Key words gut microbiota - obesity - diabetes - osteoporosis
Introduction
The prevalence of metabolic disorders is increasing worldwide, leading to recognize
them as public health concerns. The most prevalent metabolic disorders are diabetes
mellitus, obesity, and osteoporosis. The involvement of both genetic and environmental
factors makes the pathophysiologies of these disorders complicated. Gut microbiota
is suggested as a potential contributor to the development of metabolic disorders
in recent years [1 ]
[2 ].
Gut microbiota is defined as the microbial community inhabiting the intestine; and
gut microbiome are its genomic contents, which are 100- to 150-fold more numerous
than the human genome [3 ]. These microbes, as an endocrine organ, play important roles in human health and
their imbalances are related to numerous diseases such as inflammatory bowel disease,
cardiovascular diseases, allergies, and metabolic disorders. Recent evidence in mice
and humans has shown that gut microbiota is linked with the development of metabolic
disorders [1 ]
[4 ]
[5 ]
[6 ].
Although only limited species of gut microbiota could be cultured by conventional
culture techniques [7 ], advances in next generation sequencing and its metagenomic applications allowed
the study of the microbiota composition in metabolic disorders without cultivation
[8 ]. Results of the human microbiome studies, which are part of the human genome projects
could have possible clinical applications like personalized medicine in the future
[8 ]. It is noteworthy that despite the inter-individual variations in gut microbiota,
serial stool collections have shown that core gut microbiota composition of an individual
remains stable over time. Therefore, susceptibility to the development of specific
diseases was different among subjects. The composition of the gut microbiota is modulated
by prenatal events, delivery methods, infant feeding, duration of lactation, complementary
foods, geographical location, and environmental factors such as life style, antibiotic
use, and dietary pattern [9 ]. It seems that these factors, effective in altering gut microbiota composition,
can be used for therapeutic purposes.
In this review, the mechanisms by which the gut microbiota may affect host metabolism
are considered, and the methods of gut microbiota modulation as novel therapeutic
strategies in metabolic disorders including obesity, diabetes, and osteoporosis are
provided, as well.
Gut Microbiota and Obesity
Gut Microbiota and Obesity
Role of gut microbiota in obesity
Due to the epidemic spread of obesity all over the world and the complications related
to weight gain in public health, gut microbiota have gained a growing interest as
an environmental factor that may affect the possibility of obesity [10 ]
[11 ]. Increased energy intake and decreased physical activity are the main causes of
obesity. In addition, various gene polymorphisms have been identified to have role
in the pathogenesis of obesity [12 ]
[13 ]. Moreover, different factors such as specific proteins in human cells and many hormonal
factors have effective roles in regulating metabolic homeostasis and weight balance
[14 ]
[15 ]
[16 ]
[17 ]. Microbiota also has been taken into consideration as a possible reason for affecting
energy homeostasis. It was suggested that gut microbita with environmental predisposition
can lead to obesity through stimulating the development of impairment in energy homeostasis
[18 ]. Numerous explorations have turned to the intestinal microbiota’s contribution to
obesity followed by exploring the first evidence of the link between obesity and intestinal
microbiota [19 ]
[20 ]. Animal studies have indicated that microbiota leads to changing the production
or secretion of molecules that affect both energy balance and energy stores (fat mass)
[21 ]
[22 ]. Bacteroidetes (Gram-negative) and Firmicutes (Gram-positive) are the main phyla
of gut bacteria. Firmicutes with more than 200 genera has the highest proportion as
the most important of which are: Mycoplasma , Bacillus , and Clostridium . Firmicutes (60–65%), Bacteroidetes (20–25%), Proteobacteria (5–10%), and Actinobacteria
(3%) together comprise about 97% of the gut microbiota [23 ]
[24 ]. On the other hand, Arumugam et al. suggested that the microbiota of most individuals
could be categorized into 3 dominant enterotypes characterized as Bacteroides , Prevotella , and Ruminococcus , which are independent of age, gender, ethnicity, or body mass index [23 ]
[25 ]. Bacteroidetes and Firmicutes are 2 main groups of gut microbiota, whose proportion
is changed in obese mice [19 ]. Administration of “western diet” to mice resulted in increased abundance of bacteria
of the phylum Firmicutes and decreased abundance of bacteria of the phylum Bacteroidetes
[26 ]
[27 ]. Human studies have also evaluated the gut microbiota in obese individuals and have
documented a reduction in Bacteroidetes accompanied by a rise in Lactobacillus species belonging to the Firmicutes phylum in obese subjects [28 ]
[29 ]. On the other hand, some human studies have found different patterns in these alterations,
such as the increase in species of both Bacteroidetes and Firmicutes in overweight
women [30 ] or a decrease in Bacteroidetes with no differences in Firmicutes phylum in obese
individuals [31 ]. Finally some studies have shown no difference between Bacteroidetes (B) and Firmicutes
(F) at the phylum level [32 ]
[33 ]
[34 ]
[35 ]. Therefore, the F/B ratio could not be used as an informative biomarker in distinguishing
obese from nonobese individuals. The earlier studies in this field have focused on
microbiota changes in phyla proportion. In recent years, novel next generation sequencing
technology based on the analysis of the 16SrRNA bacterial gene allowed for the identification
of the bacteria that colonize our gut in the species level. In a recent case-control
study in obese and normal weight school-aged children, the relative abundance of bacterial
and fungal gut microbes was evaluated. Obese children revealed a significantly lower
abundance in Akkermansia muciniphyla , Faecalibacterium prausnitzii , Bacteroides/Prevotella group, Candida spp. , and Saccharomyces spp. compared to normal-weight children [36 ].
Recent studies reveal that Lactobacillus spp. and bifidobacterium spp. , which are the main bacterial population of the small intestine are not all the same
and they may have different characteristics according to the species. For example,
within the genus Lactobacillus , L . plantarum and L. paracasei are associated with leanness whereas L. reuteri is associated with obesity [37 ]. Drissi et al. have revealed that weight gain-associated Lactobacillus spp. appears to have limited ability in the catabolism of fructose or glucose and might
reduce ileal brake effects. Whereas the weight protection-associated Lactobacillus spp. have developed defense mechanisms for enhanced glycolysis and defense against oxidative
stress [38 ]. In a recent animal study, Lactobacillus sakei OK67 ameliorated high-fat diet-induced obesity in mice by inhibiting gut microbiota
lipopolysaccharide production and nuclear factor-κB activation and inducing colon
tight junction protein expression [39 ].
Some studies have reported that Akkermansia muciniphila has been founded at a lower concentration in obese individuals. This kind of gut
species has potentially protective effects against obesity, metabolic conditions,
inflammation, and insulin resistance. So it is a good candidate for consideration
as a probiotic [40 ].
Using the Shannon index, species diversity within the gut has been reported to be
lower in obese subjects [41 ]. However, it should be noted that metagenomic studies nowadays often rely on matching
bacterial DNA sequences to reference databases, and these existing sequence databases
could accordingly miss important unrecognized bacteria.
Germ-free mice transplanted with the microbiome from obese donors gained significantly
more weight compared to germ-free mice transplanted with the microbiome from lean
donors, which implies a causal role for the microbiome in obesity and weight gain
[19 ]. However, the contribution of gut microbiota to obesity in humans is unclear and
more human studies are needed to evaluate the species level and their changes to reveal
the gut microbiota composition and modulation as novel diagnostic or therapeutic strategies
to treat obesity and related complications. Major issues while comparing the results
of different human studies of intestinal microbiota are potential confounders and
some existing technical differences including differences in taxonomy database, taxonomy
assignment algorithm, DNA extraction protocols, and PCR primers [41 ]. Moreover, potential confounding effects of diet, previous use of antibiotics, age,
gender, and smoking status on microbiota composition and function should be controlled
in obesity-related microbiome studies [42 ].
Underlying mechanisms in obesity
The gut micobiota might affect energy balance in human through several mechanisms.
Fermentation of indigestible dietary compounds serves as an energy source to the host
and plays a critical role in releasing of satiety hormones [43 ]
[44 ]. The possible effect of gut microbiota is associated with producing short-chain
fatty acids (SCFAs) through fermentation of dietary fiber [45 ]. The major microbiotic phyla affecting SCFA production in the gut are Firmicutes
and Bacteroidetes, as well as the minor phyla Melainabacteria [45 ]. SCFAs, especially butyrate significantly increases plasma levels of gastric inhibitory
peptide (GIP), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), insulin, and amylin,
which would have a net effect on slowing digestion and nutrient intestinal transit,
promoting satiety, and increasing plasma insulin. Acetate is reported to increase
leptin released by fat cells; propionate increases G-protein mediated secretion of
PYY and GLP-1 in the gut and controls the rates of lipolysis and lipogenesis in fat
cells [46 ]
[47 ].
Gut microbiota can facilitate the extraction of calories from ingested dietary substances
through increasing the absorption of monosaccharides from the gut [19 ]. Carbohydrate response element-binding protein (ChREBP) and liver sterol response
element-binding protein type-1 (SREBP-1) were demonstrated to be involved in the absorption
of monosaccharides in the intestine and hepatic lipogenesis induced by the gut microbiota
[48 ]. The other mechanism is the central effect of gut microbiota on leptin signaling
[49 ]
[50 ]
[51 ]. The mice with a mutation in the leptin gene (metabolically obese mice) have different
microbiota compared with other mice without the mutation [20 ]. Germ-free mice have significantly increased antiobesity molecule GLP-1 and also
reduced anorexigenic brain-derived neurotrophic factor (Bdnf), and leptin resistance
associated suppressor of cytokine signaling 3 (Socs3) expressions in both the brainstem
and hypothalamus, in comparison with conventionally raised mice. As a consequence,
the suppression of any of these molecules by microbes leads to weight gain [49 ].
Considering the chronic low grade inflammation state in obesity, a new hypothesis
has been proposed correlating intestinal flora and obesity. In high-fat diet animal
models, the inflammation that leads to diabetes and obesity has been suggested to
be triggered by the lipopolysaccharides (LPS) of gram-negative bacteria [52 ]. Increase in the uptake of LPS and the permeability of the intestine leads to a
systemic inflammation [53 ]. Everard et al. have shown that microflora bacteria interacting with the mucus layer
may have a critical effect on obesity [40 ]. Another mechanism involved in weight control by intestinal microbiota is regulation
of fasting-induced adipose factor (FIAF) expression. FIAF is a protein produced by
enterocyte, which has an inhibitory effect on lipoprotein lipase (LPL). Unbalanced
gut microbiota can suppress FIAF expression and increase LPL activity and triglyceride
accumulation in adipose tissue [54 ] ([Fig. 1 ]).
Fig. 1 The mechanisms underlying the effects of gut microbiota on metabolic disorders. a , Obesity : Short chain fatty acids (SCFAs) produced via fermentation of indigestible polysaccharides
stimulate the release of gut hormones glucagon like peptide-1 (GLP-1) and Peptide
YY (PYY). These hormones promote satiety, and regulate eating behaviors through central
nervous system (CNS). SCFAs also regulate energy extraction and lipogenesis and decrease
gut permeability. Improved gut barrier function decreases the uptake of lipopolysaccharides
(LPS) and systemic inflammation, which results in body weight control. Gut microbiota
also regulate expression of fasting-induced adipose factor (FIAF), which inhibits
lipoprotein lipase (LPL) activity and fat storage. b , Osteoporosis : The effects of gut microbiota on bone mass are mediated through immune system which
regulates osteoclastogenesis. Moreover, other contributing mechanisms include absorption
and synthesis of vitamins and minerals and regulation of gut-derived serotonin which
has a suppressive effect on the osteoblasts. c , Diabetes : SCFAs stimulate intestinal gluconeogenesis, which improves glucose tolerance. Moreover,
SCFAs could improve insulin sensitivity by increasing GLP-1 and PYY. Unbalanced gut
microbiota triggers metabolic endotoxemia and inflammation by increasing LPS which
affects insulin sensitivity. The positive and negative signs are indicative of beneficial
and harmful effects, respectively.
Modulation of gut microbiota in obesity
Studies have indicated that the microbiota composition can be affected by external
disturbances such as diet, disease, and environment [55 ]
[56 ]. Dietary changes could lead to 57% of the total structural variation in gut microbiota
whereas changes in genetics explain no more than 12% [57 ]. Prebiotics and probiotics are examples of dietary manipulation of the gut microbiota.
Probiotics are defined as ‘live microorganisms that their administration in adequate
amounts causes health benefits on the host’ [58 ]. The most commonly used probiotic microorganisms have been the following genera:
Lactobacillus, Bifidobacterium, Saccharomyces, Enterococcus, Streptococcus, Pediococcus,
Leuconostoc, and Bacillus. However, as probiotic properties have been shown to be
strain specific, identification of particular strains is very important. On the other
hand, it is also demonstrated that probiotics are safe and beneficial for healthy
individuals, caution in selecting of probiotics for immunocompromised patients or
patients with a leaky gut is needed [59 ].
A prebiotic is an ingredient that its fermentation leads to beneficial changes in
the gut microbiota [60 ]. There is evidence that rise in Bifidobacterium spp. produced by some prebiotics is accompanied by an increase in GLP1 and PYY secretion
by the intestine. These 2 molecules have favorable effects on insulin resistance and
the functionality of beta cells [61 ]
[62 ]
[63 ]. In addition, the modulation of gut microbiota with prebiotics increases GLP2 production
in the colon, which is associated with higher expression of zonula occludens-1 (ZO-1),
tight junction protein, that decrease plasma LPS through improving the mucosal barrier
function [63 ]
[64 ]. Various compounds including lactulose, lactitol, galacto-oligosaccharides, fructo-oligosaccharides,
inulin, isomalto-oligosaccharides, polydextrose, resistant starch and gums can act
as prebiotic [65 ]. Metagenomics studies could be helpful to assess the concept of prebiotic activity
of different compounds. Studies on the prebiotic effect of various dietary fiber and
polyphenols food sources are being conducted.
Fecal microbiota transplantation (FMT), a method that transfers intestinal bacteria
from a healthy donor into a patient, is also considered as an important “physiologic”
factor in the prevention and treatment of metabolic dysregulation. This method may
be effective in improving the obesity, insulin resistance, and metabolic syndrome
[66 ]. FMT from lean donors to individuals with metabolic syndrome significantly increased
insulin sensitivity, fecal butyrate concentrations, microbial diversity, and the relative
abundance of bacteria related to the butyrate-producing Roseburia intestinalis [67 ]. The effects of FMT on weight control, however, needs to be explored in future clinical
trials and it should be noted that like all personalized medicines, some interventions
may not only be ineffective in controlling an individual’s obesity, they may even
be an additional risk factor.
Gut Microtobia and Diabetes
Gut Microtobia and Diabetes
Role of gut microbiota in diabetes
Changes in the gut microbiota were observed during the lifespan from infancy to elderly
[68 ]
[69 ]. Different factors that influence these alterations can lead to metabolic disorders
such as diabetes. For instance the gut microbiota of babies born vaginally is similar
to their mothers, but those delivered by caesarean section have delayed microbial
colonization by Bacteroides , Bifidobacterium , and Lactobacillus . Therefore, the incidence of type 1 diabetes mellitus (T1DM) has been noted to occur
more frequently in them [70 ]
[71 ]. Studies in children with a high genetic risk for type 1 diabetes revealed significant
differences in the gut microbiota between children who developed autoimmunity and
those who remained healthy. In these children strong association between Bacteroides dorei and type 1 diabetes was discovered. Therefore, increase in Bacteroides dorei abundance may be useful for predicting T1D autoimmunity in genetically susceptible
infants [72 ].
Alteration of gut microbiota composition has been also observed in type 2 diabetes
mellitus (T2DM). Studies have indicated that there is a significant reduction of Firmicutes
and Clostridia , while the relative proportion of Bacteroidetes and Betaproteobacteria increases in type 2 diabetic patients compared with the healthy persons [5 ]. Recent studies demonstrated that disrupted mucus-bacterial interactions might be
contributing to gut dysbiosis and inflammation. Artificial sweeteners and 2 commonly
used emulsifiers including carboxymethylcellulose and polysorbate-80, which were components
of processed foods, induced adiposity and glucose intolerance/metabolic syndrome via
altering gut microbiota composition [73 ]
[74 ].
Animal studies showed that transplantation of gut microbiota from conventionally raised
obese mice to germ-free mice leads to a significant increase in body fat content and
insulin resistance in recipient mice [19 ]
[75 ]. Some studies showed significantly higher levels of Lactobacillus species and lower levels of Clostridium species in the T2DM group [76 ]
[77 ]. Moreover, the abundance of Bifidobacterium decreases in obese individuals and T2DM patients [78 ]. Researchers have identified 47 metagenomic linkage groups in the T2DM-associated
gene markers from the gut metagenome. They indicated that the abundance of butyrate-producing
Clostridiales including Roseburia and Faecalibacterium prausnitzii , which have a protective role against T2DM, decreased significantly in patients with
T2DM but the proportion of Clostridiales that do not produce butyrate increased [76 ]. Zhang et al. revealed that patients with T2DM have increased the proportion of
Firmicutes and Clostridia in comparison with healthy individuals, and the level of Betaproteobacteria increased significantly in the prediabetes and T2DM [79 ]. Therefore, special gut bacterial strains may act as early diagnostic markers for
identification of subjects at risk of T2DM.
Underlying mechanisms in diabetes
The possible mechanisms through which gut microbiota is associated with obesity may
be related to diabetes as well. One of these mechanisms is the essential role of the
gut microbiota in the fermentation of indigestible dietary polysaccharides into SCFAs
that act as regulators of food or energy intake and inflammation [80 ]
[81 ]. SCFAs, acetate, propionate, and butyrate, bind to G protein-coupled receptors (GPCRs)
such as GPR41 and GPR43, in the enteroendocrine cells [82 ]. SCFAs-mediated activation of GPR43 in the adipose tissue prevented fat accumulation
by suppressing insulin signaling [83 ]. Moreover, activated GPR43 in the intestine could increase insulin sensitivity by
stimulating the secretion of GLP-1 [84 ].
Since insulin resistance and T2DM are associated with low-grade inflammation, the
inflammatory effective factors such as change in gut microbiota can be a possible
mechanism for them [85 ]
[86 ]. Gut microbiota is full of molecules such as lipopolysaccharide (LPS) and peptidoglycan,
which can lead to inflammation and related metabolic disorders [52 ]. Alteration in gut microbiota triggers metabolic endotoxemia and inflammation by
LPS- and CD14/toll-like receptor (TLR) 4-dependent mechanisms [61 ]. LPS, lipids, fatty acids and chemokines stimulate c-Jun N-terminal kinase (JNK)
and IκB kinase (IKK)-β pathways intracellularly. IKKβ activates family of nuclear
factor (NF)-κB transcription factors and promotes the expression of many mediators
of inflammation that can result in insulin resistance. JNK increases the phosphorylation
of insulin receptor substrate (IRS)-1 at serine sites and decreases normal signal
transduction by the insulin receptor/IRS-1 axis, therefore this leads to insulin resistance
[87 ]. Furthermore, tight junction proteins such as zonulaoccludens (ZO)-1 and occludin
in intestinal epithelial cells reduce gut permeability and inflammatory markers and
improve insulin resistance accordingly [88 ].
Dietary soluble fibers stimulate intestinal gluconeogenesis (IGN), which exert an
antidiabetic effect contrary to the general idea that gluconeogenesis impairs glucose
tolerance [89 ]. The expression of IGN gene is stimulated by butyrate through a cAMP-dependent mechanism,
but propionate activates IGN gene expression through a gut-brain axis [89 ]. The IGN released glucose signals the brain by the peripheral nervous system and
exerts beneficial effects on dietary intake and glucose tolerance [90 ] ([Fig. 1 ]).
Modulation of gut microbiota in diabetes
The modulation of gut microbiota is a novel therapeutic strategy for glycemic control
performed by known components such as prebiotics, probiotics, and some drugs like
metformin. Probiotics may have antidiabetic effects due to the compositional changes
of the intestinal microbiota [5 ]. Studies indicated that probiotic consumption led to a healthier gut microbiota
and has been identified as an effective supplementary treatment in insulin resistance
and its related complications [91 ]
[92 ]. Bifidobacteria and Lactobacilli are commonly used strains of probiotics in functional foods and dietary supplements
[93 ]. Studies have indicated that the consumption of L. acidophilus , L. casei , L. lactis , and L. plantarum DSM15313 decreases the glycemic curve, insulin resistance, and HbA1c [94 ]
[95 ]. Marques et al. showed that γ-aminobutyric acid (GABA)-producing Lactobacillus brevis attenuated hyperglycemia in streptozotocin-induced type 1 diabetes rat models [96 ]. Probiotics may exert antidiabetic properties via immune-modulatory effects [87 ]
[97 ]
[98 ]. Further research is warranted into dosage magnitude, and mechanism of probiotics’
effects [98 ].
Prebiotics, which are fermentable polysaccharides, promote SCFA production, stimulate
the growth of beneficial bacteria such as Bifidobacterium , and improve gut barrier function [99 ]. Therefore, prebiotics improve gut permeability, decrease metabolic endotoxemia,
reduce inflammation, and improve glucose intolerance [51 ]
[64 ].
Metformin can also affect the gut microbiota. Shin et al. have demonstrated that metformin
can increase the abundance of Akkermansia muciniphila , mucin-degrading bacteria, in the gut of mice fed a high fat diet. Therefore, metformin
may exert its antidiabetic effects by modulation of the gut microbiota through increasing
the Akkermansia muciniphila population [100 ]. Moreover, results of in vitro study investigated the effects of acarbose on ruminal
fermentation characteristics and the composition of the microbiota revealed that the
proportion of Firmicutes and Proteobacteria was decreased and the percentage of Bacteroidetes,
Fibrobacteres, and Synergistetes was increased in acarbose group compared with the
control group. This study documented that acarbose could be useful for preventing
the accumulation of LPS in the rumen [101 ].
Recent articles indicated the fecal microbiota transplantation as a new potential
therapeutic option in T2DM. Vrieze et al. reported that fecal microbiota transplantation
from lean donors to obese subjects with metabolic syndrome increased butyrate-producing
bacteria and improved insulin sensitivity [67 ]. In future, well-designed trials are needed to develop a new treatment for diabetes.
Gut Microbiota and Osteoporosis
Gut Microbiota and Osteoporosis
Role of gut microbiota in osteoporosis
Osteoporosis, a major bone health concern, could result in a huge economic burden
on health care systems. The bone health depends both on how much bone is acquired
until peak bone mass is attained at 20–30 years of age and on the rate of the subsequent
bone loss. Hereditary and environmental factors are major determinants of the variances
in peak bone mass and age-related bone loss [102 ]
[103 ]. The potential of gut microbiota to affect bone health is a rather new area of investigation.
Recent evidences have demonstrated gut microbiota as a regulator of bone mass mediated
through effects on the immune system [6 ].
Unbalanced microbial composition of the gut microbiota has been suggested to be involved
in different inflammatory diseases, within and outside the gastrointestinal tract,
including inflammatory bowel diseases, rheumatoid arthritis, allergies, obesity, and
metabolic syndrome [104 ]
[105 ]. Moreover, inflammatory and autoimmune conditions have been associated with low
bone mass, suggesting the relationship between the immune system and bone metabolism
[106 ].
Bone-forming osteoblasts and bone-resorbing osteoclasts are responsible for bone remodeling.
The skeleton provides hematopoietic stem cells, which differentiate into osteoclasts
or immune cells (T cells) depending on local microenvironment status [107 ]. Evidences indicate that low-grade inflammation affects bone turnover and subsequently
bone mass [108 ]. Therefore, it was suggested that gut microbiota, which is correlated with immune
system, could work as a regulator of bone mass and a new gut microbiota-bone research
field, known as osteomicrobiology was proposed.
The germ-free mouse is a useful model to study the effects of gut microbiota on bone
mass. Sjogren et al. demonstrated that the absence of gut microbiota in germ-free
mice was associated with increased bone mass. It was found that bone marrows of germ-free
mice have fewer CD4+ T cells and osteoclast precursors compared to conventionally
raised mice. These fewer CD4+ T cells in bone marrows are caused by fewer CD4+ T cells
recirculating in the blood and secondary lymphoid tissue resulting in a decreased
expression of inflammatory cytokines [6 ].
As human grows older, osteoporosis become more prevalent, in a way that one in 3 women
and one in 5 men experience osteoporotic fracture after the age of 50 [109 ]. Although gut microbiota varies widely among individuals, there are significant
changes in gut microbial composition of older adults. Gut microbiota shift from obligate
anaerobes to facultative anaerobes in the elderly, leading to inflammation. Gut microbiota
in older adults have higher amounts of pathogenic Proteobacteria and Bacilli and lower
amounts of anti-inflammatory Lactobacilli [110 ]. Evidence indicated that as elderly move from living in the community to long-term
care facilities, large microbial changes occurred in their gut microbiota [111 ]. These changes alter bone and body composition and increase the risk of osteoporosis.
It seems that the analysis of the gut microbiota composition in osteoporotic subjects
could evaluate the possible associations between bone mineral density and specific
bacterial phyla, genera, and specious. Moreover, the analysis of the gut microbiota
composition in cohort studies can be used to determine the predictive role of the
gut microbiota for low bone mass and osteoporotic fractures risk.
Underlying mechanisms in osteoporosis
It was proposed that the most probable mechanism by which gut microbiota affects bone
mineral density involves the immune system, which in turn regulates osteoclastogenesis
[108 ]. Moreover, SCFAs could regulate inflammation and possibly exerts their direct effects
on bone [112 ]. Direct effect of butyrate on bone cells was the inhibition of osteoclast formation.
Furthermore, it was found that SCFAs could regulate osteoclastogenesis indirectly
through affecting on T cells in the colon [112 ]. In addition to osteoclastogenesis suppression, gut microbiota enhance absorption
and synthesis of various vitamins and minerals including vitamins K and B12, calcium,
and magnesium, which increase bone density and strength [109 ]
[113 ]. The effects of prebiotic and probiotic supplementation on gut microbiota composition
and mineral absorption needs to be further investigated. Although, it should be considered
that how precise could the fecal microbiome composition reflect the microbiome of
intestinal active site for mineral absorption.
Studies have shown that gut microbiota also can influence bone mass by the neurotransmitter
serotonin. Several microbial species directly synthesize serotonin, some others, however,
regulate the availability of tryptophan as a serotonin precursor. Serotonin has a
suppressive effect on osteoblast and may control bone mass via this pathway [114 ]
[115 ]
[116 ] ([Fig. 1 ]).
Modulation of gut microbiota in osteoporosis
The microbiota composition of osteoporotic subjects could be modulated by dietary
manipulation like prebiotics and probiotics. Prebiotic supplementation in animal models
altered gut microbiota in favor of bifidobacteria and increased short chain fatty acids, and improved mineral absorption and bone density
as well [113 ]
[117 ].
Studies have shown that different Lactobacillus strains, including L. reuteri , L. paracasei , and L. plantarum supplementation suppressed bone loss in ovariectomized mouse models [118 ]
[119 ]. Therefore, it was proposed that the gut microbiota composition could be involved
in the bone loss experienced by postmenopausal women who lose the immunosuppressive
effects of estrogen. Lactobacillus reuteri also decreased intestinal inflammation and increased bone density in healthy male
mice and type 1 diabetic mice [120 ]
[121 ]. Moreover, yacon flour in combination with B. longum , as a synbiotic food, helped to increase the concentration of minerals in the bones
of rats [122 ].
Taken together, as certain probiotic bacteria may benefit bone and others may harm
bone by promoting inflammation, future randomized clinical trials are needed to assess
the possible effects of probiotic and prebiotic supplementation on bone health.
Conclusion and Future Perspectives
Conclusion and Future Perspectives
From the grounds up, the development of new strategies for prevention and control
purposes for the rapid spreading of metabolic disorders are critical. Recent studies
implicate that metabolic phenotypes are associated with altered intestinal microbiota
composition compared to healthy counterparts. However, most of the published human
studies are associative and causality of gut microbiota in metabolic disorders should
be investigated in further research in order to allow using gut microbiota modulation
as a target for preventing or treating human metabolic disorders. Integration of gut
metagenomics studies with other high-throughput techniques like metabolomics can expand
our knowledge of the gut microbiota-host interactions and will discover underlying
cellular and molecular mechanisms involved in metabolic health. Apprehending the role
of gut microbiota in the modulation of host metabolism can provide novel therapeutic
strategies. Future studies to identify specific bacterial species associated with
metabolic phenotypes can help in providing therapeutic solutions by modulating the
gut microbiota.
The ways through which the modulation of intestinal microbiota might be achieved include
dietary intervention using prebiotics and probiotics or microbial transplantation
from healthy donors. Administrations of prebiotics, as a dietary method of gut microbiota
modulation, resulted in an increase in the lactobacillus and bifidobacterium species
and also a dose-dependently increase in the satiety hormones levels including GLP-1
and PYY. Studies are ongoing to select the best type of prebiotics with beneficial
effects on metabolic health. Furthermore, as many medicinal plants are used for the
treatment of metabolic disorders throughout the world whose effects may be linked
to the modulation of gut microbiota, prebiotic properties of these herbal medicines
should be investigated [123 ]
[124 ]
[125 ].
Moreover, the selection of new probiotic strains including Faecalibacterium prausnitzii , Akkermansia muciniphila , and Bacteroides uniformis , which efficiently modulate the human gut microbiome in preclinical trials is a new
strategy to improve metabolic disorders [126 ].
Fecal microbiota transplantation (FMT) has been demonstrated to alter the gut microbiota
of the recipient. Ongoing placebo-controlled trials are being conducted in humans
to examine if microbiota transplantation can improve metabolic health. Fecal transplantation
studies might reveal the causality relationship between specific intestinal bacterial
strains and metabolic health. However, critical issues including host immune response,
determination of suitable donors, and preparation of donor samples before treatment
should be considered in FMT.
Regarding the primary driving sources of metabolic disorders, investigating the gut
microbiota composition in genetic variants of metabolic disorders could be effective
in order to implement more personalized treatment. Although the association between
gut microbiota and obesity-related metabolic abnormalities has been shown in recent
studies, a proportion of obese individuals are free of metabolic abnormalities. The
mechanisms underlying this protective profile of the metabolically healthy obese are
not known. On the other hand, metabolically nonobese individuals are a subgroup of
normal weight subjects with a variety of obesity-related co-morbidities. Future studies
are needed to investigate the differences in microbiota composition between these
different metabolic phenotypes. This knowledge can result in new therapeutic areas
in the field of obesity and metabolic disorders. Moreover, osteosarcopenic obesity,
the concurrent appearance of obesity and low bone and muscle mass is a condition whose
etiological studies are limited. Evaluating the gut microbiota composition in this
condition could be useful for developing a new strategy to improve the health outcomes.
