Biomedicine & Pharmacotherapy 111 (2019) 537–547

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Biomedicine & Pharmacotherapy

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Probiotic supplements might not be universally-effective and safe: A review T

a b,⁎ a,⁎⁎
Damini Kothari , Seema Patel , Soo-Ki Kim
a
Department of Animal Science and Technology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea
b
Bioinformatics and Medical Informatics Research Center, San Diego State University, San Diego, 92182, USA

A R T I C LE I N FO A B S T R A C T

Keywords: Last few decades have witnessed the unprecedented growth in the application of probiotics for promoting the
Probiotics general gut health as well as their inception as biotherapeutics to alleviate certain clinical disorders related to
Immunomodulation dysbiosis. While numerous studies have substantiated the health-restoring potentials for a restricted group of
Compromised gut microbial species, the marketed extrapolation of a similar probiotic label to a large number of partially char-
Sepsis
acterized microbial formulations seems biased. In particular, the individuals under neonatal stages and/or those
Allergy
Dietary supplements
with some clinical conditions including malignancies, leaky gut, diabetes mellitus, and post-organ transplant
Adverse effects convalescence likely fail to reap the benefits of probiotics. Further exacerbating the conditions, some probiotic
At-risk population strains might take advantage of the weak immunity in these vulnerable groups and turn into opportunistic
pathogens engendering life-threatening pneumonia, endocarditis, and sepsis. Moreover, the unregulated and
rampant use of probiotics potentially carry the risk of plasmid-mediated antibiotic resistance transfer to the gut
infectious pathogens. In this review, we discuss the safety perspectives of probiotics and their therapeutic in-
terventions in certain at-risk population groups. The embodied arguments and hypotheses certainly will shed
light on the fact why probiotic usage should be treated with caution.

1. Introduction
Probiotics (Greek; Pro: promotion, Biotic: life) are generally defined
as “live microorganisms which, when administered in adequate
amounts, confer health benefits on the host” [1]. Traditionally, a vast
array of fermented foods like yogurt, kefir, kimchi, sauerkraut, tempeh,
miso, and kombucha are part of regular diet across different cultures
and ethnicities, ranging from oriental to occidental [2,3], serving as the
conventional source of probiotic strains. In recent years, probiotics are
touted for modulating the immune system, through the restoration of
gut homeostasis [4]. As per the current state of knowledge, probiotics
encompass both bacteria (Lactobacillus, Lactococcus, Leuconostoc, Ped-
iococcus, Propionibacterium, Bifidobacterium, Bacillus, some Streptococcus,
Enterococcus, Escherichia coli) and yeast (Saccharomyces) genera [5].
Once delivered to the host, probiotics are expected to antagonize pa-
thogens such as Enterococcus faecalis, Salmonella enterica subsp. enterica
serotype Enteritidis, Listeria monocytogenes, Staphylococcus aureus and E.
coli by immune, hormonal, and neuronal manipulations [6]. To the
present date, only oral [7,8] and gut [9,10] ameliorative roles of pro-
biotics have been validated for clinical uses. However, more studies are
increasingly claiming the probiotics-mediated alleviation of disorders
related to the immune system [11], cardiovascular health [12], cancer
metastasis [13], depression [14], anxiety [15], type 2 diabetes [16],
and obesity [17], among others.
Dysbiosis, an imbalance in the composition of the microbes fol-
lowing antibiotic usage, has largely propelled the therapeutic applica-
tion of probiotics [18]. The past two decades have pushed probiotics to
the highest echelon of dietary supplements following the implementa-
tion of 'Dietary Supplement Health and Education Act, 1994' by the US
Food and Drug Administration (USFDA), allowing their marketing and
over-the-counter sales as health supplements under relatively flexible
laws [19]. Since probiotics are considered more as food or health
supplements, they do not undergo rigorous clinical trials, unlike cura-
tive drugs. Especially, the probiotics-fortified foods including curd,
yogurt, ice cream, and cereals are being promoted without mentioning
the adequate parameters like formulation, efficacy, and consumer
safety. Altogether these loose criteria have resulted in skewed policies
for governing probiotic formulations with unsubstantiated health
claims, across different continents and countries. Only recently, the
safety profiles of different probiotics as a function of different genera,
species, and strains, coupled with their relevance to diverse individuals
or at-risk population, have attracted enough attention [20–22]. Of note,
sepsis in cardio-surgical patient [23], anaphylactic allergic response in
sensitive individuals [24], systemic fungemia in elderly

⁎
Corresponding author at: Bioinformatics and Medical Informatics Research Center, San Diego State University, 5500 Campanile Dr, San Diego, CA, 92182, USA.
⁎⁎
Corresponding author.
E-mail addresses: seemabiotech83@gmail.com, Patel3@rohan.sdsu.edu (S. Patel), sookikim@konkuk.ac.kr (S.-K. Kim).

https://doi.org/10.1016/j.biopha.2018.12.104
Received 4 July 2018; Received in revised form 9 December 2018; Accepted 23 December 2018
0753-3322/ © 2018 Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
D. Kothari et al.
immunocompromised patients [25], and the risk of horizontal gene
transfer (HGT) of antibiotic resistance to pathogenic microbes [26],
among many other issues due to probiotic usage have been reported.
Diverse groups of individuals respond differently to foods, drugs, and
dietary supplements, depending on their age, gender, host factors, and
co-morbidities [27,28]. Hence, the present review presents a compre-
hensive scrutiny of the proclaimed health effects of probiotic formula-
tions, underscoring their rationale of clinical administration in certain
population groups. Hence, we maintain that it is much better to be
pragmatic than harboring an unsubstantiated notion about the ther-
apeutic applications of probiotics. Although many studies have cohe-
sively endorsed the health-building roles of probiotics, they certainly do
not present the holistic and consistent picture. In this regard, besides
the strain-specific health effects, dosage, efficacy, and potency of mi-
crobial species formulations [21], the immune response of the con-
sumers must be comprehensively studied. With new discoveries and
better grasp on the mechanistic of immune system, it has now become
clear that the host biochemical milieus and the host-microbe interac-
tions are the decisive factors which determine the probiotics efficacy
and safety for individual recipients. It is a matter of concern as most
people think that probiotics are perfectly safe and widely efficacious.
This is certainly not the case, and it would be more useful to present a
genuine picture, since it appears that adverse events are poorly reported
in the randomized clinical trials (RCTs) of probiotics [29]. Keeping this
in mind, the present review documents the current knowledge on the
safety of probiotic administration in the at-risk population as well as
identifies the priorities or needs for future research. Especially, the 'risk-
benefit' ratios for the clinical administration of specific probiotic for-
mulations among the at-risk population, including pre-term infants and
those with critical illness, AIDS, organ transplantation, necrotizing
enterocolitis (NEC), cancer, inflammatory bowel diseases, diarrhea, and
allergy have mainly been focused.
2. Safety, efficacy, and associated risks of probiotics in the at-risk
population
Probiotics are generally considered safe for a healthy population.
Several pieces of evidence of benefits with probiotic therapy were also
reported in at-risk population groups (Table 1). Although the precise
mechanisms of probiotics mediated clinical benefits are unclear, they
are conjectured to act through revamping gastrointestinal tract (GIT)
microbiota, maintaining/protecting intestinal epithelium, reducing in-
flammation, and modulating the immune profile. Previously, the joint
FAO/WHO [30] guidelines on probiotic evaluation reported that pro-
biotics may theoretically be linked to four specific types of side effects
in patients with underlying medical conditions: "(1) systemic infections;
(2) deleterious metabolic activities; (3) excessive immune stimulation
in susceptible individuals; and (4) gene transfer". The at-risk population
groups are broadly characterized by the weakened immune system, gut
dysbiosis and/or impaired intestinal barrier, and therefore, it is im-
portant to carefully assess the safety associated with deliberate ad-
ministration of living microorganisms (i.e., probiotics). Moreover, the
availability of limited or mixed evidences of benefits from several
probiotic intervention studies owing to the variability in a target po-
pulation, probiotics formulations administered, clinical and statistical
heterogeneity, study limitations, and small sample sizes further ne-
cessitates the comprehensive safety evaluation for at-risk population
groups. Below, we discuss these theoretical threats for clinical probiotic
administration in different at-risk population groups, though they are
not separate but inter-linked. Also, the risks associated with the un-
restricted dietary intake of probiotics have been cataloged in Table 2.
2.1. Infections caused by probiotic administration
Bacterial translocation typically refers to the passage of viable in-
digenous bacteria from the GIT to extraintestinal sites (bloodstream),
538
Biomedicine & Pharmacotherapy 111 (2019) 537–547
due to an impaired intestinal barrier, immunosuppression, or gut pre-
maturity [31]. Bacterial translocation to sterile niches has been ob-
served following stroke, cirrhosis, and trauma, among a range of other
conditions [32,33]. It has been speculated that the intestinal mucosa
adhesion capacity [34] or mucolytic activity [35] of probiotic strains
might carry out a role in their translocation. Probiotic translocation
might result in some clinical infections, including systemic and loca-
lized infections [34]. Predominantly, infections associated with specific
probiotics include sepsis, endocarditis, localized, and opportunistic in-
fections via bacteremia (bacteria in the blood) or fungemia (fungi in the
blood).
2.1.1. Sepsis
Sepsis is a clinical syndrome characterized by systematic in-
flammation and circulatory malfunctions following the pathogenic in-
fection like bacteremia or fungemia. It is one of the most common
causes of morbidity and mortality in critically ill patients [34] and pre-
term infants [36]. These populations are indeed highly prone to develop
bacterial and fungal sepsis due to several factors including gut dys-
biosis, weak immunity, use of invasive procedures and devices, use of
broad-spectrum antibiotics and other drugs, possible bacterial translo-
cation, the lack of nutrients, and nosocomial infections [34,37].
Growing pieces of evidence support the beneficial role of probiotics in
critically ill and neonates (Table 1). Nevertheless, the ingestion of live
microorganisms (probiotics) in rare instances might surplus the risk of
sepsis as evidenced by several studies (Table 2), raising the safety
concern of routine probiotic use in such population. Recently, the lar-
gest trial for 'Probiotics in Very Pre-term Infants (PiPS)' revealed no
difference in the risk of NEC and sepsis between the probiotics and
control treated groups. The results of the PiPS trial also questioned the
published meta-analyses those supported the routine probiotic therapy
in pre-term infants. Of note, the authors did not endorse any harms of
probiotic intervention for treating pre-term infants [38].
Among lactobacilli, L. rhamnosus strains are mostly associated with
human sepsis, suggesting their high potential to translocate [31]. Lac-
tobacillus sp. bacteremia is rarely fatal, albeit it may serve as a marker of
more serious underlying disease [39]. A review including 89 patients
with Lactobacillus bacteremia reported the mortality rate of 26% in 1-
month and 48% in 1-year following infection onset [40]. Few cases
were reported for Bifidobacterium-mediated sepsis and bacteremia
(Table 2). One study reported sepsis associated with E. coli NISSLE 1917
probiotic strain in low-birth weight infants [41]. Saccharomyces bou-
lardii (a subtype of S. cerevisiae) based probiotic supplementary therapy
is well-established to prevent antibiotic-associated diarrhea and treat
recurrent Clostridium difficile associated diarrhea [25]. However, several
cases of fungemia and sepsis associated with this probiotic have also
been reported in patients with chronic diseases or critical illness
(Table 2). These findings have led to the inference that probiotics might
not be harmless to immunocompromised patients/consumers, unlike
immune-competent individuals. Nevertheless, there are scarce reports
describing the probiotic-mediated sepsis in humans, the other side of
the coin simply emphasizes the safe clinical administration or dietary
consumption of probiotics in humans. In other words, the problem can
be with the host and not with the probiotics strain. If bacteria are
capable of restoring homeostasis, yet host gut is porous and inner
mucus layer-devoid, bacteria will migrate to sterile regions. Some in-
dividuals have leaky gut where mucosal integrity is invasion-prone, and
breaching of which can cause infections, sepsis, and/or fungemia [5].
The evidences point toward the relation between low leukocyte count,
neutropenia, high inflammatory markers, and traversal of gut-dwelling
probiotic strains into bloodstream. It is the reason most cases with
sepsis are immunocompromised patients, cancer patients, and pre-term
infants.
2.1.2. Infective endocarditis
Another noteworthy point highlighting the potentially adverse
 D. Kothari et al.

Table 1
Efficacy studies of probiotic therapy in risk population.
Disease Study No. of RCTs and patients Population Outcome References

NEC Systematic review and 24 RCTs; 5529 patients Infants < 37 weeks gestational age or < 2500 g Effective, safe and well tolerated [92]
meta-analysis birth weight, or both
NEC Systematic review and 20 RCTs involving 5982 patients Very low birth weight (< 1500 g) & pre-term (< Reduced risk of NEC and mortality [93]
meta-analysis 37 weeks gestational age) infants
NEC Systematic review and 44 studies (30 RCTs and 14 Pre-term infants Prevented severe NEC and late-onset sepsis, and reduced mortality [94]
meta-analysis observational studies)
VAP Systematic review and 9 RCTs; 1119 patients Critically ill adults Reduced incidence of ICU-acquired pneumonia and shortened ICU-stay; safe [95]
meta-analysis with no adverse effects
VAP Systematic review and 8 RCTs; 1083 patients Critically ill adults Reduced VAP cases and shortened ICU-stay but no change in mortality rate; [96]
meta-analysis conferred benefits but insufficient evidence of safety and efficacy
VAP RCT 150 patients Critically ill children (≤ 12 years) Effective and safe to lower the incidence of VAP, shortened hospital and ICU- [97]
stay;
VAP RCT 235 patients Critically ill adults Effective and safe for preventing VAP and the acquisition of potentially [98]
pathogenic microorganism’s colonization.

539
VAP Systematic review and 30 RCTs; 2972 patients Critically ill adults Reduced incidence of infections including VAP [99]
meta-analysis
IBS RCT 84 patients 20-70 years Improved quality of life; no adverse effects [100]
IBS Systematic review and 15 RCTs; 1793 patients Adults and children Conferred benefits but insufficient evidence of safety and efficacy [101]
meta-analysis
IBS symptoms RCT 60 patients Colorectal cancer (> 20 years) Improved bowel symptoms and quality of life [102]
Diarrhea Systematic review and 17 RCTs & Case reports; 1530 Cancer Reduced chemotherapy-related diarrhea but significant safety concerns [103]
meta-analysis patients
Diarrhea Systematic review 39 RCTs; 9402 patients HIV patients Effective and no adverse effects [104]
Inflammation Clinical trial 20 patients HIV patients (27–72 years) Improved gut immunity and no adverse effects [105]
Postoperative infection RCT 67 patients Liver transplantation Reduced infection and shortened duration of antibiotic use; no adverse effects [106]
Postoperative infection Systematic review and 4 RCTs; 246 patients Liver transplantation (mean age 53 years) Reduced postoperative infections, shortened hospital or ICU-stay, duration of [107]
meta-analysis antibiotic use and no probiotic associated adverse effects
Postoperative infection RCT 55 patients Liver transplantation (≥18 years) Effective in postoperative infections and improved early biochemical [108]
parameters of allograft function; no effect on mortality

RCT: Randomized control trial; NEC: Necrotizing enterocolitis; VAP: Ventilator-associated pneumonia; IBS: Irritable bowel syndrome; HIV: Human immunodeficiency virus.
Biomedicine & Pharmacotherapy 111 (2019) 537–547
 D. Kothari et al.

Table 2
Risks associated with rampant dietary intake of probiotics.
Category Microorganisms Population Mechanisms References

Transmissible antibiotic resistance Lactobacillus, Pediococcus and Leuconostoc sp. – Vancomycin resistance → Staphylococcus aureus [109]
genes Lactobacillus sp. – Vancomycin resistance → Enterococcus faecalis [110]
Lactobacillus sp. – Broad spectrum antibiotic resistance (vancomycin, [26,111]
streptomycin,
gentamicin, aztreonam, and ciprofloxacin) → Staphylococcus sp.
Systemic infection Lactobacillus rhamnosus GG Pre-term infant with short gut syndrome Lactobacillus bacteremia [112]
L. rhamnosus GG Critically ill children with antibiotic related diarrhea Sepsis [113]
L. rhamnosus GG 11-month old infant with short gut syndrome Lactobacillus bacteremia [114]
L. rhamnosus GG 17-year-old boy with ulcerative colitis Lactobacillus bacteremia [115]
Lactobacillus sp. 58-year-old immunocompetent with mechanical ventilation Lactobacillus bacteremia and sepsis [116]
Three strains of L. rhamnosus 24-year-old female cardiosurgical patient Probiotic sepsis [23]
Bifidobacterium longum 74-year-old man with polymetastatic prostatic adenocarcinoma Bifidobacterium bacteremia [117]
B. longum subspecies infantis Pre-term infants Bifidobacterium bacteremia [118]
B. longum Low birth-weight infants Bifidobacterium bacteremia [119]
B. breve 2-year-old boy with Philadelphia chromosome-positive acute B- Bifidobacterium sepsis [120]
cell lymphoblastic leukemia
E. coli NISSLE strain 1917 Pre-term infants Severe sepsis [41]
Saccharomyces cerevisiae 48-year-old diabetic with multiple co-morbidities Multiple organ failure and septic shock in association with toxic [121]
megacolon and probiotic fungemia

540
S. cerevisiae var. boulardii Immunocompromised 73-year-old patient on chemotherapy Fungemia [25]
S. cerevisiae var. boulardii 8-year-old boy with respiratory distress (Intensive care unit Fungemia [122]
patient)
S. cerevisiae var. boulardii Premature neonate receiving nutrition enterally Fungal septicemia [123]
S. cerevisiae var. boulardii Critically ill patients Fungemia [82]
L. plantarum 30-year-old male with rheumatic valve disease Endocarditis [124]
L. casei 53-year-old immunocompetent patient Endocarditis [125]
L. jensenii 47-year-old immunocompetent patient Endocarditis [126]
L. paracasei 77-year-old male patient with prostate cancer Endocarditis [127]
L. acidophilus 48-year-old male with heart disease and dental manipulations Endocarditis [45]
L. rhamnosus > 65-year-old patient with hemorrhagic telangiectasia (HHT) Endocarditis [128]
Localized infection L. casei 60-year-old with renal transplant patient Intra-abdominal abscess [129]
L. paracasei 65-year-old diabetic patient Bacteremia and liver abscess [47]
L. rhamnosus 11-month-old female with trisomy 21 with respiratory viral Probiotic associated pneumonia [48]
infection
Metabolic disturbances Lactobacillus spp. – Unregulated 'bile salt hydrolase (BSH)' activity [64]
L. lactis – Biogenic amine production [63]
Allergic response L. rhamnosus GG Children (up to 4 years) Allergic rhinitis and more serious asthma [68]
L. acidophilus LAVRI-A1 Infants (6 and 12 months) Atopic sensitization [72]
L. rhamnosus GG Pregnant (4-6 weeks before expected delivery) and breastfeeding Wheezing bronchitis; atopic sensitization [130]
mothers (up to 2 years)
Bowel ischemia L. acidophilus, L. casei, L. salivarius, L. lactis, B. Critically ill patients Increased local oxygen demand [55]
bifidum, and B. lactis (acute pancreatitis)
Biomedicine & Pharmacotherapy 111 (2019) 537–547
D. Kothari et al.
clinical implications of probiotics is the risk of infective endocarditis
(IE). IE is an inflammation of the endocardium, that has been reported
as a major health concern leading to life-threatening cardiogenic ail-
ments, dysrhythmias, and septic shocks [42]. Endocarditis due to Lac-
tobacillus infection is rare but considerably a serious clinical state in
patients with high mortality rate averaging 30% [43]. The high mor-
tality was attributed to the potentially pathogenic characteristics of
Lactobacilli, which include the ability to affect platelet aggregation in
humans, form complexes with blood components including fibronectin,
fibrinogen, collagen types I and V, as well as the overwhelming pro-
duction of enzymes including glycosidases and proteases at the infec-
tion sites. Several Lactobacillus spp. have been reported to cause IE, such
as L. rhamnosus, L. casei, L. acidophilus, L. jensenii, L. plantarum and L.
paracasei (Table 2). The major risk factors linked to Lactobacillus
mediated endocarditis include impaired immunity, structural heart
disease, recent surgery, prolonged antibiotic therapy, dental infections
or procedures, and severe comorbidities [44]. Recently, probiotics
containing Lactobacillus spp. have been reported as a new risk factor for
endocarditis [45]. Therefore, any probiotic formulation and their clin-
ical administration should be carefully examined in the aforementioned
at-risk populations.
2.1.3. Localized infection
Apart from bloodstream infections, few cases of local infections
including liver abscess (intra-abdominal abscess) and pulmonary in-
fections (Lactobacillus pneumonia) were also reported following the
clinical administration of certain probiotic formulations. The liver ab-
scess is a collection of pus or infected fluid surrounded by inflamed
tissue inside the liver. Most of the probiotic-related liver abscesses are
not confirmed by strain identification [46] except for Lactobacillus
paracasei diagnosed from a 65-year-old diabetic patient [47]. The po-
tential risk factors linked to lactobacilli liver abscess are advanced age,
diabetes mellitus, liver transplantation, underlying hepatobiliary dis-
ease, and the history of malignancy [46]. Although probiotic-associated
pneumonia is very rare with only one case of Lactobacillus mediated
pneumonia was reported till date due to probiotic supplementation
[48]. This report speculated that being immunocompromised (espe-
cially having AIDS) to be the foremost primary risk factor for Lactoba-
cillus pneumonia.
2.1.4. Opportunistic infection
The opportunistic pathogens are those which infect host with
weakened/impaired immunity [49]. The stark distinction between safe
probiotics and potentially pathogenic genera might be getting blurry,
with emerging facts. A comparative genomic study of Clostridium bu-
tyricum DKU-01 strain isolated from infant feces displayed considerable
metabolic similarity with Bifidobacterium and Streptococcus genera on
fructo-oligosaccharide (FOS) utilization [50]. However, some strains of
Clostridium species have earlier been linked to infant's fatal botulism
and NEC [51]. The risk of Lactobacilli and Bifidobacteria-associated
opportunistic infections is highly unlikely, however, Streptococcus and
Enterococcus that are also touted as probiotics represent opportunistic
pathogens [52].
Till date, no evidence of hemolytic activity has been reported for
lactobacilli and bifidobacteria. However, Enterococcus faecium, a normal
inhabitant of human gut was reported to produce a hemolysin [53]. It
has been shown that β-hemolytic strains of Enterococcus increased five
times the chances of death by bacteremia when compared with the
patients with bacteremia caused by non-β-hemolytic strains [54]. Since
gut microbes are prone to HGT, the acquisition of hemolysin producing
genes is not an unlikely concern. Hence, the opportunistic infection
risks of probiotics ought not to be dismissed.
2.1.5. Ischemia
Ischemia refers to the inadequate blood supply to tissues or organs
and is an exceptional etiology of acute pancreatitis. The PROPATRIA
541
Biomedicine & Pharmacotherapy 111 (2019) 537–547
trial reported increased mortality (16% vs 6%) due to bowel ischemia
(9 vs 0) in patients group subjected to enteral probiotic administration
while severe acute pancreatitis (SAD) treatment [55]. The mechanisms
of bowel ischemia by probiotics were speculated to be the increased
local oxygen demand following the administration of 10 billion pro-
biotic bacteria per day, which might potentially aggravate the critically
reduced blood flow engendering the excessive local inflammation
owing to the heightened bacterial load in small bowel wall. The dismal
results of the PROPATRIA trial discouraged many researchers through
raising the concerns about the clinical implications of probiotics for
treating the critically ill patients with pancreatitis [55]. In another
retrospective study, no positive or negative impact of probiotic treat-
ment was demonstrated in patients with predicted SAD without initial
organ failure [56].
2.2. Metabolic disturbances
Although the US Food and Drug Administration (FDA) designates
probiotics as 'Generally Recognized as Safe' (GRAS) (http://www.fda.
gov/food/Ingredientspackaging Labeling/GRAS/), surprisingly very
few systematic reports are available which signify their consumer safety
in vulnerable individuals with certain clinical conditions. For example,
metabolism upsetting effects on the GIT is another concern against the
clinical probiotic interventions. Any perturbation or refashioning of the
metabolic pathways can cause obesity, type 2 diabetes, or other meta-
bolic syndromes. This suspicion has arisen in the wake of the discovery
that gut microbiota composition affects nutrient acquisition, energy
harvest, and a myriad of host metabolic pathways [57]. Food poisoning
is a multi-factorial health concern, of which microbial biogenic amine
(BA) is one factor. Though lactic acid bacteria used in food fermenta-
tion are considered as GRAS, some of them produce BAs (e.g., cada-
verine, histamine, tyramine, agmatine, and putrescine) liberating into
the fermented dairy products, pickles [58], and beverages [59]. BAs are
neurotransmitters and immune mediators. BAs can increase or decrease
blood flow to the central nervous system and might trigger headaches
in people sensitive to these substances [60]. Some probiotic strains such
as Lactobacillus buchneri, Lactobacillus helveticus, Lactobacillus hilgardii,
and Streptococcus thermophilus can produce histamine in dairy products
[61,62]. The excess histamine can be absorbed into the bloodstream via
the lining of the GIT resulting in allergic reactions. Previously, a study
had reported that L. lactis in fermented foods might cause a significant
accumulation of cadaverine (a toxic diamine compound) over a period
of consumption [63].
The bile salt hydrolase (BSH) activity of certain probiotic strains in
the small bowel is known to lower blood cholesterol levels through
hydrolyzing the bile salts; however, unregulated expression of this en-
zyme is suspected to affect host metabolism by impairing lipid meta-
bolism, promoting gall stone depositions, and/or obesity [64,65]. In
recent years, various Lactobacillus species such as L. acidophilus, L. fer-
mentum, L. ingluviei, and L. gasseri have been reported to affect weight
gain in host species, including humans and livestock animals [66]. Al-
together, the probiotic effect in body weight was species- and strain-
specific as well as host-specific, and hence, the tendency of these pro-
ducts toward influencing the obesity in humans needs to be examined
[66,67]. Hence, we persuasively argue that any probiotic formulation
cannot be generalized under a single umbrella to have positive health
effects as it influences host metabolism differentially commensurate to
the individual's physiological state.
2.3. Allergic response
Atopic dermatitis (AD) is a chronic inflammatory skin disease with
relapsing pruritic eczema, involving allergic and immunological ab-
normalities. Previously, probiotic supplementation has been success-
fully reported for the prevention and treatment of AD in children [68]
and adults [69]; however, no empirical evidence was found which
D. Kothari et al.
supports the beneficial role of probiotics in infants (< 1 year old) [70].
In several other studies, the treatment is linked to many adverse effects
including a higher risk for allergic rhinitis and more serious asthma
[68]; increased risk of atopic sensitization [71,72]; and increased
wheezing bronchitis [71]. Moreover, Sanders et al. [21] hypothesized
that mere administration of one or a few single probiotic strains in high
numbers does not warrant a natural approach to gut colonization, but
raises the possibility of long-term side effects, especially in atopic po-
pulation.
2.4. Immunological effects
The effects of probiotics on human immune function are still con-
troversial. Augmentation of natural killer activity, T cell functions, and
cytokine production are some of the plausible mechanisms underlying
the immune regulatory activities of probiotics [73]. The elicited cyto-
kine production via probiotic supplementation might cause inordinate
immunological effects, leading to auto-immune phenomena or certain
inflammations. Therefore, the effect of probiotic administration during
auto-immune disease development needs attention. However, this risk
is purely theoretical and has not been reported in any human popula-
tion [74,75].
2.5. Horizontally-transferred antibiotic resistance
One argument against the long-term intake of probiotics entails the
risk of antibiotic selection pressure. Most strains of Lactobacillus,
Lactococcus, and Bifidobacteria used as probiotics are generally benign,
without any pathogenic risk, yet untoward exceptions like horizontal
transfer of antibiotic resistance genes to the opportunistic pathogens
sharing the gut microbiome might have serious clinical implications
[76]. The unrestrained consumption of non-specific probiotics as health
supplements coupled with the usage of broad-spectrum antibiotics ex-
erts selective pressure on gut microbiome, potentially generating multi-
resistant bacteria or yeasts, exacerbating the unlikely events of HGT
among gut commensals and pathogens (Table 2). The GIT is widely
considered as the reservoir and hotspot, engendering HGT among mi-
crobial communities, as it houses trillions of microbes in close proxi-
mity [77]. Hence, under certain conditions the antibiotic-resistant
probiotics strains might transfer antibiotic resistant genes (ABR) either
directly or indirectly to a commensal microflora inhabiting the common
gut environ. Moreover, human gut microbiota is also suggested to be a
trove of ABR genes, transferable between the transient bacteria (in-
cluding probiotics and pathogens) and the normal residents. Notably,
the tetracycline resistance genes have been well-documented to be
shared by gut microbes [78]. For instance, Lactococcus lactis has been
reported to transfer these ABR genes to Enterococcus faecalis [79], while
a number of such studies (in vitro and animal model) have been re-
viewed which highlighted the transfer of ABR genes between lactoba-
cilli and lactococci as well as the gut microbial commensals and tran-
sient pathogens [80,81]. Although studies supporting the safety of
probiotics strains far outnumber their risks, it clearly does not reflect
the holistic picture.
The inherent risks of probiotics administration in vulnerable groups
have been illustrated in Fig. 1.
3. Safety considerations and future directions
Different nations have maintained different policies for the safety of
dietary supplements and pharmaceuticals. European Food Safety
Authority (EFSA) considers all common species of probiotics as safe for
the general population. Irrespective of policies, there has always been a
risk associated with the probiotics use among the vulnerable popula-
tions [82].
It is easy to comprehend why probiotics grabbed such a significant
place in healthcare. Gut microbiota controls heart diseases, obesity,
542
Biomedicine & Pharmacotherapy 111 (2019) 537–547
depression, and pre-term birth, among many other pathologies [6,83].
So, the idea that replenishing the friendly bacteria will bring back
homeostasis is quite convincing. However, several arguments can be
made regarding the risks that probiotics pose, of which some of the
robust have been discussed below.
Considering the probiotics to be a consortium of exogenous mi-
crobes, different mechanisms of interactions and health effects for dif-
ferent genera, species, and strain within individual hosts are expected.
Moreover, the variations in probiotics formulations, dosage, and ad-
ministration modes may greatly affect the outcomes among the het-
erogeneous recipients [84]. Therefore, an appropriate strain and for-
mulation should be considered toward a particular health condition.
In general, the potential probiotic strains are being screened from
all sorts of niches including soil, feces, and fermented foods making
them remarkably distinct from those residing endogenously in the
human gut. Once ingested, the radically different gut micro-environ-
ment and immune factors might exert selection pressure on probiotic
strains to develop potential virulence factors including adhesins [85],
biogenic amines (histamine, putrescine, cadaverine, tyramine, trypta-
mine, phenylethylamine, spermine and spermidine), certain toxins
(hemolysins), and harmful enzymes (glycosidases, proteases, muci-
nases, and gelatinases) [35,86]. As reported previously, bacterial gen-
omes readily undergo genome reshuffling to adapt to the changing
environment [87]. This genomic change might lead to the emergence of
new drug-resistant strains.
Notably, the probiotic strain suspensions are frequently mixed with
sodium alginate and extruded on to calcium chloride solution. The
calcium alginate beads are then packaged to be used as probiotics [88].
What if these capsules provoke the immune system in the host? Or what
if the carbohydrates trigger the activity of glycoside hydrolases?
Moreover, the risk associated with the probiotic intake in individuals
with poor gut integrity must be thoroughly examined. Although the
reports highlighting the benefits of probiotics far outnumber those
substantiating their health risk, the propensity of at-risk population for
the associated health risk should also be considered. While strain-spe-
cific efficacy of probiotics has gained adequate empirical support, the
plasticity of strains towards lethal gene intake, crossing gut barrier,
causing shock, etc. needs greater attention. Above all, the host factors
leading to probable vulnerability toward probiotics supplementation
ought to be probed using RCTs with emphasis on specific safety con-
cerns. We briefly summarized the various criteria that should be used
for the safety evaluation of a probiotic with aided health benefits in
Table 3.
Probiotics are assemblage of live bacteria for consumption, hence,
their manufacturing, labeling, and distribution should be strictly
regulated [75]. FDA also encourages health care providers who pre-
scribe dietary supplements containing live bacteria or yeast as drugs
(for treating or preventing underlying medical conditions) to submit an
'Investigational New Drug Application' to FDA for review [89]. We
argue that FDA/WHO should exercise more prescriptive guidelines with
more stringent criteria, especially toward their clinical applications. In
this way, at-risk populations such as immunocompromised [25], neo-
nates [37], critically ill [34] and those undergoing post-surgical treat-
ments [23] might be spared of the unknown risks of the unregulated
clinical interventions of probiotics. The sporadic adverse effects of
strain-specific probiotics highlight the lack of explicit legislation in the
manufacture and distribution of probiotics for healthcare applications.
In the hype to report its beneficial effects, the negative traits have been
altogether skipped. For example, the ingestion of probiotic bacterium E.
coli NISSLE 1917 might offer relief in chronic inflammatory bowel
diseases and colitis; however, this strain can also induce genotoxicity by
peptide-polyketide elaboration and modulation of cytokine profiles in
the host [90]. This report indicated that an effective probiotic might
also have concomitant side effects like any other medication. Such
prudent reports are warranted as it is increasingly becoming clear that
‘the host micro-environment’ largely determines the salutogenic or
D. Kothari et al. Biomedicine & Pharmacotherapy 111 (2019) 537–547

Fig. 1. Schematic representation of the potential risks and their consequences associated with the clinical administration of probiotics in the at-risk population
groups. (A) Probiotic translocation by the violation of gut integrity: in leaky or inflamed or pre-mature gut, probiotics (Saccharomyces cerevisiae, Lactobacillus,
Bifidobacterium) might traverse the intestinal mucosa and enter into bloodstream or vital organs causing systemic or localized infections; (B) Virulence factors and
harmful metabolites of probiotics might lead to opportunistic infections and metabolic disturbances, respectively; (C) Horizontal transfer of antibiotic resistance
genes from probiotics to pathogenic gut bacteria and vice-versa might lead to the development of antibiotic resistant pathogens; and (D) Exaggerated immune
response through elicited cytokine production might lead to autoimmune disease or inflammation.

pathogenic behavior of microbes. In the absence of immune surveil-
lance, even a pathogen can shut down its virulence machinery, and in
the absence of immune patrolling, even a benign bacterium can become
a potential pathogen. It has been observed that under in vitro conditions
in the culture medium, the potential pathogens like Streptococcus, En-
terococcus, E. coli, S.boulardii tend to lose their virulence appendages
[43,91]. Gut microflora members contend with human immune pres-
sure yet are not pathogenic owing to a million-years-long mutualistic
co-evolution. Herein, we conjecture that the exogenously introduced
microbial species (probiotics) in at-risk population groups might dis-
rupt the endogenous native gut microflora pertaining to a variety of risk
factors. In a broader context, it can simply fail to survive and poop-out,

Table 3
Criteria for the safety evaluation of probiotics.
Safety parameters Methodology/techniques References

Strain identification DNA-based technology including genome sequencing and genetic based tools [5]
Transmissible antibiotic resistant genes Antibiotic resistant profiling, identification of antibiotic resistant genes via comparative proteomics and functional [26]
genomics; in vitro studies that mimic natural gut environment in the presence or absence of antibiotics
Toxicological studies In vitro and in vivo studies in relation to biogenic amine production, hemolysis and harmful enzyme secretion. [35]
Efficacy studies Functional characterization via in vitro and in vivo (animal and human) studies including clinical trials [86]
Target population Immune compromised (AIDS or on immunosuppressant therapy), infants (pre-term and low-birth weight), allergic, [21]
critically ill patients (bowel syndrome, central venous catheters, cardiac valve disease, severe acute pancreatitis, cancer
among many others), and pregnant women
Product formulation and labelling Composition, product purity, presence or absence of contaminants (biological or non-biological), doses information, health [131]
claims (general and specific), and adverse effects
Others Strain by-strain basis evaluation, long-term and high-dosage effects [22]

543
D. Kothari et al.
Fig. 2. Archetypal probiotics genera with potential virulence factors.
restore health or might act as a pathogen under certain clinical states in
the host. We sketched the various probiotics candidates and their likely
associated virulence factors in Fig. 2.
Nevertheless, the therapeutic potentials of probiotics remain pro-
mising if appropriate regulatory procedures with informative labeling
including warnings/precautions linked to the specific medications are
included.
4. Conclusions
The term ‘probiotics’ has been marketed in such a manner that ev-
eryone has a presumption that the consumption of these products is
always beneficial, almost a panacea, with zero risks. However, the ac-
tual scenario seems different from this idea, and hence both the facets
of the picture must be considered via risk versus benefit evaluation, to
better harness the benefits of probiotics. In this review, we highlight the
necessities for demarcating the regulation of probiotics for the general
dietary and toward clinical interventions. In our discussion, we em-
phasized that the probiotics with health claims to treat/prevent specific
ailments should be regulated and marketed as “drug” rather than
“dietary supplements” and thereby must conform to more rigorous re-
quirements. The regulatory bodies should be stricter in the market
launch of a probiotic product either as a food supplement or a bio-
therapeutic agent. Delving deeper might reveal that like all GRAS mi-
crobes are not probiotics, all probiotics might not be safe for all in-
dividuals. Especially, the host factors can be variable, and for a
particular milieu under certain clinical conditions, probiotics might be
immunogenic and/or pathogenic. Hence, this review highlights the fact
that probiotics are no 'magic bullet', and their administration under the
current pretense of microbiota restorative and immunomodulator,
might not be universally safe and effective.
Conflict of interest
There is no conflict of interest in submission of the manuscript.
Acknowledgement
This work is supported by Korea Institute of Planning and
Evaluation for Technology in Food, Agriculture, Forestry (IPET)
through Agri-Bio industry Technology Development Program, funded
by Ministry of Agriculture, Food and Rural Affairs (MAFRA) (118051-
03).
544
Biomedicine & Pharmacotherapy 111 (2019) 537–547
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