The clinical evidence for postbiotics as microbial therapeutics

Figures & data

Figure 1. Postbiotic mechanism of action. Postbiotics could act in many ways, four of which are illustrated here. Postbiotics could enhance barrier function, through the stimulation of tight junctions, or by stimulating mucous production. Postbiotics could also act through changes in the microbiome and could modulate the immune response. Created with BioRender.

Table 1. Clinical evidence for postbiotics as microbial therapeutics through intestinal barrier function enhancement.

Study design	Condition	Population	Postbiotic	Results
Evidence of efficacy in gastrointestinal disorders
Randomized, placebo-controlled trial ^Citation39	Acute watery rotavirus diarrhea	73 children aged 3 to 24 months.	Inactivated Lactobacillus LB plus fermented culture medium	Significantly shorter duration of diarrhea compared with placebo. Fewer rotavirus positive children had watery stools after 24 hours in the Lactobacillus group.
Randomized, double-blind, placebo-controlled trial^Citation40	Non-rotavirus diarrhea	Hospitalized infants aged 1–24 months	Inactivated Lactobacillus LB plus fermented culture medium	Lactobacillus LB significantly shortened diarrhea duration by 1 d (treatment group = 39.5 h ± 10.5, placebo group = 63.4 h ± 14.9, p = <0.01).
Randomized, double-blind, controlled trial^Citation41	Acute watery diarrhea	80 children aged between 3 months and 4 y	Inactivated Lactobacillus LB plus fermented culture medium	40% reduction in diarrheal illness duration in the treatment group. Diarrhea duration was significantly reduced in children who had had diarrhea for longer than 24 hours at inclusion (p = 0.044).
Prospective, randomized, double-blind, placebo-controlled trial ^Citation42	Prevention of diarrhea	377 children aged 12–48 months	Cow’s milk fermented with heat-treated Lactobacillus paracasei	The proportion of participants experiencing at least one episode of diarrhea was significantly lower in children receiving cow’s milk fermented with Lactobacillus paracasei compared with the placebo (p < 0.0001).
Multicenter, randomized, double-blind, placebo-controlled trial ^Citation43	Prevention of diarrhea	126 children aged 12–48 months	Cow’s milk fermented with heat-treated Lactobacillus paracasei	The proportion of children presenting ≥1 episode of acute gastroenteritis was significantly lower in children receiving L. paracasei (p < 0.05) compared with the placebo. They were also 22% less likely than children in the placebo group to experience and episode of diarrhea (p < 0.01).
Exploratory study ^Citation44	Antibiotic associated diarrhea	184 adults (96 on antibiotics + postbiotic and 88 on antibiotics alone)	Inactivated Lactobacillus LB plus fermented culture medium	Less diarrhea in the Lactobacillus LB group (antibiotic only: RR = 1.36, 95% CI 1.07–1.72; antibiotic + Lactobacillus: RR = 1.16, 95% CI 0.89–1.51, p = 0.046)
Randomized, controlled trial ^Citation48	Chronic diarrhea	137 adult patients	Inactivated Lactobacillus LB plus fermented culture medium	At the 2^nd and 4^th week, mean bowel frequency was significantly lower in the Lactobacillus LB group. At the end of treatment, clinical symptoms were markedly improved in the Lactobacillus LB group.
Randomized, double-blind, placebo-controlled trial ^Citation49	Irritable Bowel Syndrome	443 patients with IBS	Bifidobacterium bifidum MIMBb75	B. bifidum substantially alleviates IBS and its symptoms compared with the placebo group (risk ratio 1.7, 95% CI 1.3–2.4; p = 0 · 0007).
Functional assessment ^Citation50	Irritable Bowel Syndrome	297 patients with IBS	Inactivated Lactobacillus LB plus fermented culture medium	The average number of stools per week decreased from 17.59 ± 0.6 to 12.83 ± 0.61 after treatment (p < 0.0001). The abdominal pain score on a scale from 1–10 decreased from 4.47 ± 0.15 before treatment to 2.79 ± 0.14 after treatment (p < 0.0001). The bloating score decreased from 4.49 ± 0.18 to 2.56 ± 0.15 (p < 0.0001). The HRQOL score, which is inversely correlated with quality of life, decreased from 5.99 ± 0.14 to 3.92 ± 0.16 (p < 0.0001).
Single center, open-label, prospective, randomized trial^Citation52	Helicobacter pylori infection	120 H. pylori positive, dyspeptic volunteers	Heat stabilized Lactobacillus acidophilus LB	In the standard treatment group, eradication was successful in 42 of the 58 patients (72%). In the standard treatment plus L. acidophilus LB group, the eradication rate increased significantly to 88% (52 of 59 patients) (p = 0.03).

Table 2. Clinical evidence for postbiotics as microbial therapeutics through immune system modulation.

Study design	Condition	Population	Postbiotic	Results
Evidence of efficacy in immunity and allergies
Randomized, double-blind, placebo-controlled, parallel study ^Citation57	Examining influence on immune function and quality of life (QoL)	60 healthy adults	Heat-killed Lactobacillus plantarum L-137	Compared with a placebo, the change in Con A-induced proliferation and Th1:Th2 ratio were greater in the HK-LP group (p = 0.036 and p = 0.002, respectively). QoL improved more in the HK-LP group than innthe control group (p = 0.049 at week 8, p = 0.092 at week 12)
Randomized, double-blind, placebo-controlled trial ^Citation59	Perennial allergic rhinitis	90 subjects (adults and children)	Heat-killed Lactobacillus paracasei LP33	After 30 d of treatment, quality of life improved more for subjects taking live or heat-killed LP33 in terms of frequency (9.47 ± 2.89, 6.30 ± 2.19, vs. −3.47 ± 1.53, respectively; p < 0.0001) and level of bother (5.91 ± 3.21, 6.04 ± 2.44, vs. −2.80 ± 1.64, respectively; p = 0.004) compared with the placebo group. HK-LP33 efficacy was not inferior to the live variant.
Ex vivo cellular study^Citation60	Grass pollen allergy	Peripheral blood mononuclear cells from 10 adults with grass pollen allergy and 19 non-allergic adults	Inactivated Lactobacillus LB and non-pathogenic Escherichia coli	CD69 expression on T-lymphocytes was significantly up-regulated by both bacteria (p = 0.001). Allergen stimulation caused significantly increased CD23 expression (p = 0.008) which reduced after Lactobacillus stimulation and significantly reduced with allergen plus E. coli (p = 0.029). Lactobacillus stimulation reduced CD80 expression in the allergic group only (p = 0.021). CD86 expression increased significantly after Lactobacillus stimulation (p = 0.049) and distinctly increased after E. coli in both groups (p = 0.001). Both bacteria modulate allergic immune response through co-stimulatory molecule expression and CD23 alteration. There is clear promotion of T-helper-1 dominated response in allergic participants.
Evidence of efficacy in upper respiratory tract infections
Randomized, single-blind, placebo-controlled study ^Citation63	Examining the effect of HK L-137 on interferon-β	16 healthy female adults	Heat-killed Lactobacillus plantarum L-137	Interferon-β levels were significantly higher in the HK L-137 group before trivalent influenza vaccination compared with the control group. Vaccination resulted in little additional induction of Interferon-β. Increased type 1 interferon augments host defense against influenza A virus.
Randomized, double-blind, placebo-controlled, parallel study ^Citation65	Upper respiratory tract infections	78 healthy subjects with high psychological stress levels	Heat-killed Lactobacillus plantarum L-137	Compared with the control group, URTI incidence was significantly lower in the HK L-137 group (p = 0.011). Significant negative correlation between HK L-137 intake duration and URTI incidence, duration, severity, and medication duration. Concanavalin A-induced proliferation of peripheral blood mononuclear cells was significantly greater in the HK L-137 group compared with the control group (p = 0.048).
Prospective, randomized, double-blind, placebo-controlled trial ^Citation42	Common infectious diseases	377 children aged 12–48 months	Cow’s milk (Group A) or rice (Group B) fermented with Lactobacillus paracasei CBA L74	There number of children having at least one common infectious disease was lower in group A (48.2%) and group B (58.5%) than in the placebo group (80.3%). Upper respiratory tract infection incidence was lower in group A (48.2%) and group B (58.5%) compared with the placebo group (70.5%).
Multicenter, randomized, double-blind, placebo-controlled trial ^Citation43	Common infectious diseases	126 children aged 12–48 months	Cow’s milk fermented with Lactobacillus paracasei CBA L74	60% of children in L74 group presented at least one common infectious disease compared with 83% in the placebo group. Numbers of children presenting at least one URTI was significantly lower in the L74 group compared with the placebo (51% vs. 74%, p < 0.05)
Randomized, double-blind, placebo-controlled study ^Citation66	Viral respiratory tract infections	172 children aged 3 to 6 y	Heat-killed Pediococcus acidilactici K15	Salivary IgA levels were maintained significantly higher in the K15 group compared with the placebo. K15 significantly decreased fever duration in children with little intake of fermented food.
Randomized, placebo-controlled, double blind trial ^Citation70	Influence on levels of salivary secretory IgA	80 elderly participants	Heat-killed Lactobacillus pentosus b240	Mean salivary SIgA rate increased steadily until week 4 with a 20% increase compared to week 0. It stayed relatively stable until week 12. The increase in SIgA rate was significantly greater in the b240 group compared with the placebo group.
Randomized, double-blind, placebo-controlled trial ^Citation71	Common cold	280 elderly adults	Heat-killed Lactobacillus pentosus b240	The common cold incidence rate was 47.3% for the placebo group, 34.8% for the low-dose group and 29.0% for the high dose group (P for trend = 0.012). Quality of life increased dose-dependently.

Table 3. Clinical evidence for postbiotics as microbial therapeutics through multiple mechanisms of action.

Study design	Condition	Population	Postbiotic	Results
Evidence for efficacy in stress and neurological conditions
Randomized, double-blind, placebo-controlled study ^Citation82	Stress	60 medical students preparing for national examinations	Heat-inactivated Lactobacillus gasseri CP2305	Anxiety and sleep disturbance were significantly reduced in the CP2305 group compared with the placebo group. CP2305 also significantly shortened sleep latency and wake time after sleep onset. Salivary chromogranin A levels were also significantly lowered in the CP2305 group compared with placebo. CP2305 was also found to attenuate stress-induced decline of Bifidobacterium spp. and elevation of Streptococcus spp.
Multicenter, randomized, double-blind, placebo-controlled trial ^Citation84	Mild Alzheimer’s Disease	328 patients aged 60 to 85 y with mild Alzheimer’s Disease	Plasmalogens	The Wechsler Memory Scale-Revised improved significantly in the treatment group. In a subgroup analysis, this scale also improved significantly in females and participants under 77 y of age. The between group difference for females was statistically significant (p = 0.017), as it was for those under 77 y of age (p = 0.029). Plasma plasmalogen decreased significantly more in the placebo group compared with the treatment group.
Evidence for efficacy in metabolic syndrome
Randomized, double-blind, placebo-controlled pilot study ^Citation99	Obesity-related disorders	32 overweight/obese adults with insulin resistance	Pasteurized Akkermansia muciniphila	Insulinemia (−34.08 ± 7.12%, P = 0.006), plasma total cholesterol (−8.68 ± 2.38%, P = 0.02) and body weight (−2.27 ± 0.92 kg, P = 0.091) were reduced and insulin sensitivity improved (+28.62 ± 7.02%, P = 0.002) in the pasteurized A. muciniphila group compared with placebo. Compared with the baseline, fat mass (−1.37 ± 0.82 kg, P = 0.092) and hip circumference (−2.63 ± 1.14 cm, P = 0.091) decreased in the pasteurized A. muciniphila group.

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Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.