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Postbiotics versus probiotics: Possible new allies for human health

Article in Food Research International · June 2025

DOI: 10.1016/j.foodres.2025.116869

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 Food Research International 217 (2025) 116869

Contents lists available at ScienceDirect

Food Research International

journal homepage: www.elsevier.com/locate/foodres

Review

Postbiotics versus probiotics: Possible new allies for human health

Chiara Maria Calvanese a , Francesco Villani a , Danilo Ercolini a , Francesca De Filippis a,b,*
a
Department of Agricultural Sciences, University of Naples Federico II, via Università 100, 80055 Portici, (NA), Italy
b
Institute of Biotechnology and Food Technology, Industrial University of Ho Chi Minh City, 12 Nguyen Van Bao Street, Go Vap district, Ho Chi Minh city, Viet Nam

A R T I C L E I N F O A B S T R A C T

Keywords: Postbiotics, defined as “preparations of inanimate microorganisms and/or their components that confer a health
Inactivated microorganisms benefit to the host,” are emerging as a new frontier in nutritional and clinical research. This review aims to
Postbiotics summarize the current scientific literature on postbiotics administration, comparing the evidence associated with
Probiotics
the use of live or inactivated forms of microorganisms. The administration of a probiotic or postbiotic should not
Genomic characterization
be considered as mutually exclusive, but rather as interdependent approaches, that can be chosen based on the
Human health
Food technologies specific microorganism, the target population and its specific needs. In addition, we highlighted the potential of
Fermented foods ‘omics approaches as an efficient tool for the screening of microbial strains to identify postbiotic genetic traits.
Food supplement Finally, we discussed the issues that still limit the broad diffusion of postbiotic products on the market. Indeed,
we highlighted that there is certainly an urgent need for greater clarity and a specific regulation to encourage
research and development in the postbiotic sector.

1. Introduction diseases and diabetes, to preventing infections in the gastrointestinal

tract and oral cavity. Probiotics may also improve the immune system,
The role of nutrition in human health has been known since the time cognitive function, and facilitate nutrient absorption (Liu et al., 2024).
of Hippocrates (400 b.C.), summarized in his famous phrase “Let thy Several FFs contains potentially probiotic microorganisms, that are still
food be thy medicine and medicine be thy food”. In the current era, we alive at the moment of consumption (Valentino et al., 2024). Although
are facing with a sort of renaissance of nutrition, recognizing its the positive effects of probiotics in the prevention and treatment of
importance for the prevention and management of diseases (Witkamp & diseases have been well documented, questions remain about their
van Norren, 2018). dosage and long-term safety, especially in patients with underlying
Among the foods beneficial for human health, fermented foods (FFs) medical conditions. Their adverse effects, whether mild or severe, are
stand out, boasting a long and safe history of use. FFs are defined by the often overlooked by the huge volume of articles in the current literature
International Scientific Association on Probiotics and Prebiotics (ISAPP) describing their beneficial effects. Recent evidence has demonstrated
as “foods made through desired microbial growth and enzymatic con­ several health risks of probiotics that warrant a serious reconsideration
versions of food components” (Marco et al., 2021). of their use and further investigation (Liu et al., 2024). Indeed, the
Improving human health exploiting microbial metabolism is an development of systemic and local infections in individuals with pre-
evolving concept that is increasingly important for consumers, food existing health issues and damaged immune systems upon probiotics
manufacturers, health-care professionals and regulators (Salminen treatment has been reported, as well as the possible link with metabolic
et al., 2021). As a result of the multitude of food-microbe combinations, disorders, allergic conditions and the spreading of antimicrobial resis­
there are thousands of different types of FFs and beverages (Marco et al., tance (Liu et al., 2024). For instance, liver abscess and bacteremia has
2017). At least some forms of these products are consumed by nearly been reported after using a Lactobacillus spp. probiotic to treat Clos­
every population worldwide (Marco et al., 2017). The beneficial effects tridium difficile colitis in a 82-year-old woman (Sherid et al., 2016).
provided by FFs is closely associated with the concept of pro- and Moreover, endocarditis has been also reported in a man with prostate
postbiotics. Probiotics are “live microorganisms that, when adminis­ cancer who consumed Lacticaseibacillus paracasei probiotic (Sotoudegan
tered in adequate amounts, confer a health benefit on the host” (Hill et al., 2019). Some mild to moderate side effects, including rash, nausea,
et al., 2014). These benefits range from preventing cardiovascular flatulence, abdominal bloating, vomiting, chest pain, constipation, and

* Corresponding author at: University of Naples Federico II, Dept. of Agricultural Sciences, Via Università 100, 800055 Portici, (NA), Italy.
E-mail address: francesca.defilippis@unina.it (F. De Filippis).

https://doi.org/10.1016/j.foodres.2025.116869
Received 27 February 2025; Received in revised form 11 June 2025; Accepted 11 June 2025
Available online 16 June 2025
0963-9969/© 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
C.M. Calvanese et al. Food Research International 217 (2025) 116869

poor appetite, were observed in children assuming probiotics to treat postbiotic. However, metabolites can certainly be part of a postbiotic
diarrhea (Sotoudegan et al., 2019). Despite the widespread use of pro­ preparation since preparations with inanimate microbial biomass will
biotics, there is still a lack of conclusive scientific research regarding inevitably contain some metabolites. In summary, if metabolites are
which specific strains are best, how they should be formulated, and purified or processed from inactivated cells and the preparation does not
which the optimal dosage is. Factors such as temperature, humidity, and contain cells or their components, then they cannot be considered as
air exposure can negatively affect the survival of these beneficial bac­ postbiotic, regardless of the health benefits. Finally, the term “prepa­
teria during storage, which needs careful consideration. Incorporating ration” is chosen to imply that specific microbial biomass formulations,
probiotic cultures into functional foods presents considerable hurdles matrices and/or inactivation methods play a role in the relevant bene­
from both a commercial and technological standpoint, primarily con­ ficial effects (Salminen et al., 2021). Therefore, the production process
cerning maintaining the bacterial vitality. A significant number of live must be characterized and described in detail, and it has to be suffi­
probiotic organisms do not survive the production process, the storage ciently controlled to allow the reproducibility of the preparation
and transport conditions, or even the passage through the digestive (Vinderola, Sanders, et al., 2023c). Indeed, as already noticed (Aguilar-
system. Consequently, many of them die before they can provide any Toalá et al., 2021) the terminology proposed by ISAPP does not meet the
health benefits (Prajapati et al., 2024). objective of greater clarity but on the contrary, may be misleading, since
All these aspects have given rise to the emerging and alternative it simultaneously includes inactivated microorganisms and their specific
concept of postbiotics. Although the definition is still uncertain, and products or components. However, there should be a better distinction
there is still no clarity on the appropriate use of the term, a generally between well-defined molecular factors of microbial origin with health-
accepted definition coined by ISAPP is the following: “preparation of beneficial properties (original concept of postbiotic) and the use of
inanimate microorganisms and/or their components which confers a complex matrices derived from microbial cells, for which the molecular
health benefit to the host” (Salminen et al., 2021). Indeed, several mi­ factors beneficial to health are not precisely known (concept of para­
croorganisms may explicate a positive health effect even when they are probiotic). Technically, any microbe could be used to generate a post­
dead or inactivated, releasing in the matrix beneficial metabolites or biotic, provided that it is identified at the strain level, the preparation
through their cellular components (Pimentel et al., 2023). According to method is adequately described, and the safety and efficacy of the
this definition, several FFs, where microorganisms are dead at the preparation are demonstrated in properly conducted trials in the
moment of consumption (Salminen et al., 2021), may fall within the intended host (Vinderola, Sanders, et al., 2023c). According to the
postbiotic class. Indeed, these products may have a beneficial health existing literature, postbiotics are mainly derived from some traditional
effect, due to the presence of microbial metabolites directly released in probiotics, e.g. strains within Lactobacillus and Bifidobacterium genera, or
the matrix, or due to specific cellular components (Salminen et al., from next-generation probiotics, such as Bacteroides spp., Akkermansia
2021). Besides the nutritional benefits, it can be reasonably expected muciniphila, and other intestinal microorganisms (Wei et al., 2024).
that postbiotics have a better safety profile than probiotics (Liu et al., An important driver of the postbiotic concept is the inactivation
2024). Postbiotics would represent an effective and safe alternative, process, that can be done through thermal or non-thermal inactivation.
ensuring the similar desired effects of a probiotic therapy, while using Traditional heat treatment (pasteurization, tyndallization, autoclaving)
their non-viable counterpart, and therefore covering that portion of the ensures enzymatic and microbiological stability of the system. However,
population such as newborns, elderly people and patients with clinical the temperature and the length of the treatment influence the nutritional
states for whom the use of probiotics may be not recommended. This value and the sensory characteristics, so it may not always be the best
review aims to summarize the current scientific literature on probiotic option for postbiotics intended for use as a food or a food supplement
and postbiotic administration, comparing the evidence associated with Non-thermal inactivation treatments are a valid alternative to maintain
the use of live or inactivated forms of microorganisms. The use of a quality and sensorial properties close to those of their fresh equivalents,
probiotic or postbiotic therapy should not be intended as mutually while ensuring safety and stability. Non-thermal inactivation treatments
exclusive, but rather as closely linked and complementary, chosen ac­ include technologies such as electric field, ultrasound, high pressure, X-
cording to the specific microorganism, the target population and its rays, etc. Since the inactivation treatment may influence the result, the
needs. beneficial effect exerted by the postbiotic must be demonstrated in
relation to the pre-established treatment (Salminen et al., 2021).
2. What is known about postbiotics ISAPP also clarifies the position of fermented formulas in the defi­
nition of postbiotics. Since fermented formulas do not contain substan­
Before 2021, several definitions of postbiotics had been coined, in tial amounts of viable bacteria in the final product, if the fermenting
some cases contradictive. Therefore, aligning around a common termi­ microorganisms and the beneficial effects are adequately characterized,
nology was necessary to facilitate understanding, reduce errors, allow these products would fall under the postbiotic definition (Salminen
comparison of results and consequently advance scientific research in et al., 2021). However, the maximum concentration of active microor­
this field. The ISAPP definition (Salminen et al., 2021) of the term ganisms that are acceptable for a fermented formula to be considered as
“postbiotic” reported above has raised additional questions. Vinderola, a postbiotic is not specified.
Sanders, et al. (2023c) provided detailed answers to frequently asked Five mechanisms of action have been proposed for postbiotics: i)
questions about the ISAPP postbiotic definition. One of the most modulation of the resident microbiota (through lactic acid, short-chain
frequent questions is around the term “inanimate”, chosen in the ISAPP fatty acids (SCFAs), bacteriocins, quorum sensing, cross-feeding, adhe­
consensus definition of postbiotic. Although not a common term in sins, etc.); ii) enhancement of epithelial barrier functions (through
microbiology, this term has been used in the attempt to distinguish exopolysaccharides (EPS), SCFAs, proteins, etc.); iii) modulation of local
“inactive” from “non-viable”, as a postbiotic is undoubtedly “active” in and systemic immune responses, e.g., through MAMP-PRR (microbe-
terms of conferring a health benefit. For this reason, the term “inactive” associated molecular pattern and pattern-recognition receptor) inter­
could be misleading. Furthermore, examining the definition provided by action, indole derivates, keto acids, branched chain fatty acid; iv)
the ISAPP consensus, that focus on “inanimate microorganisms and/or modulation of systemic metabolic responses (through bile salt hydro­
their components”, it seems not to consider their metabolites. The lase, succinate, vitamins, SCFAs, etc.); and v) systemic signaling via the
reason for this lies in the etymology of the Latin term post-biotic, that nervous system (through serotonin, dopamine, acetylcholine, γ-amino­
means “after life” (Pérez-Alvarado et al., 2022). Microbial metabolites, butyric acid, etc.) (Salminen et al., 2021).
such as vitamins or short-chain fatty acids, are not living beings and By definition, postbiotics inherently have advantages over their live
therefore cannot have an “after life”. For this reason, preparations counterparts, as reported by Piqué et al. (2019) and listed below:
consisting only of metabolites have been excluded from the concept of

2
C.M. Calvanese et al. Food Research International 217 (2025) 116869

• No risk of bacterial translocation from the gut lumen to the blood in postbiotics represents an opportunity not only to elucidate their mech­
vulnerable and immunocompromised subjects; anisms of action in detail, but also to develop novel therapeutic strate­
• No chances of acquisition and transfer of antibiotic resistance genes; gies for improving health.
• Easier to be standardized, transported, and stored; Some human studies have shown that postbiotic treatment can
• Enhanced and direct interaction of the molecules released by the modulate the composition and activity of the human microbiome,
disrupted microbial cells with the target cells. indirectly influencing human health (Ji et al., 2023). While there is a
large literature focused on the therapeutic use of viable beneficial bac­
The main differences between probiotics and postbiotics are sum­ teria in clinical trials, the study of postbiotics has been relatively
marized in Fig. 1. neglected. However, scientific evidence of their beneficial health effects
is steadily accumulating, although their precise composition and un­
3. Postbiotic treatments in humans derlying mechanisms remain under investigation. In Table 1, we sum­
marized results from human clinical trials evaluating postbiotics for the
Recent years have seen significant challenges in drug development. treatment of different health conditions. The initial literature search was
High failure rates during preclinical and clinical trials, often due to the carried out on Scopus using different combinations of the keywords:
lack of efficacy or safety concerns, lead to wasted resources and pro­ “postbiotics”, “human clinical trial”, “heat-killed bacteria”, “human
longed development times. The long and complex development process, subject”, “postbiotics”, “heat-killed bacteria”. We excluded trials on
combined with stringent regulatory hurdles, further increases costs and animals and in vitro studies, articles not in English and reviews.
delays, with the average cost of developing a new drug estimated as > Table 1 shows the different types of postbiotic products used in
$2.8 billion (DiMasi et al., 2016;). While existing drugs offer numerous human clinical trials (mainly microbial lysates, heat-killed bacteria and
benefits, they also have limitations. Side effects can impact patients’ fermented formula) tested to address different health conditions
quality of life and adherence to treatment. Additionally, individual (gastrointestinal disorders, immune status, oral and skin microbiome
variations in genetics and disease can affect the efficacy. Some drugs modulation, etc.). Burta et al. (2018) tested a postbiotic formulation of
have narrow therapeutic windows, making precise dosing critical to Limosilactobacillus reuteri and Bifidobacterium brevis for alleviating
avoid adverse effects or suboptimal outcomes (Mehta et al., 2023). gastrointestinal tract disorders in adults, such as functional bloating,
Antibiotics are traditionally used to treat and prevent infections. achieving a reduction of flatulence and discomfort. Addressing the im­
Appropriate use of antibiotics saves millions of lives by providing the mune status of adults and elderly, a RTC with heat-killed Lactiplantiba­
ability to specifically kill infecting microorganisms with minimal side cillus pentosus strain b240 showed its efficacy in reducing the incidence
effects on host cells (Moser et al., 2019). However, despite their long rate of the common cold in elderly adults, indicating that this treatment
history of controlling bacterial pathogens, reckless and inappropriate might be useful in improving the resistance against infections through
use of antibiotics may negatively alter gut eubiosis, reducing microbial enhancing mucosal immunity (Shinkai et al., 2013). Moreover, Miya­
diversity (Saleh et al., 2025). In addition, the uncontrolled and wide­ zawa et al. (2015) observed that heat-killed Lactobacillus gasseri
spread use of antibiotics also contributes to the spread of antibiotic- TMC0356 enhanced immunity in the elderly, improving their natural
resistant strains, posing a significant threat to public health and defense mechanisms against pathogenic infections. Differently, a treat­
lowering the effectiveness of the treatment (Saleh et al., 2025). The ment with heat-killed Lacticaseibacillus paracasei MCC1849 was not
limitations of conventional medicine in treating human diseases neces­ useful in improving immune parameters in elderly (Maruyama et al.,
sitate the development of innovative approaches. Research on 2016). These heterogeneous results suggest that the stimulation of

Fig. 1. Comparison between probiotics and postbiotics. The discriminating factors between probiotics and postbiotics concern the mechanism of action, stability,
safety, application and limitations, apparently demonstrating a potential advantage of postbiotics over their live counterparts. ARG, Antibiotic Resistance Genes.

3
 Table 1

C.M. Calvanese et al.

Human clinical trials evaluating the impact of a postbiotic treatment.
Postbiotic type Species/strain RCT design Population Control Quantity/ Treatment length and Effect on the human Outcomes Reference
targeted group microbial loads frequency microbiome*1
inactivated

Tyndallized bacteria Limosilactobacillus reuteri and Double-blind, Adults with Yes 1 capsule Oral administration 3 Not analysed Significantly reduced (Burta et al.,
Bifidobacterium brevis multicentre, functional swelling (CFU inactivated/ times/day for 20 days abdominal distension 2018)
(Aprotecol ®) randomized dose not specified) and flatulence
study
Heat-killed bacteria Lactiplantibacillus pentosus Randomized, Elderly adults with Yes Low-dose group: 2 Oral administration, 1 Not analysed Significantly reduced (Shinkai
strain b240 double-blind, common cold × 109 CFU tablet once/ day for 20 the incidence rate of et al., 2013)
placebo- inactivated/dose; weeks the common cold in
controlled trial high-dose group: elderly adults,
with parallel 2 × 1010 indicating that b240
three-group inactivated CFU/ strain might be useful
comparison dose in improving
resistance against
infection through
mucosal immunity
Heat-killed bacteria Lactobacillus gasseri Double-blind, Healthy elderly Yes 1.0 × 109 CFU Oral administration once Not analysed Improving immunity (Miyazawa
TMC0356 placebo- inactivated/dose daily for 4 weeks in the elderly et al., 2015)
controlled
clinical trial
Non-viable probiotic Escherichia coli (DSM 17252) Randomized, Patients of both Yes 1 mL = 14 drops of 10 drops (0.71 mL) for 3 Not analysed Postbiotic treatment is (Mack et al.,
lysate (BL) and Enterococcus faecalis double-blind, sexes with IBS BL suspension times/day during week effective only in 2022)
(DSM 16440) placebo- containing the one; 20 drops (1.42 mL) patients with IBS-D
controlled, bacterial lysate of for 3 times/day during subtype after 6
multicenter (30 1.5–4.5 × 107 week two; 30 drops (2.14 months of treatment
study sites), E. coli (DSM mL) for 3 times/day
parallel group 17252) and during week 3, and
4

study 1.5–4.5 × 107 Ent. maintenance dosing of 30

faecalis (DSM drops for 3 times/day
16440). until week 26
Fermented lysate2 Lacticaseibacillus rhamnosus Randomized, Subjects with Yes CFU inactivated/ Lotion for topical Not analysed Skin barrier (Cui et al.,
VHProbi®E06, self-control study impaired skin dose not specified application, twice daily improvement with 2023)
Lacticaseibacillus paracasei barrier for 30 days effective benefits for
VHProbi® E12, people with sensitive
Lactiplantibacillus plantarum skin
VHProbi® E15 Lactobacillus
helveticus VHProbi® Y21
Bacterial lysate3 Lactiplantibacillus plantarum Pilot study Subjects with mild None CFU inactivated/ Twice daily for 4 weeks Not analysed Confer effective (Cui et al.,
VHProbi® E15 to moderate acne dose not specified benefits in people with 2022)
mild to moderate acne
Lyophilized cell 21 strains from 8 common Prospective, Children aged 6 Yes 3.5 mg of One capsule per day for 9 Not analysed Adjuvant treatment (Bodemer
lysate respiratory pathogenic randomized months to 7 years, lyophilized months with the bacterial et al., 2017)

Food Research International 217 (2025) 116869

microorganisms (i.e. (1:1), double with confirmed bacterial lysate lysate (OM-85)
Haemophilus influenzae, blind, placebo atopic dermatitis (CFU inactivated/ improves
Klebsiella ozaenae and controlled trial of (AD) diagnosis dose not specified) management of atopic
Klebsiella pneumoniae, parallel groups dermatitis
Staphylococcus aureus,
Streptococcus viridans
Streptococcus pyrogenes and
Streptococcus Pneumoniae,
Neisseria catarrhalis)
Heat-killed bacteria Lacticaseibacillus paracasei Randomized, Elderly ≥65 years of Yes 1 × 1010 heat- 1 jelly/day for 6 weeks Not analysed No significant (Maruyama
MCC1849 double-blind, age killed CFU/dose (1 differences in immune et al., 2016)
placebo- jelly) parameters
controlled study
(continued on next page)
 Table 1 (continued )
Postbiotic type Species/strain RCT design Population Control Quantity/ Treatment length and Effect on the human Outcomes Reference

C.M. Calvanese et al.

targeted group microbial loads frequency microbiome*1
inactivated

Fermented product Lactiplantibacillus plantarum Randomized, Subjects with Yes CFU inactivated/ Oral administration three Not analysed Decrease in (Oh et al.,
double-blind, impaired fasting dose not specified times per day for four postprandial glucose 2014)
placebo- glucose or type-2 weeks levels
controlled diabetes
clinical trial
Fermented infant Bifidobacterium breve C50, Randomized, 0–4-week-old non- Yes CFU inactivated/ 1 dose/day, for 17 weeks Increase in Bifidobacterium Modulation of the (Rodriguez-
milk formula4 Streptococcus thermophilus controlled, breastfed infants dose not specified spp.; decrease in intestinal microbiota Herrera
065 double-blind Clostridioides difficile of the formula-fed et al., 2022)
study infants by shifting it
towards that of
breastfed infants;
reduction of colics
Fermented milk with Lactobacillus gasseri CP2305 Double-blind, Healthy individuals Yes 1 × 1010 1 dose per day for 3 weeks Increase in Clostridium Beneficial effects on (Sawada
non-viable placebo- with a tendency CFU inactivated/ cluster IV group (included the regulation of et al., 2016)
microorganisms controlled trial towards dose (190 g) Faecalibacterium intestinal function
constipation or prausnitzii)
frequent bowel
movements (20–70
years old)
Toothpaste Lactobacillus salivarius LS97, Randomized Participants 18–30 Yes 3 × 1010 CFU Twice daily for 2 months Decrease in the relative Improvement of oral (Rui et al.,
containing Lacticaseibacillus paracasei controlled years old, healthy, inactivated/dose abundance of immunity levels 2024)
inactivated LC86, and Lactobacillus clinical trial without systemic Enterobacteriaceae,
bacteria acidophilus LA85 diseases, without Klebsiella, Escherichia in
infectious diseases; the oral microbiota of the
no obvious dental postbiotic group; increase
calculus in Ruminofilibacter and
Lactobacillus
5

Lozenges with heat- Lacticaseibacillus paracasei Randomized, Subjects with Yes 1 × 1010 CFU 3 times/day for 4 weeks Reduction of halitosis- Prevention or (Wuri et al.,
killed ET-22 double-blind halitosis inactivated/g; associated taxa (Rothia, reduction of halitosis 2023a)
microorganism placebo- tablet weight not Streptococcus) and modulation of
controlled reported human oral
clinical trial microbiota
Toothpaste Lacticaseibacillus paracasei Randomized, Adults (20–59 years Yes 0.7 × 109 Two minutes tooth Reduced Streptococcus Potential in oral (Lee et al.,
containing GMNL-143 double-blind, old) who received a CFU inactivated/g brushing twice daily for 4 mutans in crevicular fluid; microbiota 2024)
postbiotic (heat- crossover, dental prophylaxis toothpaste weeks, followed by a 1- positive relationship modulation and
killed bacteria) placebo- one week before week washout period, and between taxa related to gingivitis
controlled trial enrollment, with ≥ then crossed over to the oral health and gingival improvement
20 natural teeth, placebo for 4 weeks index changes
and diagnosed with
moderate to severe
gingivitis
Fermented powder in Lacticaseibacillus paracasei Randomized, Adults (18–65 years Yes Each tablet was 1 tablet/day for 21 days Increase in beneficial gut Modulation of human (Guo et al.,

Food Research International 217 (2025) 116869

pill-form Zhang, Lactiplantibacillus double-blind, old) who suffered 0.6 g (CFU bacteria, including gut microbiome and 2024)
plantarum p-8, placebo- from chronic inactivated/dose Dysosmobacter welbionis alleviation of
Bifidobacterium animalis controlled diarrhea not specified) and Faecalibacterium diarrhea-associated
subsp. lactis V9 crossover trial prausnitzii; reduction in symptoms
potential pathogens like
Megamonas funiformis
1
not all the studies considered in the table reported the gut microbiome analysis; RCT, Randomized Controlled Trial.
2
To obtain the fermented lysate, bacterial strains were inoculated into a fermentation medium (2 % molasses, 0.1 % peptone, 5 % collagen, 0.3 % (NH4)2HPO4 and 1000 mL of distilled water) and incubated at 37 ◦ C for
48 h. The fermented material was then homogenized using a homogenizer (APV-1000, SPXFLOW, USA) at 1000 bar and heated to 70 ◦ C for 10 min before being used in the experiments.
3
The fermentation medium contained 3 % brown sugar, 3 % collagen, 0.3 % yeast extract, 0.25 % (NH4)2HPO4, and 1000 mL distilled water. Strains of Lctiplantibacillus plantarum VHProbi® E15 were prepared for use
by subculturing in MRS broth at 37 ◦ C for 24–48 h no fewer than 2 but no more than 7 times. Afterward, the seed cultures were used to inoculated a fermentation medium with 1 % (w/v) and incubated under aerobic
conditions at 37 ◦ C for 48 h. The fermentation cultures were homogenized under 1000 bar then, the lysate was harvested as the functional ingredient after being heated at 70 ◦ C for 15 min.
4
In the experimental formula, the postbiotics were generated by subjecting 30 % of the total formula composition (Lactofidus) to a unique fermentation process involving two bacterial strains, Bifidobacterium breve C50
and Streptococcus thermophilus 065. One of the bioactive compounds that was generated in this process is 3′-galactosyllactoses (3′-GL), an oligosaccharide found in human milk, at a final level of ~25 mg/100 mL formula.
C.M. Calvanese et al. Food Research International 217 (2025) 116869

immune system may be a strain-specific effect. In addition, as proposed ginseng, in fact, ginsenosides are transformed into their more easily
for probiotic treatments, the efficacy may be affected by subject-specific absorbable and potent deglycosylated forms. The administration of this
signatures in the human microbiome, that influence the responsiveness fermented product showed a significant reduction in postprandial
(Gibbons et al., 2022; Maldonado-Gómez et al., 2016). Of particular glucose levels, suggesting that postbiotic application can also be used to
interest is the study by (Bodemer et al., 2017), where the supplement of enhance the beneficial functions of products already known for their
a lyophilized microbial lysate containing 21 strains of 8 common res­ positive properties, such as red ginseng, broadening their field of action.
piratory pathogens (i.e. Haemophilus influenzae, Klebsiella ozaenae, K. However, the study presents some limitations, including the lack of in­
pneumoniae, Staphylococcus aureus, Streptococcus viridans, S. pneumoniae, formation on the inactivation method of Lp. plantarum after freeze-
S. pyrogenes, Neisseria catarrhalis) for 9 months led to an improvement of drying. Therefore, future studies should be better designed for this goal.
atopic dermatitis in children. Therefore, even microbes that are Therefore, several evidence suggest that postbiotics of lactobacilli
considered pathogens when alive, might be effective and have a positive and bifidobacteria species can modulate the human intestinal and oral
role when applied as postbiotics. microbiome and consequently may be considered as strategic treatments
Cui et al. (2022; 2023) focused on the effects of topical application of for restoring microbial dysbiosis. Furthermore, the target populations of
postbiotics for skin treatment. Particularly, postbiotics of Lc. rhamnosus, the studies reported in Table 1 are both healthy adults and sensitive
Lc. paracasei, Lp. plantarum, L. helveticus enhanced skin barrier in people subjects (e.g., elderly and children), supporting the safety and usefulness
with sensitive skin and showed effective benefits in people with mild/ of postbiotics in these populations. In general, postbiotic administration
moderate acne. appears to have broad therapeutic potential, applicable to a wide range
In addition, the impact of postbiotics on the human oral microbiome of health conditions. However, most of the available trials are focused on
was also investigated (Table 1). Heat-killed Lc. paracasei strains, either small populations and they often lack a control group. Another impor­
alone or in combination with other species, showed a positive effect in tant limitation is the lack of information on the metabolites or cellular
modulating the oral microbiome. In particular, a randomized, double- components responsible for the effects described, that makes difficult to
blind placebo-controlled clinical trial tested heat-killed Lc. paracasei determine exactly the reasons behind this effect. Moreover, in some
ET 22 for the treatment of halitosis, demonstrating a significant reduc­ cases the absence of live microorganisms was not evaluated in the study,
tion of the oral taxa involved, Rothia and Streptococcus (Wuri et al., or an appropriate control was not used, thus making difficult to ascertain
2023). Similarly, in the study by (Lee et al., 2024), the administration of that the benefit was caused exclusively by the inanimate microorgan­
heat-killed Lc. paracasei GMNL-143 through a toothpaste was tested in isms. In addition, not all the studies reported in Table 1 clearly stated the
adults with gingivitis. A reduction of S. mutans and Aggregatibacter starting concentration of live cells that were inactivated for obtaining
actinomycetemcomitans was observed (both anaerobic bacteria related to the postbiotic. All these points highlight that comparing the results from
the initiation and progression of periodontal disease). Moreover, inac­ different studies is often not possible, as well as understanding if there is
tivated Lc. paracasei LC86, L. salivarius LS97 and L. acidophilus LA85 a dose-response effect. Considering the health outcomes reported in this
were used in a toothpaste, showing effective in modulating the oral section, there is not a sufficient number of studies to compare the same
microbiome of healthy subjects, with a decrease in the abundance of species in viable and non-viable forms for the same beneficial effect,
detrimental species, such as Enterococcus, Klebsiella, Turicibacter, and, in any case, the mechanism of action is not specified. Therefore,
Enterobacter and Prevotella and an increase in Ruminofilibacter and there is a need of well-designed clinical trial, to evaluate the impact of
Lactobacillus (Rui et al., 2024). inactivate microorganisms and identify the molecular mechanisms, as
Postbiotics also showed activity in the modulation of the gut well as the compound(s) responsible of the declared effect.
microbiome (Table 1). A fermented infant formula containing non-
viable Bif. breve C50 and S. thermophilus 065 was administered to in­ 4. Clinical trials comparing pro- and postbiotics
fants fed with artificial formula, resulting in a reduction of colic
occurrence and a modulation of the intestinal microbiota, that became In this section, we screened current literature for clinical trials
more similar to that of breastfed infants, with an increase in Bifido­ comparing the same microbial strain administered either as a probiotic
bacterium spp. (typically dominating the gut microbiota of breastfed or a postbiotic to the similar target population. The comparison may
infants) and a decrease in Clostridioides difficile (Rodriguez-Herrera come from the same or different studies. The initial literature search was
et al., 2022). In addition, a fermented milk with non-viable L. gasseri carried out using Scopus and different combinations of the keywords:
CP2305 was effective in regulating intestinal function in healthy in­ “postbiotics”, “human clinical trial”, “heat-killed bacteria”, “human
dividuals with constipation or frequent bowel movements, leading to an subject”, “probiotics”, “postbiotics”, “live bacteria”, “heat-killed bacte­
increase in Clostridium cluster IV group, known for the production of ria”. We excluded trials on animals and in vitro studies, articles not in
short-chain fatty acids (SCFAs). Therefore, the heat-inactivated strain English and reviews. In addition, we only included a study in Table 2 if
may have beneficially influenced the intestinal environment through both the live and the inactivated strain was tested, or if we could find
stimulating the production of SCFAs by the resident intestinal micro­ this comparison on similar target populations in two different studies.
biota. However, it was unclear whether the heat-inactivated strain The trials reported in Table 2 tested postbiotics for the treatment of
boosted the growth of some bacterial groups producing SCFAs or just different health conditions, including gastrointestinal disorders, im­
stimulated the metabolism of specific gut microbes towards the pro­ mune system enhancement, allergies, oral halitosis, skin hydration. In
duction of these metabolites without influencing their abundance the study by Kaila et al., 1995 Lc. rhamnosus was tested for the pre­
(Sawada et al., 2016). In another trial, a fermented powder in pill-form vention of rotavirus diarrhea in infants, both live and as inactivated form
with Lc. paracasei Zhang, L. plantarum p-8 and Bif. animalis subsp. lactis (heat-killed). In this case, the live probiotic was found to be more
V9 relieved diarrhea-associated symptoms in adults, boosting an in­ effective than the postbiotic (Table 2). However, since it is not reported
crease in beneficial intestinal bacteria, including Faecalibacterium which metabolite or cell component was responsible for this effect, it is
prausnitzii, while reducing potential pathogens such as Megamonas difficult to speculate on the reasons. Treatment with live or inactivated
funiformi. mixtures of different strains belonging to the genus Bifidobacterium (Bif.
(Oh et al., 2014) evaluated the effect of a red ginseng product fer­ breve M-16 V, Bif. longum subsp. infantis M-63, Bif. longum subsp. longum
mented with Lp. plantarum on metabolic disorders. Rather than an iso­ BB536) was also evaluated for the prevention of necrotizing enteroco­
lated effect attributable only to the inactivated microorganism, this litis, all-cause mortality, sepsis, and feeding intolerance in very preterm
study demonstrates that bioconversion driven by Lp. plantarum enhances infants (Athalye-Jape et al., 2025). Postbiotic administration was safe
the pharmacological efficacy of red ginseng, already clinically evaluated and showed no significant difference compared to the live strains,
for the treatment of type 2 diabetes. During bacterial fermentation of red although adequately designed studies are needed to evaluate the effects

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C.M. Calvanese et al. Food Research International 217 (2025) 116869

of postbiotic on clinically meaningful outcomes in preterm infants. On vital state. Based on the above, some genes involved in potential post­
the other hand, L. acidophilus was used for the treatment of acute diar­ biotic activities are reported in Table 3.
rhea in children aged 6 to 60 months (Indriyani et al., 2012). Both Several studies focused on bacteriocin production. (Toushik et al.,
treatments demonstrated a reduction in the duration and frequency of 2022) tested the inhibitory activities of a postbiotic of Leuconostoc
diarrhea and led to an improvement of weight gain. However, it has to mesenteroides J.27 against three pathogenic microorganisms (Vibrio
be pointed out that this study evaluated two commercial products with a parahaemolyticus, Pseudomonas aeruginosa and Escherichia coli). For a
different composition: the postbiotic was prepared using only L. aci­ rapid identification and characterization of the antimicrobial properties,
dophilus, while the probiotic included also other species. Therefore, the genes encoding bacteriocins, such as mesY, plnA, plnC, plnEF, curA, were
treatments cannot be adequately compared. Conversely, the same searched in the strain genome (Table 3). Similarly, genomes of Lat­
strains of Lc. paracasei and Lactococcus lactis subsp. lactis were tested ilactobacillus curvatus B.67 and L. plantarum M.2 were screened for the
against oral halitosis and skin hydration, respectively (Kimoto-Nira presence of genes encoding bacteriocins responsible for antibacterial
et al., 2012, 2014; Wuri et al., 2023). Both the studies suggested that the and antibiofilm activity against Listeria monocytogenes (Hossain et al.,
probiotic and the postbiotic had similar effects (Table 2). In addition, 2021).
some studies have demonstrated the usefulness of using probiotics as (Van Kranenburg et al., 1999) focused a genomic screening of LAB
sports nutritional supplements. In the double-blind design study by (Lee, for exopolysaccharides (EPS) production, identifying the pathways and
Ho, et al., 2022b), healthy subjects, divided into groups according to the the genes involved in their biosynthesis. EPS produced by LAB are
study criteria, assumed capsules containing live or a heat-killed Lc. known for biological activities such as antitumor, antioxidant, antiviral,
paracasei PS23 group and the impact of the treatment on exercise- antiulcer, cholesterol-lowering effects, immunomodulatory properties
induced muscle damage was evaluated, suggesting a similar effects of (Dilna et al., 2015). Furthermore, they are known for their structural and
the two treatments, showing protective and faster recovery benefits, as chemical-physical properties, boasting a wide application in different
well as reducing fatigue. Similarly, Lp. plantarum TWK10 enhanced industries (Sasikumar et al., 2017). EPS production in LAB is a complex
athletic performances and reduced inflammation caused by exercise process involving several gene cassettes and their gene products. Gly­
(Lee, Liao, et al., 2022a). These results do not indicate that the postbiotic cosyltransferase enzymes are important in enhancing EPS production
preparation was used as a medical treatment, but rather as a preventa­ (Van Kranenburg et al., 1999), thus represent a possible target for ge­
tive and/or recovery supplement for exercise-induced muscle damage. netic engineering of LAB.
Although the number of studies comparing the same strains in both Vitamins production by progenitor strains, subsequently found
the forms (pro- and postbiotic) on the same target population is still within postbiotic preparations, is another interesting feature. Vitamins
limited, data available suggest that in several cases the two formulations are micronutrients essential for the metabolism of all living organisms.
have comparable efficacy. However, these effects should be validated Indeed, even in highly industrialized countries, vitamin deficiencies,
with wider and ad-hoc designed clinical trials. In addition, the effects due to malnutrition or unbalanced diets are still very common. LAB have
observed may be influenced by several factors, including the charac­ been shown to produce several vitamins, such as B and K. Therefore, the
teristics of the specific population, as well as the strain tested, the spe­ use of vitamin-producing microorganisms represents a natural, cheap
cific molecules responsible for the targeted effect and the personalized and more sustainable alternative to the use of chemically synthesized
response. Future studies should investigate the comparison between pseudovitamins, for the production of fortified foods (Leblanc et al.,
probiotics and postbiotics, focusing on the same strains and target 2011). For example, bio-fortified fermented foods, containing LAB
populations to better understand their efficacy. producing riboflavin during fermentation have been studied (Thakur,
Tomar, & De, 2016b). Moreover, Thakur, Tomar, Brahma, and De
5. Omics’ approach to identify postbiotics (2016a) screened 60 lactobacilli strain genomes for the presence of
riboflavin biosynthesis genes. This approach allowed to identify 19
Although postbiotic mechanisms of action are mostly unknown, strains belonging to the species Limosilactobacillus fermentum, L. planta­
recent advances in the field of “omics” approaches may facilitate the rum, Lactobacillus delbrueckii subsp. bulgaricus, and Limosilactobacillus
screening of multiple strains to highlight the presence of potentially mucosae having the complete biosynthetic pathway, highlighting that
relevant traits. In order to design a novel pro- or postbiotic, a series of the presence of riboflavin biosynthesis genes is strain-specific and the
efforts are necessary to understand its functionality, as well as safety. power of a comparative genome approach to screen a high number of
Thus, a new approach, called probiogenomics, emerged, which includes potentially producing strains, thus reducing those to be tested in time-
the application of high-throughput techniques such as genomics, tran­ consuming, in vitro analyses (Table 3).
scriptomics, proteomics and metabolomics, which provide a valuable Other metabolites of postbiotic interest include SCFAs (Eslami et al.,
resource for the prediction of strain functionality and the rational se­ 2024). SCFAs are the major metabolic products of anaerobic fermenta­
lection of new, uncharacterized strains (Castro-López et al., 2021). Data tion by microbial communities that colonize the mammalian gut and the
obtained from ‘omics approaches allow an in-depth characterization of three major SCFAs, acetate, propionate and butyrate, differ considerably
physiology, functionality and mechanisms of action of the microorgan­ in their potential effects on host physiology (Louis & Flint, 2017). SCFAs
isms. Besides this, genomic screening is also important for determining play an important role in metabolic health by promoting fat oxidation,
the absence of unwanted traits, such as antibiotic-resistance genes or increasing energy expenditure. These molecules are also essential for
virulence factors. The postbiotics market is one of the fastest growing preserving gut health, controlling the satiety feeling, and lowering cal­
sectors in the food industry, most likely due to the increasing scientific orie consumption, contributing to sustainable weight loss. Moreover,
evidence supporting the positive role in consumer health. This encour­ SCFAs aid in improving glucose tolerance and insulin sensitivity, posi­
ages and accelerates the search for new microorganisms that can be used tioning them as a valuable supplementary therapy in obesity and
as potential postbiotics. However, there are gaps in the validation pro­ metabolic syndrome (Coppola et al., 2022; Eslami et al., 2024). Ap­
cedures that need to be addressed. It is important to note that although proaches targeting the terminal genes of the major butyrate- and
the multi-omics approach can provide many advantages to the actual propionate-producing pathways have been developed (Vital et al.,
investigations, there are also some challenges in the downstream anal­ 2014b). Indeed, the main enzymes (acetate CoA-transferase, phospho­
ysis, especially the correct functional interpretation of the generated transbutyrylase, butyrate kinase, propionate CoA-transferase) involved
data (Castro-López et al., 2021). Moreover, genetic screening may sup­ in the biosynthetic pathways of SCFAs have been identified (Eeckhaut
port the identification of genes involved in functional activities of in­ et al., 2011; Louis & Flint, 2017), speeding up the creation of targeted,
terest, as well as the absence of undesirable traits, allowing also to effective postbiotic treatments for obesity (Vital et al., 2014b).
identify those characteristics of a strain that are independent of their Also, phenol-derived metabolites are gaining attention in the

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Table 2
Clinical trials comparing probiotic and postbiotic administration to the similar target populations.
Species/strain Therapeutic Population targeted Control Microbial Treatment Outcomes with viable Reference
administered alive or benefits group loads ingested length and strains vs postbiotic
inactivated (live or frequency of
inactivated) assumption

Lacticaseibacillus rhamnosus / Stimulation of Infants with rotavirus None 1 × 1010 CFU/ Twice a day for IgA antibody response was (Kaila et al.,
Heat-killed specific IgA diarrhea dose (both) 5 days (both) higher in infants treated 1995)
Lacticaseibacillus rhamnosus antibody responses with viable L. casei GG than
against rotavirus in those treated with the
diarrhea inactivated form
Lacticaseibacillus paracasei ET- Oral microbiota Adults with alitosis Yes 1.0 × 1010 CFU/ 3 times/day for Both ET-22.L and ET-22. (Wuri et al.,
22 dysbiosis and dose (both) 4 weeks (both) HK can significantly inhibit 2023)
(ET-22.L)/ Heat-killed L. halitosis the production of
paracasei ET-22 undesirable odor
(ET-22.HK) compounds in subjects
with halitosis, modulating
the composition of the oral
microbiota
Lactococcus lactis subsp. Hydration of Healthy women Yes 4 × 1010 CFU/ Once a day for Both treatments were (Kimoto-
cremoris H61/ Heat-killed healthy human skin dose 8 weeks effective in the Nira et al.,
Lc. lactis subsp. cremoris improvement of skin 2012,
H61 hydration and elasticity 2014)
Lacto-B® (Lactobacillus Diarrhea and Children (6–60 Yes 1 × 109 CFU/ Twice/day for Both treatments led to a (Indriyani
acidophilus, Bifidobacterium improvement of months) with acute dose (probiotic) five days (both) reduction in the duration et al., 2012)
longum, Streptococcus weight gain diarrhea - 3 × 1010 CFU/ and frequency of diarrhea,
thermophilus) /Dialac® dose improvement in weight
(tyndallized L. acidophilus) (postbiotic) gain; no significant
differences between
treatments
Lacticaseibacillus paracasei Speed up recovery Healthy subjects Yes 1 × 109 CFU/ Twice/day for Both supplements (Lee, Liao,
PS23/ Heat-killed and reduce exercise dose (both) 6 weeks (both) significantly slowed the et al.,
Lacticaseibacillus paracasei discomfort loss of muscle strength 2022a)
PS23 after muscle injury and
significantly reduced the
production of markers of
muscle damage and
inflammation
Lactiplantibacillus plantarum Improved physical Healthy subjects Yes 1 × 1011 CFU/ Three times Both groups had significant (Lee, Ho,
TWK10/Heat-killed performance, without professional dose daily for 6 improvement in physical et al.,
Lactiplantibacillus plantarum regulation of body athletic training weeks (both) performance, and a 2022b)
TWK10 composition and reduction in exercise-
attenuation of age- induced inflammation,
related decline compared to control
groups.
Bifidobacterium breve M-16 V, Intestinal anti- Very preterm Yes 3 × 109 CFU/ Once a day for The postbiotic was safe and (Athalye-
Bifidobacterium longum inflammatory effect (gestation <32 dose (both) 3 weeks showed no significant Jape et al.,
subsp. infantis M-63, in very premature weeks) infants differences compared to a 2025)
Bifidobacterium longum infants live probiotic; clinical
subsp. longum BB536/ results were comparable
Heat-killed Bifidobacterium between groups
breve M-16 V,
Bifidobacterium longum
subsp. infantis M-63,
Bifidobacterium longum
subsp. longum BB536
Lacticaseibacillus paracasei 33 Allergic rhinitis Patients (> 5 years Yes 5 × 109 Twice/day for Significant improvement (Peng &
(LP33)/ Heat-killed induced by house- old) with perennial CFU/dose 30 days (both) in symptom scores; no Hsu, 2005)
Lacticaseibacillus paracasei dust mite allergic rhinitis (both) significant differences
33 (HK_LP33) characterized by between treatments
intermittent or
continuous nasal
symptoms for more
than 1 year
Ligilactobacillus salivarius AP- Oral-nasal mucosal 45 healthy Yes 1 × 109 CFU/ Tree times a day Both treatments exerted (Lin et al.,
32, Bifidobacterium animalis immunity participants aged dose (probiotic) (morning, their beneficial functions 2021)
subsp. lactis CP-9 and 20–40 years - 1 × 1010 CFU/ noontime, and by boosting oral
Lacticaseibacillus paracasei dose evening) for 4 abundance of Lactobacillus
ET-66 / heat-killed (postbiotic) weeks (both) and Bifidobacterium,
Ligilactobacillus salivarius reducing Strep. mutans in
AP-32 and Lacticaseibacillus the oral cavity, and
paracasei ET-66 increasing salivary IgA
concentration

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postbiotic field. In general, phenolic compounds can be classified into within microbial genomes may facilitate wide screening of multiple
two broad macro-groups based on their chemical structure: simple strains, selecting the best candidates for the preparation of formulations
phenols and polyphenols (Edo et al., 2024). Indeed, microbial meta­ targeted to specific populations of interest, moving faster to the in vitro
bolism of phenolic compounds may mediate the health benefits of di­ and in vivo testing, and finally to the scale-up of the production.
etary polyphenols, increasing their bioavailability and leading to the
biosynthesis of anti-inflammatory compounds Examples are urolithins 6. Postbiotics to market: Commercial and industrial aspects
and equol, metabolites produced by the gut microbiota from specific
types of polyphenols present in foods. So far, equol is the most studied In the early 20th century, French researchers conducted a pioneering
phenolic postbiotic for the effects in humans mainly due to its estrogenic study that led to the introduction of postbiotics on the market. Dr. Pierre
activity. Studies have shown that equol supplementation can help alle­ Boucard’s research group discovered the therapeutic potential of heat-
viating menopausal symptoms (; Aso et al., 2012: Oyama et al., 2012). treated Lactobacillus cells in relieving digestive disease symptoms.
Urolithins, coming from the microbial metabolism of ellagic acid, have Later on, a French pharmaceutical company developed a new product
gained interest recently. Animal studies have shown their antioxidant line containing heat-treated LAB cells and bacterial growth supernatant,
and anti-inflammatory activities, as well as the ability to protect the gut marking the debut of commercial postbiotics (Salazar-Lindo et al.,
epithelium andimprove gut health (Andreux et al., 2019; Ryu et al., 2007). Every year, the number of studies about postbiotics and related
2016). Indeed, a series of enzymes involved in microbial metabolism of patents grow. Concurrently, the global postbiotic market is gaining
phenolic compounds were identified in L. pentosus IG1 such as ground in the biotic sector (Heniedy et al., 2024) Some brands of post­
β-glucosidase, gallate decarboxylase, p-coumaric acid decarboxylase, biotics are already marketed as nutraceuticals, biosurfactants and food
tannase I and II (Carrasco et al., 2018). supplements. Global market statistics on the world of biotics predict a
Finally, a well-studied class of neuroactive molecules that could be promising situation in the coming years. In fact the market investment in
present in postbiotic products, i.e. molecules able to interact with the food supplements is expected to increase up to $308 billion by 2028
nervous system. Gamma-aminobutyric acid (GABA) and serotonin are (8.90 % of annual growth rate) Statista, 2025). Looking at the European
active biogenic compound synthesized by bacteria starting from pre­ market, the postbiotic products available are still a limited number
cursors such as monosodium-glutamate and tryptophan (Casertano compared with probiotics. However, several companies in the area have
et al., 2022). LAB are considered the major producers of these com­ taken up the challenge, launching on the market postbiotic products that
pounds and several of them have been isolated from fermented foods overcome the problem of the still uncertain definition of the term, i.e.
(see section 7). The ability of human lactobacilli and bifidobacteria to commercializing them in the form of tyndallized bacteria or fermented
synthesize GABA, serotonin and other neuroactive molecules remains formulas, which are already known for their beneficial effects (Table 4).
poorly characterized, therefore genomic screening of strains to identify In Table 4, we can observe that postbiotics already available on the
which of them harbor the potential for their production is of utmost market mainly fall into the categories of tyndallized bacteria and fer­
importance (Jeong et al., 2021; Natori et al., 1990; Yunes et al., 2016). mented ingredients. However, research on the effects of different types
Indeed, L. plantarum LRCC5314 contained genes that could encode the of inactivation treatments on the bacterial structure, components and on
complete biosynthetic pathway for the production of tryptophan, pre­ the maintenance of their beneficial properties, both qualitatively and
cursor of serotonin, important in stress regulation (Jeong et al., 2021; quantitatively, is still limited (Piqué et al., 2019).
Natori et al., 1990). Moreover, an in-silico analysis on 153 genomes of Certainly, the development of new culture-independent techniques
Bifidobacterium spp. and Lactobacillus spp. identified the genes gadB, and metagenomics studies of the gut microbiome has contributed to new
gadC, gadB1, gadB2, gadR, and gts involved in GABA production, sug­ discoveries. One sensational example is the postbiotic of A. muciniphila,
gesting that it is produced by most of the strains (Table 3; Yunes et al., that was inspired by numerous studies suggesting that the levels of
2016). A. muciniphila in the gut microbiome decrease in obesity and metabolic
Therefore, the search for genes involved in postbiotic activities disorders in mice and humans. Indeed, the treatment with live

Table 3
Genes potentially involved in postbiotic activities.
Species/strain Mechanisms involved Genes involved Enzymes involved Reference
in postbiotic activity

Leuconostoc mesenteroides Bacteriocins production mesY, plnA, plnC, plnEF, curA, Plantaricin S, Plantaricin NC8, Plantaricin W, Plantaricin (Hossain et al., 2021;
J.27 sakA, sakG1, entA, pedA, nis, A, Plantaricin EF, Curvacin A, Sakacin T-a, Sakacin T-β, Toushik et al., 2022)
mleA, gshR, citD, citE, citF, Sakacin A, Sakacin G1, Enterocin A, Enterocin B,
Latilactobacillus curvatus citP, metB, metK, pad, bgl Enterocin P, Pediocin A, Pediocin PA1, Nisin
B.67; Lactiplantibacillus
plantarum M.2
Limosilactobacillus reuteri EPS production Gtf, epsD, epsDE, epsDEF, glicosyltransferases (GTFs) (; Van Kranenburg
121; epsDEFG et al., 1999)
Lactococcus lactis NIZO B40
Lactobacillus spp. Riboflavin biosynthesis ribG, ribB, ribA, ribH Riboflavin byosinthesis protein (Thakur, Tomar,
Brahma, & De, 2016a)
Ruminococcaceae spp., Short-Chain Fatty Acids butCoAT, 4Hbt, But, Ato, Buk Acetate CoA-transferase, phosphotransbutyrylase, (Eeckhaut et al., 2011;
Lachnospiraceae spp., biosynthesis butyrate kinase; Louis & Flint, 2017;
Firmicutes phylum propionate CoA-transferases Vital et al., 2014a)
Lactiplantibacillus pentosus Enzymes degrading pbg2, ipdB, padA, padR, tanB, β-glucosidase, Gallate decarboxylase sub B, p-coumaric (Carrasco et al., 2018)
IG1 phenolic compounds tanA, ipdC, tanR, gacP acid decarboxylase, Transcriptional repressor, Tannase I,
Tannase II Gallate decarboxylase sub C, transport protein,
transcriptional regulator
Lactiplantibacillus plantarum Serotonin biosynthesis trpA, trpB, trpD, trpC, trpF, Tryptophan synthase (Jeong et al., 2021;
LRCC5314 via the tryptophan Natori et al., 1990)
metabolic pathway
Bifidobacteria, Lactobacillus γ-aminobutyric acid gadB, gadC, gadB1, gadB2, Glutamate decarboxylase, Glutamate/gamma-amino (Yunes et al., 2016)
spp. biosynthesis gadR, gts butyrate antiporter, transcriptional regulator, glutamyl-
tRNA synthetase

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Table 4
Postbiotics products present on the European market.
Commercial name Brand Species/strain Postbiotic Format Application Reference
type

PostBiotiX Restore POSTBIOTICA S.R. Lacticaseibacillus paracasei CNCM I- Fermented oral Supplement indicated for https://postbiotica.
L. (Milano, Italy) 5220 ingredient solution adults with digestive com/prodotto/postbiot
disorders ix-restore/
(Algieri et al., 2023)
Plas Postbiotico PLAS PHARMA SRL Lactobacillus acidophilus HA 122 Tyndallized oral Promote the balance of https://www.plasph
(Teramo, Italy) bacteria solution intestinal flora in case of arma.com/collection
diarrhea or intestinal s/integratori-naturali/p
disorders roducts/postbiotico
(Martinelli et al., 2017)
Immune Booster HERBALIFE ITALIA Saccharomyces cerevisiae (EPICOR) Fermented oral Contribute to the protection https://www.herbalife.
S.P.A. (Rome, Italy) ingredient solution of cells from oxidative stress com/it-it/u/products/i
and to the normal function of mmune-booster-ribes-
the immune system nero-21-x-3-7g-233k
(Singh et al., 2024)
Fermentix® 40 PHYTO GARDA SRL Lactobacillus acidophilus HA-122 and Tyndallized oral Promote the balance of the https://www.named.it
FORTE (Verona, Italy) Lactiplantibacillus plantarum HA-119 bacteria solution gut microbiota, contributing /it/guidaprodotti/pr
to the well-being of the odotti_phyto_gar
digestive system and support da-24/fermentix_40_f
of the immune system orte-1340
(Martinelli et al., 2017;
Rawling et al., 2023)
SkinBac Beauty PROBIOTICAL S.P. Lactiplantibacillus plantarum Tyndallized Skin Skin microbiota modulation https://skinbac.probiot
SkinBac Care A (Novara, Italy) SKINBAC™ SB01, Limosilactobacillus bacteria topical ical.com/
reuteri SKINBAC™ SB02, use
Bifidobacterium breve SKINBAC™
SB03, Ligilactobacillus salivarius
SKINBAC™ SB04, and
Bifidobacterium animalis subsp. lactis
SKINBAC™ SB05
Fermenti Lattici LARIX Lactobacillus acidophilus SGL11, Tyndallized oral Intestinal disorder https://www.larixlab
Junior LABORATORI Bifidobacterium infantis SGB03, bacteria solution oratori.it/shop/bimbi/
(Verona, Italy) Streptococcus thermophilus SGSt01 fermenti-lattici-junior/
(Li et al., 2024; Mainini
et al., 2020)
ENTEROfluid UNIFARCO S.p.A Lactobacillus acidophilus HA-122, Tyndallized oral Intestinal disorder and https://www.farmacisti
(Belluno, Italy) Lactiplantibacillus plantarum HA-119 bacteria solution support of the immune system preparatori.it/product
s/entero-fluid
(Martinelli et al., 2017;
Rawling et al., 2023)
CandiFREE NATURANDO S.R.L L. acidophilus SGL11, L. rhamnosus Tyndallized oral Female health https://www.naturan
(Bergamo, Italy) SGL06, Lc. lactis SGLc01, B. bifidum bacteria solution do.it/prodotto/donn
SGB02, B. longum SGB05, B. infantis a-candifree-integrato
SGB03 re/
(Li et al., 2024; Mainini
et al., 2020; Montorsi
et al., 2016)
Nucleo Immuno ALGEM NATURA S. Lactobacillus acidophilus SGL11, Tyndallized oral Intestinal disorders and https://www.algemnat
R.L. (Repubblica di Lactobacillus rhamnosus SGL06, bacteria solution support of the immune system ura.com/prodott
San Marino, Italy) Lactobacillus lactis SGLc01, Bifidus o/nucleo-immuno/
bifidum SGB 02, Bifidus longum (Li et al., 2024; Mainini
SGB05, Bifidus infantis SGB 03 et al., 2020; Montorsi
et al., 2016)
BIO-FLORA BIODELTA S.r.l L. casei SGL15, Streptococcus Tyndallized oral Intestinal disorder and https://www.biodelta.
(Caserta, Italy) thermophilus SGSt01, Lactobacillus bacteria solution support of the immune system it/prodotti/bio-flora
acidophilus SGL11 -bustine/
(Li et al., 2024; Mainini
et al., 2020; Montorsi
et al., 2016)
Medargan® Flato SHEDIR PHARMA Lactobacillus acidophilus Tyndallized oral Regulate gastrointestinal https://shedirpharma.
GROUP S.p.a (Piano bacteria solution motility and digestive com/prodotto/medarga
di Sorrento, Italy) function n-flato/
(Mainini et al., 2020)
The Akkermansia Metagenics Italia S. Akkermansia muciniphila Pasteurized oral Weight management and https://www.metagen
Company r.l. bacterium solution glycemic control ics.it/it_IT/i-nostri-pro
(Milan, Italy) dotti/the-akkerman
sia-company-gestione-
del-peso-a009a001
(Depommier et al.,
2019)
Pylopass™ Novozymes Limosilactobacillus reuteri DSM 17648 Spray-drying oral Anti-Helicobacter pylori https://www.novo
OneHealt inactivated solution infection zymesonehealth.com
(Bagsværd, bacteria /solutions/pylopass
Denmark) (Holz et al., 2015)
(continued on next page)

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Table 4 (continued )
Commercial name Brand Species/strain Postbiotic Format Application Reference
type

LACTOBIOTYL® SILAB (France) Lactiplantibacillus plantarum Fermented topical Preserves the balance of the https://www.silab.fr/
ingredient use skin microbiota. en/products/skincare/
108/lactobiotyl
(Duarte et al., 2022)
PHYTOBIOACTIVE Greentech Lactiplantibacillus pentosus Fermented topical Skin defense booster; https://www.greentech
BIOTILYS® (Biopôle Clermont- ingredient use Microbiota-friendly skin .fr/en/biotilys-2/
Limagne repair (Duarte et al., 2022)
- France)

A. muciniphila confirmed its activity in metabolic improvement (Cani & microorganisms during the fermentation process (Gibson et al., 2017).
de Vos, 2017) and it was later discovered that the beneficial effects are However, FFs can also contain postbiotics (Gill & Staudacher, 2023). In
due to a cell membrane protein still active when the cells are pasteurized addition to the live bacteria responsible for the fermentation process,
(Plovier et al., 2017). The possibility to administer the pasteurized cells, FFs will also contain dead cells of starter or non-starter bacteria, as well
with advantages for stability and potential shelf-life encouraged the as their metabolites (Vinderola, Cotter, et al., 2023a). For example,
testing of pasteurized A. muciniphila in a human clinical study considering yogurt, it is produced from a symbiotic culture of
(Depommier et al., 2019), demonstrating that it can be safely adminis­ S. thermophilus and L. delbrueckii subsp. bulgaricus, with a minimum load
tered to the target human population and that the inactivated form of 107 CFU/g until the expiration date. However, it may also provide a
maintains the beneficial effect in glucose metabolism modulation. fraction of non-viable microorganisms. Indeed, it is not possible to
Starting from these results, the start-up The Akkermansia Company™, attribute with certainty whether the microbial-derived health benefits
collaborating with Sacco System, has brought on the market for the first associated with yogurt consumption according to a wide range of liter­
time the A. muciniphila postbiotic. Today, this postbiotic supplement for ature are imputable solely to the live microbial population. For example,
weight management and glycemic control is available in European active β-galactosidase may still be present in the cytoplasm of dead
pharmacies and parapharmacies, after obtaining EFSA approval as a bacteria, and free, active lactase released by lysed cells may also be
novel food in 2021 (Turck et al., 2021). present in the yogurt, synergistically contributing to improved lactose
From a technological point of view, postbiotics circumvent the digestion (Ouwehand & Salminen, 1998). In conclusion, FFs are a broad
technical challenge of maintaining high doses of viable and stable mi­ category of foods that may contain defined live microbial strains (e.g.,
croorganisms in the product during the shelf-life. The use of postbiotics yogurt, some types of cheeses), undefined live microbial consortia (e.g.,
potentially extends shelf-life and simplifies packaging and trans­ kefir, kombucha, some types of cheeses, kimchi, and sauerkraut), or non-
portation. Furthermore, postbiotics can also be used in situations where viable microbes (e.g., pasteurized sauerkraut, long-ripened cheeses,
it is more difficult to control and maintain production, transport and unfiltered beers). In any case, defining FFs as postbiotics depends on the
storage conditions, such as in developing countries. level of microbiological and chemical characterization, the reproduc­
Despite their presence on the market, not all postbiotic products in ibility of the technological process used, the proven health benefits, as
Table 4 are supported by a clinical trial, while some of them have been well as the type of research performed to demonstrate the specific ca­
tested on cell lines. In some cases, only trial on the effect of the viable pacity of that product (Vinderola, Cotter, et al., 2023a). Indeed, in order
form have been found in scientific literature (Table 4). to define a FF as postbiotic, it is necessary to characterize the micro­
At the regulatory level, however, the topic of postbiotic is still biome at species and strain level, as well as the metabolites present
confusing. In the European Union, there is currently no specific regu­ (Marco et al., 2021. Moreover, while bacterial viability can be accu­
lation for inactivated microorganisms; since a demonstrated health rately measured, assessing functionality of a postbiotic FF is more
benefit is required, any use of the term postbiotic in a food or food challenging, due to its multifaceted nature and lack of established
supplement will first require approval as Novel Food by EFSA. Accord­ assessment criteria. It has to be pointed out that also the influence of the
ing to Annex 1 of Directive 2001/83/EC (later corrected by 2004/27/ food matrix composition (e.g., pH, water activity, interaction with
EC;) “a biological medicinal product is a product, the active substance of micro- and macronutrients) has to be considered. Indeed, FF matrices
which is a biological substance. A biological substance is a substance may influence the stability and the bioavailability of bioactive molecules
produced or extracted from a biological source that requires, for the released during the fermentation. For example, (Gruskiene et al., 2017)
characterization and determination of its quality, a combination of demonstrated the antibacterial effectiveness of nisin is reduced in
physical-chemical-biological tests, together with the manufacturing certain food models because it binds to lipids or gets broken down by
process and its control.” Therefore, the role of postbiotics as active natural food enzymes. The pH of the food matrix is another critical
substances for biological medical products will need to be discussed. As factor, with postbiotics generally performing better within a pH range of
there are currently no dedicated guidelines for postbiotics, an update 4 to 9 (Ramazanidoroh et al., 2024). Optimization of these parameters is
and evolution of the regulatory framework is necessary and advisable critical to ensure the stability of bioactive molecules released by post­
and will be likely boosted as new products appear on the market biotic microorganisms in FFs and further research on this topic is
(Vinderola, Druart, et al., 2023b). needed.

7. The link between traditional fermented foods and postbiotics 8. Postbiotics in food technologies

Consumers’ and scientific interest in FFs is growing due to their as­ In addition to the therapeutic effects on humans and animals, post­
sociation with the promotion of human health. Although fermentation biotics come into play as a beneficial tool to be exploited in food tech­
began as a method of preservation, today FFs are consumed also because nologies. Their potential ranges from the use as a food additive in
they can provide a variety of health benefits, from digestive health to functional foods, to the application in food packaging.
immune support (Bellikci-Koyu et al., 2022; Panahi et al., 2018;). Postbiotics derived from the metabolic processes of microorganisms,
Indeed, FFs are a source of several “biotics”, as they contain beneficial could be used as food additives of natural origin and improve the
living microorganisms and some of them also prebiotics, either already functional, nutritional and sensory aspects of various foods (Heniedy
present in the food matrix or, in some cases, produced by the et al., 2024). Postbiotics may be added before thermal processing

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Table 5 applications are provided in Table 5.

Applications of postbiotics in food industry. As we can observe in Table 5, the most explored use of postbiotics in
Species/strain Activity Application Ref food technology is the application of cell-free culture supernatant
(CFCS) for the activation of bioactive packaging and coatings, to exploit
Latilactobacillus Antibiofilm and Bioprotective (Toushik
curvatus B67 antimicrobial agents in the meat et al., 2023) their antimicrobial function against food pathogens and spoilers. The
action on sausage industry use of postbiotics is not only simpler than using the vital form of the
and abiotic microorganism but also guarantees a longer shelf-life of the packaging
surfaces against itself. Interestingly, the use of postbiotics as antimicrobial agents is very
Listeria
monocytogenes and
versatile and they maintain the functionality in meat (İncili et al., 2021;
Salmonella enterica Shafipour Yordshahi et al., 2020; Toushik et al., 2023), fish (Hua et al.,
Lactiplantibacillus Synergetic effects Postbiotic (Hua et al., 2022; Jo et al., 2021), and vegetable (Sharafi et al., 2024).
plantarum 299 V of postbiotics in fortification of a 2022) In recent years, the growing consumers’ preference for organic
combination with probiotic edible
products and reduced confidence on synthetic chemicals has shifted the
live probiotics in coating for fresh
inhibiting the salmon fillets focus towards natural preservation techniques and additives. Toushik
proliferation of et al., 2023 investigated the antimicrobial and biofilm-inhibiting prop­
food spoilers erties of a postbiotic derived from L. curvatus B67, both alone and in
Lactiplantibacillus Inhibiting the Improvement of (Jo et al., combination with the polyphenol quercetin. Toushik et al., 2023 focused
plantarum SKD4; proliferation of shelf-life of raw fish 2021)
Pediococcus stilesii food spoilers and
on two foodborne pathogens common in processed meat products:
SKD11 the production of L. monocytogenes and Salmonella enterica ser. Typhimurium. The anti­
trimethylamine microbial activity was primarily due to organic acids. The combination
Pediococcus Bioprotective Postbiotic-fortified (İncili et al., with quercetin enhanced the antimicrobial activity. Additionally, this
acidilactici activity against chitosan coating to 2021)
combination effectively inhibited biofilm formation on both biotic (pork
pathogens and improve the shelf
food spoilers life of chicken sausage) and abiotic surfaces (e.g., stainless-steel and rubber).
breast fillets Pediococcus acidilactici postbiotic alone and in combination with a
Lactiplantibacillus Bioprotective Postbiotics- (Sharafi chitosan coating was applied on chicken breast fillets stored at 4 ◦ C
plantarum activity against enriched flaxseed et al., 2024) (İncili et al., 2021). A total of 18 compounds were identified in the
pathogens and mucilage coating to
postbiotic, and it exhibited strong antioxidant activity. The postbiotic, at
food spoilers improving
postharvest quality a 50 % concentration, effectively reduced the populations of S. enterica
and shelf life of serovar Typhimurium and L. monocytogenes on the chicken fillets and
strawberry extended the shelf life of the fillets up to 12 days without significant
Lactiplantibacillus Bioprotective Antimicrobial (Shafipour
alteration in color or pH. Postbiotics were effective as antimicrobial
plantarum subsp. activity against nanopaper for meat Yordshahi
plantarum ATCC pathogens and packaging et al., 2020) agents to counteract pathogens and spoiling microbes also in fish
14917 food spoilers products (Table 5). Hua et al., 2022 focused on the biopreservation of
Latilactobacillus Bioprotective Whey protein films (del salmon fillets, that are usually stored at temperature close to 0 ◦ C, at
sakei subsp. sakei activity against supplemented with Beristain- which the metabolic activity of biopreservative bacteria is rather
NRRL B-1917 pathogens and Latilactobacillus Bauza, Mani-
limited. Postbiotics, as non-living substances, can be more efficient in
food spoilers sakei subsp. sakei López, Palou
cell-free and López- these conditions. The results showed that a coating containing a post­
supernatant to Malo, 2017) biotic of L. plantarum 299 V remained stable during refrigeration and
improve shelf-life of significantly inhibited the growth of various spoilage and pathogenic
fresh beef
taxa, including Pseudomonas spp., Enterobacteriaceae, and
L. monocytogenes on salmon fillets over a 9-day storage period.
without compromising their functionality and they are generally stable Finally, postbiotics were used in edible coatings applied to vegetable
at high temperatures and within a wide range of pH values, being suit­ products (Table 5). Sharafi et al., 2024 used a postbiotic of L. plantarum
able for the addition into different food matrices without loss of efficacy in an edible coating to maintain the postharvest quality of strawberries
(Heniedy et al., 2024). during refrigerated storage. Fruits with the coating showed significant
Furthermore, postbiotic metabolites such as exopolysaccharides, delays in the change in weight loss, pH, and total soluble solids
proteins, peptides and organic acids find application in the development compared to uncoated fruits. They also showed significant higher levels
of active packaging for the biopreservation of foods, as some of these of total phenolic, anthocyanin and flavonoid content and in the anti­
molecules have antibacterial properties and help inhibiting pathogens oxidant capacity at the end of storage.
and food spoilers (Heniedy et al., 2024). Indeed, the use of postbiotics in foods can have a dual role: they
Freeze-drying or spray drying are popular techniques to improve the improve both the nutritional value and shelf life of foods, while pro­
handling and preservation of postbiotics in food applications (Puccetti moting positive effects on human health. In addition, the use of post­
et al., 2018; Shafipour Yordshahi et al., 2020;). However, these drying biotics in food technologies could be in line with the principles of
methods can compromise their bioactivity by promoting the loss of sustainability, resource efficiency and health promotion, allowing the
antimicrobial constituents, such as hydrogen peroxide and volatile me­ reduction of chemical additives, while reducing food waste and loss.
tabolites (Hartmann et al., 2011; Prado et al., 2000). Industrial However, the effective use in food technology is still limited, and the
fermentation-based approaches are also popular for the production of advantages have to be carefully evaluated and balanced with the in­
postbiotics. Although scalable, industrial fermentation for postbiotic crease in production costs, as well as with the initial investment in the
production may present time inefficiencies and batch-to-batch vari­ necessary equipment.
ability. Scaling up postbiotic production presents challenges that may
impact the stability and bioactivity of the final product (Dunand et al., 9. Concluding remarks, limitation and future perspectives
2019). Therefore, there is a recognized need to develop optimized and
cost-effective technical and industrial processes to facilitate the In this review, we highlighted the versatility and the possible ap­
commercial-scale production of postbiotics with consistent quality plications of the emerging class of postbiotics, although many challenges
characteristics. Some examples of postbiotics in food technology remain to be addressed. The studies available in the scientific literature
speculate that postbiotics have multiple beneficial properties on human

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C.M. Calvanese et al. Food Research International 217 (2025) 116869

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