Probiotics and Disease: A Comprehensive Summary—Part 3, Cardiometabolic Disease and Fatigue Syndromes

Abstract

This article series provides a literature review of the disease-specific probiotic strains, associated with cardiometabolic diseases and fatigue syndromes, studied in published clinical trials in humans and animals. This is not an exhaustive review. The table design allows for quick access to supportive data and will be helpful as a guide for both researchers and clinicians. The goal of the probiotics and disease series is to provide clinically useful tools. The first article (part 1) focused on mental health and neurological conditions and the second article (part 2) explored cultured and fermented foods that are commonly available in the United States. This third article (part 3) explores the relationship between bacterial strains and 2 of the most prevalent diseases we have in modern society: cardiometabolic disease and fatigue syndromes. Future articles will review conditions related to respiratory, ear, nose, and throat infections and infectious diseases; autoimmunity and dermatological conditions; cancer; and gastrointestinal and genitourinary, followed by an article focused on probiotic supplements. This literature review is specific to disease condition, probiotic classification, and individual strain.

The purpose of this summary is to provide nutritionists and other medical practitioners with a reference guide for recommending health-promoting commercially produced cultured and fermented food products to patients. Research was conducted via grocery stores trips, company Web site reviews, personal communication with food company personnel, along with PubMed and EBSCO Research Premier searches. The lists contained herein are not exhaustive; however, they represent items that are commonly accessible to US consumers.

There is considerable research on the gut microbiome and role of probiotics; however, this research has not been clearly connected with clinical practice. The authors undertook a review of current literature to explore which specific probiotics and probiotic strains have been utilized in clinical and laboratory studies. To make this clinically valuable, product names of probiotics and fermented foods have been included. Finished products vary between manufacturers; thus, the researchers included brand listing to provide transparency and to facilitate a functional probiotics guide for clinicians. Exclusions of products meeting our criteria do not imply that these products are not effective—we simply were not aware of them.

Methodology

This literature review originated from a group project that was part of the requirements for a course in the doctoral program in functional and clinical nutrition at Maryland University of Integrative Health (Laurel, MD, USA). The student researchers had approximately 2 months to review the literature and synthesize the paper. The authors agreed on format, templates, and execution. Each author researched and wrote sections reviewing probiotics in relation to various health conditions with literature searches conducted in PubMed, Biomed Central, EBSCO Research Premier, PloS One, Cochrane reviews, and topic-specific open-source journals.

The review of specific probiotic products in the professional marketplace and specific probiotics products was performed using Internet searches, primarily Shop Google, in addition to topic specific databases to search for specific probiotic species including the strains listed in the research. Novel strains were cross-referenced to determine whether the strain was available only for research purposes. If a probiotic combination was used in the research, formulas that closely matched the combination were included. Formulas that contain all or most of the specific probiotics and strains were also included. The food survey focused on bacterial strains in food and includes foods that are commercially produced and commonly available in the refrigerated sections of grocery stores in the United States. Information was gleaned from commercial Web sites and by visiting grocery stores (primarily in California).

Research Overview: Cardiometabolic Diseases

Currently, 29% of US adults suffer from cardiometabolic disease,1 whereas in obese and overweight children, this number exceeds 60%.2 This number is projected to reach 40.5% by 2030 for the adult population, generating awareness for the magnitude of the epidemic.3 Genetic susceptibility as well as environmental factors are involved in the pathogenesis of cardiometabolic disease. Despite the growing evidence for this epigenetic disease model, there is an abundance of evidence for agonistic and antagonistic mechanisms of the microbiome on cardiometabolic health. Current animal studies and randomized controlled trials suggest that a multitude of bacterial strains exert an influence not only on the microbiome but have lasting benefits and consequences for the host. Currently, there is evidence to suggest a corollary between the microbiome and the following cardiometabolic diseases: obesity, insulin resistance, type 2 diabetes, nonalcoholic steatosis hepatitis, dyslipidemia, polycystic ovary syndrome, and gout.4–14

The microbiota influences nutrient use and weight changes by contributing to energy extraction. The microbiome operates in a mostly anaerobic environment,15 resulting in fermentation of chyme and fecal material. Most ferments are derived from either saccharolytic or proteolytic fermentation.16 Saccharolytic fermentation contributes to the daily energy requirement and results in the creation of short chain fatty acids including acetate, propionate, and butyrate. Diets rich in lipids are associated with a decrease of Bifidobacterium, known to produce butyrate, an anti-inflammatory, antineoplastic product promoting gut barrier integrity.16 On the negative side, proteolytic fermentation produce amines and ammonia, which are toxic.16

The chronic low-grade inflammation associated with obesity can be attenuated by targeted probiotic strains.17 Bienenstock et al16 found that overweight subjects had a decrease in beneficial bacteria, an increase in pathogenic species, and overall less diversity of species than did controls. Manipulation of gut microbiota through the administration of probiotics can improve microbial diversity and epithelial barrier integrity, and it can optimize metabolic balance, promote weight loss, and decrease disease prevalence. Thus, developing innovative treatment approaches for cardiometabolic diseases are imperative not only for disease modulation, but also for public health.

Discussion: Cardiometabolic Disease

Probiotic strains of Lactobacillus and Bifidobacterium are marketed in products for human consumption because they alter the intestinal flora. These probiotic strains may be protective of various metabolic processes by shielding the colonocytes from microbial endotoxin release and reducing innate immune system activation through increased competition with bacteriocin-producing microbial families. Bacteriocins are proteinaceous toxins that bacteria produce to prevent the growth of bacterial strains that are closely related and may be beneficial in cardiometabolic diseases.30

In relation to cholesterol, it has been shown that probiotics inhibit cholesterol hepatic recirculation. Etjahed et al61 found that L acidophilus LA-5 and B lactis BB-12 facilitated bile salt hydrolase to deconjugate bile salts resulting in a decrease of enterohepatic cholesterol circulation. This effect is 2-fold as cholesterol is the substrate for de novo synthesis of bile acids and was beneficial for those suffering from type 2 diabetes mellitus. An alternate mechanism for the decrease in cholesterol seen by probiotics is the bacterial fermentation product of short-chain fatty acids, an inhibitor of hepatic cholesterol synthesis. Last, hydroxymethylglutarate CoA, the enzymatic target of statin drugs, can also be modulated by L fermentum KC-4B, reducing the amount of cholesterol in a cultured medium.55

Research Overview: Fatigue Syndromes

Fatigue syndromes such as chronic fatigue syndrome (CFS), myalgic encephalomyelitis, systemic exertion intolerance disease, and fibromyalgia syndrome are intricately linked to gastrointestinal health. On average, approximately 60% of these patients also qualify for the clinical diagnosis of irritable bowel syndrome and 97% of CFS patients report neuropsychological disturbances.62,63 Microbial translocation induces inflammatory markers such as lipopolysaccharides (LPS), LPS-binding protein, C-reactive protein, tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and soluble CD14 in those with CFS, which results in T-helper 2 dominance.64–66 CFS patients also have dysbiotic flora with the relative ratios of Firmicutes, Lactobacillus, and Escherichia coli being considerably lower than in controls with approximately 2-fold the number of Proteobacteria (Enterobacteriaceae family). This imbalance can result in an overall decrease in anti-inflammatory bacterial species such as Bifidobacteria.65 Furthermore, the overrepresented species found in the Enterococcus and Streptococcus families are capable of producing d-lactic acid, potentially resulting in chronic acidosis in CFS patients.16 The overabundance of Prevotella suggests a strong reliance on carbohydrate intake within the population67 and lends insight into why a lower carbohydrate diet often results in a decrease in clinical symptoms.

CFS is characterized by unexplained fatigue along with a minimum of 4 of the following symptoms: memory impairment, sore throat, tender lymph nodes, muscle or joint pain, headaches, unrefreshing sleep, and postexertional malaise.64 CFS is also associated with an increase in anxiety and/or depression. The dysbiotic flora in these patients can partially explain the microbial-neuroendocrine relationship between certain species and the resultant change in hormones and neurotransmitters. Lactobacillus and Bifidobacterium species produce calming neurotransmitters such as acetylcholine and gamma-amino butyrate (GABA) respectively, whereas Escherichia species produce norepinephrine, serotonin, and dopamine and, in addition, Streptococcus and Enterococcus species produce serotonin.67 Thus, in these patients, there is the potential for the overproduction or underproduction of serotonin, a lack, of both acetylcholine and GABA, and a decrease in norepinephrine and dopamine. Microbial production of tryptophan, tyrosine and phenylalanine can be altered owing to microbial dependence on a key pathway that humans lack called the shikimate pathway.68 Furthermore, serotonin, melatonin, melanin, epinephrine, dopamine, thyroid hormone, folate, coenzyme Q₁₀, vitamin K, and vitamin E all depend on this pathway for metabolites.68 This crucial pathway can be disrupted by the consumption of glyphosate, an herbicide found in Roundup Ready Crops and in the environment.68 The metabolism of these nutrients and hormones are bacteria dependent and depending on the dietary intake of those with CFS, several critical biomolecules can be altered.

Discussion: Fatigue Syndromes

The research reviewed previously indicates that certain probiotic species can be useful in the amelioration of CFS symptoms and quality of life. Key inflammatory substances such as tumor necrosis factor α (TNF-α) and IL-6 control C-reactive protein on the transcription level elucidating the role between dysbiotic flora that have the ability to alter these proinflammatory biomolecules and disease presentation. Groeger et al64 found that supplementation with Bifidobacterium infantis 35624 for 6 to 8 weeks reduced these proinflammatory markers in 71% of those with CFS, resulting in a decrease of symptoms in 3 separate randomized, double-blind, placebo-controlled interventions. Quevrain70 also found that Faecalibacterium prausnitzii can significantly inhibit the nuclear factor κB pathway in intestinal epithelial cells by producing a protein that results in a decrease in inflammatory markers. Choppa69 found that probiotic supplementation with Lactobacillus acidophilus and L acidophilus loaded alginate beads reduced postswim fatigue time in CFS induced mice while decreasing (P < .05) oxidonitrosative stress, TNF-α levels, and restoring the diminished spleen and thymus to normal size.

Addressing more directly the neuroendocrine imbalances in CFS are 2 studies that show that supplementation with certain Lactobacillus species can reduce symptoms of anxiety as well as increase Bifidobacteria levels.62,66 Galland67 also showed that supplementation with Bacteroides fragilis decreased anxiety levels while improving excessive gut permeability, whereas Giloteaux65 found that supplementation with the bifidogenic substance Propionibacterium freudenreichii improved butyrate levels, which induces an anti-inflammatory cascade. Sullivan66 found that a blend of Lactobacillus paracasei F19, L acidophilus NCFB 1748, and B lactis BB-12 improved fatigue and quality of life via the visual analogue scales and the SF-12 Health Survey in only 2 weeks. Caution is advised for those who have short-bowel syndrome and CFS as over supplementation with d-lactate producing Lactobacilli can result in d-lactic acidosis. Galland67 presented a case report elucidating the mechanism of d-lactate overgrowth that was ameliorated by a symbiotic consisting of Bifidobacterium breve Yakult, Lactobacillus casei Shirota, and galacto-oligosaccharide with no concurrent change in diet. Overall, these studies suggest that direct modulation of the microbiome can reduce anxiety, improve quality of life, restore dysbiotic flora, and reduce inflammatory markers in those with CFS.

Nutritional Supplements Overview

Professional and commercial dietary supplements containing probiotics are widely available.71 In 2002, it was estimated that more than 100 companies in the United States marketed probiotic supplements and nearly 2 million adults used them.72 In 2012, probiotic or prebiotic use was the third most commonly used nonvitamin, nonmineral dietary supplement and global sales are projected to reach to $42 billion by the end of 2016.73,74 Using probiotics for general health versus targeting a specific health concern is more complex as the properties of probiotic species are strain specific.75 Unfortunately, there is a lack of consistency naming therapeutic strains in research and strains are often not listed on supplement labels. This makes it difficult to know if the ingredients in a product matches the ingredients used in the research and is a limitation of these tables. If the researched strain was not readily available on the label or marketing material, the brand, potentially containing the strain, was not included on the table.

The Joint Food and Agriculture Organization of the United Nations/World Health Organization Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics developed guidelines for evaluating probiotics in food.76 A combination of phenotypic and genotypic tests must be performed to determine the strain; however, regulations on species identification is not in place and supplement companies are not required to list this information on labels. During this multiseries review, it was identified that 30 species were specifically isolated for research purposes and were unavailable and another 56 strains were not commercially available. Owing to the wide variety of formulations on the market, lack of knowledge, and poor labeling, it is difficult for practitioners and consumers to determine which brand contains specific strains researched to address a particular health concern.

This table is designed to be a resource to see what is available at-a-glance. The brands were chosen by searching the probiotic strain and/strain-species in Google, several supplement companies, Probiotics Advisor,77 and the Clinical Guide to Probiotic Products.78 Based on the results and to determine what was commercially available, the search was refined using Google Shopping. In some instances, the supplement company was called to determine if the formula contained a specific species.

Table 1.

Cardiometabolic Disease

Cardiometabolic Disease	Strains	Overview	Professional and Commercial Products	Foods
Obesity, T2DM, and NAFLD
Obesity, T2DM Mohamadshahi et al18 (2014); Tonucci et al19 (2015); Sáez-Lara et al4 (2016)	L acidophilus LA-5, B animalis subsp lactis BB-12, L salivarius LS-33	Lowered HbA1c, TC, and LDL-C.	ProSynbiotic (Standard Process) Strengtia (Apex Energetics) TruBiotics (Bayer)	L acidophilus LA-5 (Nancy’s Organic cow’s milk yogurt) B lactis BB-12 (Nancy’s Organic cow’s milk kefir)
Obesity Larsen et al20 (2013); Sáez-Lara et al4 (2016)		Increase in the ratios of Bacteroides, Prevotellae, and Porphyromonas. Subjects: 50 obese adolescents.	Aloe 10 000 & Probiotics, Berry Dophilus Extra Strength (NOW) GoLive Probiotic & Prebiotic Drink Mix Hyper-Implante (InterPlexus) Probiotic Supreme (DF Designs for Health) ProtoDophilus (Protocol For Life Balance) Ultimate Intestinal Shield (Phyto Therapy) UltraFlora Spectrum (Metagenics)	None
Obesity Kadooka et al17,21 (2010, 2013); Sáez-Lara et al4 (2016)	L gasseri SBT-2055, L gasseri LG-2055 (51010 CFU)	Reduction in BMI, waist, abdominal VFA, and hip circumference and adiponectin levels; subjects: 87 subjects with high BMI and 210 adults with large VFA.	Isolated for research and not commercially available (prepared with lactic acid bacteria starter cultures); (S thermophilus and L delbrueckii sbsp bulgaricus) commonly used for conventional yogurt production and viable cells of LG2055.	None
Obesity Sharafedtinov et al22 (2013)	L plantarum (TENSIA 1.51011 CFU/g added to cheese milk before renneting)	Reduction in BMI and arterial BP value; subjects: 40 adults with obesity.	Isolated for research, from the GI of healthy Estonian children, and not commercially available.	None
Obesity Zarrati et al23,24,25 (2013a, 2013b, 2014); Sáez-Lara et al4 (2016)	L acidophilus LA-5, B lactis BB-12, L casei DN-001 (108 CFU/g)	Changes in gene expression in PBMCs as well as BMI, fat percentage, and leptin levels; 75 subjects with high BMI.	ProSynbiotic (Standard Process) TruBiotics (Bayer) Strengtia (Apex Energetics)	L acidophilus LA-5 (Nancy’s Organic cow’s milk yogurt) B lactis BB-12 (Nancy’s Organic cow’s milk kefir); L casei DN001; None
Obesity Agerholm-Larsen et al26 (2000); Sáez-Lara et al4 (2016)	E faecium, 2 strains of S thermophilus	Reduction in body weight, systolic BP, LDL-C, and increase on fibrinogen levels in 70 overweight and obese subjects.	E. faecium: Enterogenic Concentrate (Integrative Therapeutics) Nature’s Secret Ultimate Probiotic (4 billion) Health-Bac 100 grams (North American Herb & Spice) S thermophilus: BIFIDO DIGEST 60C (F) (Protocol for Life)	E faecium (None) S thermophilus (lassi, kefir, all yogurts)
Obesity, NAFLD, T2DM Rajkumar et al27 (2013); Sáez-Lara et al4 (2016)	Bifidobacteria, Lactobacilli, S thermophilus	Improvement in lipid profile, insulin sensitivity, and decrease in CRP; 60 overweight subjects.	S thermophilus: BIFIDO DIGEST 60C (F) (Protocol for Life) NOW Foods Probiotic (10 50 Billion)	Cultured dairy and dairy alternatives; fermented vegetables.
Obesity, T2DM Ivey et al28,29 (2014, 2015); Sáez-Lara et al4 (2016)	L acidophilus LA-5, B animalis subsp lactis BB-12	Reduction in fasting glucose concentration and increase in HOMA-IR; subjects: 156 overweight adults.	ProSynbiotic (Standard Process) TruBiotics (Bayer) Strengtia (Apex Energetics)	L acidophilus LA-5 (Nancy’s Organic cow’s milk yogurt) B lactis BB-12 (Nancy’s Organic cow’s milk kefir)
Obesity, NAFLD Yoo et al30 (2013); Park et al31 (2013)	L curvatus HY-7601, alone or in combination with L plantarum KY-1032	↓ Body weight gain; ↓ hepatic lipid droplet accumulation and adipocyte size; ↓ cholesterol in plasma and liver; ↓ gene expressions of fatty acid synthesis enzymes; ↓ proinflammatory cytokines (TNF-α, IL-6, IL-1β, and MCP); ↓ fatty acid oxidation-related genes (PGC1α, CPT1, CPT2, and ACOX1) in the liver.	Isolated for research purposes only.	None
Obesity, NAFLD Wang et al32 (2015)	L paracasei CNCM I-4270, L rhamnosus I-3690, B animalis subsp lactis I-2494	↓ Body weight gain; ↓ macrophage infiltration into epididymal adipose tissue; ↓ hepatic steatosis; ↑ glucose-insulin; homeostasis (strain-specific) attenuation of obesity comorbidities; effects on MS-associated phylotypes of gut microbiota in mice.	Isolated for research purposes only.	None
Obesity, NAFLD, T2DM An et al33 (2011)	LAB supplement (B pseudocatenulatum SPM-1204, B longum SPM-1205, B longum SPM-1207; 108–109 CFU)	↓ Body weight gain and fat accumulation; ↓ blood serum levels of total cholesterol, HDL-C, LDL-C, triglyceride, glucose, leptin; ↓ liver toxicity biomarkers (AST, ALT).	Isolated from stool for research purposes.	None
Obesity, T2DM Chen et al34 (2012)	B adolescentis	↓ Body weight gain and visceral fat accumulation; ↑ insulin sensitivity.	Isolated from stool for research purposes.	None
Obesity, NAFLD Zhao et al35 (2012)	P pentosaceus LP-28/L plantarum SN-13T (as comparator)	↓ Body weight gain, visceral fat accumulation, and liver lipid contents (triglyceride and cholesterol); ↓ hepatic lipid droplet accumulation and adipocyte size; ↓ lipid metabolism-related genes (CD36, SCD1, PPARγ).	P pentosaceus LP-28 (isolated from longan fruit [E longana] for research purposes. L plantarum SN13T (plant derived and isolated for research purposes).	None
Obesity, T2DM, NAFLD Gauffin et al36 (2012)	B uniformis CECT-7771	↓ Body weight gain, visceral fat accumulation and liver lipid contents (triglyceride and cholesterol); ↑ small adipocyte numbers; ↓ serum cholesterol, triglyceride, glucose, insulin, and leptin levels; ↑ oral tolerance to glucose; ↓ dietary fat absorption (reduced number of fat micelles in enterocytes); ↑ immune defence mechanisms;	Isolated from stools of healthy infants (mean age, 5.7 y; range, 1.0–10.8 y) for research purposes.	None
Obesity, NAFLD Everard et al37 (2014)	S boulardii	↓ Body weight gain and fat mass; ↓ hepatic steatosis and total liver lipids content; ↓ decreases hepatic (50% decrease in CD11c macrophages level, F4/80, IL-1β and MCP-1mRNA); ↓ systemic inflammation (↓ plasma cytokine concentrations of IL-6, IL-4, IL-1β and TNF-α).	Designs for Health (FloraMyces) Digestive Probiotic for Travelers (NatureMade) Florastor (Biocodex) Strengtia (Apex Energetics)	None
Obesity, NAFLD, T2DM Kim et al38 (2013); Park et al39 (2015); Ritze et al40 (2014)	L rhamnosus GG	↓ Body weight gain and fat mass; ↑ insulin sensitivity; ↑ expression of genes related to glucose metabolism (GLUT4 mRNA in skeletal muscle); ↑ adiponectin production in adipose tissue; ↑ AMPK in skeletal muscle and adipose tissue; ↑ glucose tolerance; ↑ Insulin-stimulated Akt phosphorylation and GLUT4 translocation in skeletal muscle; ↓ endoplasmic reticulum (ER) stress in skeletal muscle; ↓ M1-like macrophage activation in white adipose tissues; ↓ liver inflammation and steatosis (protection from NAFLD development); ↓ duodenal IκB protein levels and restoration of the duodenal tight junction protein concentration; ↓ portal LPS; ↓ TNF-α, IL-8R, and IL-1β mRNA expression in the liver.	Advanced Multi-Billion Dophilus (Solgar) Advanced 40+ Acidophilus (Solgar) Digestive Health Probiotic, Kids Chewables & Packets (Culturelle) UltraFlora Baby (Metagenics) Walgreens Probiotic Lactobacillus GG	None
Obesity, T2DM, NAFLD Yadav et al41 (2006)	L lactis	↓ HbA1C; ↓ fasting blood glucose, insulin, free fatty acids and triglyceride.	Obtained from National Collection of Dairy Cultures for research purposes.	Activia yogurt (Redwood); Hill Farm goat milk kefir
Obesity, NAFLD Yin et al42 (2010); Reichold et al43 (2014)	Bifidobacteria L66-5, L75-4, M13-4, FS31-12; B adolescentis	↓ Liver triglyceride, total cholesterol and total lipid deposition (all 4 strains, but in strain-dependent manner, more pronounced for B L66-5); ↓ serum triglyceride and total cholesterol (all 4 strains, but in strain-dependent manner, more pronounced for B L66-5 and B FS31-12); ↓ body weight gain (B L66-5); ↑ body weight gain (B M13-4); no changes in body weight gain L75-4 and FS31-12; ↓ liver inflammation and steatosis (protection from NASH development); ↓ formation of reactive oxygen species; ↓ activation of NF-κB; no effect on portal LPS, TLR-4, and Myd-88 mRNA expression in livers.	BL66-5, L75-4, M13-4, and FS31-12-isolated from healthy volunteers’ fresh feces for research purposes. B adolescentis: Cultured in brain, heart under anaerobic conditions for research purposes.	None
Obesity, NAFLD Plaza-Diaz et al44 (2014)	L paracasei CNCM I-4034, B breve CNCM I-4035, L rhamnosus CNCM (or mixture of 3 strains)	↓ Triacylglycerol liver content (for L rhamnosus, B breve or the mixture); ↓ neutral lipids liver content (for all 4 probiotic groups); ↓ serum LPS levels (for all 4 probiotic groups); ↓ serum TNF-α levels (for B breve, L rhamnosus, or the mixture); ↓ serum IL-6 levels (for L paracasei).	Isolated from feces of exclusively breast-fed infants for research purposes.	None
Obesity, T2DM, NAFLD Savcheniuk et al45 (2014)	14 alive probiotic strains (Lactobacillus, Lactococcus, Bifidobacterium, Propionibacterium, Acetobacter)	↓ Body weight gain and visceral fat accumulation; ↓ liver lipid contents (protection from NAFLD development); ↓ serum cholesterol, triglyceride, glucose, insulin and leptin levels; ↑ insulin sensitivity (decreased HOMA-IR, increased adipocytokine.	Propionibacterium: Securil, Nutricology Acetobacter: Not available	Various cultured and fermented foods.
Obesity Kobyliak et al46 (2016)	Bacteroidates, (Bacteroides)↓, Bacteroidates, (Prevotella)↑, ↑Bacillales, (Bacillus)↑, Lactobacillus↓, Clostridiales, (Clostridium)↑, Actinomycetales↑, Bifidobacteriales↓, (Bifidobacterium)	The alteration of microbiota in gut in the conditions of obesity.	Broad spectrum probiotic providing Bifidobacterium and Lactobacillus.	None
T2DM Hartstra et al47 (2014)	Firmicutes	Levels are increased in T2DM.	Phylum of bacteria (not available)	None
T2DM Hartstra et al47 (2014)	Bacteroidetes	Levels are decreased in T2DM	Phylum of bacteria (not available)	None
T2DM Hartstra et al47 (2014)	Intestinal bacterial species	Levels are increased in T2DM.	Not applicable	None
T2DM Hartstra et al47 (2014)	Roseburia	Levels are decreased in T2DM.	Not available	None
T2DM Hartstra et al47 (2014)	E halii	Levels are decreased in T2DM.	Not available	None
T2DM Hartstra et al47 (2014)	F prauznitzii	Levels are decreased in T2DM.	Not available	None
T2DM Hartstra et al47 (2014)	L gasseri	Levels are increased in T2DM.	Not available	None
T2DM Bayat et al48 (2016)	C ficifolia, Probiotic yogurt	Alone or in combination; ↓FBS & A1C levels.	Not applicable	Yogurt (unspecified)
T2DM Hariri et al49 (2015); Bayat et al48 (2016)	L plantarum A-7	Decreased methylation process, SOD, and 8-OHDG; subjects: 40 patients with T2DM.	Provided in probiotic soy milk	None
T2DM Ejtahed et al50,51 (2010, 2012); Sáez-Lara et al4 (2016)	L acidophilus LA-5, BB lactis BB-12	Reduced fasting blood glucose and antioxidant status; TC and LDL-C improvement; subjects: 2 studies (60 patients with T2D 64 patients with T2D).	Combination of L acidophilus LA-5, B lactis BB-12: ProSynbiotic (Standard Process) TruBiotics (Bayer) Strengtia (Apex Energetics)	L acidophilus LA-5 (Nancy’s Organic cow’s milk yogurt) B lactis BB-12 (Nancy’s Organic cow’s milk kefir)
Dyslipidemia
Shimizu et al10 (2015); Taranto et al52 (2000); Gilliland & Speck53 (1977)	Fermented milk product, L acidophilus, L reuteri, S thermophilus, L streptococcus, L thermophilus, L rhamnosus	This meta-analysis shows that fermented milk products are effective in decreasing TC and LDL-C levels and probiotic preparations are effective in decreasing TC levels. Therefore, probiotic supplementation (fermented milk products and probiotic preparations) could be useful in the primary prevention of hypercholesterolemia and may lead to reductions in risk factors for CVD. L acidophilus deconjugates bile acids into free acids that are excreted more rapidly from the intestinal tract than are conjugated bile acids. Because free bile salts are excreted from the body, the synthesis of new bile acids from cholesterol can reduce the total cholesterol concentration in the body.	Strengtia (Apex Energetics)	Fermented milk products: lassi, kefir, yogurt (check ingredients list for specific stains).
Ettinger et al54 (2014)	L rhamnosus GG GR-1, PL-60, NCIMB-30242; L sakei NR28; Lactobacillus/ Bifidobacterium multistrain; L plantarum PL-62, 299-V; L reuteri NCIMB-30242	Weight reduction, prevent ischemia in I/R injury attenuate heart failure, cardiac hypertrophy, reduced adipose tissue mass; weight reduction; reduce BMI in obese adults, reduce serum cholesterol; produce ACE-inhibitory peptides; reduce adipose tissue mass; reduce severity of ischemia in I/R injury lower serum cholesterol.	Lactobacillus GG: Walgreens Probiotic Lactobacillus GG Advanced Multi-Billion Dophilus (Solgar) L rhamnosus GR-1: Pro-B (Rephresh) Women’s Fem Dophilus (Jarrow Formulas) UltraFlora Women’s (Metagenics) Clinicians Flora Restore (Douglas Pharmaceuticals) L rhamnosus NCIMB 30242: Microbiome Plus+ (Gastrointestinal Probiotics) Natural Health Probiotic (Cardioviva) L plantarum 299V: Jarrow Formulas Ideal Bowel Support Probiotic Supplement (GoodBelly) Probiotic GX (Nature’s Bounty) Probiata Digestion Support and Critical Care (Kyolic) Probiotic Balance (Sundown Naturals) Heart Healthy Probiotic Solutions (Dr Sinatra) Digestive Health Probiotic (Nature Made) Sibiotica (Apex Energetics) L reuteri NCIMB 30242: Cardioviva (UAS Labs)	L plantarum 299V (GoodBelly Probiotic Drinks) Other strains (None)
Cholesterol
Aggarwal et al55 (2013)	L fermentum KC4-B	Lactobacilli, hydrolyses the bile salts and hydroxyl steroid dehydrogenase, degrades the bile salts, interrupts the enterohepatic circulation of the bile acids; Lactobacilli inhibit hydroxy methyl glutarate CoA; L fermentum KC-4B reduced the cholesterol in medium by 14.8 mg.	Not available	None
Stroke
Sun et al11 (2016)	C butyricum	C butyricum is able to exert neuroprotective effects against I/R injury mice through antioxidant and antiapoptotic mechanisms, and reversing decrease of butyrate contents in the brain might be involved in its neuroprotection.	C butyricum: AOR Probiotic-3 Miyarisan (630 Tablets)	Common in fermented milk and cheeses.
Gout
Li et al12 (2014)	Strain DM9218 (analysis of this strain 16S rRNA sequences showed that DM-9218 has the highest similarity [99%] to L plantarum WCFS-1)	Showed high inhibitory activities to E coli and S aureus; DM9218-A is a promising candidate as an adjunctive treatment in patients with hyperuricemia, especially during the onset period of disease.	Colonized from Chinese sauerkrauts for research purposes (not commercially available).	None
NASH/NAFLD
Vajro et al56 (2011); Sáez-Lara et al4 (2016)	L rhamnosus GG (1.2109 CFU/d)	Decreased ALT and PG-PS IgA antibodies; subjects: 20 obese children with NAFLD.	Walgreens Probiotic Lactobacillus GG Advanced Multi-Billion Dophilus (Solgar)	None
Aller et al57 (2011); Sáez-Lara et al4 (2016)	L bulgaricus, S thermophilus (5.01011 CFU/d)	Decreased ALT and γ-GTP levels; subjects: 28 adults individuals with NAFLD.	Dr Ohhira’s Probiotics Professional Formula Dr Ohhira’s Probiotics Original Formula MegaFood (MegaFlora) VSL#3 (Sigma Tau Pharmaceuticals, Inc)	All Yogurt containing “Live and active cultures.”
Nabavi et al58 (2014); Sáez-Lara et al4 (2016)	L acidophilus LA-5, B breve subsp lactis BB-12	Reduced serum levels of ALT, ASP, TC, and LDL-C; subjects: 72 patients with NAFLD.	ProSynbiotic (Standard Process) TruBiotics (Bayer) Strengtia (Apex Energetics) Sibiotica (Apex Energetics)	L acidophilus LA-5 (Nancy’s Organic cow’s milk yogurt) B lactis BB-12 (Nancy’s Organic cow’s milk kefir)
Alisi et al59 (2014); Sáez-Lara et al4 (2016)	B thermophilus, L thermophilus, S thermophilus	Improved fatty liver severity, decreased BMI, and increased GLP1/aGLP1; subjects: 44 obese children with NAFLD.	Found in most probiotic formulas.	Various cultured and fermented foods.
PCOS
Guo et al14 (2016)	Increasing of Lactobacillus and Clostridium, and decreasing of Prevotella (with fecal microbiota transplant)	After treating PCOS rats with Lactobacillus and FMT from healthy rats, estrous cycles were improved in all 8 rats in FMT group, and in 6 of the 8 rats in Lactobacillus transplantation group with decreasing androgen biosynthesis; microbiota interventions through Lactobacillus and FMT transplantation were beneficial in PCOS rats.	Not applicable	None
Tremellen et al60 (2012)	Bifidobacteria, Lactobacterium (combined with prebiotic food source [inulin, fructose oligosaccharide])	Likely to improve intestinal barrier function, resulting in a reduction in transfer of LPS across the mucosal wall, reducing metabolic endotoxaemia. A probiotic mediated increase in colonocyte production of the satiety hormone GLP-1 will reduce energy intake, producing a drop in adipose tissue mass and a decrease in inflammation, with a resulting further improvement in gut mucosal barrier function. The net reduction in colonic mucosal permeability and resulting metabolic endotoxemia will lead to an improvement in insulin receptor function, a drop in serum insulin and a normalization of ovarian function.60	Flora8 (PromoPharma) Probiotic + Prebiotic Flora Renew (Family Flora) Sunbiotics Potent Probiotics With Organic Prebiotics Powder	Cultured dairy products with inulin or FOS as ingredients.

Abbreviations: T2DM, type 2 diabetes mellitus; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PCOS, polycystic ovary syndrome; LAB, lactic acid bacterium; HbA_1C, hemoglobin A_1C; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; BMI, body mass index; VFA, visceral fat area; BP, blood pressure; PBMC, peripheral blood mononuclear cell; HOMA-IR, homeostasis model assessment of insulin resistance; IL, interleukin; MCP, monocyte chemotactic protein; MS, multiple sclerosis; HDL-C, high-density lipoprotein cholesterol; AST, aspartate transaminase; ALT, alanine transaminase; IL-4, interleukin 4; ER, endoplasmic reticulum; LPS, lipopolysaccharide; NF-κB, nuclear factor κB; CVD, cardiovascular disease; I/R; ischemia-reperfusion; FMT, fecal microbiota transplant; GI, gastrointestinal; FOS, fructooligosaccharide.

Table 2.

Fatigue Syndromes

Fatigue Syndrome	Strains	Overview	Professional and Commercial Products	Foods
Groeger et al64 (2013)	B infantis 35624	Reduce systemic proinflammatory biomarkers; 71% of CFS patients had decreased levels of CRP, TNF-α, and IL-6, when fed B infantis 35624. TNF-α and IL-6 control CRP on the transcription level.	B infantis 35624: Align Probiotic Digestive Care (Procter & Gamble)	None
Choppa et al69 (2012)	LAB, LAB-loaded alginate beads	“Immobility and PSF were found to increase considerably in FST rats (665 ± 22 s and 196 ± 6 s) as compared with the naïve (32 ± 7 s and 22 ± 2 s) at 20 days, establishing severe fatigue like behavior. FST control group exhibited significant (P < .05) hypertrophy of spleen, hypertrophy of thymus, and increased oxido-nitrosative stress in brain and tumor necrosis factor-α (TNF-α) levels in serum.” Probiotic supplementation attenuated postswim fatigue time and reduced (P < .05) oxidonitrosative stress and TNF-α levels and restored the spleen and thymus to normal size.	L acidophilus beads: Probiotic Acidophilus BioBeads (Natrol, Inc) Theralac Probiotic (Master Supplements) Strengtia (Apex Energetics) L acidophilus: Widely available in probiotic supplements.	Yogurt, kefir, (Nancy’s Organic yogurts)
Rao et al62 (2009)	L casei Shirota (Yakult Honsha, Tokyo, Japan)	Resulted in a significant rise in both Lactobacillus and Bifidobacteria as well as a significant decrease in anxiety symptoms (P = .01) in CFS patients.	Not available	Yakult
Rao et al62 (2009)	L plantarum 299-V	Resulted in significant rise in fecal Bifidobacteria levels. “Bifidobacteria can boost plasma tryptophan levels and alter serotonin and dopamine turnover in areas of the brain associated with depression and anxiety.”	Digestive Health Probiotic (Nature Made) Heart Healthy Probiotic Solutions (Dr Sinatra) Ideal Bowel Support, 10 Billion Organisms V-Capsules (Jarrow Formulas) Probiata Digestion Support and Critical Care (Kyolic) Plantadophilus-3 Billion CFU (Transformation Enzymes) Probiotic Balance (Sundown Naturals) Probiotic GX (Nature’s Bounty) Probiotic Supplement (GoodBelly) UltraFlora Intensive Care (Metagenics)	GoodBelly
Sullivan et al66 (2009)	L paracasei sbsp paracasei F-19, L acidophilus NCFB-1748, B lactis BB-12 (together); Lactobacillus F-19, L acidophilus NCFB-1748, B lactis BB-12	Results in fatigue and quality of life improvements based on visual analogue scales and the SF-12 Health Survey after 2 wk.	L paracasei sbsp paracasei F19: Gene-filus F19 (Siffra Farmaceutici) L acidophilus NCFB 1748: Not available (grown for research purposes). B lactis BB-12: Metabiotic (Procter & Gamble) TruBiotics (Bayer)	No commonly available foods in the United States.
Giloteaux65 et al (2016); Quevrain70 et al (2016)	F prausnitzii	Is significantly decreased in those with CFS and produces an anti-inflammatory protein capable of “inhibiting the NF-κB pathway in intestinal epithelial cells and to prevent colitis in an animal model.”	Isolated for research purposes only.	None
Galland67 (2014)	B fragilis	Associated with decreased anxiety in CFS patients. “Corrects excessive gut permeability, alters gut microbial composition, and ameliorates deficits in communication and stereotypic, anxiety-like, and sensorimotor behaviors in the maternal immune activation model.”	Not applicable	B fragilis (None)
Giloteaux et al65 (2016)	P freudenreichii	Bifidogenic substance that increases butyrate. Butyrate modulates hormone and cytokine secretion and activates anti-inflammatory processes.	Securil (Nutricology)	Bacterium found in Swiss cheese, produces substances that enhance growth of Bifidobacteria.
Galland67 (2014)	Lactobacillus sp	“Some species of Lactobacillus are d-lactate producers and high-dose β-glucan (found in oats and barley) can increase intestinal permeability.” Case report showing that a symbiotic: B breve Yakult and L casei Shirota as probiotics and galacto-oligosaccharide as a prebiotic resolved the acidosis in a man with short-bowel syndrome. Suggest a probiotic that is free of Lactobacillus and high-dose β-glucan.	Lactobacillus sp: Widely available in dietary supplements. B breve Yakult, L casei Shirota: Not available.	Fermented dairy products. Fermented soy products. Fermented vegetables.

Abbreviations: CFS, chronic fatigue syndrome; CRP, C-reactive protein; TNF-α, tumor necrosis factor α; IL-6, interleukin 6; LAB, lactic acid bacterium.

Table 3.

Supplemental Information on Cardiometabolic Diseases and Fatigue Syndromes

Disease	Supplement	Probiotic Strain(s)
Dyslipidemia	Advanced Multi-Billion Dophilus (Solgar)	Lactobacillus GG
Dyslipidemia	Digestive Health Probiotic (Nature Made)	L plantarum 299V
Dyslipidemia	Heart Healthy Probiotic Solutions (Dr Sinatra)	L plantarum 299V
Dyslipidemia	Jarrow Formulas Ideal Bowel Support	L plantarum 299V
Dyslipidemia	Pro-B (Rephresh)	L rhamnosus GR-1
Dyslipidemia	Probiata Digestion Support and Critical Care (Kyolic)	L plantarum 299V
Dyslipidemia	Probiotic Balance (Sundown Naturals)	L plantarum 299V
Dyslipidemia	Probiotic GX (Nature’s Bounty)	L plantarum 299V
Dyslipidemia	Probiotic Supplement (GoodBelly)	L plantarum 299V
Dyslipidemia	UltraFlora Women’s (Metagenics)	L rhamnosus GR-1
Dyslipidemia	Walgreens Probiotic Lactobacillus GG	Lactobacillus GG
Dyslipidemia	Women’s Fem Dophilus (Jarrow Formulas)	L rhamnosus GR-1
Fatigue syndrome	Align Probiotic Digestive Care (Proctor & Gamble)	B infantis 35624
Fatigue syndrome	Digestive Health Probiotic (Nature Made)	L plantarum 299V
Fatigue syndrome	Gene-filus F19 (Siffra Farmaceutici)	L paracasei sbsp paracasei F19
Fatigue syndrome	Heart Healthy Probiotic Solutions (Dr Sinatra)	L plantarum 299V
Fatigue syndrome	Isolated for research purposes only	F prausnitzii
Fatigue syndrome	Jarrow Formulas Ideal Bowel Support (10 Billion) Organisms V-Capsules	L plantarum 299V
Fatigue syndrome	Not available	L casei strain Shirota (Yakult Honsha, Tokyo, Japan)
Fatigue syndrome	Not Available	B fragilis
Fatigue syndrome	Not available	B breve Yalult L casei Shirota
Fatigue syndrome	Probiata Digestion Support and Critical Care (Kyolic)	L plantarum 299V
Fatigue syndrome	Probiotic Acidophilus BioBeads (Natrol, Inc)	L acidophilus-loaded alginate beads
Fatigue syndrome	Probiotic Balance (Sundown Naturals)	L plantarum 299V
Fatigue syndrome	Probiotic GX (Nature’s Bounty)	L plantarum 299V
Fatigue syndrome	Probiotic Supplement (GoodBelly)	L plantarum 299V
Fatigue syndrome	Securil (Nutricology )	P freudenreichii
Fatigue syndrome	Theralac Probiotic (Master Supplements)	L acidophilus alginate
Fatigue syndrome	TruBiotics (Bayer)	B lactis BB-12
Fatigue syndrome	Ultraflora Balance (Metagenics)	L acidophilus NCFB 1748
Fatigue syndrome	Widely available in dietary supplements	Lactobacillus species
Gout	Isolated and colonized from Chinese sauerkrauts for research purposes (not commercially available	Strain DM9218 (analysis of this strain 16S rRNA sequences showed that DM9218 has the highest similarity [99%] to Lactobacillus plantarum WCFS1)
NAFLD	BIFIDO DIGEST 60C (F) (Protocol for Life)	S thermophilus
NAFLD	Isolated - cultured in brain, heart under anaerobic conditions for research purposes	B adolescentis
NAFLD	Isolated for research purposes only	L curvatus HY7601 alone or in combination with L plantarum KY103
NAFLD	Isolated from healthy volunteers’ fresh feces for research purposes	Bifidobacteria L66-5, L75-4, M13-4, and FS31-12
NAFLD	NOW Foods Probiotic (10 50 Billion)	S thermophilus
NASH/NAFLD	Advanced Multi-Billion Dophilus (Solgar)	L rhamnosus GG (1.2109 CFU/d)
NASH/NAFLD	Dr Ohhira’s Probiotics Original Formula	L bulgaricus, S thermophilus (5.01011 CFU/d)
NASH/NAFLD	MegaFood (MegaFlora)	L bulgaricus, S thermophilus (5.01011 CFU/d)
NASH/NAFLD	ProSynbiotic (Standard Process)	L acidophilus LA-5, B breve subsp lactis BB-12
NASH/NAFLD	TruBiotics (Bayer)	L acidophilus LA-5, B breve subsp lactis BB-12
NASH/NAFLD	Walgreens Probiotic Lactobacillus GG	L rhamnosus GG (1.2109 CFU/d)
NASH/NAFLD	Widely available (found in most probiotic formulas)	B thermophilus, L thermophilus, S thermophilus
Obesity	BIFIDO DIGEST 60C (F) (Protocol for Life)	S thermophilus
Obesity	Enterogenic Concentrate (Integrative Therapeutics)	E faecium
Obesity	GoLive Probiotic & Prebiotic Drink Mix	L salivarius LS-33
Obesity	Health-Bac 100 grams (North American Herb & Spice)	E faecium
Obesity	Hyper-Implante (InterPlexus)	L salivarius LS-33
Obesity	Isolated - cultured in brain, heart under anaerobic conditions for research purposes	B adolescentis
Obesity	Isolated for research and not commercially available - prepared with lactic acid bacteria starter cultures (Streptococcus thermophilus and Lactobacillus delbrueckii ssp. bulgaricus) commonly used for conventional yogurt production and viable cells of LG2055	L gasseri SBT-2055, L gasseri LG-2055 (51010 CFU)
Obesity	Isolated for research purposes only	L curvatus HY-7601 alone or in combination with L plantarum KY-1032
Obesity	Isolated for research, from the GI of health Estonian children, and not commercially available	L plantarum TENSIA (1.51011 CFU/g added to cheese milk before renneting)
Obesity	Isolated from healthy volunteers’ fresh feces for research purposes	Bifidobacteria L66-5, L75-4, M13-4, and FS31-12
Obesity/T2DM	Isolated from stool for research purposes.	B adolescentis
Obesity	Nature’s Secret Ultimate Probiotic (4 billion)	E faecium
Obesity	Probiotic Supreme DF (Designs for Health)	L salivarius LS-33
Obesity	ProSynbiotic (Standard Process)	L acidophilus LA-5, B animalis subsp lactis BB-12
Obesity	ProSynbiotic (Standard Process)	L acidophilus LA-5, B lactis BB-12 L casei DN001 (108 CFU/g)
Obesity	ProSynbiotic (Standard Process)	L acidophilus LA-5, B animalis subsp lactis BB-12
Obesity	TruBiotics (Bayer)	L acidophilus LA-5, B animalis subsp lactis BB-12
Obesity	TruBiotics (Bayer)	L acidophilus LA-5, B lactis BB-12, L casei DN001 (108 CFU/g)
Obesity	TruBiotics (Bayer)	L acidophilus LA-5, B animalis subsp lactis BB-12
Obesity	Ultimate Intestinal Shield (Phyto Therapy)	L salivarius LS-33
Obesity	UltraFlora Spectrum (Metagenics)	L salivarius LS-33
Obesity/NAFLD	Florastor (Biocodex)	S boulardii (Biocodex)
Obesity/NAFLD	Strengtia (Apex Energetics)	S boulardii
Obesity/NAFLD	Designs for Health	S boulardii
Obesity/NAFLD	Isolated for research purposes (plant derived)	L plantarum SN13T as comparator
Obesity/NAFLD	Isolated from feces of exclusively breast (fed infants for research purposes)	L paracasei CNCM I-4034, B breve CNCM I-403, L rhamnosus (CNCM or mixture of 3 strains)
Obesity/NAFLD	Isolated from longan fruit (Euphoria longana) for research purposes	P pentosaceus LP28
Obesity/NAFLD	Isolated for research purposes only	L paracasei CNCM I-4270, L rhamnosus I-3690, B animalis subsp lactis I-2494
Obesity/NAFL/T2DM	Advanced Multi-Billion Dophilus (Solgar)	L rhamnosus GG
Obesity/NAFLD/T2DM	Isolated from stool for research purposes	Lactic acid bacterium supplement (B pseudocatenulatum SPM-1204, B longum SPM-1205, B longum SPM-1207 (108–109 CFU)
Obesity/NAFL/T2DM	Walgreens Probiotic Lactobacillus GG	L rhamnosus GG
Obesity/T2DM/NAFLD	Isolated and obtained from National Collection of Dairy Cultures for research purposes.	L lactis
Obesity/T2DM/NAFLD	Isolated from stools of healthy infants (mean age, 5.7 y; range, 1.0–10.8 y) for research purposes	B uniformis CECT 7771
Obesity/T2DM/NAFLD	Not available	Acetobacter
O Obesity/T2DM/NAFLD	Securil (Nutricology)	Propionibacterium
PCOS	Flora8 (PromoPharma)	Bifidobacteria and Lactobacterium combined with prebiotic food source (inulin, fructose oligosaccharide)
PCOS	Probiotic + Prebiotic Flora Renew (Family Flora)	Bifidobacteria and Lactobacterium combined with prebiotic food source (inulin, fructose oligosaccharide)
PCOS	Sunbiotics Potent Probiotics with Organic Prebiotics Powder	Bifidobacteria and Lactobacterium combined with prebiotic food source (inulin, fructose oligosaccharide)
T2DM	BIFIDO DIGEST 60C (F) (Protocol for Life)	S thermophilus
T2DM	Not available	Roseburia
T2DM	Not available	E halii
T2DM	NOW Foods Probiotic (10 50 Billion)	S thermophilus
T2DM	ProSynbiotic (Standard Process)	L acidophilus LA-5, B animalis subsp lactis BB-12
T2DM	ProSynbiotic (Standard Process)	L acidophilus LA-5, B animalis subsp lactis BB-12
T2DM	TruBiotics (Bayer)	L acidophilus LA-5, B animalis subsp lactis BB-12
T2DM	TruBiotics (Bayer)	L acidophilus LA-5, B animalis subsp lactis BB-12
T2DM	Not available	F prauznitzii
T2DM	ProSynbiotic (Standard Process)	L acidophilus LA-5, B lactis BB-12 combination
T2DM	Provided in probiotic soy milk	L plantarum A7
T2DM	TruBiotics (Bayer)	L acidophilus LA-5, B lactis BB-12 combination

Abbreviations: NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; T2M, type 2 diabetes mellitus; PCOS, polycystic ovary syndrome.