European Journal of Clinical Nutrition

https://doi.org/10.1038/s41430-018-0135-9

REVIEW ARTICLE

A review of probiotic supplementation in healthy adults: helpful or

hype?
Saman Khalesi 1 Nick Bellissimo2 Corneel Vandelanotte1 Susan Williams1 Dragana Stanley3
● ● ● ● ●

Christopher Irwin4

Received: 6 November 2017 / Revised: 16 January 2018 / Accepted: 9 February 2018

© Macmillan Publishers Limited, part of Springer Nature 2018

Abstract
Probiotic supplements have a positive impact on several health outcomes. However, the majority of published studies have
focused on populations with specific health pathologies. Therefore, this study reviewed the current literature on the health
effects of probiotic consumption in “healthy adults.” The findings from this review may help guide consumers, researchers,
and manufacturers regarding probiotic supplementation. Relevant literature published between 1990 and August 2017 was
reviewed. Studies were included if they were experimental trials, included healthy adults, used live bacteria, and had
1234567890();,:

accessible full-text articles published in English. Included studies were classified according to common foci that emerged.
Forty-five studies were included in this review. Five foci emerged: gut microbiota changes (n = 15); immune system
response (n = 16); lipid profile and cardiovascular disease risk (n = 14); gastrointestinal discomfort (n = 11); and female
reproductive health (n = 4). Results suggest that probiotic supplementation in healthy adults can lead to transient
improvement in gut microbiota concentration of supplement-specific bacteria. Evidence also supports the role of probiotics
in improving immune system responses, stool consistency, bowel movement, and vaginal lactobacilli concentration. There is
insufficient evidence to support the role of probiotics to improve blood lipid profile. Probiotic consumption can improve in
the immune, gastrointestinal, and female reproductive health systems in healthy adults. However, this review failed to
support the ability of probiotics to cause persistent changes in gut microbiota, or improve lipid profile in healthy adults. The
feasibility of probiotics consumption to provide benefits in healthy adults requires further investigation.

Introduction human longevity and yoghurt consumption (containing

lactobacilli strains of bacteria used for fermentation) were
The use of fermented products can be traced back to ancient observed [2, 3]. It was also around this time when belief
Egyptian and Middle-Eastern civilizations, when fermen- originated that fermented products could alter the microflora
tation was a method of food preservation [1]. However, it of the large intestine and reduce toxin production in the
was not until the early 1900s that associations between intestine [2, 3]. In the early 1900s Bifidobacterium was first
isolated and was hypothesized to have anti-pathogenic
effects [1]. The next major advancement was in the 1960s,
when the term “probiotic” was first coined for bacterial
* Saman Khalesi species deemed to be beneficial to the gastrointestinal (GI)
[email protected] tract. However, it was not until 2001 that the World Health
[email protected]
Organization formally defined probiotics as “live micro-
1
Physical Activity Research Group, Appleton Institute, School of organisms, which, when administered in adequate amounts,
Health Medical and Applied Sciences, Central Queensland confer a health benefit on the host” [4].
University, Rockhampton, QLD, Australia The ability of probiotics to impart health benefits has
2
School of Nutrition, Ryerson University, Toronto, ON, Canada prompted increased scientific interest for several decades.
3
School of Health Medical and Applied Sciences, Central Evidence from animal and human studies has demonstrated
Queensland University, Rockhampton, QLD, Australia potentially favorable benefits of probiotics, including
4
Menzies Health Institute, School of Allied Health Sciences, modulating the number and diversity of beneficial gut
Griffith University, Gold Coast, QLD, Australia microbiota [5, 6]; reducing symptoms associated with
 S. Khalesi et al.

various GI disorders [7, 8]; improving blood cholesterol Study eligibility and selection
levels and blood lipid profile [9, 10]; removal of myco-
toxins [11]; reducing blood pressure and hyperten- Studies were included if they (1) were experimental trials,
sion [12]; improving blood glucose tolerance and diabetes (2) included adults, aged 18 years and older, (3) used live
control [13, 14]; and enhancing mental state and cognitive bacteria (probiotics), (4) included healthy adults, and (5)
function [15]. had accessible full-text publications in English. Healthy
The translation of these health benefits in the public adults were defined as individuals with no reported status of
forum has led to increased demand for probiotic products/ the chronic or acute diseases, including cardiovascular
supplements over the last decade. This has prompted a disease (CVD), obesity (body mass index (BMI) ≥ 30 kg/
rapid increase in the development of new probiotic- m2), liver disease, diabetes, chronic GI problems, auto-
containing foods and supplements for the consumer mar- immune disease, cancer, psychological disorder, etc. Adults
ket [16]. While research has demonstrated positive effects who reported having symptoms consistent with the common
of probiotic consumption on several health outcomes, the cold, who were overweight (BMI 25–29.9 kg/m2) or smo-
majority of the published literature is in populations with kers, were not excluded. Studies were excluded if probiotic
underlying pathologies. Evidence supporting the health- treatment was mixed with other ingredients, or if pregnant
promoting effects of probiotics in healthy adults is limited women or both healthy and unhealthy adults were included
and less consistent [17, 18]. Despite this, probiotic manu- as participants in one group.
facturers promote the use of their product to a broader The searched literature was initially screened by
consumer market than those with specific health condi- reviewing titles and abstracts. The full text of all relevant
tions. Whether probiotic supplementation conveys benefit records was then reviewed. Two researchers were involved
in healthy individuals is questionable. Therefore, this study in the screening process and review of the literature. Eli-
aimed to review the literature on the health effects of gible articles were only included when agreement was
probiotic consumption in “healthy adults.” The results of reached between the two researchers. In the case of any
this review may guide the decision-making of consumers, disagreement, a third reviewer was involved.
researchers, and manufacturers regarding probiotic
supplementation. Data collection and synthesis

Eligible literature was classified based on the most promi-

Methods nent themes that emerged from the literature search. Studies
with similar outcomes were grouped if more than three trials
Literature search were classified in the relevant group [gut microbiota chan-
ges, immune system response, lipid profile and CVD risk,
Due to the number of outcomes included and the wide GI discomfort, and female reproductive health]. In each
variety of studies varying in study design, experimental group, methodology characteristics and outcomes were
setting, and dependent measures (e.g., immune response to extracted. A narrative synthesis was used to review the
different viruses or a different population of older and effect of probiotics consumption on outcomes in each
younger adults), a systematic review was not performed. classification. The Cochrane Handbook for Systematic
However, a systematic approach was employed to search Review of Interventions [20] was followed as a guideline to
and review the relevant literature. The online databases review literature.
PubMed (MEDLINE), Cumulative Index to Nursing and
Allied Health Literature, and Cochrane Library (Central)
were searched from 1990 through to August 2017. The Results
reference lists of included studies were also manually
searched for relevant studies. Following a PICOS (popula- Forty-five studies were included in the overall review. A
tion, intervention, comparison, outcome, setting) approach, summary of the review process and study selection criteria
the online literature search used a combination of the fol- is presented in Fig. 1.
lowing basic and MeSH (medical subject headings) terms:
“healthy volunteers” or “healthy adults” as the population; Gut microbiota colonization
“probiotics”, “lactobacillus”, or “bifidobacterium” as the
intervention; “placebo” or “control” as the comparison; The proposed health benefits of probiotics are often initially
“controlled trials” or “non-controlled trials” as the study measured at the gut microbiota level [6]. Changes in the
design. During the preparation and presentation of this concentration and composition of intestinal microorganisms
review, the PRISMA guidelines were followed [19]. would suggest that probiotics are effective, at least in terms
 not necessarily be required for changes in the gut micro-
Identification # of records identified
through database searching biota [31]. The passage of probiotic bacteria (e.g., bifi-
n=148 dobacteria) itself through the gut may be sufficient to
Records excluded reduce colonies of pathogenic bacteria by reducing their
(n=60): Not adults adhesion and competitive nature [34].
# of records (duplicates
Screening

(2); Non-healthy An ideal environment modulating the colonization of

removed) screened
participants (16); Just
through title and abstract probiotics is one with adequate food to support the growth
prebiotic (2); No
n=116
control arm (2); Non of healthy bacteria and reduce competition [25]. The host’s
relevant (38)
diet is an important determinant of gut microbiota biodi-
11 full-text articles versity. Fermentable carbohydrate supports the growth and
Eligibility

# of full-text articles excluded, reasons:

assessed for eligibility colonization of selective bacteria in the gut. The term
1. Mixed ingredients
n=56 with no control (n=1) “prebiotics” [35] is used in reference to these fermentable
2. Synbiotic mixture fibers that resist gastric acidity and are able to stimulate the
(n=6)
growth and activity of beneficial bacteria in the gut [36].
3. Both healthy and
Although commercially available (i.e., inulin, fructo-oligo-
Included

# of studies included non-healthy

in qualitative synthesis participants with no saccharides, and galacto-oligosaccharides), these fibers are
n=45 separate arms (n=4)
abundant in natural foods such as fruits and vegetables [36].
Fig. 1 Flow diagram of the review process for the effect of probiotic Evidence suggests that prebiotic consumption can improve
supplementation in healthy adults the fecal count of beneficial bacteria (especially bifido-
bacteria) [37, 38] and maintain gut health.
of colonization [6]. In all, 15 studies from the literature When gut microbiota dysbiosis exists (e.g., diarrhea),
search were included in this classification group. Findings prebiotics alone may not be able to return gut microbiota to
from these studies are summarized in Table 1. Of the its equilibrium. Despite skepticism about the influence of
15 studies include, 14 suggested that probiotic supple- probiotics on the gut microbiota of healthy adults, probio-
mentation is likely to increase the fecal count of specific tics have proven beneficial effects when dysbiosis exists [7,
bacterial strains administered in healthy adults. However, 39]. Aging is also associated with a relative dysbiosis in gut
changes in the total count, diversity, and composition of gut microbiota. Reductions in bifidobacteria count, diversity,
microbiota were only reported in three studies [6, 21, 22]. It and an increase in pathogenic bacteria are observed in the
also appears that changes in the gut microbiota of healthy elderly [40, 41]. Lahti et al. [23] reported that probiotic
adults following probiotic supplementation are temporary supplementation in healthy elderly adults could improve
and return to pre-treatment levels within 1–3 weeks once this age-related dysbiosis (Table 1). Overall, it seems that
supplementation has ceased [23, 24]. probiotic supplementation in healthy adults can lead to an
No obvious conclusions regarding the effects of dose, increase in the colonization of specific probiotic strains.
duration or strain of probiotics on changes in gut micro- However, this increase may be transient and return to
biota can be made based on the studies included in this baseline after supplementation stops. Further studies need to
review (Table 1). In order to transition through the GI focus on the sustainability of probiotic colonization in gut
tract and colonize the gut, probiotics need to be viable microbiota.
(i.e., contain adequate live bacteria) and resistant (i.e.,
survive) to stomach acidity and bile salts [25, 26]. Some Immune system response
probiotic strains of the Bifidobacterium and Lactobacillus
species such as B. animalis lactic [27], L. acidophilus Probiotics have been proposed to improve intestinal defense
johnsonii [27, 28], and L. casei Shirota [29] are reported mechanisms against pathogenic microorganisms, enhance
as being resistant to low pH environments, thus appear to the immune system, and reduce the likelihood of respiratory
have good survival rates. In addition, L. acidophilus, B. infections [42, 43]. Sixteen studies from the literature search
longum, and B. infantis have demonstrated good resis- were included in this classification group, with findings
tance to bile salts [30, 31]. Encapsulation and micro- summarized in Table 2. Eight studies reported the effect of
encapsulation manufacturing techniques have provided probiotic consumption on common respiratory infections
more efficient ways of delivering probiotics and preser- such as cold and flu. All of the three studies reporting on the
ving their viability [32]. Although these methods may effect on the common cold support a beneficial effect of
improve the survival of bacteria, they do not guarantee probiotic supplementation at increasing immunity against
colonization of the probiotic bacteria in the intestine. The the common cold in healthy adults (albeit in a limited
type of bacteria and the GI environment [33] also influ- number of studies; Table 2). Reductions in the incidence
ence bacterial colonization. However, colonization may [44, 45], duration [44, 46], and symptoms [44, 46]
Table 1 Characteristics of included studies for the effect of probiotics on gut microbiota changes
Study [ref.] Design; Intervention/control, Duration; age; Probiotic; dose (per day), CFU Outcome effect; reported side effects
location supplement participants
(m/f)

Bjerg et al. RC, DB, P; Probiotic capsule/ 4 wk; 20–54 L. casei; 1.0 × 1010 Significant increase in the specific strain after intervention but no effect on overall
[68] Denmark placebo y; 64 (32/32) composition of gut
Brown CO, RC; Poi probiotic drink 14 wk; 18–64 L. lactic + L. streptococcus; No significant change in the total concentration of gut bacteria; no side effects
et al. [99] USA (non-dairy based)/ y; 18 (8/10) 1.9–3.9 × 108
control
Ferrario CO, RC, Probiotic 4 wk; 23–55 L. paracasei DG; 2.4 × 1010 Significant increase in healthy bacteria genus, and reduction in bacteria associated with
et al. [6] DB; Italy supplements/ y; 34 (19/15) disease (reduction in Blautia:Coprococcus ratio); no side effects
placebo
Guillemard RC,DB, P; Fermented dairy 12 wk; 72–80 L. paracasei (L. casei) + S. Significant increase in specific strain during probiotic consumption
et al. [100] France drink/placebo drink y; 537 (198/ thermophilus + L. bulgaricus; 1.0 ×
339) 109
Hanifi et al. RC, DB, P; Probiotic capsule/ 4 wk; 18–50 B. subtilis; 1.0 × 1010 Significant increase in the specific strain after intervention; no side effect
[101] USA placebo y; 81 (40/41)
Irwin et al. P, RC, DB; Probiotic 8 wk; 26.2 ± L. acidophilus + B. lactis; 2.5 × 1010 Increase in fecal count of specific strains after intervention. Some GI discomfort
[5] Australia supplements/ 8.4 y; 19 (10/
placebo 9)
Klein et al. P, RC, CO; Probiotic yoghurt/ 5 wk; 25 ± 3 L. acidophilus + B. lactis; 9.4 × 108 Significant increase in the specific strain after intervention
[69] Germany placebo y; 26 (13/13)
Lahti et al. RC, DB, P; Probiotic drink/ 3 wk; 23–44 L. rhamnosus GG; 1.5 × 1010 Significant increase in the specific strain after intervention, reduced to pre-treatment
[23] Finland placebo y; 25 (7/18) 3 weeks’ follow-up
Mai et al. P, RC, DB; Probiotic capsules 12 dy; 12 L. acidophilus + B. longum; 1 × 109 Significant increase in fecal count of specific strains after intervention
[25] USA in gelatin or Pearls
Nyangale RC, DB, P; Probiotic capsule 28 dy; 65–80 B. coagulans; 1.0 × 109 Significant increase in Facalibacterium and Bacillus coagulans;
et al. [56] UK y; 36 917/ 25)
Plaza-Diaz RC, P; Spain Probiotic capsule/ 30 dy; 20–35 B. breve + L. rhamnosus or L. Significant increase in fecal count of specific strains after intervention. L. rhamnosus
et al. [21] placebo y; 23 (14/9) paracasei/B. breve/L. rhamnosus increased all Lactobacillus genus. Most changes remained after 15 days’ follow-up
separately; 9 × 109
Rampelli RC, DB, P; Probiotic biscuit/ 30 dy; 71–88 B. longum + L. helveticus; 1.0 × 109 Reduced the pathogen bacteria (i.e. Clostridium cluster Xi, C. difficile, C. perfringens,
et al. [22] Italy placebo y; 32 (13/19) E. faecium) and increase in the probiotics B. longum and Lactobacillaceae. Improved
age-related changes in gut microbiota
Wang et al. SA; China Probiotic drink 14 dy; 20–40 L. casei Shirota; 1.0 × 1010 Significant increase in fecal count of specific strain after intervention. The count
[29] y; 25 (9/16) decreased after follow-up but remained higher than baseline; no side effects
Wassenaar SA; Probiotic capsule Single dose; 5 E. coli G1/2, G3/10, G4/9, G6/7, G5, High colonization of the specific strains for a period of 10–30 weeks after single dose;
et al. [102] Germany (3/2) and G8; 2 × 109 mild GI discomfort
Wind et al. RC, DB, P; Probiotics sachets/ 3 wk; 42 ± 16 L. rhamnosus; 1.0 × 1011 Significant increase in the specific strain after supplementation, reduced back to pre-
[24] The placebo y; 34 (14/20) intervention within 1 week’s follow-up; no side effects
Netherlands
CO cross-over, DB double blind, P parallel, RC randomized controlled trial, SA single arm
S. Khalesi et al.
Table 2 Characteristics of included studies for the effect of probiotics on immune system response
Study [ref.] Design; Intervention/control Duration; age; Probiotic; dose (per day), CFU Outcome effect; reported side effects
location participants (m/
f)

Baron [43] SA; USA Probiotic capsule 30 dy; 33–63 y; B. coagulans; 2.0 × 109 Significant increase in TNF-α after in vitro exposure of T cells to flu A; no side
10 (5/5) effects
Berggren RC, DB, Probiotics capsule/ 12 wk; 18–65 y; L. plantarum + L. paracasei; 1.0 × 109 Significant reduction in the incidence of common cold, the duration, and the
et al. [44] P; Sweden placebo 318 (180/92) symptoms of common cold. Reduction in inflammatory B lymphocytes
de Vrese et al. RC, DB, Probiotics with 12 wk; 36 ± 13 L. gasseri + B. longum + B. bifidum; Significant reduction in the duration and symptoms of common cold, and days
[46] P; multivitamin/ y; 242 (94/148) 5.0 × 107 with fever. Increase in CD8+ and CD4+ immune cells
Germany multivitamin
Dong et al. RC, SB, Probiotic drink/ 4 wk; 55–74 y; L. casei Shirota; 1.3 × 1010 Significant increase in NK cell activity and CD25 in T cells. A trend toward
[53] CO; UK placebo drink 30 (12/18) increase in anti-inflammatory cytokine IL-10 to pro-inflammatory IL-12
Gill et al. [52] SA; New Probiotic milk 3 wk; 63–84 y; B. lactis; 5.0 × 1010 Increase in CD4+; CD25+ and NK cells. Increase in the in vitro phagocytose and
Zealand 30 (12/18) tumoricidal activity of natural killer cells
Guillemard RC, DB, Fermented dairy 12 wk; 72–80 y; L. paracasei (L. casei) + S. thermophilus Decreased duration of upper respiratory tract infection. No differences in the
et al. [100] P; France drink/placebo drink 537 (198/339) + L. bulgaricus; 1.0 × 109 severity of symptoms
Harbige et al. SA; UK Probiotic drink 8 wk; 18–49 y; L. casei Shirota; 6.5 × 109 Significant increase in T-cell activation markers and NK cell markers. Significant
[51] 14 (6/8) reduction in inflammatory makers IL-12 and IL-4 and pro-inflammatory cytokines
Jespersen RC, DB, Probiotic drink/ 6 wk; 18–60 y; L. paracasei (L. casei); 1.0 × 109 No effect of probiotics on immune response to flu vaccine. No effect on severity
et al. [47] P; placebo drink 1104 (453/ 651) or incidence of flu symptoms. A shorter duration of symptoms
Denmark
Kekkonen RC, DB, Probiotic drink/ 12 wk; 22–69 y; L. rhamnosus GG; 4.0 × 1010 No significant effect on incidence of respiratory infection or GI symptoms, but
et al. [50] P; Finland placebo 141 (125/16) shortened the duration of symptoms in healthy marathon runners
Klein et al. P, RC, Probiotic yoghurt/ 5 wk; 25 ± 3 y; L. acidophilus + B. lactis; 9.4 × 108 Significant increase in the phagocytic activity of monocytes and granulocytes, but
[69] CO; placebo 26 (13/13) no change in the level of inflammatory markers
Germany
Makino et al. P, R; Probiotic yoghurt/ 8–12 wk; 59–84 L. bulgaricus + S. thermophiles; Significant reduction in the risk of catching cold, and increase in NK cell activity
[45] Japan placebo y; 92 2.0–8.8 × 108
Naruszewic RC, DB, Probiotic drink/ 6 wk; 35–45 y; L. plantarum; 2.0 × 1010 Significant reduction in markers of oxidative stress (F2-isoprostanes) and pro-
et al. [55] P; Sweden placebo 36 (18/18) inflammatory marker IL-6 in heavy smokers
Nyangale RC, DB, Probiotic capsule/ 28 dy; 65–80 y; B. coagulans; 1.0 × 109 Significant increase in anti-inflammatory cytokine IL-10. No effect on NK or
et al. [56] P; UK placebo 36 (17/25) TNF-α
Parra et al. RC, DB, Probiotic yoghurt/ 8 wk; 51–58 y; L. casei; 108–1010 Increase in NK cell activity and oxidative burst capacity of monocytes. No change
[54] P; Spain placebo 23 in other immune factors
Van RC, DB, Probiotic drink/ 176 dy; 55–101 L. casei Shirota; 1.3 × 1010 No significant effect on the incidence or symptoms of flu
Puyenbroeck P; placebo drink y; 737 (184/553)
et al. [48] Belgium
West et al. RC, DB, Probiotic sachet/ 150 dy; 18–60 B. animalis subsp. lactis; 2.0 × 109or L. Significant reduction in the risk of respiratory illness
[49] P; placebo y; 465 (241/ acidophilus and B. animalis lactis; 5.0 ×
Australia 224) 109
CO cross-over, DB double blind, P parallel, RC randomized controlled trial, SA single arm
Table 3 Characteristics of included studies for the effect of probiotics on lipid profile and cardiovascular disease risk
Study [ref.] Design; Intervention/control Duration; age; Probiotic; dose (per day), CFU Outcome effect; reported side effects
location participants (m/f)

Agerbaek et al. RC, DB, P; Probiotic drink/ 6 wk; 44 y; 58 E. faecium + S. thermophilus Significant reduction in TC and LDL-C
[65] Denmark placebo (28/0)
Bjerg et al. [68] RC, DB, P; Probiotic capsule/ 4 wk; 20–54 y; L. casei; 1.0 × 1010 Significant reduction in TG
Denmark placebo 64 (32/32)
Cox et al. [62] RC, DB, P; Probiotic sachet/ 150 dy; 18–60 y; B. animalis subsp. lactis; 2.0 × 109or L. acidophilus and B. No significant change. Significant reduction in
Australia placebo 465 (241/ 224) animalis lactis; 5.0 × 109 insulin after double-strain supplementation
de Roos et al. RC, DB, P; Probiotic yoghurt/ 6 wk; 39.9 ± 8.7 L. acidophilus; 4.8 × 109 – 2.7 × 1010 No significant changes in lipid profile and BMI
[18] Netherlands control yoghurt y; 78 (22/56)
Greany et al. RC, SB, P; Probiotic capsule/ 8 wk; 18–36 y; L. acidophilus and B. longum; 1.0 × 109 No significant change
[63] USA placebo 55 (22/33)
Higashikawa, RC, DB, P; Probiotic yogurt/ 6 wk; 37.3 ± L. plantarum SN35N; 2 × 1010 No significant change
et al. [61] Japan placebo yoghurt 12.2 y; 24 (6/18)
Higashikawa RC, DB, P; Probiotic yogurt/ 6 wk; 35.1 ± L. plantarum SN13T; 2 × 1010 Significant reduction in TC and LDL
et al. [61] Japan placebo yoghurt 11.6 y; 22 (7/15)
Hulston et al. RC, P; Probiotic drink/ 4 wk; 24 ± 2 y; 8 L.s casei Shirota (CFU not reported) Significant reduction in TG, no significant changes in
[70] England placebo, +over (7/1) BMI, FBG, or insulin level
eating
Irwin et al. [5] DB, R, P; Probiotic/placebo 8 wk; 27.9 ± 6.5 L. acidophilus, B. lactic; 2.5 × 1010 No significant change. Significant increase in BMI
Australia capsule y; 10 (5/5) and FBG
Klein et al. [69] P, RC, CO; Probiotic yoghurt/ 5 wk; 25 ± 3 y; L.acidophilus + B. lactis; 9.4 × 108 Significant reduction in TG
Germany placebo 26 (13/13)
Naruszewicz RC, DB, P; Probiotic drink/ 6 wk; 35–45 y; L. plantarum; 2.0 × 1010 No significant change in lipid profile, BMI, FBG, or
et al. [55] Sweden placebo 36 (18/18) insulin level
Osterberg et al. RC, DB, P; Probiotic capsule/ 4 wk; 22.4 ± 1.4 B. longum + B. infantis + B. breve + L. acidophilus + L. Lower increase in BMI after high-fat diet, no
[71] USA placebo + high-fat y; 9 (9/0) paracasei + L. bulgaricus + L. plantarum + S. thermophilus; differences in FBG
diet 9.0 × 1011
Rajkumar et al. RC, SB, P; Probiotic capsule/ 6 wk; 40–60 y; B. longum + B. infantis + B. breve + L. Acidophilus + L. Significant reduction in TC and TG, increase in
[67] India placebo 15 paracasei + L. bulgaricus + L. plantarum + S. thermophilus HDL-C, and reduction in FBG and insulin sensitivity
Rizkalla et al. RC, CO; Yoghurt with live 15 dy; 20–60 y; L. bulgaricus + S. thermophilus; ≥1.0 × 107 No significant changes in lipid profile, FBG, or
[64] France culture/heated 12 (12/0) insulin levels
yoghurt
Sadrzadeh- RC, DB, P; Probiotic yoghurt/ 6 wk; 19–49 y; B. lactis + L. acidophilus; 3.9 × 107 Significant reduction in TC and increase in HDL-C,
Yeganeh et al. Iran control 90 (0/90) no significant change in BMI
[66]
CO cross-over, DB double blind, FBG fasting blood glucose, HDL-C high-density lipoprotein cholesterol, P parallel, RC randomized controlled trial, TC total cholesterol, TG triglyceride
S. Khalesi et al.
associated with common cold are commonly observed in the blood lipid profile of healthy adults cannot be reliably
healthy adults when a probiotic intervention is determined from this work.
administered. A summary of results from the present review of litera-
In contrast, the effect of probiotic supplementation on ture for the effect of probiotic consumption on blood lipid
immune responses against influenza infection in healthy profile of healthy adults is presented in Table 3. Of the
adults is less consistent [43, 47, 48]. In vitro exposure of 14 studies (15 trials, 1 study with 2 separate arms [61]), 7
T cells collected from 10 individuals (supplied with pro- reported no significant changes in the concentration of
biotics for 30 days) to the influenza A virus showed a various blood lipid profile markers following probiotic
significant increase in TNF-α [43]. This suggests enhance- consumption [18, 55, 61–64]. Three studies reported a
ment of T-cell responses to a respiratory tract infection. significant reduction in TC [61, 65–67]. Reductions in TG
These findings are supported in a larger study (n = 465 [67–70], LDL-C [61, 65], and an increase in HDL-C [66,
participants supplemented with probiotics for 150 days), 67] were also reported. Furthermore, in 1 study, 6 weeks of
which indicated a significantly reduced risk of respiratory probiotics treatment in healthy adults who were heavy
illness [49]. However, these findings are in contrast with the smokers [55] demonstrated improvements in markers of
results of several other studies indicating that probiotic oxidative stress (F2-isoprostanes) and the pro-inflammatory
supplementation had no influence on the incidence [47, 48, marker IL-6, supporting the cardio-protective effect of
50] or severity [47, 48] of the flu. probiotics. Despite this, to date only a small number of
The effect of probiotics on immune function of healthy individual studies have demonstrated benefits of probiotics
adults are summarized in Table 2. Ten studies reported and the collective evidence is not inclusive for the beneficial
improvement in the immune function by activating T lym- effect of probiotics consumption on blood lipid profile of
phocytes, including cytotoxic plus and T helper cells (CD8 healthy adults.
+ and CD4+) after probiotic consumption [46, 51, 52], Changes in BMI were reported in six studies (Table 3).
increase natural killer (NK) cell activity [45, 51, 53, 54], Of these, four reported no significant changes [18, 55, 66,
reduce the pro-inflammatory cytokines interleukin (IL)-12, 70] and one reported a significant increase in BMI after
IL-6, and IL-4 [51, 53, 55], and increase anti-inflammatory probiotic supplementation [5]. One of the studies assessed
cytokines IL-10 [53, 56]. However, there is no consistent the BMI increase after 4 weeks of high-fat diet and reported
and clear relationship between the effects observed and the a lower increase in BMI in the probiotic group compared to
dose, duration, and type of probiotic strains administered. placebo [71]. Due to a low number of studies included and
Overall, it appears that probiotic supplementation in healthy inconsistent results, a conclusion cannot be reached for the
adults can improve immune function and the immune effect of probiotics on BMI of healthy adults. Seven studies
response to common cold infections. However, the immune also reported changes in fasting blood glucose (FBG) and
response to influenza infection and the effective duration, insulin levels. Of these, four reported no significant changes
dose, and type of probiotics supplementation require further in FBG or insulin levels [55, 64, 70, 71], two reported a
investigation. reduction in FBG and insulin level [62, 67], and one
reported an increase in FBG after probiotic supplementation
Lipid profile and CVD risk in healthy adults [5]. Similar to BMI, the evidence is
inconclusive for the beneficial effect of probiotics on FBG
Elevated low-density lipoprotein cholesterol (LDL-C) and and insulin level in healthy adults.
triglycerides (TG), low levels of high-density lipoprotein Although underlying mechanisms of the effect of pro-
cholesterol (HDL-C), increase in BMI, blood glucose, and biotics on lipid profile are not completely understood, the
pro-inflammatory markers are major risk factors of CVD cholesterol binding and assimilation ability of probiotics
[57]. The potential of probiotics to support a reduction in and their ability to deconjugate bile salt (to reduce its
inflammation markers in healthy adults has been dis- solubility and absorbability) are proposed as the potential
cussed in the previous section. The effect of probiotic mechanisms of action [59]. Bacteria in the gut also have the
consumption on changes to blood lipid profile has been ability to produce short-chain fatty acids (SCFAs; such as
investigated in several systematic reviews and meta- acetate, butyrate, and propionate) through fermentation of
analyses [9, 58–60]. Collectively, findings from these dietary fibers [72]. SCFAs are shown to lower hepatic
reviews and meta-analyses suggest an improvement in cholesterol synthesis and regulate cholesterol metabolism
blood lipid profile, especially in total cholesterol (TC) and [73]. Both lactobacilli and bifidobacteria are able to produce
LDL-C levels. However, these studies included both SCFAs. Recently proposed next generation of probiotics
healthy and unhealthy adults (including conditions such such as Akkermansia muciniphila and Faecalibacterium
as hypercholesterolemia, CVD, diabetes, and obesity). prausnitzii have also shown to have a high SCFA-
Thus, conclusions regarding the influence of probiotics on producing ability from dietary fibers [74, 75].
 S. Khalesi et al.

GI discomfort

Significant improvement in the number of weekly bowel movement and

Significant improvement in the number of weekly bowel movement and

2 wk; 28.7 ± 10.6 y; 68 B. animalis ssp. lactis Bf-6; No effect on the colonic transit time, bowel movement, or frequency of
Although constipation is often considered as a symptom of
a health condition, irregularities in bowel movement, eva-
cuation disorder, abdominal discomfort, and bloating may

Significant reduction in the incident of hard or lumpy stool

occur in response to aging and changes in dietary, lifestyle,
and psychological factors in otherwise healthy individuals
Significant improvement in the defection frequency [76, 77]. These changes also influence the bacterial flora of

Significant improvement in the defection frequency

the intestine. A diet high in fat, for example, is known to
cause dysbiosis in gut microbiota [78]. Aging has also been
associated with a decrease in the number and diversity of
bifidobacteria [79]. Benefits of probiotic supplementation in
Outcome effect; reported side effects

the treatment and management of many types of diarrhea

reduction in abdominal irritation

reduction in abdominal irritation

and constipation have been reported in unhealthy popula-

tions [7, 8]. Table 4 summarizes the evidence of the effect
of probiotics consumption on GI health of healthy adults.
Of the four studies included (six trials, two studies had two
arms [61, 76]), an improvement in the bowel movement,
defection frequency, and stool consistency was reported in
constipation

five studies [61, 76, 77]. One study did not observe
improvements in the colonic transit time or bowel move-
ment [80]. However, this study had the shortest duration of
supplementation among the identified trials. Overall, it
L. casei Shirota; 6.5 × 109
Probiotic; dose (per day),

6 wk; 35.1 ± 11.6 y; 22 L. plantarum SN35N; 2 ×

6 wk; 35.1 ± 11.6 y; 22 L. plantarum SN13T; 2 ×

L. plantarum + B. breve;

B. animalis subspecies

appears that probiotic supplementation may be effective at

improving stool consistency, bowel movement, and redu-
Table 4 Characteristics of included studies for the effect of probiotics on gastrointestinal discomfort

cing irritation caused by abdominal bloating. The relevant

lactis; 5 × 109

mechanisms of probiotics in this action remain unclear.

However, fermentation of non-digestible carbohydrates and
2 × 1010

CO cross-over, DB double blind, P parallel, RC randomized controlled trial, TB triple blind

5 × 109
CFU

production of SCFA and carbon dioxide, removal of other

1010

1010

intestinal gases [76], and the anti-inflammatory effect of

Fermented milk/placebo 3 w; 35.4 ± 14.2 y; 19

probiotics have been suggested [8] as potential mechanisms.

Probiotic blend/placebo 30 dy; 24–71 y; 110

Probiotic blend/placebo 30 dy; 24–71 y; 110

participants (m/f)

Female reproductive system health

Duration; age;

From birth until after puberty, lactobacilli are the pre-

(50/60)

(50/60)

(7/15)

(7/15)

(0/68)

(11/8)

dominant microorganisms populating the vaginal microbial

environment [81]. However, after puberty the microbial
environment changes due to menstruation, hormonal chan-
Intervention/control

ges, intercourse, infections, and hygiene [82]. This often

Merenstein et al. RC, TB, CO; Probiotic yoghurt/
Probiotic yogurt/

Probiotic yogurt/
placebo yoghurt

placebo yoghurt

results in a vaginal environment that is not predominant in

lactobacilli bacteria for the majority of women [81],
increasing susceptibility to urogenital infections such as
placebo

urinary tract infection and bacterial vaginosis [83]. The

effect of probiotic supplementation on maintaining female
reproductive health is summarized in Table 5. Four studies
RC, DB, P;

RC, DB, P;

RC, DB, P;

RC, DB, P;

(five trials, one study had two arms [84]) have examined the
Belgium
location
Design;

RC, P;
Japan

Japan

effects of oral supplementation or vaginal suppositories

USA
Italy

Italy

with lactobacilli as a means of improving the vaginal

environment. Among these, four trials have suggested there
Sakai et al. [77]
Del Piano et al.

Del Piano et al.

was a significant increase in the level of vaginal lactobacilli

Higashikawa

Higashikawa
Study [ref.]

et al. [61]

et al. [61]

[81, 84–86]. Supplementation with L. acidophilus, L.

rhamnosus, or L. fermentum increased vaginal lactobacilli
[76]

[76]

[80]

levels in healthy women [81, 84–86]. The increase in

 L. acidophilus + L. rhamnosus; Significant increase in vaginal concentration of specific bacteria

Significant increase in vaginal lactobacilli and reduce in yeast

vaginal lactobacilli population seems to prevent and reduce
the incidence of vaginal infections in otherwise healthy

Significant improvement in the vaginal flora and health

adult women [82].

Effect of probiotics on psychological health

Significant increase in vaginal lactobacilli

after intervention and a week follow-up

Although the focus of this review thus far has been on

No significant change in vaginal flora

Probiotic; dose (per day), CFU Outcome effect; reported side effects

physiological health outcomes, it is important to acknowl-

edge that probiotics consumption may also influence psy-
chological health—an essential domain of overall well-
being. Conceptualization of the brain-gut axis has intro-
duced a link between psychological health and gut micro-
flora [87, 88]. Psychological distress can reduce the number
and diversity of intestinal microorganisms by changing
intestinal transit time, acidity, mucus secretion, stress hor-
mones, and immune response [87]. Conversely, the gut
microbiota can influence a hosts’ nervous system (gut-brain
axis) by producing signaling molecules (e.g., polypeptides)
L. rhamnosus + L. fermentum;

L. rhamnosus + L. fermentum;

L. rhamnosus + L. paracasei;

and modulating neuronal signaling mechanisms [87]. A

recent meta-analysis of five randomized controlled trials
examining the effect of probiotics supplementation on
L. rhamnosus GG

depression score suggests that probiotics supplementation

can induce a significant reduction in depression scale score
CO cross-over, DB double blind, P parallel, RC randomized controlled trial, SA Single arm, TB triple blind

[89]. Although the reduction observed in the subgroup of

108–109
1 × 1010

individuals with major depressive symptoms (−0.73, 95%

Table 5 Characteristics of included studies for the effect of probiotics on female reproductive health

confidence interval (CI): −1.37 to −0.09, ρ = 0.03) was

109

109

greater than their healthy counterparts (−0.25, 95% CI:

Duration; age; participants

−0.47 to −0.03, ρ = 0.03), the meta-analysis suggests

De Alberti et al. [85] RC, DB, P; Italy Probiotic capsule/placebo 14 dy; 33.2 ± 9.7 y; 20

7 dy; 29.8 ± 7.1 y; 35

probiotic consumption can reduce depression symptoms in

Probiotic capsule/placebo 60 dy; 19–46 y; 64

28 dy; 31 ± 8 y; 33

28 dy; 31 ± 8 y; 33

healthy adults [89]. Similarly, a recent systematic review

and meta-analysis of seven randomized controlled trials
indicate a significant improvement in subclinical symptoms
(including reduced stress, depression, and anxiety; 0.34;
(m/f)

95% CI: 0.07 to 0.61, ρ = 0.01) can be achieved in healthy

adults following probiotic supplementation [90]. Both stu-
dies reported including trials with good methodology
Probiotic suppositories
Design; location Intervention/control

quality and low risk of bias. Collectively, evidence from

RC, DB, Canada Probiotic capsule

RC, DB, Canada Probiotic capsule

these studies suggests that probiotic supplementation may

improve psychological symptoms in healthy adults.

Discussion
RC, P; London

Demand for probiotic food and supplements has increased

Verdenelli et al. [81] SA, Italy

over the past few decades. Globally, the probiotic market is

expected to have up to an 8% compound annual growth rate
increase from 2014 to 2020 [91]. This prompts continued
interest in research regarding the health benefits of probio-
tics. Although consumption of probiotics has beneficial
Reid et al. [86]

Reid et al. [84]

Reid et al. [84]

effects on several health outcomes, the majority of findings

Study [ref.]

are related to populations with specific health conditions or

disease. This raises an important question as to whether the
health benefits provided by probiotics are limited to
 S. Khalesi et al.

individuals with underlying pathologies. Thus, in the cur- pathogenic microorganisms in the intestine, maintaining
rent review, we explored the effects of probiotics con- symbiosis through regular consumption of probiotics foods
sumption in otherwise healthy adults. Overall, results from and/or supplements is essential. This is particularly impor-
this review suggest that probiotics supplementation in tant in older adults, where age-related decreases in immune
healthy adults generate an improvement in gut microbiota. function [97] may increase vulnerability to a variety of
However, despite gut microbiota changes occurring with infections.
probiotics, these changes appear to be limited to a transient The present review did not find sufficient evidence to
increase in the bacterial count of the specific strain admi- support a blood lipid profile lowering effect of probiotics in
nistered. This implies that supplementation with probiotics healthy adults. These findings are in contrast with several
may need to be an ongoing process in order to maintain gut systematic reviews and meta-analyses suggesting probiotic
microbiota changes in healthy adults. Gut microbiota is consumption facilitates improvements in blood lipids [9,
sensitive to multiple factors, such as lifestyle, aging, and 58–60]. This disagreement is likely due to the inclusion of
disease. Even in apparently healthy individuals, changes in both healthy and unhealthy (participants with a high base-
diet quality and alcohol intake can significantly affect gut line level of blood lipids) populations, hence a greater
symbiosis. A diet poor in fruit and vegetable intake (as a opportunity for improvements in lipid profiles was afforded
good source of prebiotics) may not provide the food in these previous reviews. Similarly, BMI, FBG, and insulin
required for probiotic survival and maintenance. This may level of healthy adults were not significantly affected by
explain the constant need for probiotic food and supple- probiotic consumption in the present review. These find-
ments to maintain gut symbiosis and health. Furthermore, in ings, however, are in contrast to previous systematic review
older adults with age-related dysbiosis, probiotic supple- and meta-analysis of the effect of probiotics on BMI [98]
mentation appears to improve and reduce dysbiosis. and FBG [13]. This can be explained by the inclusion of
The transient effect of probiotics on gut microbiota may participants with underlying pathologies (obese or diabetic).
also be explained by the viability of probiotic microorgan- For example, Nikbakht et al. [13] included trials with high
isms. Evidence suggests that viability of probiotics could and normal FBG participants with an overall significant
differ from the number of viable cells declared on the effect of probiotics consumption on FBG reduction. How-
product label [92]. Although drying processes during pro- ever, their subgroup analysis results showed no significant
biotic production may have a negative impact on viability, changes in participants with normal FBG level. This can
different drying methods (air-drying, freeze-drying, and explain the findings of the current review reporting no
spray-drying) have diverse effects on probiotic strains in significant effect of probiotics on FBG of healthy adults.
terms of both viability and functionality [93]. Although The current review also found some evidence for the
viability is acknowledged as a prerequisite for the health effect of probiotics as a means of relieving abdominal dis-
benefits of probiotics, few interventions have reported the comfort and improving bowel movement irregularities in
viability of probiotics during the period of supplementation. healthy adults. Although probiotics have been reported as
Evidence suggests that non-viable probiotic strains may also beneficial for these conditions [77], definitive conclusions
confer some positive health outcomes [92] however, this cannot be made and further research is required to clarify
requires further investigation. these findings in healthy adult populations. Probiotic con-
The current review also suggests that probiotic con- sumption also appears to offer some benefits in maintaining
sumption in healthy adults may improve immune function, female reproductive health by improving the lactobacilli
particularly in response to common upper respiratory count of the vaginal environment to prevent urogenital
infections; reducing their incidence and/or symptom infections. Again however, the low number of eligible
severity. This is particularly important since improved studies included in this review suggest that further investi-
immune function via probiotics may reduce the antibiotic gation is required to support any dietary guidance provided
needs in infections, thus reduce the risk of antibiotic resis- for these conditions.
tance [94]—one of the greatest global threat of present Although the effect of probiotics supplementation on
decade [95]. Probiotics may enhance the immune response psychological symptoms of healthy adults was not reviewed
by activating T lymphocyte cells, increasing NK cell in-depth in this paper—as this has already been done else-
activity and anti-inflammatory cytokines (e.g., IL-10), and where—results of recent meta-analyses suggest improve-
reducing pro-inflammatory cytokines (e.g., IL-12 and IL14). ments in depression, stress, and anxiety following probiotic
These findings are in agreement with a recent meta-analysis supplementation [89, 90]. However, in most studies inclu-
(including both healthy and unhealthy populations) indi- ded in these meta-analyses, changes in gut flora were not
cating that probiotic consumption may have a protective reported. Furthermore, psychological symptoms are typi-
effect against the common cold [96]. As gut microbiota is cally measured using subjective self-reported scales and
typically considered the first line of defense against questionnaires, with different scales often administered
across studies. Thus, it is important to consider these lim- 2. Fuller R. Probiotics: an overview. Human health: Springer Series
itations when translating the findings. Nevertheless, pro- in Applied Biology, Springer, London; 1994. p. 63–73.
3. Metchnikoff II. The prolongation of life: optimistic studies:
biotic supplementation may confer psychological benefits in
London: Butterworth-Heinemann; 1907.
healthy individuals and further exploration of these effects 4. FAO/WHO. Guidelines for the evaluation of probiotics in food.
is warranted. Joint FAO/WHO Working Group Report on Drafting Guidelines
To our knowledge, the present review is first to assess the for the Evaluation of Probiotics in Food London, Ontario,
Canada, 30 April 30 and 1 May 2002.
evidence for a range of health-related outcomes of probiotic
5. Irwin C, Khalesi S, Cox AJ, Grant G, Davey AK, Bulmer AC,
consumption in healthy adults. However, the present study et al. Effect of 8-weeks prebiotics/probiotics supplementation on
does have some limitations. First, it was not possible to alcohol metabolism and blood biomarkers of healthy adults: a
employ a complete systematic review approach due to the pilot study. Eur J Nutr. 2017. https://doi.org/10.1007/s00394-
017-1437-8.
differences in study design, participant characteristics, and
6. Ferrario C, Taverniti V, Milani C, Fiore W, Laureati M, De Noni
dependent measures included in this review. Therefore, it I, et al. Modulation of fecal Clostridiales bacteria and butyrate by
limited the potential of the review to assess the methodo- probiotic intervention with Lactobacillus paracasei DG varies
logical quality and bias risk of included studies. However, among healthy adults. J Nutr. 2014;144:1787–96.
7. Guarino A, Guandalini S, Lo Vecchio A. Probiotics for pre-
of the 45 studies included in this review, the majority were
vention and treatment of diarrhea. J Clin Gastroenterol. 2015;49:
randomized (n = 38), included blinding (n = 32) and had S37–45 Suppl 1.
similar control or placebo groups (n = 38). Second, the low 8. Ford AC, Quigley EM, Lacy BE, Lembo AJ, Saito YA, Schiller
number of studies included in the review of GI health and LR, et al. Efficacy of prebiotics, probiotics, and synbiotics in
irritable bowel syndrome and chronic idiopathic constipation:
female reproductive health outcomes limits the conclusions
systematic review and meta-analysis. Am J Gastroenterol.
that can be drawn from these research areas. Also, probiotic 2014;109:1547–61. quiz 6, 62.
characteristics are strain-specific and due to variations in the 9. Guo Z, Liu XM, Zhang QX, Shen Z, Tian FW, Zhang H, et al.
probiotic strains used in the included studies, a conclusion Influence of consumption of probiotics on the plasma lipid
profile: a meta-analysis of randomised controlled trials. Nutr
cannot be made on the effective strains.
Metab Cardiovasc Dis. 2011;21:844–50.
With ongoing increases in the manufacturing and mar- 10. Sun J, Buys N. Effects of probiotics consumption on lowering
keting of probiotics to the general public there is a need for lipids and CVD risk factors: a systematic review and meta-
the benefits of probiotics to be better understood. Although analysis of randomized controlled trials. Ann Med.
2015;47:430–40.
this review suggests that healthy adults (and in particular,
11. Nikbakht Nasrabadi E, Jamaluddin R, Mutalib A, Khaza’ai H,
older adults) may achieve some health benefits from the Khalesi S, Mohd Redzwan S. Reduction of aflatoxin level in
consistent use of probiotics, probiotic supplementation may aflatoxin‐induced rats by the activity of probiotic Lactobacillus
have a similar fate to multivitamins. That is, they may be casei strain Shirota. J Appl Microbiol. 2013;114:1507–15.
12. Khalesi S, Sun J, Buys N, Jayasinghe R. Effect of probiotics on
effective in specific cases or conditions. More research on
blood pressure: a systematic review and meta-analysis of ran-
the probiotic use is necessary to develop a stronger body of domized, controlled trials. Hypertension. 2014;64:897–903.
evidence for their efficacy across both healthy and unheal- 13. Nikbakht E, Khalesi S, Singh I, Williams LT, West NP, Colson
thy population groups. Additionally, interventions with N. Effect of probiotics and synbiotics on blood glucose: a sys-
tematic review and meta-analysis of controlled trials. Eur J Nutr.
follow-up periods are required to assess the sustainability of
2016;57:95–106.
probiotic use and their effect in healthy adults. Until further 14. Sun J, Buys NJ. Glucose- and glycaemic factor-lowering effects
research is conducted, the benefits and feasibility of pro- of probiotics on diabetes: a meta-analysis of randomised
biotic consumption in healthy adults remain uncertain and it placebo-controlled trials. Br J Nutr. 2016;115:1167–77.
15. Foster JA, Lyte M, Meyer E, Cryan JF. Gut microbiota and brain
would be prudent to advise consumers that supplementation
function: an evolving field in neuroscience. Int J Neuropsycho-
with probiotics may be more effective in specific population pharmacol. 2016;19:1–7.
groups and those with underlying pathologies. 16. Kumar H, Salminen S, Verhagen H, Rowland I, Heimbach J,
Bañares S, et al. Novel probiotics and prebiotics: road to the
market. Curr Opin Biotechnol. 2015;32:99–103.
Compliance with ethical standards 17. Kristensen NB, Bryrup T, Allin KH, Nielsen T, Hansen TH,
Pedersen O. Alterations in fecal microbiota composition by
Conflict of interest The authors declare that they have no conflict of
probiotic supplementation in healthy adults: a systematic review
interest.
of randomized controlled trials. Genome Med. 2016;8:52.
18. de Roos NM, Schouten G, Katan MB. Yoghurt enriched with
Lactobacillus acidophilus does not lower blood lipids in healthy
References men and women with normal to borderline high serum choles-
terol levels. Eur J Clin Nutr. 1999;53:277–80.
19. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting
1. McFarland LV. From yaks to yogurt: the history, development,
items for systematic reviews and meta-analyses: the PRISMA
and current use of probiotics. Clin Infect Dis. 2015;60:S85–90.
statement. Ann Intern Med. 2009;151:264–9.
Suppl 2.
 S. Khalesi et al.

20. Higgins JP, Green S. Cochrane handbook for systematic reviews and modulates the fecal microbiota and immune function of
of interventions: Cochrane Book Series, John Wiley & Sons, overweight adults. J Nutr. 2013;143:324–31.
Ltd, Chichester, UK; 2008. 39. Johnston BC, Ma SS, Goldenberg JZ, Thorlund K, Vandvik PO,
21. Plaza-Diaz J, Fernandez-Caballero JA, Chueca N, Garcia F, Loeb M, et al. Probiotics for the prevention of Clostridium
Gomez-Llorente C, Saez-Lara MJ, et al. Pyrosequencing analysis difficile-associated diarrhea: a systematic review and meta-
reveals changes in intestinal microbiota of healthy adults who analysis. Ann Intern Med. 2012;157:878–88.
received a daily dose of immunomodulatory probiotic strains. 40. Woodmansey EJ, McMurdo MET, Macfarlane GT, Macfarlane
Nutrients. 2015;7:3999–4015. S. Comparison of compositions and metabolic activities of fecal
22. Rampelli S, Candela M, Severgnini M, Biagi E, Turroni S, microbiotas in young adults and in antibiotic-treated and non-
Roselli M, et al. A probiotics-containing biscuit modulates the antibiotic-treated elderly subjects. Appl Environ Microbiol.
intestinal microbiota in the elderly. J Nutr Health Aging. 2004;70:6113–22.
2013;17:166–72. 41. Mariat D, Firmesse O, Levenez F, Guimaraes V, Sokol H, Dore
23. Lahti L, Salonen A, Kekkonen RA, Salojärvi J, Jalanka- J, et al. The Firmicutes/Bacteroidetes ratio of the human
Tuovinen J, Palva A, et al. Associations between the human microbiota changes with age. BMC Microbiol. 2009;9:123.
intestinal microbiota, Lactobacillus rhamnosus GG and serum 42. Rooks MG, Garrett WS. Gut microbiota, metabolites and host
lipids indicated by integrated analysis of high-throughput pro- immunity. Nat Rev Immunol. 2016;16:341–52.
filing data. PeerJ. 2013;1:e32. 43. Baron M. A patented strain of Bacillus coagulans increased
24. Wind RD, Tolboom H, Klare I, Huys G, Knol J. Tolerance and immune response to viral challenge. Postgrad Med.
safety of the potentially probiotic strain Lactobacillus rhamnosus 2009;121:114–8.
PRSF-L477: a randomised, double-blind placebo-controlled trial 44. Berggren A, Lazou Ahrén I, Larsson N, Önning G. Randomised,
in healthy volunteers. Br J Nutr. 2010;104:1806–16. double-blind and placebo-controlled study using new probiotic
25. Mai V, Waugh S, Byrd D, Simpson D, Ukhanova M. Novel lactobacilli for strengthening the body immune defence against
encapsulation improves recovery of probiotic strains in fecal viral infections. Eur J Nutr. 2011;50:203–10.
samples of human volunteers. Appl Microbiol Biotechnol. 45. Makino S, Ikegami S, Kume A, Horiuchi H, Sasaki H, Orii N.
2017;101:1419–25. Reducing the risk of infection in the elderly by dietary intake of
26. Fontana L, Bermudez-Brito M, Plaza-Diaz J, Munoz-Quezada S, yoghurt fermented with Lactobacillus delbrueckii ssp. bulgaricus
Gil A. Sources, isolation, characterisation and evaluation of OLL1073R-1. Br J Nutr. 2010;104:998–1006.
probiotics. Br J Nutr. 2013;109:S35–50.Suppl 2. 46. de Vrese M, Winkler P, Rautenberg P, Harder T, Noah C, Laue
27. Mainville I, Arcand Y, Farnworth ER. A dynamic model that C, et al. Effect of Lactobacillus gasseri PA 16/8, Bifidobacterium
simulates the human upper gastrointestinal tract for the study of longum SP 07/3, B. bifidum MF 20/5 on common cold episodes:
probiotics. Int J Food Microbiol. 2005;99:287–96. a double blind, randomized, controlled trial. Clin Nutr.
28. Lo Curto A, Pitino I, Mandalari G, Dainty JR, Faulks RM, John 2005;24:481–91.
Wickham MS. Survival of probiotic lactobacilli in the upper 47. Jespersen L, Tarnow I, Eskesen D, Morberg CM, Michelsen B,
gastrointestinal tract using an in vitro gastric model of digestion. Bügel S, et al. Effect of Lactobacillus paracasei subsp. paracasei,
Food Microbiol. 2011;28:1359–66. L. casei 431 on immune response to influenza vaccination and
29. Wang R, Chen S, Jin J, Ren F, Li Y, Qiao Z, et al. Survival of upper respiratory tract infections in healthy adult volunteers: a
Lactobacillus casei strain Shirota in the intestines of healthy randomized, double-blind, placebo-controlled, parallel-group
Chinese adults. Microbiol Immunol. 2015;59:268–76. study. Am J Clin Nutr. 2015;101:1188–96.
30. Kailasapathy K, Chin J. Survival and therapeutic potential of 48. Van Puyenbroeck K, Hens N, Coenen S, Michiels B, Beunckens
probiotic organisms with reference to Lactobacillus acid- C, Molenberghs G, et al. Efficacy of daily intake of Lactobacillus
ophilus and Bifidobacterium spp. Immunol Cell Biol. casei Shirota on respiratory symptoms and influenza vaccination
2000;78:80–8. immune response: a randomized, double-blind, placebo-
31. Bezkorovainy A. Probiotics: determinants of survival and growth controlled trial in healthy elderly nursing home residents. Am J
in the gut. Am J Clin Nutr. 2001;73:399s–405s. Clin Nutr. 2012;95:1165–71.
32. Riaz QU, Masud T. Recent trends and applications of encapsu- 49. West NP, Horn PL, Pyne DB, Gebski VJ, Lahtinen SJ, Fricker
lating materials for probiotic stability. Crit Rev Food Sci Nutr. PA, et al. Probiotic supplementation for respiratory and gastro-
2013;53:231–44. intestinal illness symptoms in healthy physically active indivi-
33. Mortazavian AM, Mohammadi R, Sohrabvandi S. Delivery of duals. Clin Nutr. 2014;33:581–7.
probiotic microorganisms into gastrointestinal tract by food 50. Kekkonen RA, Vasankari TJ, Vuorimaa T, Haahtela T, Julkunen
products. In: Brzozowski T, editor. New advances in the basic I, Korpela R. The effect of probiotics on respiratory infections
and clinical gastroenterology. Croatia: InTech. p 121–146. and gastrointestinal symptoms during training in marathon run-
34. Kamada N, Chen GY, Inohara N, Núñez G. Control of pathogens ners. Int J Sport Nutr Exerc Metab. 2007;17:352–63.
and pathobionts by the gut microbiota. Nat Immunol. 51. Harbige LS, Pinto E, Allgrove J, Thomas LV. Immune response
2013;14:685–90. of healthy adults to the ingested probiotic Lactobacillus casei
35. Gibson GR, Roberfroid MB. Dietary modulation of the human Shirota. Scand J Immunol. 2016;84:353–64.
colonic microbiota: introducing the concept of prebiotics. J Nutr. 52. Gill HS, Rutherfurd KJ, Cross ML, Gopal PK. Enhancement of
1995;125:1401. immunity in the elderly by dietary supplementation with the
36. Slavin J. Fiber and prebiotics: mechanisms and health benefits. probiotic Bifidobacterium lactis HN019. Am J Clin Nutr.
Nutrients. 2013;5:1417–35. 2001;74:833–9.
37. Walton GE, van den Heuvel EG, Kosters MH, Rastall RA, 53. Dong H, Rowland I, Thomas LV, Yaqoob P. Immunomodula-
Tuohy KM, Gibson GR. A randomised crossover study inves- tory effects of a probiotic drink containing Lactobacillus casei
tigating the effects of galacto-oligosaccharides on the faecal Shirota in healthy older volunteers. Eur J Nutr.
microbiota in men and women over 50 years of age. Br J Nutr. 2013;52:1853–63.
2012;107:1466–75. 54. Parra MD, Martinez de Morentin BE, Cobo JM, Mateos A,
38. Vulevic J, Juric A, Tzortzis G, Gibson GR. A mixture of trans- Martinez JA. Daily ingestion of fermented milk containing
galactooligosaccharides reduces markers of metabolic syndrome Lactobacillus casei DN114001 improves innate-defense capacity
 in healthy middle-aged people. J Physiol Biochem. increases in body mass and fat mass during high‐fat diet in
2004;60:85–91. healthy young adults. Obesity. 2015;23:2364–70.
55. Naruszewicz M, Johansson M, Zapolska-Downar D, Bukowska 72. LeBlanc JG, Chain F, Martín R, Bermúdez-Humarán LG,
H. Effect of Lactobacillus plantarum 299v on cardiovascular Courau S, Langella P. Beneficial effects on host energy meta-
disease risk factors in smokers. Am J Clin Nutr. bolism of short-chain fatty acids and vitamins produced by
2002;76:1249–55. commensal and probiotic bacteria. Microb Cell Fact. 2017;16:79.
56. Nyangale EP, Farmer S, Cash HA, Keller D, Chernoff D, Gibson 73. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud
GR. Bacillus coagulans GBI-30, 6086 modulates Faecalibacter- D-J, Bakker BM. The role of short-chain fatty acids in the
ium prausnitzii in older men and women. J Nutr. interplay between diet, gut microbiota, and host energy meta-
2015;145:1446–52. bolism. J Lipid Res. 2013;54:2325–40.
57. DiRienzo DB. Effect of probiotics on biomarkers of cardiovas- 74. Derrien M, Collado MC, Ben-Amor K, Salminen S, de Vos WM.
cular disease: implications for heart-healthy diets. Nutr Rev. The Mucin degrader Akkermansia muciniphila is an abundant
2014;72:18–29. resident of the human intestinal tract. Appl Environ Microbiol.
58. Shimizu M, Hashiguchi M, Shiga T, Tamura HO, Mochizuki M. 2008;74:1646–8.
Meta-analysis: effects of probiotic supplementation on lipid 75. Derrien M, Vaughan EE, Plugge CM, de Vos WM. Akkermansia
profiles in normal to mildly hypercholesterolemic individuals. muciniphila gen. nov., sp. nov., a human intestinal mucin-
PLoS ONE. 2015;10:e0139795. degrading bacterium. Int J Syst Evol Microbiol.
59. Cho YA, Kim J. Effect of probiotics on blood lipid concentra- 2004;54:1469–76. Pt 5
tions: a meta-analysis of randomized controlled trials. Medicine. 76. Del Piano M, Carmagnola S, Anderloni A, Andorno S, Ballarè
2015;94:e1714. M, Balzarini M, et al. The use of probiotics in healthy volunteers
60. Wu Y, Zhang Q, Ren Y, Ruan Z. Effect of probiotic Lactoba- with evacuation disorders and hard stools: a double-blind, ran-
cillus on lipid profile: a systematic review and meta-analysis of domized, placebo-controlled study. J Clin Gastroenterol.
randomized, controlled trials. PLoS ONE. 2017;12:e0178868. 2010;44:S30–4.
61. Higashikawa F, Noda M, Awaya T, Nomura K, Oku H, 77. Sakai T, Makino H, Ishikawa E, Oishi K, Kushiro A. Fermented
Sugiyama M. Improvement of constipation and liver function by milk containing Lactobacillus casei strain Shirota reduces inci-
plant-derived lactic acid bacteria: a double-blind, randomized dence of hard or lumpy stools in healthy population. Int J Food
trial. Nutrition. 2010;26:367–74. Sci Nutr. 2011;62:423–30.
62. Cox AJ, West NP, Horn PL, Lehtinen MJ, Koerbin G, Pyne DB, 78. Murphy EA, Velazquez KT, Herbert KM. Influence of high-fat-
et al. Effects of probiotic supplementation over 5 months on diet on gut microbiota: a driving force for chronic disease risk.
routine haematology and clinical chemistry measures in healthy Curr Opin Clin Nutr Metab Care. 2015;18:515–20.
active adults. Eur J Clin Nutr. 2014;68:1255–7. 79. Biagi E, Candela M, Fairweather-Tait S, Franceschi C, Brigidi P.
63. Greany KA, Bonorden MJ, Hamilton-Reeves JM, McMullen Ageing of the human metaorganism: the microbial counterpart.
MH, Wangen KE, Phipps WR, et al. Probiotic capsules do not Age. 2012;34:247–67.
lower plasma lipids in young women and men. Eur J Clin Nutr. 80. Merenstein DJ, D’Amico F, Palese C, Hahn A, Sparenborg J,
2008;62:232–7. Tan T, et al. Short-term, daily intake of yogurt containing Bifi-
64. Rizkalla SW, Luo J, Kabir M, Chevalier A, Pacher N, Slama G. dobacterium animalis ssp. lactis Bf-6 (LMG 24384) does not
Chronic consumption of fresh but not heated yogurt improves affect colonic transit time in women. Br J Nutr.
breath-hydrogen status and short-chain fatty acid profiles: a 2014;111:279–86.
controlled study in healthy men with or without lactose mal- 81. Verdenelli MC, Cecchini C, Coman MM, Silvi S, Orpianesi C,
digestion. Am J Clin Nutr. 2000;72:1474–9. Coata G, et al. Impact of probiotic SYNBIO((R)) administered
65. Agerbaek M, Gerdes LU, Richelsen B. Hypocholesterolaemic by vaginal suppositories in promoting vaginal health of appar-
effect of a new fermented milk product in healthy middle-aged ently healthy women. Curr Microbiol. 2016;73:483–90.
men. Eur J Clin Nutr. 1995;49:346–52. 82. Recine N, Palma E, Domenici L, Giorgini M, Imperiale L, Sassu
66. Sadrzadeh-Yeganeh H, Elmadfa I, Djazayery A, Jalali M, C, et al. Restoring vaginal microbiota: biological control of
Heshmat R, Chamary M. The effects of probiotic and conven- bacterial vaginosis. A prospective case-control study using
tional yoghurt on lipid profile in women. Br J Nutr. Lactobacillus rhamnosus BMX 54 as adjuvant treatment against
2010;103:1778–83. bacterial vaginosis. Arch Gynecol Obstet. 2016;293:101–7.
67. Rajkumar H, Mahmood N, Kumar M, Varikuti SR, Challa HR, 83. Borges S, Silva J, Teixeira P. The role of lactobacilli and pro-
Myakala SP. Effect of probiotic (VSL#3) and omega-3 on lipid biotics in maintaining vaginal health. Arch Gynecol Obstet.
profile, insulin sensitivity, inflammatory markers, and gut colo- 2014;289:479–89.
nization in overweight adults: a randomized, controlled trial. 84. Reid G, Beuerman D, Heinemann C, Bruce AW. Probiotic
Mediat Inflamm. 2014;2014:348959. Lactobacillus dose required to restore and maintain a normal
68. Bjerg AT, Sorensen MB, Krych L, Hansen LH, Astrup A, vaginal flora. FEMS Immunol Med Microbiol. 2001;32:37–41.
Kristensen M, et al. The effect of Lactobacillus paracasei subsp. 85. De Alberti D, Russo R, Terruzzi F, Nobile V, Ouwehand AC.
paracasei L. casei W8(R) on blood levels of triacylglycerol is Lactobacilli vaginal colonisation after oral consumption of
independent of colonisation. Benef Microbes. 2015;6:263–9. Respecta((R)) complex: a randomised controlled pilot study.
69. Klein A, Friedrich U, Vogelsang H, Jahreis G. Lactobacillus Arch Gynecol Obstet. 2015;292:861–7.
acidophilus 74-2 and Bifidobacterium animalis subsp lactis 86. Reid G, Charbonneau D, Erb J, Kochanowski B, Beuerman D,
DGCC 420 modulate unspecific cellular immune response in Poehner R, et al. Oral use of Lactobacillus rhamnosus GR-1 and
healthy adults. Eur J Clin Nutr. 2008;62:584–93. L. fermentum RC-14 significantly alters vaginal flora: rando-
70. Hulston CJ, Churnside AA, Venables MC. Probiotic supple- mized, placebo-controlled trial in 64 healthy women. FEMS
mentation prevents high-fat, overfeeding-induced, insulin resis- Immunol Med Microbiol. 2003;35:131–4.
tance in humans. Br J Nutr. 2015;113:596–602. 87. Rhee SH, Pothoulakis C, Mayer EA. Principles and clinical
71. Osterberg KL, Boutagy NE, McMillan RP, Stevens JR, Frisard implications of the brain-gut-enteric microbiota axis. Nat Rev
MI, Kavanaugh JW, et al. Probiotic supplementation attenuates Gastroenterol Hepatol. 2009;6:306–14.
 S. Khalesi et al.

88. Takada M, Nishida K, Kataoka-Kato A, Gondo Y, Ishikawa H, 96. Kang E-J, Kim SY, Hwang I-H, Ji Y-J. The effect of pro-
Suda K, et al. Probiotic Lactobacillus casei strain Shirota relieves biotics on prevention of common cold: a meta-analysis of
stress-associated symptoms by modulating the gut-brain inter- randomized controlled trial studies. Korean J Fam Med.
action in human and animal models. Neurogastroenterol Motil. 2013;34:2–10.
2016;28:1027–36. 97. Montecino-Rodriguez E, Berent-Maoz B, Dorshkind K. Causes,
89. Huang R, Wang K, Hu J. Effect of probiotics on depression: a consequences, and reversal of immune system aging. J Clin
systematic review and meta-analysis of randomized controlled Invest. 2013;123:958–65.
trials. Nutrients. 2016;8:8. 98. Zhang Q, Wu Y, Fei X. Effect of probiotics on body weight and
90. McKean J, Naug H, Nikbakht E, Amiet B, Colson N. Probiotics body-mass index: a systematic review and meta-analysis of
and subclinical psychological symptoms in healthy participants: randomized, controlled trials. Int J Food Sci Nutr.
a systematic review and meta-analysis. J Altern Complement 2015;67:571–80.
Med. 2017;23:249–58. 99. Brown AC, Shovic A, Ibrahim SA, Holck P, Huang A, Brown
91. Probiotic market by application (food and beverages, dietary AC, et al. A non-dairy probiotic’s (poi) influence on changing
supplements, animal feed) by end users (human probiotics, ani- the gastrointestinal tract’s microflora environment. Altern Ther
mal probiotics)-global industry analysis, size, share, growth and Health Med. 2005;11:58–64.
forecast 2014–2020. In: Transparency market research. 2015. 100. Guillemard E, Tondu F, Lacoin F, Schrezenmeir J. Consumption
Abany, United States. Accessed December 2017. https://www.tra of a fermented dairy product containing the probiotic Lactoba-
nsparencymarketresearch.com/probiotics-market.html. cillus casei DN-114001 reduces the duration of respiratory
92. Lahtinen SJ. Probiotic viability—does it matter? Microb Ecol infections in the elderly in a randomised controlled trial. Br J
Health Dis. 2012;23:10–14. Nutr. 2010;103:58–68.
93. Iaconelli C, Lemetais G, Kechaou N, Chain F, Bermudez- 101. Hanifi A, Culpepper T, Mai V, Anand A, Ford AL, Ukhanova
Humaran LG, Langella P, et al. Drying process strongly affects M, et al. Evaluation of Bacillus subtilis R0179 on gastrointestinal
probiotics viability and functionalities. J Biotechnol. viability and general wellness: a randomised, double-blind,
2015;214:17–26. placebo-controlled trial in healthy adults. Benef Microbes.
94. Ouwehand AC, Forssten S, Hibberd AA, Lyra A, Stahl B. Pro- 2015;6:19–27.
biotic approach to prevent antibiotic resistance. Ann Med. 102. Wassenaar TM, Beimfohr C, Geske T, Zimmermann K.
2016;48:246–55. Voluntarily exposure to a single, high dose of probiotic
95. Conly J, Johnston B. Where are all the new antibiotics? The new Escherichia coli results in prolonged colonisation. Benef
antibiotic paradox. Can J Infect Dis Med Microbiol. 2005;16:159–60. Microbes. 2014;5:367–75.