Vsl 3 side effects


Generic Name: bifidobacterium, lactobacillus, and streptococcus (BIF eye doe bak TEER ee um, LAK toe ba SIL us, and STREP toe KOK us)
Brand Name: VSL#3

Medically reviewed by Drugs.com on Apr 18, 2019 – Written by Cerner Multum

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What is VSL#3?

VSL#3 is a medical food used as a probiotic, or “friendly bacteria” to maintain a healthy digestive tract (stomach and intestines).

VSL#3 is used in people with irritable bowel syndrome, ulcerative colitis, or an ileal pouch.

Not all uses for VSL#3 have been approved by the FDA. This product should not be used in place of medication prescribed for you by your doctor.

VSL#3 may also be used for purposes not listed in this product guide.

Important Information

Do not use this product without medical advice. Follow all directions on the product label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

Before taking this medicine

Before using this product, talk to your healthcare provider. You may not be able to use VSL#3 if you have certain medical conditions.

VSL#3 is available in capsule, tablet, powder, and chewable tablet formulations. Do not use different formulations at the same time without medical advice.

Ask a doctor, pharmacist, or other healthcare provider if it is safe for you to use this product if you have:

  • milk allergy or lactose intolerance; or

  • if you are taking an antibiotic medication.

It is not known whether VSL#3 will harm an unborn baby. Do not use this product without medical advice if you are pregnant.

It is not known whether bifidobacterium, lactobacillus, and streptococcus passes into breast milk or if it could harm a nursing baby. Do not use this product without medical advice if you are breast-feeding a baby.

Do not give any herbal/health supplement to a child without medical advice.

How should I take VSL#3?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Your doctor may occasionally change your dose.

Check your product label to see whether you should take this product with or without food.

Mix the oral powder with cold water or a non-carbonated drink or soft food (applesauce, yogurt, ice cream). Eat or drink this mixture right away. Do not save it for later use.

You may also open the capsule and sprinkle the probiotic into a cold drink or cold soft food, following the same directions for the oral powder.

Mix this product only with a cold liquid or soft food.

Call your doctor if your symptoms do not improve, or if they get worse while using VSL#3.

Store this product in the refrigerator, do not freeze. Heat or humidity may affect the live bacteria in this product, making it less effective.

Throw away this product if the expiration date on the label has passed.

If you need to store this product out of a refrigerator, it will keep for up to 2 weeks at room temperature without affecting the live bacteria. Protect the probiotic from heat, humidity, and direct light.

What happens if I miss a dose?

Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra VSL#3 to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking VSL#3?

Do not mix the oral powder with hot liquids or foods.

VSL#3 side effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Common side effects may include:

  • stomach bloating or discomfort.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect VSL#3?

Other drugs may interact with bifidobacterium, lactobacillus, and streptococcus, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Further information

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Copyright 1996-2018 Cerner Multum, Inc. Version: 1.02.

Medical Disclaimer

More about VSL#3 (bifidobacterium infantis / lactobacillus acidophilus / streptococcus thermophilus)

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  • 7 Reviews
  • Drug class: probiotics

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Review of Visbiome, Formerly VSL#3

Review Rating:

Best for: digestive health

Product Options: capsules or powder

Shipping: ships with ice pack

Buy on Amazon for best price (around $72)

Transparency Disclosure: for each person who buys Visbiome by clicking a link on this review, Probiotics.org receives a small percentage of the sale. We would strongly recommend Visbiome without compensation, but I want you to know all our potential motivations for Probiotics.org writing this review. Thank you for supporting Probiotics.org

A quick note on this Visbiome review:

If you’re looking for the old VSL#3 probiotic, it is now called Visbiome.

VSL#3 lost the license to the their probiotic formula. Now, Visbiome uses the exact old VSL#3 formula that was clinically proven in many research studies…and has legions of fans who could only find relief with VSL#3.

I spoke with the Marc Tewey, the CEO of Visbiome, and he assured me that Visbiome’s probiotic strains are exactly the same as the old VSL#3…they even use the exact same Italian factory that produced VSL#3 before.


4 Reasons You Should Buy Visbiome VSL#3

I’m happy that Visbiome has taken over the VSL#3 formula because my review of VSL#3 was extremely positive. Here are 4 strong reasons for taking Visbiome.

  1. Optimized for digestive health
  • Many individuals with sensitive stomachs or other inflammatory bowel conditions rely on Visbiome to provide their digestive systems with a daily reinforced boost of powerful probiotics to increase digestive capacity and daily comfort. My friend’s wife was able to going into remission from Chrons by taking Visbiome VSL#3 and eating correctly.
  • Super strong
    • Visbiome is one of the strongest probiotics around. At 450 billion CFU, it was the first “mega-strong” probiotic on the market. There is even a prescription only version that has 900 billion CFU per dose.
  • Extensively studied
    • Visbiome is one of the few probiotic products that has extensive clinical research study behind it.
  • Free of most allergens
    • This product is gluten free, soy free, nut free, shellfish free. It does contain trace amounts of dairy.

    Even if you do not have any preexisting digestive issues, the beneficial bacteria contained in Visbiome VSL#3 can optimize gut function leading to enhanced nutrient intake.

    4 Reasons Not To Take Visbiome

    This review of Visbiome wouldn’t be complete without telling you who shouldn’t take this probiotic.

    Here are 4 reasons Visbiome may not be right for you:

    1. Too expensive
    • At around $72 per month, that means this probiotic will cost you $864 per year. You get what you pay for, but that will be cost prohibitive for many.
  • Too strong
    • If a product is too strong for you, you may experience probiotic side effects. Over the counter versions of Visbiome contain up to 450 billion CFU per serving. To put that in perspective, Dr. Ohhira’s probiotic contains less than 1 billion per serving…and some people complain of side effects with 450x weaker probiotics.
  • Refrigeration
    • This product requires refrigeration which may not be appropriate for people who travel frequently.
  • Trace amounts of dairy
    • Though this product does not contain gluten or soy, it has trace amounts of dairy.
    • On their website they say Visbiome contains this much dairy per capsule: 0.01 g lactose per 200 capsules

    Refrigeration Requirements

    Visbiome contains temperature sensitive live bacteria, so it needs to be refrigerated to ensure these bacteria stay potent to deliver their beneficial digestive effect. However, for those traveling or unable to meet this requirement, Visbiome may be kept at room temperature for up to 1 week without damaging its effectiveness.

    Visbiome now has temperature sensitive packaging. So you can tell if Visbiome got too hot over time.

    Since this product needs to be refrigerated when shipped, .

    Visbiome on Amazon Ships With Ice Packs

    Since this product needs to be kept cold, .

    Strong Scientific Evidence for Visbiome

    There are over 60 clinical research studies focused on exploring the benefits of taking Visbiome formula every day. I’ll summarize a few of these studies now:

    • (Visbiome) improves bowel frequency and health perceptionA
    • (Visbiome) reduce inflammation and enhance gut immune health in people living with HIVB
    • (VSL#3) Induces remission in patients with ulcerative colitis,C and helps with remission in childrenD
    • (VSL#3) Improves liver function for liver disease patients (children and adult)E,F,G

    Probiotic Formula

    All Visbiome products use the same exact blend of probiotic strains. They’ve been tested in over 60 medical food human clinical trials. You probably recognize that these probiotic strains are exactly the same ones as in the old VSL#3 formula.

    What Probiotic Strains Are in Visbiome?

    Here are the 8 strains they use:

    • Lactobacillus paracasei DSM 24733
    • Lactobacillus plantarum DSM 24730
    • Lactobacillus acidophilus DSM 24735
    • Lactobacillus helveticus DSM 24734
    • Bifidobacterium longum DSM 24736
    • Bifidobacterium infantis DSM 24737
    • Bifidobacterium breve DSM 24732
    • Bifidobacterium thermophilus DSM 24731

    Product Options

    There are currently 2 product options for purchasing Visbiome. You can take it as a capsule, or as an unflavored powder. VSL#3 used to have more options, so I’m sure that Visbiome will follow suit soon.

    Visbiome Powder

    The powder form of this product is flavorless, mixes well, and can be put in any drink that isn’t hot. Boiling hot coffee or tea will kill some of the expensive bacteria in this product. For best results, I would mix this in room temp water, or non iced drinks. Refrigerator temperature drinks are okay too.

    Inactive Ingredients in Packets

    Other than the 450 billion probiotic bacteria cells (CFU) in each pouch, they also have some cornstarch in the powder. I assume it’s because it mixes well.

    Visbiome Capsules

    Inactive Ingredients in Capsules

    As far as I can tell, the first 4 ingredients are used for a) making the capsule machines run smoother b) improving consistency of the dose put into each capsule. I think there is no solid evidence that these substances are harmful. Though I wouldn’t take them just for fun.

    The 5th inactive ingredient is just a normal veggie capsule.

    1. Microcrystalline cellulose
    2. stearic acid
    3. silicon dioxide
    4. magnesium sterate
    5. vegetable capsule (hydroxypropyl methylcellulose)

    Dietary Considerations

  • Extremely trace amounts of diary:
    • Visbiome is classified as a gluten-free food, but contains extremely trace amounts of dairy products…you would consume 1/100th of a gram of diary in 3 months of taking the product.
  • Vegetarian – .003 grams of diary from being vegan
    • Additionally, the capsule casing is composed of a 99.9999% plant-based material, meeting the preferences of those individuals committed to a vegetarian lifestyle.
  • Sugar free
    • The capsule and plain flavored versions of this product do not contain any sugar.

    Buy on Amazon:

    Review Rating:

    Best for: digestive health

    Product Options: capsules or powder

    Shipping: ships with ice pack

    Buy on Amazon for best price (around $72)

    Want a 5 Star Probiotic?

    Review Rating:


    Mechanisms of Immunomodulation by Specific Members of the Intestinal Microbiota

    Evidence from both in vitro and animal model studies supports a role for L. casei and the VSL#3 probiotic combination in enhancing integrity of the intestinal barrier (Madsen et al., 2001; Llopis et al., 2005). Probiotic derived DNA has been shown to have immunomodulating properties through a TLR9-dependent pathway (Rachmilewitz et al., 2004).

    Polysaccharide A isolated from the gut commensal Ba. fragilis protects mice from experimental colitis intestinal inflammation through changes in local immunomodulation (Mazmanian et al., 2008). This immunomodulatory molecule also has the ability to promote the development of CD4+ T cells and could therefore be important for proper development of oral tolerance (Mazmanian et al., 2005). Another microbial surface molecule, lipoteichoic acid from Lactobacillus plantarum, was recently found to prevent excessive immune cell activation via NOD2-related signaling pathways (Kim et al., 2011).

    Understanding the totality of the interactions between the numerous members of the microbiota present in each individual is a major challenge due to the complexity of the intestinal microbiota, the large individual variability in microbiota, and the influence of host genetics. Nevertheless, significant progress has been made in identifying cornerstone species that have specific effects on the mucosal immune system or host physiology. The starting point for many studies has been the changes in microbiota associated with human disease. In adult IBD patients, for example, Proteobacteria and in particular E. coli are increased in abundance while the Firmicutes and Bacteroides are decreased as a proportion of the entire taxa. Phylogenetic typing of the E. coli present in IBD patients revealed a dominant presence of the B2 phylogenetic group carrying pathogenic traits, which are designated pathobionts to distinguish them from acquired infectious agents. These so-called adherent and invasive E. coli (AIEC) are distinct from the acquired pathogenic E. coli such as EPEC, ETEC, and EHEC (Chassaing and Darfeuille-Michaud, 2011). One prototype strain of AIEC designated LF82 has been characterized in detail and was shown to bind to the CEACAM6 receptor expressed on epithelial cells (Barnich et al., 2007). Expression of CEACAM6 is increased in inflamed tissue, explaining the increased abundance of E. coli on the mucosal biopsies of IBD patients (Darfeuille-Michaud et al., 2004; Barnich and Darfeuille-Michaud, 2010). Unlike acquired infectious pathogens, the pathobionts appear to require additional factors to cause disease. In the case of AIEC, pathogenesis is associated with genetic factors linked to increased risk for IBD (Lapaquette et al., 2012). Other commensals that can initiate gut inflammation and pathology when colonizing a genetically susceptible host include Helicobacter hepaticus, SFB, P. mirabilis, and K. pneumoniae. Additionally, long-term antibiotic use can lead to overgrowth of the pathobiont C. difficile, which causes toxin-mediated pseudomembranous colitis associated with severe diarrhea, abdominal pain, and fever.

    SFB have an unusually close association with their human and animal hosts and can be identified beneath the mucus layer, mainly in the terminal ileum where they may attach to epithelial cells. They have been identified in several vertebrates and invertebrates and in mammals they rapidly expand in number after weaning and decrease again in adults. Identification of SFB in humans has been elusive but recent SFB 16S rRNA-specific PCR detection showed SFB colonization to be age dependent in humans. The majority of individuals were colonized within the first 2 years of life but SFB disappeared by the age of 3 years (Yin et al., 2013). The ability of SFB to induce Th17 cells in the host lamina propria resulted from a fortuitous observation that the same in-bred mouse strain from different suppliers (Taconic or Jackson Laboratories) differed considerably in the percentage of LP Th17 cells (Ivanov et al., 2009). Comparative analysis of the microbiota in these two sources of mice revealed SFB to be absent in the Jackson mice that have low percentage of Th17 cells. Cohousing of Jackson mice with Taconic mice was subsequently shown to transfer SFB to Jackson mice and increase the percentage of LP Th17 cells in the LP (Ivanov et al., 2009). Although SFB are unculturable, germ-free mice monocolonized with SFB were obtained using preparations of spores from feces of Taconic mice, which resulted in the induction of Th17 in the LP. The ability to induce Th17 effector cells was shown to be relatively specific for SFB and appears to occur directly in the lamina propria (LP) via the subpopulation of CX3CR1+ cells adhering to the epithelium (Ivanov et al., 2009). This induction of Th17 cells was important in protection against oral infection with Citrobacter rodentium (Ivanov et al., 2009). Furthermore, SFB has been shown to drive pathology in mouse models of rheumatoid arthritis and multiple sclerosis via the induction of inflammatory Th17 cells, demonstrating that this bacterium can act as a pathobiont in the context of host autoimmunity (Wu et al., 2010).

    In contrast to the pathobionts described above some members of the intestinal microbiota stimulate anti-inflammatory mechanisms, which can suppress inflammation. Faecalibacterium prausnitzii initially gained attention because the numbers of this normally abundant anaerobe are substantially decreased in IBD patients. Faecalibacterium prausnitzii strain A2-165 and its supernatant from in vitro grown cultures has been shown to attenuate clinical parameters of trinitrobenzenesulfonic acid (TNBS)-induced colitis in mice (Sokol et al., 2008). One possible mechanism is attributed to an unidentified component in the culture supernatant of in vitro grown F. prausnitzii that inhibited NF-κB activation and IL-8 secretion induced by IL-1β in Caco-2 cells (Sokol et al., 2008). Butyrate was shown not to inhibit NF-κB in experiments with Caco-2 cells in vitro (Sokol et al., 2008), although it is anticipated to have an anti-inflammatory effect in vivo. Other possible mechanisms contributing to the protective effect of F. prausnitzii in colitis might be related to its capacity to induce relatively large amounts of IL-10 and low amounts of IL-12 in peripheral blood mononuclear cells (Sokol et al., 2008). Induction of IL-10 in LP dendritic cells may influence the induction of regulatory T cells in the lymphoid tissue or enhance their activity. Interestingly, other members of the Clostridium clusters IV and XIVa increased transforming growth factor-β (TGF-β) production and promoted Treg cell accumulation in the colon after colonization of mice with a defined mix of Clostridium strains (Atarashi et al., 2011). Furthermore, oral inoculation of Clostridium during the early life of conventionally reared mice resulted in resistance to colitis and systemic IgE responses in adult mice (Atarashi et al., 2011).

    Another commensal, Ba. fragilis, has been shown to have unique immunomodulatory effects through surface polysaccharide A (PSA). The polysaccharide can protect animals from intestinal inflammation by suppressing IL-17 production (Mazmanian et al., 2008). It was also shown that colonization of germ-free animals with Ba. fragilis induces the development of inducible Tregs, leaving natural Tregs unaffected (Bercik et al., 2010) in a TLR2-dependent fashion. Moreover, PSA can provide protection in animal models of colitis through repression of proinflammatory cytokines associated with the Th17 lineage (Ochoa-Reparaz et al., 2010).

    The examples highlighted above provide some of the major advances in our understanding of how specific commensal organisms shape host immunity. In the future, we can expect that many more species and immunomodulatory molecules will be elucidated.

    It is now clear that certain members of the microbiota can promote the expansion of specific effector or regulatory T cells. SFB, for example, promote inflammatory Th17 cells, but in a healthy intestine this contributes to host defenses against pathogenic microbes, presumably by inducing antimicrobial peptides and thereby enhancing mucosal barrier function. However, in the context of autoimmune and inflammatory diseases Th17 cells can contribute to pathology. In the healthy gut Th17 responses are kept in balance by Tregs, which are induced by Clostridium species, and specific components of bacteria such as the PSA from Ba. fragilis. Other members of the microbiota such as F. prausnitzii have anti-inflammatory properties that can prevent colitis, suggesting that they also play a role in maintaining homeostasis. More knowledge is needed to identify the specific microbial species and factors that are required for the induction of mucosal Tregs. The same is true of other microbes that have been shown to prevent or treat diseases in animal models or play a role in homeostasis. This will provide us with a better understanding of how the gut microbiota regulates immune homeostasis and may suggest potential therapeutic options for treating human diseases such as IBD and allergies.

    Furthermore, members of the microbiota termed pathobionts appear to take on pathogenic properties in individuals with IBD and colon cancer and perhaps for diseases not involving the intestine. However, it is not yet clear whether some pathobionts can trigger disease in susceptible individuals with genetic and environmental alterations, or if they are a consequence of the altered immune status. A better understanding of the pathogenic processes involving the microbiota and how the immune system shapes host immunity may also lead to novel therapies for chronic human diseases.

    VSL#3 DS Side Effects

    Generic Name: bifidobacterium infantis / lactobacillus acidophilus / streptococcus thermophilus

    Note: This document contains side effect information about bifidobacterium infantis / lactobacillus acidophilus / streptococcus thermophilus. Some of the dosage forms listed on this page may not apply to the brand name VSL#3 DS.

    Applies to bifidobacterium infantis / lactobacillus acidophilus / streptococcus thermophilus: oral capsule, oral powder for reconstitution


    Do not use this product without medical advice. Follow all directions on the product label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

    Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

    Common side effects may include:

    • stomach bloating or discomfort.

    This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

    Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

    Some side effects may not be reported. You may report them to the FDA.

    Medical Disclaimer

    More about VSL#3 DS (bifidobacterium infantis / lactobacillus acidophilus / streptococcus thermophilus)

    • Drug class: probiotics

    Consumer resources

    Other brands: VSL#3

    • Dietary Supplementation



    UC is a chronic inflammatory disease of the colon involving still largely unknown interactions between genetic, environmental, and immunological factors.

    UC is characterized by flare-ups of inflammation and periods of remission or quiescence that can be achieved or maintained by drugs having, as a common denominator, anti-inflammatory and/or immunosuppressive properties (5-aminosalicylates, 6-mercaptopurine, azathioprine, and anti-TNFα antibodies). If left without any maintenance drug, about 70% of patients will relapse within 12 months (2), and many patients on maintenance drugs will still require step-up therapy.

    After the initial report by Gionchetti et al. (3) on pouchitis, followed by other confirmatory clinical studies, it is now accepted that VSL#3, a combination of probiotic bacteria, can place this disease in remission or quiescence in a large number of patients with a J-pouch, as recommended in the guidelines of international gastroenterological associations (10,11).

    We report the results of an Italian multicenter study aimed at evaluating the efficacy of the specific probiotic product, VSL#3, for the treatment of mild-to-moderate UC used in conjunction with standard treatment. Our study is a double-blind randomized placebo-controlled trial on adult patients affected by relapsing mild-to-moderate UC, in which VSL#3 or placebo was added to the standard treatment, and aimed to assess the decrease in UCDAI score of 50% or more. For ethical reasons, the “placebo” group was a group in which the patients continued to take their standard treatment (5-ASA and/or immunosuppressant), with the simple addition of a placebo.

    Overall, VSL#3 was significantly superior to the placebo in reducing the activity of mild-to-moderate UC (primary end point). A significantly higher proportion of patients in the VSL#3 group experienced an improvement in their UCDAI score of at least 50% at week 8 over those who received placebo (63.1% vs. 40.8%, P=0.010). As a secondary end point, 31 individuals (47.7%) in the VLS#3 group and 23 individuals (32.4%) in the placebo group experienced remission by the end of 8 weeks, reaching results that did not show a significant difference (PP P=0.069; ITT P=0.132). We believe that this might represent a type II error and that a larger study might have had enough power to detect a statistically significant difference. None of the patients in the VSL#3 group experienced any worsening of symptoms during follow-up ( Tables 6 and ​and7),7), whereas five individuals in the placebo group showed a deterioration in their clinical status and had to be withdrawn from the study. No significant difference in stool frequency, physician rating of disease activity, and mean endoscopy scores was detected between the two groups (P= n. s. (not significant)). However, VSL#3 patients had a significant reduction in rectal bleeding compared with the placebo group (PP P=0.014; ITT P=0.036). Finally, no major adverse event was reported in either group. To confirm the efficacy of VSL#3, we also considered the patients who dropped out because of clinical ineffectiveness. In the “placebo” group, five patients abandoned the study for this specific reason (7%), whereas all VSL#3 patients completed the study.

    VSL#3 has proven to be effective by colonizing the host, changing the epithelial function and the immune response. Experimentally, in murine models of colitis, VSL#3 prevents redistribution and reduced expression of sealing tight-junction proteins (12) and specifically stimulates the expression of genes associated with lipid, xenobiotic, and peroxisome proliferator-activated receptor signaling (13).

    The roles of probiotics in managing active UC have also been reported in literature. Studies have reported Escherichia coli 1917 Nissle to be as effective as low-dose mesalamine in preventing a relapse of quiescent UC (14,15,16) and treatment with Saccharomyces boulardii for 4 weeks was shown to induce clinical remission in 71% of patients with mild-to-moderate disease; however, very few patients were enrolled to draw any conclusions (17). Moreover, S. boulardii should be managed with caution, especially in immunocompromised patients (e.g., in patients under immunosuppressant treatment) (18).

    Other studies have reported the efficacy of VSL#3 in patients affected by UC (19). An open-label study (20) showed that in 5-ASA allergic or nonresponsive UC patients, VSL#3 was able to colonize the intestine and suggested that the product may be useful in maintaining remission (15 out of 20 patients remained in remission during the 1-year study). Thereafter, an open-label study found that 77% of mild-to-moderate UC patients obtained remission with 3,600 billion CFU/day of VSL#3 at 6 weeks (6). An Italian randomized, controlled study found that VSL#3 900 billion CFU/day added to low-dose balsalazide shows better results in treating active UC than balsalazide or mesalazine alone (5). Two studies with VSL#3 in pediatric UC have recently been carried out; the first one is an open-label study showing that 56% of pediatric patients obtained remission, with a combined remission/response rate of 61% (21), and the second one is a double-blind placebo-controlled trial, showing that VSL#3 supplementation was only able to induce remission in 92.8% of UC children compared with 36.4% with steroid alone, and was effective in maintaining remission in 78.6% of patients during a 12-month follow-up compared with 26.7% in the placebo group (22).

    Although the design of our study was similar, we recorded a higher placebo response compared with the Sood et al. (23) study (40% in our trial vs. 10% in Indian trial). The high “placebo” response rate of our study (40.8% of placebo patients had a 50% reduced UCDAI) may be easily explained by the continuous standard medical treatment provided to all the patients and allows for the statistically borderline results reached in this study for obtaining remission and mucosal healing. A possible suggestion for future studies, in addition to increasing the number of enrolled patients, may be to extend the study period to 12 weeks, expecting, as the Sood et al. (23) study proved, that a longer treatment with VSL#3 will offer more divergence from the placebo group. As stated by a recent review, another possible explanation for this high “placebo” response is that the country in which the study is conducted significantly influences the placebo response rate (24). In particular, studies carried out exclusively in Europe have a significantly higher placebo remission rate than studies outside Europe, ranging from 20.8% to 33.6% (24). Our placebo results are therefore in line with the literature estimates. This high percentage of placebo response may also account for some results of this study. For example, the failure to improve stool frequency vs. placebo may be very relevant to patients. We found VSL#3 better than placebo when we assessed the objective parameters (UCDAI, rectal bleeding, remission, and mucosal healing). On the contrary, subjective parameters (stool frequency and physician rating of disease activity) do not seem to improve so significantly under VSL#3 treatment. Two reasons may explain these conflicting results. First, the “placebo” response may affect some subjective parameters (e.g., stool frequency). The second is that unchanged stool frequency may be related to overlapping irritable bowel syndrome, as this sometimes affects patients with inflammatory bowel disease (25).

    An important point of discussion to be addressed is the rationale of this study. People may argue that a higher dose of 5-ASA therapy might be just as well tolerated and may be more convenient and less expensive for obtaining remission. This may be a rational and advisable approach. However, we need a new therapeutic approach to relapsing UC, especially when the patient is already under treatment with immunosuppressors. Increased doses of mesalazine formulations may be safe and effective in obtaining remission, but the azo-bonded formulations may be compromised by secretory diarrhea at doses providing >2–2.4 g/day of mesalazine (26). Moreover, biologics are at higher risk of severe side effects and are much more expensive than a high-dose probiotic treatment in obtaining remission in relapsing UC. On the contrary, VSL#3 is classified as a food or food supplement in most countries and is characterized by a very high safety profile that has also been confirmed throughout this study. The safety of VSL#3 has also been proven in pediatric inflammatory bowel disease and intensive care unit patients (21,22,27).

    Of course, once remission has been obtained, physicians also need to know how these patients should be managed in the longer term, i.e., with maintenance doses of probiotic. A clinical trial assessing the optimal dose of VSL#3 in maintaining remission of UC is needed.

    Another criticism may be that the VSL#3 dose used in this study is quite high, compared with other studies reporting an effect on remission of UC or pouchitis (7). This choice was based on the assumption that a high probiotic concentration is needed to treat an extensive and active colonic disease. Of course, the optimal dose to maintain remission may be much lower (e.g., one sachet daily for the maintenance of remission in pouchitis (3), and, as stated, a further trial assessing the optimal dose of VSL#3 in maintaining remission of UC is needed.

    In this trial, probiotics and 5-ASA seem to have a synergistic activity. It is unclear how the association between probiotic and 5-ASA may take effect. It is possible that VSL#3 may function in synergy with, or perhaps increases, the anti-inflammatory action of 5-ASA compounds. 5-ASA compounds are potent inhibitors of several inflammatory mediators, such as leukotrienes, prostaglandins, and platelet-activating factor, all of which have roles in the pathogenesis of UC (28). In addition, 5-ASA compounds inhibit the production of interleukin-1 and free radicals and have an intrinsic antioxidant activity (29). Probiotics reduce inflammation by a number of mechanisms, including alteration of the mucosal immune system, competitive exclusion of proinflammatory pathogens, production of antimicrobial factors such as bacteriocins and other metabolites (28,30), and support of increased intestinal barrier function (31,32). At present, on the basis of what has recently been published for acetaminophen, we cannot exclude the possibility that gut bacteria may be the principal target for drugs, and that by manipulating the gut flora in the drug treatment, the outcome can be improved (33).

    We do not know whether similar results could have been obtained only by increasing the 5-ASA daily dosage by up to 4 g, provided that the incidence of 5-ASA-related side effects remains unchanged regardless of whether the dose is set at 2 g or 4 g. However, independent of any economic considerations (VSL#3, being a probiotic, is not covered by insurance policies), we believe that the association between 5-ASA and VSL#3 should be preferred, even to a high-dose 5-ASA regimen or to the 5-ASA/immunosuppressant association for the treatment of UC patients with mild-to-moderate UC. Our opinion is based on the fact that, because the mammalian genome does not encode for all functions required for proper immunological responses, it is therefore evident that humans depend on critical interactions with their microbiome for health (34,35).

    In conclusion, our study found that the addition of the high-potency probiotic mixture VSL#3 to the standard UC treatment is able to induce significant symptomatic improvement of relapsing mild-to-moderate UC compared with the placebo group on standard treatment only. This double-blind, placebo-controlled study found that VSL#3 is also able to improve the clinical picture, reduce symptoms, and improve the endoscopic appearance of the colonic mucosa. Therefore, VSL#3 may be considered as a safe and effective option for patients suffering from relapsing mild-to-moderate UC, to avoid or delay the administration of steroids, immunosuppressants, and biologics.

    Note to Healthcare Professionals and Patients Regarding the Recent Jury Verdict: Claudio De Simone et al v. VSL Pharmaceuticals, Inc. et al

    Professor Claudio De Simone, the inventor of the high potency probiotic previously sold under the brand name, “VSL#3*”, recently won a unanimous jury verdict in Federal Court against VSL Pharmaceuticals, Inc., Alfasigma USA, and Leadiant Biosciences, Inc. Elements of the case are relevant to those who work with high potency probiotics.

    The litigation was the product of a business dispute between Claudio De Simone and his former business partners. In the early 1990s, De Simone invented the De Simone formulation, a high potency, eight strain probiotic product. The formulation and associated patent were licensed to the VSL Pharmaceuticals, Inc. company (“VSL Inc”). The De Simone Formulation was subsequently sold under the brand name, VSL#3* from 2002 to 2016 (VSL#3 is a registered trademark of VSL Inc). When De Simone terminated his relationship with VSL Inc., the company attempted to produce a copy of the original formulation and pass off the counterfeit as the original product. A legal dispute arose concerning the ownership of the proprietary formulation and claims which were being made about this copy “VSL#3*” product.

    The jury’s finding of false advertising relied upon formidable evidence presented to them that the new version of VSL#3, which is manufactured in Italy, is materially different in composition and efficacy from the original De Simone Formulation manufactured in the United States. And, as a result, VSL#3 can no longer be associated with the rich clinical history that applies to the original De Simone formulation. As of the time of trial, VSL Inc. had not completed a single study on its new formulation showing it performs the same as the original formulation. In this case, the jury unanimously found that the distributors were liable for false advertising, based on overwhelming evidence which showed that they misrepresented new VSL#3® to be the same as the original, which was made with the De Simone Formulation.

    Outcomes of the Litigation in Federal Court:

    • The seller of VSL#3 in the U.S., Alfasigma USA, was found liable for false advertising under the Lanham Act for making false statements related to the composition and clinical history of new “VSL#3.”
    • It was determined that the Know-How required to manufacture the De Simone formulation probiotic is the exclusive property of Professor Claudio De Simone.
    • VSL Inc was found to be in breach of contract to De Simone and ordered to pay compensatory damages. VSL Inc. and Leadiant were also found to have been unjustly enriched and were required to pay additional compensation to De Simone.

    In the months since the trial, various actions were taken against the VSL#3 product around the world:

    • In the United States (US), major wholesalers of the VSL#3 product in the United States have recently decided to discontinue purchases/sales of the product—Amazon, Cardinal Health, McKesson, CVS/Caremark, Walgreens, and Rite Aid.
    • In Canada, the VSL#3® product was removed from the market, effective November 15, 2018.
    • Six universities in the US and Europe (including Stanford University, Emory University, University of Wisconsin-Madison, and University of Louisville) have halted human clinical trials using VSL#3 in response to the very serious public health concerns that have been raised.
    • As of this publication date, six published comparative studies have found stark differences between VSL#3 containing the De Simone Formulation and the new “knock off” product.1,2,3,4,5,6
    • The European Society for Clinical Nutrition and Metabolism (ESPEN) issued a correction to its guidelines for Clinical Nutrition in Inflammatory Bowel Disease7, withdrawing the trademark “VSL#3” and replacing this with the generic term “De Simone Formulation”.
    • The peer-reviewed journal, Medicine, issued an erratum replacing “VSL#3” with “De Simone Formulation” in the article, “The clinical effects of probiotics for inflammatory bowel disease: A Meta-analysis”.8
    • In Germany,the District Court of Hamburg, Germany ordered the local distributor of VSL#3 (Ferring) to stop making a series of claims in reference to the effectiveness of the current probiotic formulation commercialized under the brand VSL#3®

    Ongoing False Representations by Alfasigma:

    A federal jury has already unanimously found that Alfasigma has made false statements to patients and healthcare professionals. As of the date of this letter their efforts to mislead consumers continues:

    Alfasigma Claims:

    The Facts

    Studies performed on the original probiotic formulation sold under the name “VSL#3”, “…can be relied on to show efficacy and safety of the Italian-made product.”9

    – To date, not one bridging study has been published on the new VSL#3.

    – The sole study Alfasigma relies on to establish equivalence only evaluated the genetics of the two products and not the clinical activity.10

    – The authors of that study had to issue a correction because they could not be sure that the tested product actually was commercial VSL#3.11

    That genetic similarity alone is sufficient to establish the equivalence of original formulation and the new knock off VSL#3

    – Genetic similarity of live probiotic organisms is not sufficient to establish clinical equivalence.12

    – The Alfasigma position ignores the basic biological concept of “nature vs nurture.”

    Regarding the recent litigation “…the verdict contained no specific findings concerning the quality, production, efficacy or safety of VSL#3.”9

    – There was so much evidence presented at trial which questioned the quality, production, efficacy and safety of the new VSL#3 that the Jury could not possibly rule on every specific scientific finding.

    – The Jury looked at the totality of the of evidence and ruled unanimously that Alfasigma was falsely advertising.

    New VSL#3 contains the same 8 strains as the original.9

    – At trial, significant evidence was presented to show that new VSL#3 actually only contained 7 strains as of the time of the trial.

    Alfasigma claims their new product is the same as the original because the strains are genetically similar.

    – Changes in the production and fermentation methods of probiotics can result in performance changes (even when the genetics is the same).13,14,15,16

    – New VSL#3 is not fermented with the necessary dairy ingredients, which are critical to the health and vitality of these yogurt bacteria.

    Alfasigma attempts to link the new VSL#3 back to the original by pointing to a few early studies performed on prototypes of the product made prior to 2000.9

    – Alfasigma fails to acknowledge that these early prototypes were created under the direction of the product inventor using his proprietary Know-How and with dairy based fermentation methods.

    – New VSL#3 is made without dairy and without the inventor’s proprietary formula.

    Alfasigma endeavors to provide scientific support for its product by citing a genetic characterization study performed by Douillard, et al.9,10

    – The study in question does not establish the clinical or genetic equivalence of the original formulation vs the new VSL#3.

    – The study was performed only on individual strains given to the investigators by the company and not on commercial VSL#3 product.

    – The authors of the study had to publish a correction to the original publication conceding that they had not tested commercial VSL#3 product11

    – Supplementary Table 3 (Genome sequencing statistics S3 Table) of the analysis indicates that of two of the reported strains genetically correspond to the same strain, suggesting that there were only 7 strains in the VSL#3 formulation at the time of the study (Bifidobacterium_animalis_lactis_Bi_07_uid163693/NC_017867.gbk)

    The original De Simone formulation, which was previously sold under the name, VSL#3 is currently available in the United States and Canada only under the name, Visbiome. The Visbiome brands are available online at www.visbiome.com, on Amazon, or by special order from a variety of pharmacies.

    We invite you to learn more at www.visbiome.com or by contacting ExeGi Pharma at [email protected]

    *VSL#3® is a registered trademark and is manufactured exclusively for, VSL Pharmaceuticals, Inc. Visbiome® is manufactured exclusively for ExeGi Pharma, LLC and is not affiliated with, endorsed by, or distributed by VSL Pharmaceuticals, Inc.

    1. Biagioli et al. Metabolic Variability of a Multispecies Probiotic Preparation Impacts on the Anti-inflammatory Activity. Frontiers in Pharmacology. 2017.
    2. Cinque et al. VSL#3 probiotic differently influence IEC-6 intestinal epithelial cell status and function. Journal of Cellular Physiology.
    3. Cinque et al. Production Conditions Affect the In Vitro Anti-Tumoral Effects of a High Concentration Multi-Strain Probiotic Preparation. Journal PLOS ONE. 2016.
    4. Trinchieri, et al. Efficacy and Safety of a Multistrain Probiotic Formulation Depends from Manufacturing. Frontiers in Immunology. 2017
    5. Palumbo, et al. The Epithelial Barrier Model Shows That the Properties of VSL#3 Depends from Where it is Manufactured. Endocrine, Metabolic, & Immune Disorders. 2019, 19, 1-8
    6. Biagioli, et al. Divergent Effectiveness of Multispecies Probiotic Preparation on Intestinal Microbiota Structure Depends on Metabolic Properties. Nutrients 2019 11(2), 325.
    7. Forbes, et al. Corrigendum to: ESPEN guideline: Clinical nutrition in inflammatory bowel disease
    8. Erratum: Jia et al. The clinical effects of probiotic for inflammatory bowel disease: A meta-analysis. 97; 51:e13792
    9. Alfasigma Jan 31, 2019 Dear Healthcare Provider Letter
    10. Douillard et al. Comparative genomic analysis of the multispecies probiotic-marketed product VSL#3. PLoS One 2018; 16;13(2):e0192452
    11. Douillard et al. Correction: Comparative genomic analysis of the multispecies probiotic marketed product VSL#3. PLoS One 2018; 13(8): e0203548
    12. Sanders ME, Klaenhammer TR, Ouwehand AC, et al. Effects of genetic, processing, or product formulation changes on efficacy and safety of probiotics. Annals of the New York Academy of Sciences 2014; 1309(1): 1±18.
    13. Grzesakowiak è, Isolauri E, Salminen S, Gueimonde M. Manufacturing process influences properties of probiotic bacteria. Br J Nutr. 2011 Mar; 105(6):887±94. Epub 2010 Nov 9. PMID: 210592
    14. Nivoliez et al. Influence of manufacturing processes on in vitro properties of the probiotic Lactobacillus rhamnosus Lcr35.Ò Journal of Biotechnology (2012) 236-241.
    15. Saarela MH, Alakomi HL, Puhakka A, Matto J. Effect of the fermentation pH on the storage stability of Lactobacillus rhamnosus preparations and suitability of in vitro analyses of cell physiological functions to predict it. J Appl Microbiol 2009; 106(4): 1204±12
    16. Deepika G, Green RJ, Frazier RA, et al. (2009) Effect of growth time on the surface and adhesion properties of Lactobacillus rhamnosus J Appl Microbiol 107, 1230–1240.

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