• Supports Healthy Weight Management*
• Promotes Gut Barrier Function*
• Promotes Intake of Less Calories*
• Supports Reduction of Body Fat Mass*

At the turn of the 20th century, Nobel Prize laureate Ilya Metchnikov introduced the concept that bacteria in yogurt can support the neutralization of gut pathogens, which may, in turn, support longevity. Since then, the role of beneficial bacteria in human health has become well established in the literature and continues to evolve. In 2002, the FAO (Food and Agriculture Organization of the United Nations) and WHO (World Health Organization) working group experts established a definition of probiotics as “live strains of strictly selected microorganisms, which, when administered in adequate amounts, confer a health benefit on the host.” Results of clinical studies have suggested a positive effect of supplemental probiotics on a wide range of health concerns, including gastrointestinal issues, allergies, immune support, and weight-management.*[1-7] Epithelial integrity is key to the function of the gastrointestinal tract, and according to in vitro and animal research, disturbance of this integrity appears to be linked to metabolic disorders. To address the potential effects of consuming specific probiotic bacteria to protect epithelial cells from the effects of pathogenic bacteria, Caco-2 cells were treated with cell-free supernatants (CFSs) of four probiotics— Bifidobacterium lactis‡ 420 (B420), Bifidobacterium lactis HN019, Lactobacillus acidophilus NCFM, and Lactobacillus salivarius Ls-33— and by a cell-free supernatant of a pathogenic bacteria Escherichia coli (EHEC) O157:H7. Tight junction integrity, as well as expression of cyclooxygenases, were measured with results suggesting that the B420 CFS counteracted the damage done by the EHEC CFS.[8] One cannot be certain that B420 CFS would prevent junction damage by live bacteria EHEC, but the results suggest that probiotic bacteria produce soluble metabolites that appear to protect epithelial cells and positively influence cytokine balance. Awareness of the existence and activity of soluble bacterial metabolites in vitro leads to speculation whether the same metabolites are also formed in the intestine with similar effects in vivo. However, the evidence presented does seem to suggest that oral consumption of B420 probiotic may benefit epithelial integrity.* In animal research, the potential benefit of B420 in reducing high-fat, diet-induced body weight gain and diabetes was studied with results indicating a reduction of fat mass and glucose intolerance in both obese and diabetic mice. Reduced intestinal mucosal adherence and decreased levels of plasma lipopolysaccharide suggested a mechanism related to reduced translocation of gut microbes.*[9] HOWARU® Shape B420 (Bifidobacterium animalis subsp lactis B420) The in vitro and experimental animal studies discussed above-utilized B420 with positive results in improving epithelial integrity and potential for a role in weight management. These results led to the need for a human trial to validate these effects. In a double-blind, placebocontrolled study in overweight volunteers (N = 225) aged 18-65, the effects of B420 and the combination of B420 with a prebiotic fiber on body-fat mass and other weight-related parameters were investigated. The authors speculated that the underlying mechanism for reduction of body fat mass could have been related to circulating zonulin (a potential marker of gut barrier function) and C-reactive protein (CRP), speculation that had been supported by previous findings with experimental animals. Subjects were not required to make changes in dietary or exercise habits. Body composition was monitored with dual-energy X-ray absorptiometry, and the primary outcome was a relative change in body fat mass when treatment groups were compared to placebo. Other outcomes included anthropometric measurements, food intake, and blood and fecal biomarkers. Although results indicated that B420 in combination with the prebiotic offered the most significant benefits when compared to placebo (4.5% reduction in body fat mass), B420 alone (1010 CFU/day) resulted in reduced body fat mass of 4.0% with changes in fat mass being most pronounced in the abdominal region and in waist circumference. Significantly reduced caloric intake was also shown in both groups compared to placebo, and there were no differences between groups in the incidence of adverse events.*[7] Building on the data reported for B420 thus far, investigators looked into whether changes in the gut microbiota were associated with clinical benefits and obesity-related issues. Fecal and plasma samples obtained from a subset (n = 134) of the participants in the above mentioned clinical trial were assessed at baseline, two, four, and six months as well as one-month post-intervention. Consumption of B420 resulted in alterations of the specific gut microbiota Lactobacillus and Akkermansia muciniphila. Akkermansia muciniphila, often in lower amounts in obese individuals with metabolic dysfunction, is associated with improved metabolic health. This strain supports gut barrier function and improves obesity-related markers and thus supports the probiotic benefits of B420.[10] More clinical trials are warranted to confirm these effects in larger participant populations and to further elucidate the underlying mechanisms.*

Clinical Applications

• Supports a Healthy Microbiome*
• Replenishes Good Bacteria in the Gut*
• Supports the Natural Immune Response*
• Supports Lactose Digestion*
• Supports Bowel Regularity*

Probiotic Ultra Max 350 Billion features a diverse blend of HOWARU® and FloraFIT ® probiotic strains to support a healthy gut microbiome. Each strain is well-researched and identity-verified and has been genetically characterized and properly classified for your safety and assurance. These strains were not only selected for their health benefits and complementary actions but also for their viability and stability. To protect the bacteria from light and moisture, each flavoring- and sweetener-free serving of Probiotic Ultra Max 350 Billion comes in an opaque, foil-lined stick pack.*

Discussion

Multiplicity of microbiota species is characteristic of the GI microbiome in healthy individuals, and a loss in species has adverse effects.Dietary diversity and taking a variety of probiotic species and strains are methods that help support a healthy microbiome.[1,4] Probiotic Ultra Max 350 Billion provides 18 different strains belonging to 13 different species of three different genera. The HOWARU and FloraFIT strains that comprise this formula are stable, proven, and trusted worldwide.*

Featured Strains: Bifidobacterium lactis HN019 and Lactobacillus rhamnosus HN001

B lactis HN019 and L rhamnosus HN001 have been studied extensively in vitro and in vivo (in animals and humans) to establish beneficial effects and safety.[5-20] In human research, B lactis HN019 significantly decreased mean whole-gut transit time in adults compared to placebo.[8] Supplementation also had a positive effect on functional GI symptoms, as were self-reported by patient surveys. In a randomized, double-blind, placebo-controlled human dietary intervention study in subjects 60 or more years of age, supplementary HN019 resulted in desirable changes in the intestinal microflora, including significant increases in bifidobacteria and lactobacilli.[13] HN019 has also shown promising effects on parameters of cardiovascular and metabolic health. Compared with baseline and control group values, individuals taking 27 billion CFU had a significant reduction in body mass index, significant improvements in cholesterol and low-density lipoprotein metabolism, and significant decreases in tumor necrosis factor-alpha and interleukin-6.[19] In a three-week study, individuals consuming low-fat/low-lactose milk supplemented with HN019 or HN001 showed increased immune activity when compared to a milk-alone run in.[10] These increases were significantly correlated with age; that is, subjects older than 70 years experienced significantly greater improvements than those under 70 years. Researchers suggest that these results demonstrate the ability of HN019 and HN001 to combat some of the deleterious effects of immunosenescence on cellular immunity.[10] Animal studies demonstrate the ability of HN001 to support natural and acquired immunity as well as promote resistance.[17,18] More recently, human studies have demonstrated HN001’s protective effect on skin health in genetically susceptible individuals.*[7,11]

Other Strains in Probiotic Ultra Max 350 Billion Have Demonstrated Probiotic Effects in Either In Vitro or In Vivo Research:

• Cause the development of inhibition zones around Clostridium difficile, Salmonella typhimurium, Staphylococcus aureus, Escherichia coli, and Listeria monocytogenes in agar assays*[20]
• Populate vaginal tissue*[21]
• Induce moderate maturation and activation of dendritic cells*[22]
• Degrade oxalates*[23]
• Increase IgA and IgG responses*[25]
• Reduce levels of E coli and enterococcus after antibiotic therapy*[26]
• Help increase and recover numbers of intestinal lactobacilli and/or bifidobacteria*[27]
• Promote well-being in relation to intestinal cytokine production*[28,29]
• Improve gastrointestinal health and well-being when under challenge*[27,29]
• Help maintain upper respiratory health*[30]
• Alter the fecal microbiota in obese subjects*[31]
• Maintain healthy fluid balance and integrity of intestinal wall*[32]
• Support intestinal barrier function*[32]

Genetic Testing, Acid and Bile Tolerance, Adhesion

Each of the lactic acid-producing strains in Probiotic Ultra Max 350 Billion has a history of safe consumption and, based on testing,

is regarded to have excellent probiotic potential.[20,33,34] Each bacterium has been genetically characterized and properly classified by

independent labs. The organisms have demonstrated tolerance to low pH conditions (hydrochloric acid and pepsin at pH3 for one hour at 37°C), tolerance to bile at concentrations existing in the duodenum, and the ability to adhere to human epithelial cell lines (Caco-2 and HT-29). Adhesion is thought to be an important factor affecting these bacteria’s length of time in the intestines, their ability to modulate immune function, and their ability to take up intestinal “real estate” in competition with other organisms.*[34]

Many of the strains have had additional studies performed, which include testing for the following[20]:

Competitive Inhibition – The ability of probiotics to maintain a healthy microbial balance in the gut is unquestionably important to its usefulness. Probiotics produce inhibitory compounds that limit the growth of other organisms, they compete with other organisms for adhesion sites and nutrients, and they inhibit the production of toxins, among other actions.*

Cytokine and Immune Modulation – Microbiota are key elements in the body’s defense system. Cytokines regulate immune system function, and the ability of many of the strains in Probiotic Ultra Max 350 Billion to upregulate or downregulate various cytokines has been demonstrated.*

Antibiotic Resistance – Antibiotic susceptibility patterns are an important means of indicating the potential of an organism to be readily inactivated by antibiotics used in human therapy. Importantly, acquired antibiotic resistance or antibiotic resistance transfer have not been detected in any of these strains.*

Directions

Dissolve the contents of one stick pack (350 billion CFUs‡)†† into 1-2 oz of pure water and consume once daily, or take as directed by your healthcare practitioner. Consult your healthcare practitioner prior to use. Individuals taking medication should discuss potential interactions with their healthcare practitioner. Do not use if tamper seal is damaged.

Does Not Contain

Wheat, gluten, soy, animal or dairy products, fish, shellfish, peanuts, tree nuts, egg, artificial colors, artificial sweeteners, or artificial preservatives