March 1, 2018
Several studies evaluating the efficacy of probiotics in different areas of health and application have been published in recent years. Current research on probiotics indicates innovative trends in the areas of cognition, prenatal and infant nutrition, and immune support via “inactive” strains, among others.
Brain health: Mood and cognition
The term “psychobiotics,” according to Mal Evans, Ph.D., scientific director, KGK Science, was coined in 2013 by John F. Cryan, Ph.D., to describe an emerging branch of probiotic research with psychological implications. “Psychobiotics are bacteria that harness the gut-brain axis to influence stress, mood, anxiety and cognition,” she said. “The possibility of influencing brain and behavior, without the toxicity profile of traditional psychiatric interventions, has attracted growing research interest in the field of probiotics.”
Bifidobacterium longum 1714 was shown to reduce stress levels and improve memory in healthy volunteers, consistent with the promising preclinical findings for this strain.1
Early intervention with probiotic Lactobacillus rhamnosus GG may benefit cognitive health in later years. A 2015 publication showed supplementation with Lactobacillus rhamnosus GG in infants during the first six months of life reduced the risk of neuropsychiatric disorders later in childhood. At the age of 13 years, six out of 35 (17.1%) children in the control group were diagnosed with attention deficit hyperactivity disorder (ADHD) or Asperger’s syndrome, while no child in the probiotic group developed ADHD or Asperger’s.2
A study published in 2017 aimed to evaluate the effect of Lactobacillus rhamnosus HN001 (from DuPont) given during pregnancy and postpartum on symptoms of maternal depression and anxiety in the postpartum period.3 This was a secondary outcome, the primary outcome being eczema in the offspring at 12 months of age. For the study, 423 women were randomized to placebo or HN001 starting at 14 to 16 weeks gestation until six months postpartum. Results showed mothers in the probiotic treatment group reported significantly lower depression scores and anxiety scores than those in the placebo group.
In a 2017 publication, oral administration of Lactobacillus fermentum CECT5716 (from Biosearch Life’s Hereditum® line) for 16 weeks in women who received a preventive dose of antibiotic in the context of delivery led to fewer instances of mastitis compared to placebo.4 Sixteen women in the probiotic group developed mastitis versus 30 women in the control group. Therefore, the oral administration of L. fermentum CECT5716 during lactation decreased by 51% the incidence rate of clinical mastitis.
The probiotic strain has also been shown to reduce the incidence of gastrointestinal (GI) and respiratory infections in infants,5 and has been proven well-tolerated and safe in infants aged 1 to 6 months.6
Prenatal nutrition and infant health are key areas of interest for researchers. Bérengère Feuz, marketing manager at Lallemand Health Solutions, pointed to the ongoing trial “The Effect of Probiotics on Maintenance of Health in Pregnancy and Infants,” supporting her company’s interest in the topic.
Ideal for supporting women of childbearing age at risk of iron deficiency is Probi FerroSorb®, by Viva 5 Corporation, is a combination of Lactobacillus plantarum 299v (LP299V®), vitamin C, folic acid and iron designed to increase iron absorption while maintaining a digestive health without the constipation sometimes experienced with iron supplementation programs.
A meta-analysis of four studies showed Lactobacillus rhamnosus GG may reduce episodes of ear and upper respiratory tract infections in healthy children.7
Lactobacillus casei DN0114 001 was effective in reducing incidence and duration of common infectious disease in a study of 638 young children8 and another study of stressed adults.9
In a double-blind study, a proprietary blend of probiotics (HOWARU® Protect Kids, from DuPont Nutrition & Health) supported respiratory health with symptom duration shortened from 6.5 to 3.5 days, a decrease in incidences of respiratory symptoms, an 80% reduction in antibiotic use and a reduction in the number of sick days by almost half compared to placebo.10
In seniors, daily intake of Bifidobacterium lactis HN019™ (HOWARU® Protect Senior, from DuPont Nutrition & Health) by healthy, elderly adults showed B. lactis HN019™ enhanced cellular immune activity.11 All doses of the probiotic increased Bifidobacterium population significantly during intervention, when compared to pre-intervention levels. In the same study, potentially harmful bacteria (enterobacteria) decreased significantly in high- and medium-dose groups.
Results of a randomized, double-blind, placebo-controlled trial sought to evaluate the impact of probiotic strain Lactobacillus coryniformis K8 CECT5711 (from Biosearch Life) on immune response to the influenza vaccine and to assess the effects on symptoms related to respiratory infections. For the study, 98 nursing home residents over the age of 65 years were randomly assigned to receive L. coryniformis K8 CECT5711 (3 × 109 CFU/day) or a placebo for two weeks before influenza vaccination.12 The primary outcome was the percentage of seroconversion. The secondary outcomes were the incidence of influenza-like illness (ILI) and respiratory symptoms associated with respiratory infections during the five-month follow-up period. The serum cytokine and immunoglobulin levels were also evaluated. Results showed the percentage of responders to the vaccination was higher in the probiotic group than in the control group. L. coryniformis ingestion was associated with a significantly lower incidence of respiratory symptoms commonly associated with respiratory infections and lower consumption of analgesics.
Probiotics are defined as live organisms that benefit human health. These bacteria proliferate in the gut and pump out beneficial metabolites and other byproducts.
“However, in recent years, dead microbes have been also shown to exhibit beneficial effects that are equivalent to, or even greater than, live microbes,” said Yoshitaka Hirose, Ph.D., group manager, House Wellness Foods, dubbing these inactive bacteria “immunobiotics. They are defined as the microbe which promotes [the] immune system through activation of gut immunity, and thus include dead microbes.”
Heat-killed Lactobacillus plantarum L-137 (HK L-137), an immunobiotic strain isolated from fermented food, induces interleukin 12 (IL-12) or type I interferon (IFN), which lead to a T helper (Th) 1 type immune response and subsequent antiallergic, antitumor or antiviral effects in mouse models, he explained.13,14,15 Further, oral intake of HK L-137 has been shown to increase Th1-related immune functions, health-related quality of life, production of type I IFN and decrease the incidence of upper respiratory tract infection in healthy subjects.16,17,18
In an in vitro study published in 2017, the inactivated probiotic Bacillus coagulans GBI-30, 6086 (Staimune™, from Ganeden/Kerry) activated human immune cells and altered the production of both immune-activating and anti-inflammatory cytokines and chemokines.19 Of special importance, research noted, is the selective upregulation of the G-CSF growth factor involved in postinjury and postinflammation repair and regeneration. “This suggests that important immunogenic cell wall components, such as lipoteichoic acid, are undamaged after the inactivation and retain the complex beneficial biological activities previously demonstrated for the cell walls from live B. coagulans GBI-30, 6086 (GanedenBC30, from Ganeden/Kerry) probiotic bacteria,” researchers wrote.
Heat-inactivated L. salivarius CECT 5713 prevented adhesion of Streptococcus mutans—a bacterial species involved in dental caries—to hydroxyapatite, according to a 2017 publication.20 Researchers concluded the inactive bacteria could be used as a strategy to reduce salivary concentration of this oral pathogen.
Recent research supports the role of probiotics in managing exercise-induced inflammation and muscle damage.
Bifidobacterium breve BR03 and Streptococcus thermophilus FP4 reduced inflammation and improved the inflammatory response to exercise in a recent double-blind, randomized, placebo-controlled, crossover study of 16 healthy, resistance-trained men.21 For the study, each participant consumed a probiotic capsule containing 5 billion microencapsulated live cells of B. breve BR03 and S. thermophilus FP4 or placebo daily for 21 days prior to performing amuscle-damaging exercise of elbow flexors. Performance of elbow flexors and a marker of inflammation (interleukin-6 [IL-6]) were measured prior to and following the exercise. Ingestion of the probiotics attenuated performance and range-of-motion decrements following muscle-damaging exercise. The probiotics also reduced baseline inflammation and improved inflammatory response to exercise.
In a double-blind, randomized, placebo-controlled study of 23 collegiate female athletes, a strain of Bacillus subtilis (as DE111®, from Deerland Enzymes) had significant effects on body composition and athletic performance when consumed along with adequate post-workout nutrition.22 The athletes completed the same 10-week resistance training program during offseason, which consisted of three to four workouts per week of upper- and lower-body exercises and sport-specific training. The athletes consumed DE111 or placebo supplement in conjunction with a recovery protein drink immediately following resistance and sport-specific training for the entire 10-week program.
A 2017 publication evaluated the effects of co-administration of Bacillus coagulans GBI-30, 6086 (GanedenBC30) with β-hydroxy-β-methylbutyrate (HMB) calcium (CaHMB) to CaHMB alone on inflammatory response and muscle integrity during 40 days of intense military training.23 Results supported HMB supplementation to attenuate the inflammatory response to intense training, and found the combination of BC30 with CaHMB may be more beneficial than CaHMB alone in maintaining muscle integrity during intense military training.
A combination of Bifidobacterium lactis Bi-07® and Lactobacillus acidophilus NCFM® (HOWARU® Protect Sport, from DuPont Nutrition & Health) consumed daily over a five-month period was shown to reduce risk of an upper respiratory illness and delay time to respiratory tract illness compared to placeboin physically active adults. The study showed significantly extended exercise duration and significantly improved training duration.24
“The prevalence of allergic diseases has been dramatically rising in the United States and other developed nations over recent decades,” said Ralf Jäger, Ph.D., scientific advisor at Pharmachem Laboratories, a division of Ashland. “Growing evidence suggests a partial role for the microbiome in the development of these allergic diseases.”
Among the earliest and most common food allergic diseases of infancy, per Jäger, is intolerance or allergy to cow’s milk protein, “yet its pathophysiology is not well understood.”
Administration of probiotic Lactobacillus rhamnosus GG resolved symptoms of four clinically diagnosed cases quickly and completely, with the range of time from probiotic initiation to symptom resolution between seven and 28 days, according to a 2016 publication.25 The probiotic, when administered to infants with cow’s milk allergy, in combination with extensively hydrolyzed casein for six months, led to the development of tolerance to cow’s milk in 42% of infants who received the probiotic/casein combination, compared to zero who received casein only, when tested via an oral food challenge 12 months after treatment.26 “Most tolerant infants showed a significant increase in fecal butyrate levels,” Jäger said. “L. rhamnosus GG promotes tolerance in infants with CMA by influencing the bacterial community structure of the infant gut.”
Looking to the impact of probiotics on Celiac disease and gluten intolerance, B. breve BR03 showed a positive effect on decreasing the production of pro-inflammatory cytokine TNF-alpha in children (10.4 ± 4.2 years) with Celiac disease, consuming a gluten-free diet.27
Gut and digestive health continue to be top areas of research for probiotics, including a recent study showing the benefits of probiotics on protein digestion.
In a randomized, placebo-controlled, parallel group study, supplementation with one tablet of Sabinsa’s LactoSpore® (each tablet containing 2×109 cfu Bacillus coagulans MTCC 5856) per day for 90 days, in addition to standard treatment, resulted in a significant decrease (p<0.01) in the clinical symptoms of diarrhea-predominant irritable bowel syndrome (IBS) such as bloating, vomiting, diarrhea, abdominal pain and stool frequency when compared to placebo group.28 Additionally, the LactoSpore group showed decreased disease severity based on physician’s global assessment and better IBS-quality of life compared to placebo.
In a 2017 publication, supplementation with Bacillus subtilis (as DE111) led to a healthier bowel index as measured by the Bristol Stool Chart scale.29 For the study, 50 people were evaluated by their stool profile, food diary and questionnaire while taking the probiotic or placebo daily for 105 days. Researchers concluded DE111 supported regularity by improving occasional constipation and/or diarrhea in healthy individuals.
Bifidobacterium lactis is another strain supporting healthy bowel movements. A Chinese study found that women who consumed yogurt containing Bifidobacterium lactis DN-173 010 averaged 1.5 more bowel movements than the placebo group.30
A 2015 meta-analysis of 21 randomized controlled trials concluded Saccharomyces boulardii yeast reduced the risk of antibiotic-associated diarrhea.31
In a recent publication, the effects of probiotics on digestion of plant proteins was evaluated. For the study, three plant proteins, from pea, soy and rice, were digested in an in vitro model of the stomach and small intestine in the absence and presence of GanedenBC30.32 Results showed enhanced protein digestion by BC30 by dual benefit: enhanced amino acid bioavailability from plant proteins in the upper GI tract and a healthier environment in the colon.
To ensure consumers receive the benefits of probiotics, compliance and efficacy are challenges to consider. According to Arthur Radcliffe, business development manager, Lonza Consumer Health & Nutrition, probiotics are delivered in myriad ways, including via foods, drinks, sachets, sticks, pessaries for feminine application, tablets, chewable tablets, powder, and confectionery forms of chocolate, gum, gummies and mints, among others. He pointed to research from Mintel showing capsules are a top choice for delivery of probiotics, with more than 41% of supplement launches globally from 2015 to 2017 coming in a capsule.
“We see consumers gravitating to probiotics capsules for their host of benefits,” Radcliffe said, adding they’re versatile, can eliminate excess packaging, are convenient and easy to consume.
Capsules can also address challenges that can negatively influence the integrity of the probiotic such as stability and effective delivery to the intestines.
Probiotic stability is challenged by both processing and shelf life requirements. “The pressure and heat from the tableting process is harsh and can compromise the stability of probiotics,” Radcliffe said. “Transportation and storage issues—such as length of time, temperature fluctuation and exposure to moisture—can put probiotics in other delivery forms at risk for degradation or early activation.” Capsule technologies can address these challenges to deal with the concerns of stability and targeted delivery to the intestines.
Allen AP et al. “Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers.” Transl Psychiatry. 2016;6:e939-e939.
Pärtty et al. “A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial.” Pediatr Res. 2015;77(6):823-8.
Slykerman RF et al. “Effect of Lactobacillus rhamnosus HN001 in Pregnancy on Postpartum Symptoms of Depression and Anxiety: A Randomised Double-blind Placebo-controlled Trial.” EBioMedicine. 2017.
Hurtado et al. “Oral administration to Nursing Women of Lactobacillus fermentum CECT5716 Prevent lactational Mastitis Development: A Randomized Controlled Trial.” Breastfeeding Medicine. 2017;12(4):202-209.
Maldonado et al. “The human milk probiotic Lactobacillus fermentum CECT 5716 reduces the incidence of gastrointestinal and respiratory infections in infants. A Randomized Controlled Trial comparing a prebiotic containing follow-on formula vs the same formula plus probiotic.” J Pediatr Gastroenterol Nutr. 2012 Jan;54(1):55-61.
Gil-Campos et al. “Lactobacillus fermentum CECT 5716 is safe and well tolerated in infants of 1 to 6 months of age: A Randomized Controlled Trial.” Pharmacol Res. 2012 Feb;65(2):231-8.
Liu S et al. “Lactobacillus rhamnosus GG supplementation for preventing respiratory infections in children: a meta-analysis of randomized, placebo-controlled trials.” Indian Pediatr. 2013;50:377-381.
Merenstein D et al. “Use of a fermented dairy probiotic drink containing Lactobacillus casei (DN-114 001) to decrease the rate of illness in kids: the DRINK study A patient-oriented, double-blind, cluster-randomized, placebo-controlled, clinical trial.” Eur J Clin Nutr. 2010;64:669-677.
Guillemard E et al. “Effects of consumption of a fermented dairy product containing the probiotic Lactobacillus casei DN-114 001 on common respiratory and gastrointestinal infections in shift workers in a randomized controlled trial.” J Am Coll Nutr. 2010;29:455-468.
Leyer GJ et al. “Probiotic Effects on Cold & Influenza-Like Symptom Incidence and Duration in Children.” Pediatrics. 2009;124:e172-e179.
Harsharnjit G et al. “Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019.” The American Journal of Clinical Nutrition. 2001;74(6):833-839.
Fonollá et al. “Effects of the Lactobacillus coryniformis K8 CECT5711 on the immune response to influenza vaccination and the assessment of common respiratory symptoms in elderly subjects: a randomized controlled trial.” Eur J Nutr. 2017 Nov 9. DOI: 10.1007/s00394-017-1573-1.
Murosaki S et al. “Heat-killed Lactobacillus plantarum L-137 suppresses naturally fed antigen–specific IgE production by stimulation of IL-12 production in mice.” J Allergy Clin Immunol. 1998 Jul;102(1):57-64.
Murosaki S et al. “Antitumor effect of heat-killed Lactobacillus plantarum L-137 through restoration of impaired interleukin-12 production in tumor-bearing mice.” Cancer Immunol Immunother. 2000 Jun;49(3):157-64.
Maeda N et al. “Oral administration of heat-killed Lactobacillus plantarum L-137 enhances protection against influenza virus infection by stimulation of type I interferon production in mice.” Int Immunopharmacol. 2009 Aug;9(9):1122-5.
Hirose Y et al. “Daily Intake of Heat-Killed Lactobacillus plantarum L-137 Augments Acquired Immunity in Healthy Adults.” J Nutr. 2006 Dec;136(12):3069-73.
Arimori Y et al. “Daily intake of heat-killed Lactobacillus plantarum L-137 enhances type I interferon production in healthy humans and pigs.” Immunopharmacol Immunotoxicol. 2012 Dec;34(6):937-43.
Hirose Y et al. “Oral intake of heat-killed Lactobacillus plantarum L-137 decreases the incidence of upper respiratory tract infection in healthy subjects with high levels of psychological stress.” J Nutr Sci. 2013 Dec 6;2:e39.
Jensen GS et al. “Inactivated probiotic Bacillus coagulans GBI-30 induces complex immune activating, anti-inflammatory, and regenerative markers in vitro.” Journal of Inflammation Research. 2017;10:107-17.
Sañudo et al. “In vitro and in vivo anti-microbial activity evaluation of inactivated cells of Lactobacillus salivarius CECT 5713 against Streptococcus mutans.” Oral Biology. 2017;84:58-63.
Jäger et al. “Probiotic Streptococcus thermophilus FP4 and Bifidobacterium breve BR03 Supplementation Attenuates Performance and Range-of-Motion Decrements Following Muscle Damaging Exercise.” Nutrients. 2016;8:642.
“The effect of probiotic supplementation on body composition, muscle thickness, and athletic performance in Division I collegiate athletes,” presented at the International Society of Sport Nutrition (ISSN) Annual Conference. 2017.
Yftach G et al. “Combined effect of Bacillus coagulans GBI-30, 6086 and HMB supplementation on muscle integrity and cytokine response during intense military training.” Journal of Applied Physiology. 2017;123(1):11-18.
West N et al. “Probiotic supplementation for respiratory and gastrointestinal illness symptoms in healthy physically active individuals.” Clinical Nutrition. 2014;33(4):581-87.
Martin et al. “Presumed Allergic Proctocolitis Resolves with Probiotic Monotherapy: A Report of 4 Cases.” Am J Case Rep. 2016;17:621-4.
Berni Canani et al. “Lactobacillus rhamnosus GG-supplemented formula expands butyrate-producing bacterial strains in food allergic infants.” The ISME Journal 2016;10:742-750.
Klemenak et al. “Administration of Bifidobacterium breve Decreases the Production of TNF-a in Children with Celiac Disease.” Dis. Sci. 2015;60:3386-3392.
Majeed et al. “Bacillus coagulans MTCC 5856 supplementation in the management of diarrhea predominant irritable bowel syndrome: a double blind randomized placebo controlled pilot clinical study.” Nutr J. 2016. DOI: 10.1186/s12937-016-0140-6.
Cuentas et al. “The Effect of Bacillus subtilis DE111 on the Daily Bowel Movement Profile for People with Occasional Gastrointestinal Irregularity.” J Prob Health. 2017;5:4.
Yang Y.-X. et al. “Effect of a fermented milk containing Bifidobacterium lactis DN-173010 on Chinese constipated women.” World J Gastroenterol. 2008;14:6237.
Szajewska H, Kołodziej M. “Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea.” Aliment Pharmacol Ther. 2015;42:793-801.
Keller D et al. “Bacillus coagulans GBI-30, 6086 increases plant protein digestion in a dynamic, computer-controlled in vitro model of the small intestine (TIM-1).” Beneficial Microbes. 8(3):491-496.
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