Critical ReviewsTM in Biomedical Engineering, 47(5):427 – 436 (2019)

Alleviation of Fertility Disorders Based on Probiotics

Induced Immune System Improvement: A Review
Sunil Kumar Mohapatra,a Suvartan Ranvir,b,* Pranali Nikam,a & John Davidb
a
ICAR-National Dairy Research Institute, Karnal, 132001, India; bWarner College of Dairy Technology, Sam
Higginbottom University of Agriculture Technology and Sciences, Allahabad, 211007, Uttar Pradesh, India
*Address all correspondence to: Suvartan Ranvir, Warner College of Dairy Technology, Sam Higginbottom University of Agriculture Technology
and Sciences, Rewa Road, Naini, Allahabad 211007, Uttar Pradesh, India; Tel.: +7404940759, E-mail: [email protected]

ABSTRACT: Infertility is a worldwide problem affecting a large percentage of the population. Several products and
techniques have been adopted to alleviate infertility condition, but the most recent and promising result was obtained
through supplementation of probiotics. Continuous research on probiotics opened up a previously unknown area of its
role as a modern medicine in improving fertility. New research findings suggest a profertility effect of several probiotics
strains through alleviation of various fertility based disorders and modulation of the immune system. The goal of this
review is to cover all the major fertility based disorders, particularly highlighting the role of probiotics in improving
fertility through alleviation of such fertility based disorders.

KEY WORDS: probiotics, fertility based disorders, stress, hyperlipidemia, obesity, diabetes

I. INTRODUCTION due to an elevation in core body temperature (fever)

that commonly occurs during infections.7 However,
The definition given in the Oxford English Dictio- certain disease conditions like hepatitis B and HIV
nary for infertile is “the inability to give birth or have also been reported to cause a reduction in sperm
procreate.” World Health Organization (WHO) and quality due to a state of chronic low-grade infections.
International Committee for Monitoring Assisted Reports suggest that the severity of the infectious
Reproductive Technology (ICMART) redefine in- load is directly proportional to the reduction in sperm
fertility as a couple’s failure in pregnancy after 12 quality.8
months of unprotected sexual intercourse and preg- In males, the inevitable reduction in circulating
nancy attempts.1 Infertility is a worldwide problem testosterone occurs with increasing age. This reduc-
affecting 8% to 12% of couples (50 to 80 million tion in testosterone is associated with many adverse
couples) during their reproductive lives.2 In humans, conditions, including reduced spermatogenesis, li-
it has been established that nearly 40% of the issues bido, sexual function, and physical functions.9 Var-
involved with infertility are attributable to a male ious dietary factors and diet-induced obesity have
factor, another 40% due to a female factor, and 20% been shown to enhance the risk for late-onset male
result from combined male and female factors.3 hypogonadism and low testosterone production in
Various lifestyle factors, such as early start age both humans and mice.10
in the family, nutrition, weight management, exer- To alleviate such problems, several products,
cise, mental stress, self-medication without prescrip- such as injectable synthetic testosterone, testosterone
tion, consumption of caffeine, and occupational and enanthate (Delatestryl)11 and testosterone undeca-
environmental risks, may affect fertility.4 Fever and noate (Aveed),12 and testosterone pellets (Testopel),13
other systemic infections have been shown to re- are used to treat symptoms of low testosterone in
duce male fertility through a significant reduction in men. However, these products can have certain
sperm count, motility, morphology, and DNA integ- profound side effects like prostatitis, tightening of
rity,5 along with a marked reduction in the fertilizing throat, difficulty in breathing, difficulty in swallow-
capacity of the sperm.6 The root cause for the reduc- ing, shortness of breath, chest pain, dizziness, faint-
tion in sperm quality was previously postulated to be ing, sweating, rash, hives, itching, and even prostate

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428 Mohapatra et al.

cancer. Scientists have also tried various new mate- Among all these fermented food products, yogurt is
rials, including carbon nanotubes (CNTs), as a scaf- the most popular and important vehicle for the deliv-
fold for maintaining the spermatogonial cells and to ery of probiotic bacteria.20,23 The yogurt is tradition-
enhance fertility through in vitro approaches.14 But ally prepared by using thermophilic protosymbiotic
still, there is a dire need for a safe alternative. One cultures of Lactobacillus bulgaricus and Streptococ-
of the most promising alternatives can be probiotics, cus thermophilus.24 Yogurt acts as a probiotic carrier
which have proven their potential as a natural remedy food that is considered an easy food to incorporate
to improve reproductive health and performance.15 probiotics, which results in high probiotic viability.25
Sir Alexander Fleming created a golden era Probiotic ice cream has been introduced in the mar-
by accidentally discovering penicillin from the kets during the last few decades, and these products
fungus, Penicillium chrysogenum. This discovery were developed by incorporating probiotic cultures
revolutionized medicine around the world, and the into ice cream products. Ice cream is a functional
antibiotic has become an essential part of all med- food that is rich in vitamins and minerals, and the
ications. The main drawback of using an antibiotic addition of probiotic cultures enhances its nutritional
is that it not only kills the harmful bacteria but also properties.20,26 Probiotic cheese has been developed
damages the beneficial bacteria present in our gut by adding probiotic bacteria into cultured cheese.27,28
microbiome. To protect the good bacteria in our gut, In such products, viability of most probiotic strains
probiotics are now being used, which has widened were affected by the antagonistic interaction between
the field of medicine.16 Probiotic administration cheese starter cultures and probiotic bacteria, as well
prompts a marked enhancement in both specific and as acid production in these cultured products.29,30 Ke-
nonspecific immune responses through activation of fir can be considered a natural probiotic fermented
macrophages, increase in the levels of cytokines and milk. It is an acidic-alcoholic fermented milk prod-
immunoglobulins, and an increase in the activity of uct, with uniform creamy consistency and a slightly
natural killer cells.17 sour taste. Milk is fermented with kefir grains, a small
cluster of microorganisms held together by a poly-
II. PROBIOTIC FOOD PRODUCTS saccharide matrix named kefiran, and/or starter cul-
tures prepared from grains.31 Kefir grains look like
Probiotics are defined as “live microorganisms pieces of coral or small clumps of cauliflower, which
which when administered in adequate amounts contain a complex mixture of the lactic acid bacteria
confer a health benefit on the host.”18 The species Lactobacillus, Lactococcus, and Leuconostoc; acetic
of Lactobacillus and Bifidobacterium are most acid bacteria; and yeast mixture.32 Several types of
commonly used as probiotics, but the yeast Sac- probiotic fruits and vegetable products have been de-
charomyces cerevisiae and some Escherichia coli veloped and marketed, such as fruits and vegetable
and Bacillus species are also used as probiotics. juices, dried fruits, fermented vegetables, and veg-
Lactic acid bacteria, including Lactobacillus spe- etarian deserts.33–36 Probiotic meat products are dry
cies, which have been used for preservation of food sausages fermented without heating. In addition to
by fermentation for thousands of years, can serve a the high nutritional value, the characteristics of this
dual function by also potentially imparting health type of meat make it an ideal food matrix for pro-
benefits. Strictly speaking, however, the term pro- biotic delivery to humans. It is a fermented product,
biotic should be reserved for live microbes that so the addition of probiotic bacteria will not alter the
have been shown in controlled human studies to product’s sensorial characteristics. Also, it is not heat
impart a health benefit.19 treated, and so the viability of probiotic bacteria will
Currently, hundreds of probiotic food products not be reduced. Commonly used lactic acid bacterial
are manufactured and consumed around the world. strains in meat starter cultures are Lactobacillus ca-
The example of probiotic food products are yogurt, sei, Lactobacillus curvatus, Lactobacillus pentosus,
kefir, probiotic ice cream, fermented milk, cheeses, Lactobacillus plantarum, Lactobacillus sakei, Pedi-
probiotic fruits and vegetables, and probiotic meat.18–22 ococcus acidilactici and Pediococcus pentosaceus.37

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Probiotics Induced Immune System Improvement429

III. ROLE OF PROBIOTICS IN ALLEVIATION OF the proinflammatory cytokine IL-17.39 According

INFERTILITY RELATED LIFESTYLE FACTORS to Poutahidis and colleagues, consumption of pro-
biotic L. reuteri increases both testicular weight
A. Probiotics Induce Reproductive Fitness along and cross-sectional area of seminiferous tu-
in Aged Individuals and Improves bules and their germ cell population.38 L. reuteri
Fertility by Increasing Testicular Weight also counteracts age-related testicular atrophy and
and Testosterone Production induces an elevation in serum testosterone. The
probiotic also increases interstitial Leydig cell ar-
Current lifestyle trends in modern society, charac- eas and Leydig cell number, which ultimately re-
terized by caloric abundance and reduced physical capitulates the reproductive fitness in aged mice.38
activity underlies the current epidemic of obesity, From all these studies, it is quite evident that cer-
including its recent emergence in previously un- tain strains of probiotic have a promising and pro-
affected populations such as developing countries found effect on improving fertility via an unknown
and children. This alarming increase affects fer- mechanism. The ameliorating effects of different
tility in both males and females. Intense research probiotics are summarized in Table 1.
efforts have focused on understanding the under-
line mechanisms by which excess nutrients and B. Probiotics Reduce Stress and Improve
adiposity result in infertility and finding more ef- Fertility
fective, therapeutic, and preventive measures to
alleviate infertility. Some scientists have reported The adverse effects of various stressors on the re-
that administration of Lactobacillus reuteri along productive cycle of both domestic and laboratory
with controlled diet increases testicular weight and animals have been recorded in detail. Stressors are
testosterone level in males.38 Others have reported generally categorized into two groups, namely en-
the antiaging effects of L. reuteri supplementation vironmental stress and management related stress.40
in aged mice, through induction of beneficial in- Grandin et al. reviewed the stress related to han-
tegumentary effects and manifestation of luxuriant dling the animals, such as from rough handling
hair. Interestingly both these effects were asso- during artificial insemination, stressful health-care
ciated with modulation of regulatory T cells and procedures, and isolation of animals. These situ-
interleukin 10 (IL-10)–linked downregulation of ations lead to profound adverse effects on animal

TABLE 1: Ameliorating effects of different probiotics on fertility based disorders

Experimental subjects Fertility based disorders Probiotics species alleviating Refs.
fertility based disorders
Human Age related infertility Lactobacillus reuteri Poutahidis et al.38
Levkovich et al.39
Human, rat, mice Stress related infertility Lactobacillus helveticus Messaoudi et al.46
Bifidobacterium longum Ait-Belgnaoui et al.47
Human, rat, mice Hyperlipidemia related Bifidobacterium spp. Mann and Spoerry51
infertility Lactobacillus spp.
Rat, mice Obesity related Lactobacillus plantarum Lee et al.56
infertility Lactobacillus gasseri Kang et al.57
Bifidobacterium breve Kondo et al.58
Mice, rat Diabetes related Lactobacillus rhamnosus GG Kim et al.67
infertility Lactobacillus johnsonii
Lactobacillus casei

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430 Mohapatra et al.

reproduction by influencing their internal physiol- C. Probiotics Alleviate Hyperlipidemia and

ogy and disrupting normal reproductive functions.41 Improve Male Fertility
Some studies suggest that feeding a high-fat diet
(HFD) to C57BL/6 obesity-prone mice causes a In recent years, much attention has been focused on
profound increase in endoplasmic reticulum (ER) the association of serum lipid profiles with sperm
stress through a marked increase in the expression lipid content, semen quality, and male infertility.
of the Ddit3 gene and possibly disturbing reproduc- Reports suggest that a high fat diet induces nutri-
tive functions in mice.42 tional obesity and hyperlipidemia, and it has an ad-
The etiological factor for progression of any verse effect on testicular development and hormonal
disease is somehow linked with stress, and cer- profile in pubertal rats and rabbits.50 A high lipid diet
tain afflictions like gastrointestinal, physical, and can induce obesity and increases the apoptosis of
psychological complications are also induced by the testicular spermatogenic cell population.50 This
stress. Exciting studies have revealed that probiot- hyperlipidemic condition indicates a probable etio-
ics and gut microbiota have a profound role in al- logical cause for the reduction in fertility.42 These
tering behavior and brain neurochemistry. Complex reports indicate that dyslipidemia is an important
central nervous system disorders can be eliminated factor contributing to male infertility. Therefore,
through modulating gut microbiota and exploring regulation of serum lipid profile may be useful to
the emerging concept of the microbiota–gut–brain some extent, for proper male reproductive function
axis.43 Some scientists have observed that certain and management of male infertility. According to
probiotic strains, such as Lactobacillus fermentum, Mann and Spoerry, there is a profound reduction
express various stress-related proteins during com- in total serum cholesterol associated with lactic
promised situations44,45 that not only assist in the acid bacteria.51 Some scientists have also noted that
process of stress tolerance but also might contribute oral administration of g-oryzanol improved glu-
to reproductive health. Messaoudi and colleagues cose-stimulated insulin secretion following reduc-
have confirmed psychotropic-like properties of Lac- tion of exaggerated ER stress and apoptosis in mice
tobacillus helveticus R0052 and Bifidobacterium fed a high fat diet.52
longum R0175. In their study, they found that oral
administration of these two strains to rats and hu- D. Probiotics Have a Profound Anti-Obesity
man subjects profoundly alleviates psychological Effect
conditions, such as anxiety, depression, and stress.46
Other scientists also confirmed a relief from psycho- Obesity is a global health problem reaching epi-
logical stress by the administration of probiotic Lac- demic proportions, with 1.6 billion adults classi-
tobacillus farciminis, possibly through attenuation fied as overweight and another 400 million adults
of the hypothalamic-pituitary-adrenal (HPA) axis classified as obese.53 In the last 5 to 10 years, re-
and prevention of gut leakiness.47 Ait-Belgnaoui et search has revealed that maternal obesity is as-
al., have reported a beneficial effect of L. helveti- sociated with changes in oocytes that negatively
cus and B. longum in alleviating brain activity de- impact embryo development and reduce subse-
regulations induced by chronic stress.48 Scientists quent pregnancy establishment after in vitro fertil-
have also reported that the stress induced by ma- ization.54 Studies have also revealed that males fed
ternal separation in rat pups changes their intestinal a high fat diet to induce obesity had reduced sperm
physiology and causes colonic dysfunction. Their motility and decrease in percentage of sperm with
results confirmed that administration of probiotics normal morphology.55 Also, there is marked evi-
reduces gastrointestinal stress induced by maternal dence of various dietary factors and diet-induced
separation, possibly through modulating HPA axis obesity that have been shown to increase the risk
activity.49 These results indicate that, in addition to for late-onset male hypogonadism and low testos-
the antiaging effects, some strains of probiotics also terone production in both humans and mice (Fig.
relieve stress via different mechanisms. 1). Hyperinsulinemia and hyperglycemia have

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Probiotics Induced Immune System Improvement431

also been shown to decrease sperm quantity and using Bifidobacterium breve strain B-3 at 108 or
quality and therefore could be attributing to the re- 109 CFU/day. Their results suggested an effective
duced fertility seen in obese men. Hormonal alter- reduction in the risk of obesity by using B. breve
ations associated with male obesity are depicted in B-3 strain.58
Fig. 2.
In relation to this, Lee et al., observed the an- E. Antidiabetic Effect of Probiotics
tiobesity effect of trans-10, cis-12 conjugated lin-
oleic acid produced by L. plantarum PL62 strain. Diabetes has become the world’s biggest threat to
They also reported that obesity can be treated by human health in this modern era. The incidence of
replacing the conjugated linoleic acid (CLA) with diabetes mellitus in both children and adults has
trans-10, cis-12 conjugated linoleic acid–pro- been found to be increasing at an alarming rate.59
ducing L. plantarum PL62 strain.56 Kang et al. According to the WHO report, around 177 mil-
investigated the suppressive effect of Lactobacil- lion people have already been affected by diabetes
lus gasseri (isolated from human breast milk) on worldwide, and the figure is projected to increase
body weight gain and adipose tissue mass in di- to more than 300 million by 2025.60 Studies on an-
et-induced overweight rats.57 The data obtained imal models have strongly suggested that diabetes
from their study suggested an alternative method mellitus has a profound effect on reducing fertil-
for treatment of obesity and weight-related prob- ity and fecundity in diabetic male animals.61 Some
lems using the L. gasseri BNR17 strain. Kondo scientists have also observed a profound amelio-
and colleagues evaluated the antiobesity effect on rative effect of probiotic strain L. fermentum RS 2
C57BL/6J high fat diet–induced obese mice by on alloxan-induced diabetic rats, through various

FIG. 1: Obesity related male hypogonadism (adapted from Tremellen68)

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432 Mohapatra et al.

FIG. 2: Proposed pathways for hormonal alterations associated with male obesity (adapted from Hammoud et al.74)

in vivo studies.62 There are certain bioactive pep- et al. reported that administration of the probiotic
tides present in functional foods (e.g., probiotics) Lactobacillus rhamnosus GG (LGG) has a profound
that are also quite promising for managing type 2 antidiabetic effect by improving insulin sensitivity
diabetes.63 and reducing lipid accumulation. The underlying
Some of the human trials show that there is mechanism involves stimulation of adiponectin
profound derangement in the hypothalamic–pi- secretion and activation of AMP-activated protein
tuitary–testicular axis along with reduced semen kinase (AMPK).67
quality in an insulin-dependent diabetic man. Also,
structural defects were observed in sperm mor- IV. PUTATIVE MECHANISM OF PROBIOTIC
phology and spermatogenesis that ultimately lead ACTION ON IMPROVING FERTILITY
to a reduction in male fertility.64 Another mecha-
nism for alterations in the male reproductive sys- Recently, Kelton Tremellen and colleagues proposed
tem in an insulin-dependent diabetic individual has a theory called Gut Endotoxin Leading to a Decline
been put forward by Ballester et al. They proposed IN Gonadal function (GELDING) to establish a
a gonadotropin related mechanism (linked to fol- probable mechanism for male hypogonadism due to
licle stimulating hormone [FSH] and luteinizing obesity.68 According to the hypothesis, the main eti-
hormone [LH]) for a reduction in fertility in strep- ological factor for the progression of male hypogo-
tozotocin-induced diabetic individuals.65 Profound nadism is the breakdown of gut barrier integrity due
decreases in serum FSH, LH, prolactin, and growth to a high fat and high calorie diet. This increases the
hormone levels have been observed in people who permeability of the intestine to bacterial endotoxins
have diabetes, resulting in impaired spermatogene- (lipopolysaccharides [LPS]), which elicit a state of
sis and altered Leydig cell function.66 Recently, Kim chronic low-grade inflammation throughout the body

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Probiotics Induced Immune System Improvement433

(metabolic endotoxemia). Such persistent inflamma- reactive oxygen species.73 On the other hand, stud-
tion also alters the physiology of testes and ovaries, ies have revealed that consumption of probiotics has
which impairs reproductive function and reduces lev- immunomodulatory effects on our immune system,
els of the male and female sex hormones testosterone possibly by activating various immune cells, such as
and estrogen, respectively.68 Ingesting probiotics im- macrophages and dendritic cells, and by modulating
proves the integrity of the intestinal epithelial barrier the level of different cytokines. More specifically,
and prevents the entry of these bacterial endotoxins probiotics downregulate proinflammatory cytokines,
into the blood circulation, thus alleviating systemic such as IL-1b, TNF, IL-6, and IL-17, and upregu-
inflammation and testosterone depletion. late the anti-inflammatory cytokines, such as IL-10,
Currently, no experimental data support a direct through modulating the regulatory T cells. It also in-
link between the presence of endotoxins and pro- creases the activity of natural killer cells and elevates
gression of male hypogonadism. However, studies the levels of immunoglobulins.
in women have confirmed a direct correlation be-
tween endotoxemia and a decrease in the production V. CONCLUSIONS
of progesterone.69 Several animal studies have also
suggested that LPS contribute to testicular dysfunc- Undoubtedly, infertility is a very serious issue, and
tion. It is well established that Leydig cells express the current approaches to treat infertility are not com-
Toll-like receptor 4 (TLR4) for endotoxins.70 Thus pletely safe. Therefore, there is a dire need to have
the administration of LPS to experimental animals safe alternative treatments. Certain strains of probi-
directly affects their Leydig cell function and reduces otics may become optimal infertility treatments in
the testosterone production from the cells.71 This re- the future. Probiotics contain live microorganisms
duction in testosterone production is mostly medi- such as Lactobacillus and Bifidobacterium species,
ated through decreased expression of steroidogenic which colonize our intestinal epithelium and elim-
acute regulatory (StAR) protein activity (a protein inate pathogenic bacteria. They also improve the
that plays a key role in the initial transfer of choles- integrity of the gut barrier. They reduce systemic
terol into mitochondria, where it is later converted inflammation by modulating our immune system
into testosterone) in the Leydig cells.72 Normally through regulatory T cells, thus increasing testoster-
within the testicular interstitium, Leydig cells and one production and fertility in human beings.
macrophages are close to each other. The activation
status of macrophages provides essential growth and VI. FUTURE DIRECTIONS
differentiation factors for the development of the
Leydig cells along with testosterone production.73 The exact mechanisms of how probiotics improve
However, during metabolic endotoxemia these mac- fertility are still unclear; thus, robust and rigorous re-
rophages get activated and produce proinflammatory search is required to explore these untouched areas.
cytokines like interleukin-1 (IL-1) and tumor necro- Future research should be directed toward identify-
sis factor (TNF) along with the production of reac- ing the probiotic strains that greatly improve fertility,
tive oxygen species (ROS) which ultimately affects through in vitro or in vivo approaches. Understanding
the Leydig cells, thereby reducing their testosterone the mechanisms of how probiotics improve fertility
production in them.71,72 Furthermore, due to such im- may not only help to select the beneficial strains but
mune stimulatory conditions, leydig cells themselves also foster the development of novel strategies for
start producing inflammatory cytokines (IL-1b, the treatment and prevention of infertility conditions.
TNF, and IL-6) which further amplifies the activa-
tion of neighboring macrophages.70 Tremellen and
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