Therapeutic Use of Postbiotics: Gastrointestinal,Immune,and Metabolic Effects

Abstract

Postbiotics are a heterogenous group of compounds that may include inactivated bacterial cells or components or metabolic products of bacteria. These substances have been shown to have a wide variety of healthy effects via their anti-inflammatory, immune-modulating, and metabolic effects. Postbiotics have both direct and indirect effects on the gut microbiome and gut barrier function. They have been studied for gastrointestinal disorders, including irritable bowel syndrome, inflammatory bowel disease, and diverticulosis. Clinical trials have also been conducted examining the immune effects of postbiotics, as well as their impact on muscle and metabolic function. This article reviews clinical evidence for the use of postbiotics and discusses limitations and directions for future research.

Keywords

postbiotics butyrate immunity gastrointestinal disorders metabolism

Introduction

The importance of the gut microbiome in human health has been increasingly appreciated as a vital contributor to overall health. The microbiome is a complex system with trillions of microorganisms, composed not only of bacteria but also of viruses and fungi. The human microbiome modulates nutrient and energy absorption as well as gastrointestinal (GI) function and metabolism. It is also a key player in host immunity. The gut flora participate in the development and training of host immune cells, and the immune system in turn regulates the microbiome (70%–80% of the body’s total immune cell population is located in the gut). This crosstalk between the immune system and the gut microbiome acts as an important regulator of not only gut function but also inflammation and metabolic health.^1–3

Gut flora also produce a number of metabolites that are bioactive and, in some cases, even essential for human health. These include short chain fatty acids (SCFAs), such as propionate or butyrate, bile acid metabolites, choline metabolites, vitamins (such as vitamin K2 and B vitamins), branched-chain fatty acids, indole derivatives, lipopolysaccharide (LPS), and peptidoglycan. These metabolites in turn perform a vast array of functions, such as regulating intestinal barrier function, acting as antioxidants, regulating bile acids and lipids, performing as enzymatic cofactors, acting as direct antimicrobials, and modulating appetite and insulin secretion.⁴

As our knowledge of the importance of the gut microbiome to human health has grown, interest in factors that might modulate the microbiome has also grown at a rapid pace. The use of probiotics (supplementary microorganisms) and prebiotics (substances that are utilized by the gut flora for their own metabolic function) has increased. Postbiotics are an additional area of interest. Postbiotics have been defined by the International Scientific Association of Probiotics and Prebiotics as a “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host.” By definition, this means a postbiotic would need to contain inactive microbial cells.⁵ Other authors propose a broader definition, including bacterial metabolites or metabolic byproducts under the umbrella of postbiotics, with or without the inclusion of microbial components or cells.⁶ Zolkiewicz et al. define postbiotics as “any substance released by or produced through the metabolic activity of the microorganism, which exerts a beneficial effect on the host, directly or indirectly.”⁷ This may include SCFAs, exopolysaccharides (EPSs), vitamins, teichoic acids, bacteriocins, enzymes, or peptides. These substances may be either secreted by live bacteria or released as a result of bacterial lysis. Heat-killed bacteria and yeast-derived products may also fit into this definition. While this broader definition has been adopted for the purpose of discussion in this article, readers may keep in mind that the definition of postbiotics is a subject of ongoing debate. It seems possible that this definition may shift and change over time as better-defined approaches for the measurement of inanimate microbes, whole and fragmented cells, and inclusion/exclusion and quantity of metabolic byproducts in proposed postbiotic supplements are further clarified.

Therefore, the term “postbiotic” may encompass a large number of highly heterogenous substances. But in any case, a postbiotic supplement would contain no live bacteria (unlike probiotics, which contain beneficial live microorganisms). Postbiotics may therefore offer a more stable product with improved shelf-life at a wider variety of ambient temperatures.⁸ They may also offer the advantage of gaining the benefits of specific flora, without requiring supplementation of the bacteria itself.⁹

In this article, we will review the therapeutic use of postbiotic supplements. Needless to say, the bulk of the clinical research on postbiotics pertains to GI conditions. Postbiotics have been studied in people with functional GI disorders, irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD). Additional effects of postbiotics go beyond the GI tract, however, where these natural products are shown to impact muscular and metabolic health, as well as immune system function.

GI Health

Postbiotics are thought to improve GI health through a number of important mechanisms. They may impact the microbiome both directly and indirectly. For example, bacteriocins have a direct antimicrobial effect and may disrupt biofilm formation. Other postbiotics, such as SCFAs, are well known for their key function in maintaining gut health. Butyrate, in particular, serves as a primary energy source for colonocytes, responsible for ∼70% of the colonocyte’s energy needs. Butyrate crosses the colonocyte cell membrane and can then be oxidized into carbon dioxide within the mitochondria to form adenosine triphosphate. All three major SCFAs (butyrate, propionate, and acetate) also bind to G-protein coupled receptors on colonic epithelial, adipose, and immune cells, resulting in improved cytokine regulation and an anti-inflammatory effect.¹⁰ Additionally, because they favorably impact the molecular structure of enterocytes, postbiotics may improve intestinal barrier function. This may also result in a general antimicrobial effect.⁷ Postbiotics may stimulate tight junctions or improve intestinal mucus secretion.⁸ Intestinal barrier function can be enhanced by postbiotic EPSs, while SCFAs may protect against LPS-induced disruption of the gut barrier.⁸ Additionally, SCFAs may modulate gut motility via their direct effects on enteric neurons, modulation of serotonin function, and regulation of interstitial cells of Cajal.¹¹

SCFAs¹²

SCFAs are fatty acids with carbon atom numbers below six.

Roughly 80% of total SCFAs in mammalian large intestine are acetic, propionic, and butyric acids.

Total concentrations of these acids in the intestinal lumen range from 60 mmol/kg up to 150 mmol/kg.

Fecal SCFA concentrations are fairly constant, in order of decreasing concentration: acetate > propionate ≥ butyrate.

Butyric acid is naturally found in butter, hard cheeses, goat and sheep milk, yogurt, and some fermented foods (such as sauerkraut, pickles, and fermented soy foods) but in small quantities that likely are not significant for gut health.

Butyric acid is an oily liquid that is water soluble and has an unpleasant, rancid odor. The sodium salt of butyric acid (sodium butyrate) is a solid. It is considered to be a more stable molecule with lower odor, and it readily converts to butyric acid in an aqueous solution.

Postbiotics’ effects on the microbiome have been confirmed in a number of clinical trials. These trials demonstrate the ability of postbiotic supplementation to reduce potential gut pathogens while increasing beneficial gut flora, including Dysosmobacter welbionis, F. prausnitzii, and Bifidobacterium species.¹³ In healthy people with mild-to-moderate digestive symptoms, 8 weeks of treatment with a heat-treated Bifidobacterium longum CECT 7347 supplement resulted in a significant increase in the abundance of fecal Faecalibacterium and Anaerobutyricum genera, both of which were positively correlated with butyrate concentrations.¹⁴ Additional studies also demonstrate an effect of postbiotics on the oral microbiome, with a reduction in halitosis-causing bacteria, improvement in markers of oral immunity, or alterations favorable for gingival health seen in clinical trials.¹³

These effects might also benefit people receiving antibiotic treatment by mitigating antibiotic-associated microbial changes. In a randomized controlled trial (RCT) in otherwise healthy people receiving antibiotics for non-GI infections (such as sinusitis or ear infections), participants were given either a placebo or a postbiotic supplement taken during and for 10 days after the course of antibiotics, along with a commercially available probiotic containing a variety of Lactobacillus and Bifidobacterium spp. In this trial, the postbiotic supplement contained herbs (Withania somnifera, Sambucus nigra, and Astragalus membranaceus) that had been fermented with Lactobacillus and Bifidobacterium. At the completion of the trial, people who took the postbiotic along with antibiotics and probiotics had significantly higher fecal bacterial alpha diversity (+40%, inverse Simpson index) compared with people taking the placebo. The increase in alpha diversity was driven by augmentation of beneficial taxa, in particular anaerobic Firmicutes, specifically Lachnospiraceae. Additionally, postbiotic treatment resulted in a reduction of fecal Escherichia/Shigella species, an effect that persisted for the 10 days after antibiotic treatment, compared with placebo.¹⁵

Postbiotics in Diarrhea, Constipation, and IBS

The various benefits of postbiotics described above would certainly be pertinent for people experiencing IBS. In a randomized, double-blind, placebo-controlled crossover trial, 69 adults ages 18–35 with chronic diarrhea (defined as persistent diarrhea for ≥6 months, with loose or watery stool [Bristol type 5, 6, or 7] occurring at least 25% of the time over the preceding 3 months) were enrolled. Participants took either a placebo or the postbiotic supplement for 21 days, followed by a 14-day washout, then crossover to the opposite intervention. The postbiotic supplement consisted of a heat-treated and dried fermentation of Lacticaseibacillus paracasei Zhang, L. plantarum p-8, and Bifidobacterium animalis subsp. lactis V9. At the completion of the trial, use of the postbiotic resulted in significant improvements in Bristol stool scale score, defecation frequency, urgency, and anxiety (P < 0.05 for all). The overall improvement rate for diarrhea was 89.86%. Additionally, levels of beneficial fecal bacteria (such as D. welbionis and F. prausnitzii) increased, while potential pathogens (such as Megamonas funiformis) decreased. Gut levels of the bacteriophage Microviridae also increased. Fecal butyric acid levels increased with use of the postbiotic. Analysis of fecal amino acid profiles indicated that postbiotics probably improved diarrhea by modulating tryptophan-5-hydroxytryptamine and tryptophan–kynurenine pathways. The postbiotic supplement was well tolerated, with no adverse effects reported.¹⁶

In another trial in 200 people with diarrhea-predominant IBS, subjects were randomized to one of three groups. Participants took either a probiotic (B. longum CECT 7347 at a dose of 1 × 10⁹ colony-forming units [CFUs]/day), a postbiotic (heat-treated B. longum CECT 7347 at a dose of 2.5 × 10⁹ cells/day), or a placebo for 12 weeks. Both the probiotic and postbiotic groups saw significant improvements in IBS symptoms compared with placebo. The mean decrease in IBS-Symptom Severity Scale scores from baseline to 12 weeks was −173.70 ± 75.60 for the probiotic and −177.60 ± 79.32 for the postbiotic compared with −60.44 ± 65.5 for placebo (P < 0.0001 for both). The number of days with normal stool type (Bristol 3, 4, or 5) increased from 1.45 and 0.95 days per week at baseline to 4.63 and 4.36 days at 12 weeks in the probiotic and postbiotic groups, respectively. There were no significant adverse events in any arm of the study.¹⁷

Supplementation with butyrate itself also appears to be beneficial in patients with IBS. In a pediatric trial in children ages 4 through 17 diagnosed with IBS, participants were randomized to either calcium butyrate 500 mg/day or a placebo for 8 weeks, with a 4‐week follow‐up period after. Treatment success was significantly greater in the butyrate group (defined as a decrease of ≥ 50% in the visual analog scale [VAS] score; 73% vs. 3.8%, P < 0.0001). Overall VAS and GI symptom rating scale scores were significantly improved in children taking butyrate both at 8 weeks and at the completion of follow-up 4 weeks after. Fecal levels of SCFA-producing gut flora (Lachnospiraceae and Ruminococcus gauvreauii) increased. Pro-inflammatory flora, in contrast (such as R. gnavus), decreased. The authors note that such alterations would be consistent with improved gut barrier function and gut immune homeostasis. There were no adverse effects or side effects reported, confirming safety of calcium butyrate in this group of pediatric patients.¹⁸

Butyrate supplementation also appears to be helpful in adults with IBS. In a study of 66 people with IBS receiving standard pharmacologic agents (such as mebeverine, bulking agents, stool softeners, simethicone, and loperamide), participants were randomized to either sodium butyrate 300 mg/day or a placebo for 12 weeks. At 4 weeks, the frequency of abdominal pain during defecation significantly decreased (P = 0.0032). By 12 weeks, there was a decrease in the frequency of spontaneous abdominal pain, postprandial abdominal pain, abdominal pain with defecation, urge after defecation, and constipation (P = 0.0132, P = 0.0031, P = 0.0002, P = 0.01, and P = 0.0493, respectively). There were no significant adverse events with the use of butyrate.¹⁹

Postbiotics have also been clinically studied in people with functional constipation. In a placebo-controlled crossover trial (N = 110 with functional constipation per Rome IV criteria), participants took either a postbiotic or placebo for 3 weeks, followed by a 2-week washout period, then crossover to the opposite intervention. The postbiotic utilized in this trial was a proprietary blend prepared by fermenting soy protein, skimmed milk powder, and sodium citrate with L. paracasei Zhang, L. plantarum P-8, and B. lactis V9. Following postbiotic administration, there was significant improvement in the frequency of complete, spontaneous bowel movements (19.12% improvement, P = 0.047). Utilizing an intent-to-treat (ITT) analysis, stool straining scores also significantly improved with the use of the postbiotic (34.67% reduction in straining scores, P = 0.003). Supplementation with the postbiotic resulted in significantly greater fecal abundance of L. paracasei, L. plantarum, and Clostridium sp001916075 (P < 0.05). Also of interest was the finding that the use of the postbiotic improved scores related to the quality of life (QOL) measures for physical discomfort and worrying compared with placebo (P = 0.048 and P = 0.047, respectively). The authors noted that the positive effects of postbiotic use were lost after the washout period, suggesting that continued administration of postbiotics beyond a 3-week period would be necessary to maintain a therapeutic effect in these people with functional constipation.²⁰

Diverticulosis

Diverticulosis is a fairly common concern, with roughly 60% of people age ≥60 in industrialized countries expected to develop diverticula (although symptomatic disease might only occur in 10%–25% of people). In a randomized trial in people with diverticulosis, participants were given either sodium butyrate 300 mg daily or a placebo for 12 months (N = 52, 30 receiving butyrate and 22 placebo). The number of occurrences of clinical diverticulitis during the 12 months of the trial was 2 (6.67%) in the butyrate group and 7 (31.8%) in the placebo group (P = 0.0425). Additionally, improvement in subjective symptoms was higher in the butyrate group. In response to the question “Did you observe adequate relief of diverticulosis related to abdominal pain or discomfort within the past 12 months?”, 55.67% of subjects in the butyrate group responded yes compared with 22.73% in the placebo group (P = 0.0143). There were no adverse events in either study arm.²¹

Helicobacter pylori Infection

A postbiotic intervention has also been studied in people with functional dyspepsia and Helicobacter pylori infection. In a randomized, double-blind, placebo-controlled trial, participants were given either placebo or a postbiotic supplement (2 × 10¹⁰ spray-dried L. reuteri DSM17648 cells) twice daily, along with standard eradication therapy (esomeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily) for 14 days and for another 14 days after completion of standard eradication treatment. The postbiotic preparation in this trial is specifically thought to coaggregate with H. pylori, reducing the adherence of H. pylori to gastric mucosa. A total of 66 people were randomized to the postbiotic group and 63 to the placebo group. At the completion of the trial, eradication of H. pylori was seen in 96.7% of the postbiotic group and in 86.0% of the placebo group (P = 0.039). There were no serious adverse effects seen in the trial, and 1 person each in the postbiotic group and placebo group discontinued medication due to side effects (lumbar pain in one person and bitter taste in the mouth in the other).²²

Postbiotics in IBD

Postbiotics are thought to be a promising option in people with IBD due to their immunomodulating and anti-inflammatory effects. SCFAs in particular may hold promise in these conditions, providing a fuel source for colonic cells while also supporting gut barrier integrity. Butyrate supplementation in people with IBD has been the subject of three clinical trials.

In Facchin et al.’s 2020 double-blind, placebo-controlled pilot study, 49 people with IBD (19 with Crohn’s disease [CD] and 30 with ulcerative colitis [UC]) received either sodium butyrate 1800 mg a day or placebo as an adjunct to standard therapy and for a period of 2 months, to assess butyrate’s effect on the microbiome. Additionally, 18 healthy volunteers provided fecal samples for microbiome comparison. At baseline, the microbiome of IBD patients differed from that of healthy volunteers (specifically, showing significantly lower microbiota richness, P < 0.001). Following supplementation with butyrate for 2 months, participants experienced an enrichment of SCFA-producing bacteria (in people with UC, Lachnospiraceae spp. increased, while in those with CD, Butyricicoccus levels increased). Improved QOL (as assessed by the Inflammatory Bowel Disease Questionnaire) from baseline to 2 months was seen for people taking butyrate compared with placebo (P = 0.0184), with the greatest effect seen in people with UC (P = 0.0284).²³

In Firozzi et al.’s 2024 double-blind RCT, 36 people with mild-to-moderate UC were randomized to either placebo or sodium butyrate 600 mg daily for 12 weeks. Compared with people taking the placebo, those who received butyrate experienced a significant decrease in levels of fecal calprotectin (−133.82 ± 155.62 vs. 51.58 ± 95.57, P < 0.001). Additionally, people taking butyrate had significant reductions in C-reactive protein levels (CRP, −0.36 [−1.57, −0.05] vs. 0.48 [−0.09–4.77], P < 0.001). Supplementation with butyrate resulted in improved sleep quality (per the Pittsburgh sleep quality index, −2.94 ± 3.50 vs. 1.16 ± 3.61, P < 0.001) as well as QOL (IBDQ-9: 17.00 ± 11.36 vs. −3.50 ± 6.87, P < 0.001). Interestingly, administration of sodium butyrate was also found to upregulate the expression of genes related to circadian rhythm (cryptochrome-1: 1 2.22 ± 1.59 vs. 0.63 ± 0.49, P < 0.001; cryptochrome-2: 2.15 ± 1.26 vs. 0.93 ± 0.80, P = 0.001; period circadian regulator 1: 1.86 ± 1.77 vs. 0.65 ± 0.48, P = 0.005); brain and muscle arnt-like 1: 1.85 ± 0.97 vs. 0.86 ± 0.63, P = 0.003).²⁴ This finding may be especially important since people with active IBD have been shown to have reduced levels of these clock genes in inflamed tissue, and sleep quality in these same individuals has been shown to correlate with disease severity.²⁵

Lastly, in Karlowicz et al.’s 2025 multicenter, double-blind, placebo-controlled RCT, 98 people with mild-to-moderate UC receiving standard therapy took either a placebo or sodium butyrate 600 mg daily as an adjunct for 8 weeks. Primary outcomes were as follows: •

Clinical improvement was defined as a ≥3-point reduction in total Mayo score (TMS)

•

Clinical remission was defined as TMS ≤2, rectal bleeding subscore = 0, stool frequency ≤1

•

Endoscopic improvement defined as ≥1-point reduction

•

Endoscopic remission defined as Mayo score = 0

•

Biochemical remission defined as fecal calprotectin ≤250 µg/g.

In ITT analysis, compared with those taking placebo, people who supplemented with butyrate experienced significant clinical improvement, endoscopic improvement, and rates of both clinical and biochemical remission (P = 0.001, P = 0.004, P = 0.001, and P = 0.005, respectively). In those taking butyrate, 51% (N = 26) had clinical improvement, and 25.5% (N = 12) had endoscopic improvement. In addition, 31.4% achieved clinical remission, while 42.2% achieved biochemical remission (N = 16 and N = 21, respectively). For people achieving clinical remission, there was a strong positive association between fecal butyric acid levels and the TMS score (P = 0.003).²⁶

Immune Effects

Beyond gut function, postbiotics have immunomodulatory properties as well. SCFAs, for example, may enhance the differentiation of regulatory T cells (Tregs) in the gut while also upregulating the formation of peripheral Tregs. Postbiotic compounds from Bacillus coagulans and B. breve modulate the production of various cytokines, promote T helper (Th) activity, and induce dendritic cell maturation and survival. The combination of these effects likely favors improved immune balance, limiting Th1-mediated immune responses and enhancing the activity of Th2.⁷ Indeed, in a study of healthy subjects (N = 60, mean age 56.3) given 50 mg daily of a heat-killed Lactobacillus plantarum L-137 (HK-L137) supplement for 12 weeks, the Th1:Th2 ratio was significantly augmented in people taking the postbiotic compared with controls taking a placebo (P = 0.002). This effect would be consistent with a reduction in the risk for the occurrence of atopic and infectious conditions.²⁷

In people with environmental allergies (to dust mites), a postbiotic appears to work comparably to a probiotic for reducing allergy symptoms. A total of 90 patients were enrolled in a double-blind, placebo-controlled RCT, with one group receiving a placebo, another receiving live probiotic L. paracasei 33 (5 × 10⁹ CFU), and another receiving heat-killed L. paracasei 33 (again, 5 × 10⁹ CFU) for 30 days. For both the probiotic and postbiotic groups compared with placebo, frequency of symptoms and level of bother decreased after 30 days of treatment (9.47 ± 2.89 and 6.30 ± 2.19 vs. −3.47 ± 1.53, respectively; P < 0.0001; and 5.91 ± 3.21, 6.04 ± 2.44, vs. −2.80 ± 1.64, respectively; P = 0.004). The efficacy of the postbiotic was noninferior to that of the probiotic. There were no adverse effects with either the probiotic or postbiotic.²⁸

A handful of studies have also looked at the question of postbiotics’ effects on upper respiratory tract infections (URIs). Table 1 summarizes these clinical trials.

These trials demonstrated a variety of immune-related effects with the use of postbiotics.^29–31 This included a reduction in the incidence, duration, and severity of URI with the use of postbiotics in adults.^30,31 In a study in elderly adults, perception of general health also increased with the use of postbiotics.³⁰ In children, the addition of a postbiotic for 16 weeks was only effective in reducing the occurrence of fever in those who were not regularly consuming fermented foods already.²⁹

Supplementation with postbiotics has also been shown to modulate natural killer (NK) cell activity. In a placebo-controlled double-blind RCT using a heat-treated L. plantarum LM1004 (HT-LM1004) supplement, healthy adults (N = 97, age 19–75) were randomized to either placebo or a postbiotic (HT-LM1004 2 × 10¹⁰ cells) for 8 weeks. There was a significant increase in NK cell activity in people taking the postbiotic (28.69 ± 7.82% at baseline to 32.03 ± 9.88% at 8 weeks, P < 0.001), and the increase in NK cell activity was significantly higher with the postbiotic than with placebo (P = 0.036). People who took the postbiotic also experienced an upregulation of serum interleukin-12 (IL-12) levels (P < 0.001), although there was no significant difference in IL-12 levels overall between the postbiotic and placebo groups (P > 0.05). There were no significant side effects with use of the postbiotic.³²

Table 1.

Clinical Trials of Postbiotics for Upper Respiratory Tract Infections

Author	Subjects	Intervention	Outcomes
Hirose et al. 2013	78 healthy subjects (mean age 50.6, 39 each in the control and postbiotic groups) who scored high on psychological distress subscale of the Brief Job Stress Questionnaire	HK-137 10 mg vs. placebo for 12 weeks	URI incidence was significantly lower (19 people in the postbiotic group; 24 people in the control group) in the HK L-137 group than the control group (P = 0.011). URTI duration and severity, and duration of medication use to manage symptoms were all significantly negatively correlated with duration of HK L-137 intake (P = 0.005, P = 0.007, and P = 0·008)
Shinkai et al. 2013	300 elderly adults (age 65+)	Subjects randomized to either low- or high-dose postbiotic Lactobacillus pentosus strain b240 (2 × 10⁹ or 2 × 10¹⁰ cells, respectively) or placebo for 20 weeks	Incidence of the common cold was 47.3%, 34.8%, and 29.0% for the placebo, low-dose, and high-dose postbiotic groups, respectively (P for trend = 0·012). Additionally, general health perception, as determined by the SF-36, increased in the b240 groups in a dose-dependent manner (P < 0.025)
Hishiki et al. 2020	172 healthy children aged 3–6 years	Placebo vs. heat-killed Pediococcus acidilactici K15 at a dose of 5 × 10¹⁰ bacteria, for 16 weeks	There was no significant difference in days with fever between the two groups (2.24 ± 2.54 in the postbiotic group, 2.67 ± 3.43 for placebo). However, looking at a subgroup analysis for children who did not regularly consume fermented foods or yogurt, those taking the postbiotic had significantly fewer days with fever (1.69 ± 2.08 vs. 3.17 ± 3.98, P = 0.042)

SF-36, short form 36; URI, upper respiratory tract infection.

Metabolic Effects

Postbiotics may provide metabolic benefits through their modulation of gut flora, immune effects, anti-inflammatory properties, or protection against intestinal infection.³³ SCFAs are also thought to improve metabolic health by increasing fat oxidation, thereby improving energy expenditure. SCFAs also improve glucose tolerance and insulin sensitivity while also modulating the sensation of satiety, leading to a reduction in calorie consumption that may aid a patient’s efforts toward weight loss.¹³

In a double-blind, placebo-controlled RCT, 100 people with body mass index (BMI) ranging from 23.0 to 29.9 (mean age 41.4) took either a postbiotic supplement of HK-L137 10 mg daily or a placebo for 12 weeks. Aspartate aminotransferase (AST) and alanine aminotransferase decreased in the postbiotic group to a greater degree than in controls (P = 0.02 for both). Additionally, total cholesterol (TC) and low-density lipoprotein decreased significantly with use of the postbiotic (P < 0.05 for both). Of some interest was the finding that the effects of HK-L137 were most pronounced in those subjects with elevated CRP levels, suggesting that this intervention might hold greater metabolic benefits for people with higher levels of inflammation.³³

One study has demonstrated a change in biometric indicators with the use of a postbiotic supplement. In an 8-week placebo-controlled double-blind RCT, people with overweight or obesity (N = 66) were randomized to one of the following three groups: •

120 g of yogurt containing a postbiotic Akkermansia muciniphila (10 billion CFU)

•

120 g of yogurt containing a postbiotic L. rhamnosus (10 billion CFU)

•

Unfortified yogurt as a placebo.

At the conclusion of the trial, people in the Akkermansia group experienced significant reductions in waist circumference (−4.3 cm/−1.7 in, P = 0.003), the waist-to-height ratio (P = 0.004), body fat percentage (P = 0.032), AST levels (P = 0.045), and appetite scores (P = 0.047) compared with controls. These effects were not seen in the Lactobacillus postbiotic group (as an example, change in waist circumference with the Lactobacillus postbiotic was −1.6 cm/−0.6 in, and in the placebo group was −1.3 cm/−0.5 in).³⁴

Butyrate supplementation has also shown metabolic benefits. In Fogacci et al.’s study (in healthy Caucasian people with nonalcoholic fatty liver disease), 50 subjects were given either a placebo or calcium butyrate 500 mg daily (which was combined with zinc gluconate 5 mg and vitamin D3 500 international units) for 3 months. The fatty liver index improved significantly with the use of butyrate compared with baseline values (P < 0.05). The difference was also significant compared with placebo (P < 0.05). The hepatic steatosis index also improved significantly with the use of butyrate (P < 0.05). Additionally, TC, triglycerides, and gamma-glutamyl transferase all improved with the use of butyrate (P < 0.05 for all).³⁵

Postbiotics might also help improve insulin sensitivity. In a small (N = 17) randomized, double-blind, placebo-controlled study in people with obesity, participants were randomized to either a postbiotic or a placebo for 12 weeks. The postbiotic provided a heat-treated Pediococcus acidilactici (CECT 9897) at a dose of 1 × 10¹⁰ cells daily. Use of the postbiotic resulted in a small but statistically significant reduction in hemoglobin A1c (−0.22 ± 0.07%; P = 0.018) compared with placebo. Additionally, subjects in the postbiotic group saw a reduction of diastolic blood pressure (−8.8 ± 3.2 mm Hg, P = 0.029) compared with those in the placebo group. Significant improvements were also seen in weight (−1.55 ± 1.5 kg; P = 0.04), BMI (−0.59 ± 0.5 points; P = 0.04), and fat mass (−1.95 ± 1.3 kg; P = 0.016) with the use of the postbiotic.³⁶

Postbiotics might also improve or protect muscle function. In a double-blind, placebo-controlled RCT in elderly people (N = 100, mean age 65.03 ± 3.83 years), the effects of a pasteurized Akkermansia muciniphila HB05 (HB05P) supplement on muscle function were compared with those of a placebo. Subjects took either HB05P at a dose of 1 × 10¹⁰ cells/day or the matched placebo for 12 weeks. While grip strength did not change in this trial, people taking the postbiotic did experience significant improvements in peak torque and peak torque per body weight (using a left leg extensor test) compared with those taking placebo (P = 0.0103 and P = 0.0052, respectively). Additionally, supplementation with HB05P led to significant increases in follistatin levels compared with the placebo (P = 0.0063). There were no significant adverse effects reported.³⁷

Follistatin

Follistatin is a propeptide that binds and neutralizes myostatin (a member of the transforming growth factor-β family of regulatory proteins).

Myostatin is a muscle-specific secretory protein that limits muscle growth.

By reducing myostatin activity, follistatin increases muscle strength and mass.

Follistatin gene therapy is being studied as a therapeutic for muscular disorders such as muscular dystrophy.

In a study in menopausal women, the effects of butyrate as a postbiotic on muscle function have also been examined. A group of postmenopausal women took sodium butyrate 570 mg daily (N = 70) or a placebo (N = 76) for 12 weeks. Supplementation with butyrate resulted in significantly improved grip strength and physical performance scores (assessed via the short physical performance battery; P < 0.05 for both). Additionally, butyrate supplementation led to improvement in markers of gut barrier function, reducing plasma zonulin and LPS-binding protein levels (again, P < 0.05 for both). There were modest improvements in respiratory muscle strength with the use of butyrate, as well as small reductions in markers of inflammation and oxidative stress (P < 0.05 for all).³⁸

Additional trials of postbiotics prepared from heat-killed L. plantarum TWK10 (TWK10) demonstrate a variety of muscle effects.^39–41 In healthy males aged 20–40 given TWK10 for 6 weeks, exercise endurance time significantly increased compared with controls (P = 0.0028) as did muscle weight (P = 0.0275), while both right and left hand grip strength increased (P = 0.0002 and P = 0.0140). Additionally, levels of serum lactate and ammonia during an exercise challenge were significantly reduced with the postbiotic compared with control (P < 0.0001 and P = 0.0153).⁴¹ In adults ages 20–30 given TWK10 (3 × 10¹⁰ CFU or 9 × 10¹⁰ CFU) for 6 weeks, the postbiotic improved exercise performance in a dose-dependent fashion while improving fatigue. The higher dose postbiotic also led to improvements in body fat and muscle mass.³⁹ And, in elderly subjects given TWK10 for 6 weeks, there was a tendency toward improved muscle mass, grip strength, lower limb muscle strength, gait speed, and balance at the 6-week mark, but notably these effects increased and became more significant as subjects continued to take the postbiotic up to 18 weeks (P < 0.05), suggesting that postbiotics may have a greater effect on muscle function in older subjects if continued for longer durations.⁴⁰

Discussion

Postbiotics are a highly heterogenous group of natural substances that may contain inactivated microbial cells (or components), bacterial metabolites, or metabolic byproducts. A feature shared by all of these natural substances is the absence of live bacteria, as would be found in probiotics. For this reason, postbiotics are thought to have a favorable safety profile, making them a viable option in newborns, elderly individuals, or people in compromised clinical states that may make the use of probiotics inappropriate.¹³ Indeed, the studies described above have generally found postbiotics to be safe and well-tolerated in various clinical scenarios.

The studies detailed in this article have demonstrated a variety of effects with the use of postbiotic supplements. The main targets of postbiotics that have been clinically assessed are GI health, metabolic function, and immune function. Postbiotics have been clinically evaluated in people with both IBS and IBD. They have been studied in people with allergies, as well as for their effects in reducing the incidence of URI. In studies examining their metabolic effects, they have been shown to have hypolipidemic and insulin-sensitizing properties. And in studies of muscle function, postbiotics exert a variety of benefits as well.

One of the challenges in studying postbiotics may include a lack of consensus on definition and terminology. As mentioned above, highly heterogenous substances might be considered postbiotics. Comparing the effects of such heterogenous substances to determine optimum dosing and constituents may represent an area of future research opportunity. This would also lead to more uniform quality standards and a better understanding of the clinical indications for various postbiotic preparations. Additionally, the number of trials that have compared postbiotic preparations to the equivalent live-bacteria probiotic is very limited. This makes it difficult to say for certain if postbiotics have a different safety profile or therapeutic effects than the equivalent probiotic.¹³ Future clinical trials comparing these substances would be needed to clarify the effects and optimum uses of postbiotic supplements.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.▪

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Therapeutic Use of Postbiotics: Gastrointestinal,Immune,and Metabolic Effects

Abstract

Keywords

Introduction

GI Health

SCFAs 12

Postbiotics in Diarrhea, Constipation, and IBS

Diverticulosis

Helicobacter pylori Infection

Postbiotics in IBD

Immune Effects

Metabolic Effects

Follistatin

Discussion

Footnotes

Author Disclosure Statement

Funding Information

References

SCFAs¹²