Cline, G.W.; Zhang, D.; Cardone, R.L.; Petersen, K.F.; Kibbey, R.G.; Goodman, A.L.; Shulman, G.I.
Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature 2016, 534, 213–217. [CrossRef]
61. Yamaguchi, Y.; Adachi, K.; Sugiyama, T.; Shimozato, A.; Ebi, M.; Ogasawara, N.; Funaki, Y.; Goto, C.; Sasaki, M.; Kasugai, K.
Association of intestinal microbiota with metabolic markers and dietary habits in patients with type 2 diabetes. Digestion 2016, 94,
66–72. [CrossRef]
62. Backhed, F.; Manchester, J.K.; Semenkovich, C.F.; Gordon, J.I. Mechanisms underlying the resistance to diet-induced obesity in
germ-free mice. Proc. Natl. Acad. Sci. USA 2007, 104, 979–984. [CrossRef]
63. López, M. EJE PRIZE 2017: Hypothalamic AMPK: A golden target against obesity? Eur. J. Endocrinol. 2017, 176, R235–R246.
[CrossRef]
64. Castellanos, N.; Diez, G.G.; Antúnez-Almagro, C.; Bressa, C.; Bailén, M.; González-Soltero, R.; Pérez, M.; Larrosa, M. Key Bacteria
in the gut microbiota network for the transition between sedentary and active lifestyle. Microorganisms 2020, 8, 785. [CrossRef]
[PubMed]
65. Martinez, J.E.; Kahana, D.D.; Ghuman, S.; Wilson, H.P.; Wilson, J.; Kim, S.C.; Lagishetty, V.; Jacobs, J.P.; Sinha-Hikim, A.P.;
Friedman, T.C. Unhealthy Lifestyle and Gut Dysbiosis: A Better Understanding of the Effects of Poor Diet and Nicotine on the
Intestinal Microbiome. Front. Endocrinol. 2021, 12, 649. [CrossRef]
66. Castellanos, N.; Diez, G.G.; Antúnez-Almagro, C.; Bailén, M.; Bressa, C.; González Soltero, R.; Pérez, M.; Larrosa, M. A critical
mutualism–competition interplay underlies the loss of microbial diversity in sedentary lifestyle. Front. Microbiol. 2020, 10, 3142.
[CrossRef]
67. Barton, W.; Penney, N.C.; Cronin, O.; Garcia-Perez, I.; Molloy, M.G.; Holmes, E.; Shanahan, F.; Cotter, P.D.; O’Sullivan, O. The
microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional
metabolic level. Gut 2018, 67, 625–633. [CrossRef]
68. Karkman, A.; Lehtimäki, J.; Ruokolainen, L. The ecology of human microbiota: Dynamics and diversity in health and disease.
Ann. N. Y. Acad. Sci. 2017, 1399, 78–92. [CrossRef] [PubMed]
69. Kern, T.; Blond, M.B.; Hansen, T.H.; Rosenkilde, M.; Quist, J.S.; Gram, A.S.; Ekstrøm, C.T.; Hansen, T.; Stallknecht, B. Structured
exercise alters the gut microbiota in humans with overweight and obesity—A randomized controlled trial. Int. J. Obes. 2020, 44,
125–135. [CrossRef]
70. Cronin, O.; Barton, W.; Skuse, P.; Penney, N.C.; Garcia-Perez, I.; Murphy, E.F.; Woods, T.; Nugent, H.; Fanning, A.; Melgar, S. A
prospective metagenomic and metabolomic analysis of the impact of exercise and/or whey protein supplementation on the gut
microbiome of sedentary adults. mSystems 2018, 3, e00044-18. [CrossRef]
Nutrients 2021, 13, 3999 13 of 15

71. Mahdieh, M.S.; Maryam, J.; Bita, B.; Neda, F.; Motahare, M.; Mahboobeh, B.; LeBris, S.Q.; Kalani Behrooz, S. A pilot study on the
relationship between Lactobacillus, Bifidobacterium counts and inflammatory factors following exercise training. Arch. Physiol.
Biochem. 2021, 1–10, in press. [CrossRef]
72. Motiani, K.K.; Collado, M.C.; Eskelinen, J.-J.; Virtanen, K.A.; Löyttyniemi, E.; Salminen, S.; Nuutila, P.; Kalliokoski, K.K.;
Hannukainen, J.C. Exercise training modulates gut microbiota profile and improves endotoxemia. Med. Sci. Sports Exerc. 2020, 52,
94. [CrossRef] [PubMed]
73. Chiang, J.Y.; Pathak, P.; Liu, H.; Donepudi, A.; Ferrell, J.; Boehme, S. Intestinal Farnesoid X Receptor and Takeda G Protein Couple
Receptor 5 Signaling in Metabolic Regulation. Dig. Dis. 2017, 35, 241–245. [CrossRef] [PubMed]
74. Prawitt, J.; Abdelkarim, M.; Stroeve, J.H.; Popescu, I.; Duez, H.; Velagapudi, V.R.; Dumont, J.; Bouchaert, E.; van Dijk, T.H.; Lucas,
A.; et al. Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes 2011, 60, 1861–1871.
[CrossRef] [PubMed]
75. den Besten, G.; van Eunen, K.; Groen, A.K.; Venema, K.; Reijngoud, D.J.; Bakker, B.M. The role of short-chain fatty acids in the
interplay between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 2013, 54, 2325–2340. [CrossRef]
76. Chambers, E.S.; Viardot, A.; Psichas, A.; Morrison, D.J.; Murphy, K.G.; Zac-Varghese, S.E.; MacDougall, K.; Preston, T.; Tedford,
C.; Finlayson, G.S. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance
and adiposity in overweight adults. Gut 2015, 64, 1744–1754. [CrossRef]
77. Dupraz, L.; Magniez, A.; Rolhion, N.; Richard, M.L.; Da Costa, G.; Touch, S.; Mayeur, C.; Planchais, J.; Agus, A.; Danne, C.; et al.
Gut microbiota-derived short-chain fatty acids regulate IL-17 production by mouse and human intestinal gammadelta T cells.
Cell Rep. 2021, 36, 109332. [CrossRef]
78. Caesar, R.; Reigstad, C.S.; Backhed, H.K.; Reinhardt, C.; Ketonen, M.; Lunden, G.O.; Cani, P.D.; Backhed, F. Gut-derived
lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in
mice. Gut 2012, 61, 1701–1707. [CrossRef]
79. Ricquier, D. Uncoupling protein 1 of brown adipocytes, the only uncoupler: A historical perspective. Front. Endocrinol. 2011, 2, 85.
[CrossRef]
80. Mills, E.L.; Pierce, K.A.; Jedrychowski, M.P.; Garrity, R.; Winther, S.; Vidoni, S.; Yoneshiro, T.; Spinelli, J.B.; Lu, G.Z.; Kazak, L.
Accumulation of succinate controls activation of adipose tissue thermogenesis. Nature 2018, 560, 102–106. [CrossRef]
81. Newgard, C.B.; An, J.; Bain, J.R.; Muehlbauer, M.J.; Stevens, R.D.; Lien, L.F.; Haqq, A.M.; Shah, S.H.; Arlotto, M.; Slentz, C.A.;
et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to
insulin resistance. Cell Metab. 2009, 9, 311–326. [CrossRef]
82. Mace, O.J.; Tehan, B.; Marshall, F. Pharmacology and physiology of gastrointestinal enteroendocrine cells. Pharm. Res. Perspect.
2015, 3, e00155. [CrossRef] [PubMed]
83. Estaki, M.; Pither, J.; Baumeister, P.; Little, J.P.; Gill, S.K.; Ghosh, S.; Ahmadi-Vand, Z.; Marsden, K.R.; Gibson, D.L. Cardiores-
piratory fitness as a predictor of intestinal microbial diversity and distinct metagenomic functions. Microbiome 2016, 4, 42.
[CrossRef]
84. Byrne, C.S.; Chambers, E.S.; Morrison, D.J.; Frost, G. The role of short chain fatty acids in appetite regulation and energy
homeostasis. Int. J. Obes. 2015, 39, 1331–1338. [CrossRef] [PubMed]
85. Yang, Y.; Shi, Y.; Wiklund, P.; Tan, X.; Wu, N.; Zhang, X.; Tikkanen, O.; Zhang, C.; Munukka, E.; Cheng, S. The association between
cardiorespiratory fitness and gut microbiota composition in premenopausal women. Nutrients 2017, 9, 792. [CrossRef]
86. Vander Wyst, K.B.; Ortega-Santos, C.P.; Toffoli, S.N.; Lahti, C.E.; Whisner, C.M. Diet, adiposity, and the gut microbiota from
infancy to adolescence: A systematic review. Obes. Rev. 2021, 22, e13175. [CrossRef]
87. Gohir, W.; Ratcliffe, E.M.; Sloboda, D.M. Of the bugs that shape us: Maternal obesity, the gut microbiome, and long-term disease
risk. Pediatr. Res. 2015, 77, 196–204. [CrossRef]
88. Chen, X.; Sun, H.; Jiang, F.; Shen, Y.; Li, X.; Hu, X.; Shen, X.; Wei, P. Alteration of the gut microbiota associated with childhood
obesity by 16S rRNA gene sequencing. PeerJ 2020, 8, e8317. [CrossRef]
89. Huang, J.; Liao, J.; Fang, Y.; Deng, H.; Yin, H.; Shen, B.; Hu, M. Six-Week Exercise Training with Dietary Restriction Improves
Central Hemodynamics Associated with Altered Gut Microbiota in Adolescents with Obesity. Front. Endocrinol. 2020, 11, 569085.
[CrossRef]
90. Huang, J.; Lai, Q.; Wang, D.; Yin, H.; Liao, J.; Wang, S.; Xu, F.; Hou, X.; Hu, M. Effects of Exercise Training with Dietary Restriction
on Arterial Stiffness, Central Hemodynamic Parameters and Cardiac Autonomic Function in Obese Adolescents. Diabetes Metab.
Syndr. Obes. 2019, 12, 2157–2163. [CrossRef]
91. Cho, K.Y. Lifestyle modifications result in alterations in the gut microbiota in obese children. BMC Microbiol. 2021, 21, 10.
[CrossRef]
92. Nicolucci, A.C.; Hume, M.P.; Martínez, I.; Mayengbam, S.; Walter, J.; Reimer, R.A. Prebiotics reduce body fat and alter intestinal
microbiota in children who are overweight or with obesity. Gastroenterology 2017, 153, 711–722. [CrossRef] [PubMed]
93. Wolters, M.; Ahrens, J.; Romaní-Pérez, M.; Watkins, C.; Sanz, Y.; Benítez-Páez, A.; Stanton, C.; Günther, K. Dietary fat, the gut
microbiota, and metabolic health—A systematic review conducted within the MyNewGut project. Clin. Nutr. 2019, 38, 2504–2520.
[CrossRef] [PubMed]
Nutrients 2021, 13, 3999 14 of 15

94. Kjølbæk, L.; Benítez-Páez, A.; Del Pulgar, E.M.G.; Brahe, L.K.; Liebisch, G.; Matysik, S.; Rampelli, S.; Vermeiren, J.; Brigidi, P.;
Larsen, L.H. Arabinoxylan oligosaccharides and polyunsaturated fatty acid effects on gut microbiota and metabolic markers in
overweight individuals with signs of metabolic syndrome: A randomized cross-over trial. Clin. Nutr. 2020, 39, 67–79. [CrossRef]
[PubMed]
95. Dieterich, W.; Schuppan, D.; Schink, M.; Schwappacher, R.; Wirtz, S.; Agaimy, A.; Neurath, M.F.; Zopf, Y. Influence of low
FODMAP and gluten-free diets on disease activity and intestinal microbiota in patients with non-celiac gluten sensitivity. Clin.
Nutr. 2019, 38, 697–707. [CrossRef]
96. Hansen, L.B.; Roager, H.M.; Søndertoft, N.B.; Gøbel, R.J.; Kristensen, M.; Vallès-Colomer, M.; Vieira-Silva, S.; Ibrügger, S.; Lind,
M.V.; Mærkedahl, R.B. A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults. Nat. Commun.
2018, 9, 4630. [CrossRef]
97. Roager, H.M.; Vogt, J.K.; Kristensen, M.; Hansen, L.B.S.; Ibrügger, S.; Mærkedahl, R.B.; Bahl, M.I.; Lind, M.V.; Nielsen, R.L.;
Frøkiær, H. Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of
the gut microbiome: A randomised cross-over trial. Gut 2019, 68, 83–93. [CrossRef]
98. Plaza-Diaz, J.; Ruiz-Ojeda, F.J.; Gil-Campos, M.; Gil, A. Mechanisms of action of probiotics. Adv. Nutr. 2019, 10, S49–S66.
[CrossRef]
99. Tenorio-Jiménez, C.; Martínez-Ramírez, M.J.; Castillo-Codes, D.; Arraiza-Irigoyen, C.; Tercero-Lozano, M.; Camacho, J.; Chueca,
N.; García, F.; Olza, J.; Plaza-Díaz, J. Lactobacillus reuteri V3401 reduces inflammatory biomarkers and modifies the gastrointesti-
nal microbiome in adults with metabolic syndrome: The PROSIR study. Nutrients 2019, 11, 1761. [CrossRef]
100. Fontana, L.; Plaza-Díaz, J.; Robles-Bolívar, P.; Valente-Godínez, H.; Sáez-Lara, M.J.; Abadía-Molina, F.; Gómez-Llorente, C.; Gil, Á.;
Álvarez-Mercado, A.I. Bifidobacterium breve CNCM I-4035, Lactobacillus paracasei CNCM I-4034 and Lactobacillus rhamnosus
CNCM I-4036 Modulate Macrophage Gene Expression and Ameliorate Damage Markers in the Liver of Zucker-Leprfa/fa Rats.
Nutrients 2021, 13, 202. [CrossRef]
101. Martín, R.; Miquel, S.; Benevides, L.; Bridonneau, C.; Robert, V.; Hudault, S.; Chain, F.; Berteau, O.; Azevedo, V.; Chatel, J.M.
Functional characterization of novel Faecalibacterium prausnitzii strains isolated from healthy volunteers: A step forward in the
use of F. prausnitzii as a next-generation probiotic. Front. Microbiol. 2017, 8, 1226. [CrossRef]
102. Depommier, C.; Everard, A.; Druart, C.; Plovier, H.; Van Hul, M.; Vieira-Silva, S.; Falony, G.; Raes, J.; Maiter, D.; Delzenne, N.M.
Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: A proof-of-concept exploratory
study. Nat. Med. 2019, 25, 1096–1103. [CrossRef] [PubMed]
103. Cani, P.D.; Van Hul, M. Novel opportunities for next-generation probiotics targeting metabolic syndrome. Curr. Opin. Biotechnol.
2015, 32, 21–27. [CrossRef] [PubMed]
104. Zmora, N.; Zilberman-Schapira, G.; Suez, J.; Mor, U.; Dori-Bachash, M.; Bashiardes, S.; Kotler, E.; Zur, M.; Regev-Lehavi, D.; Brik,
R.B.-Z. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome
features. Cell 2018, 174, 1388–1405.e1321. [CrossRef] [PubMed]
105. Suez, J.; Zmora, N.; Zilberman-Schapira, G.; Mor, U.; Dori-Bachash, M.; Bashiardes, S.; Zur, M.; Regev-Lehavi, D.; Brik, R.B.-Z.;
Federici, S. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT.
Cell 2018, 174, 1406–1423.e1416. [CrossRef]
106. Dewulf, E.M.; Cani, P.D.; Claus, S.P.; Fuentes, S.; Puylaert, P.G.; Neyrinck, A.M.; Bindels, L.B.; de Vos, W.M.; Gibson, G.R.; Thissen,
J.-P. Insight into the prebiotic concept: Lessons from an exploratory, double blind intervention study with inulin-type fructans in
obese women. Gut 2013, 62, 1112–1121. [CrossRef]
107. Tsilingiri, K.; Barbosa, T.; Penna, G.; Caprioli, F.; Sonzogni, A.; Viale, G.; Rescigno, M. Probiotic and postbiotic activity in health
and disease: Comparison on a novel polarised ex-vivo organ culture model. Gut 2012, 61, 1007–1015. [CrossRef]
108. Plovier, H.; Everard, A.; Druart, C.; Depommier, C.; Van Hul, M.; Geurts, L.; Chilloux, J.; Ottman, N.; Duparc, T.; Lichtenstein, L.
A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and
diabetic mice. Nat. Med. 2017, 23, 107–113. [CrossRef]
109. Mohr, A.E.; Jager, R.; Carpenter, K.C.; Kerksick, C.M.; Purpura, M.; Townsend, J.R.; West, N.P.; Black, K.; Gleeson, M.; Pyne, D.B.;
et al. The athletic gut microbiota. J. Int. Soc. Sports Nutr. 2020, 17, 24. [CrossRef]
110. Hughes, R.L.; Holscher, H.D. Fueling Gut Microbes: A Review of the Interaction between Diet, Exercise, and the Gut Microbiota
in Athletes. Adv. Nutr. 2021, nmab077, in press. [CrossRef]
111. Slimani, M.; Nikolaidis, P.T. Anthropometric and physiological characteristics of male soccer players according to their competitive
level, playing position and age group: A systematic review. J. Sports Med. Phys. Fit. 2019, 59, 141–163. [CrossRef]
112. Morkl, S.; Lackner, S.; Muller, W.; Gorkiewicz, G.; Kashofer, K.; Oberascher, A.; Painold, A.; Holl, A.; Holzer, P.; Meinitzer, A.; et al.
Gut microbiota and body composition in anorexia nervosa inpatients in comparison to athletes, overweight, obese, and normal
weight controls. Int. J. Eat. Disord. 2017, 50, 1421–1431. [CrossRef] [PubMed]
113. Durk, R.P.; Castillo, E.; Marquez-Magana, L.; Grosicki, G.J.; Bolter, N.D.; Lee, C.M.; Bagley, J.R. Gut Microbiota Composition
Is Related to Cardiorespiratory Fitness in Healthy Young Adults. Int. J. Sport Nutr. Exerc. Metab. 2019, 29, 249–253. [CrossRef]
[PubMed]
114. Soltys, K.; Lendvorsky, L.; Hric, I.; Baranovicova, E.; Penesova, A.; Mikula, I.; Bohmer, M.; Budis, J.; Vavrova, S.; Grones, J.;
et al. Strenuous Physical Training, Physical Fitness, Body Composition and Bacteroides to Prevotella Ratio in the Gut of Elderly
Athletes. Front. Physiol. 2021, 12, 670989. [CrossRef]
Nutrients 2021, 13, 3999 15 of 15

115. Scheiman, J.; Luber, J.M.; Chavkin, T.A.; MacDonald, T.; Tung, A.; Pham, L.D.; Wibowo, M.C.; Wurth, R.C.; Punthambaker, S.;
Tierney, B.T.; et al. Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate
metabolism. Nat. Med. 2019, 25, 1104–1109. [CrossRef] [PubMed]
116. O’Donovan, C.M.; Madigan, S.M.; Garcia-Perez, I.; Rankin, A.; O’Sullivan, O.; Cotter, P.D. Distinct microbiome composition and
metabolome exists across subgroups of elite Irish athletes. J. Sci. Med. Sport 2020, 23, 63–68. [CrossRef]
117. Mitchell, J.H.; Haskell, W.; Snell, P.; Van Camp, S.P. Task Force 8: Classification of sports. J. Am. Coll. Cardiol. 2005, 45, 1364–1367.
[CrossRef]
118. Egan, B.; Zierath, J.R. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab. 2013, 17,
162–184. [CrossRef]
119. World Health Organization. Global Recommendations on Physical Activity for Health; World Health Organization: Geneva, Switzer-
land, 2010.
120. Codella, R.; Luzi, L.; Terruzzi, I. Exercise has the guts: How physical activity may positively modulate gut microbiota in chronic
and immune-based diseases. Dig. Liver Dis. 2018, 50, 331–341. [CrossRef]
121. Castaner, O.; Goday, A.; Park, Y.M.; Lee, S.H.; Magkos, F.; Shiow, S.T.E.; Schroder, H. The Gut Microbiome Profile in Obesity: A
Systematic Review. Int. J. Endocrinol. 2018, 2018, 4095789. [CrossRef]
122. Baker, J.M.; Al-Nakkash, L.; Herbst-Kralovetz, M.M. Estrogen-gut microbiome axis: Physiological and clinical implications.
Maturitas 2017, 103, 45–53. [CrossRef]
123. Clark, A.; Mach, N. Exercise-induced stress behavior, gut-microbiota-brain axis and diet: A systematic review for athletes. J. Int.
Soc. Sports Nutr. 2016, 13, 43. [CrossRef] [PubMed]