Probiotics benefits and side effects, studies regarding their medical uses
Feb 27 2014, by
Ray Sahelian, M.D.

Probiotics and prebiotics are two food ingredients that have physiologic benefits and effects through the gastrointestinal tract. Once you buy a probiotic supplement, you should refrigerated it to prolong the shelf life. There are many that are sold in health food stores and online. It is difficult to know which are effective and which are not since very little testing has been done comparing the hundreds of different products.

The mammalian gastrointestinal tract harbors a highly diverse microbial population termed the microbiome, which plays a major role in nutrition, metabolism, protection against pathogens, and development of the immune system. It is estimated that at least 1000 different bacterial species cohabit the human intestinal tract.

Enteric coating
Some sources say you must take enteric-coated capsules so that the probiotics will bypass the stomach and stomach acid (which they say destroys the probiotics) and be released in the intestines. Other sources say that stomach acid does not destroy the probiotics and that enteric-coated capsules are an unnecessarily expensive method of getting your probiotics. Example: Yogurt has worked for what, centuries, to provide probiotics' health benefits. What is the truth?
    I asked Dr. S.K. Dash, President of UAS Laboratories, Inc. and an expert in this field. He responded, "Probiotics are acid and bile resistant. Not only do they pass stomach acid, they implant in the intestine, produce digestive enzymes, vitamins, lactic acid and natural antibiotics. Probiotics do not need enteric coating to be effective."

Enhanced Probiotics System, 60 Vegetarian Capsules
Jarrow Formulas
Higher Potency 4.4 Billion Organisms per capsules
Dairy Free
Vegetarian
Enteric Coated!
Room Temperature Stable! No Refrigeration Required!
For Intestinal and Immune Health

buy Probiotic Supplement, Individually Blister Sealed

How to use: Take at the end of a meal since by then the stomach acid is diluted and more of the bacteria can make it to the colon.

Buy Probiotic supplement for its gastrointestinal benefits

Jarro-Dophilus enhanced probiotics system is room temperature stable, but preferably refrigerate to safeguard product from heat. Blister packaging each capsule provides extra protection to the bacteria against moister and oxygen. At time of manufacture, each capsule contains approximately 4.4 Billion organisms. Jarro-Dophilus enhanced probiotics system is room temperature stable and enteric-coated, delivering directly into the intestines 8 different species of probiotics representing 4 genera of bacteria: Lactobacilllus acidophillus, Bifidobacterium, Lactococcus and Pediococcus Bifodobacteria longum BB536 (moringa strain) has been shown to colonize, stimulate immune response and suppress intestinal pathogens. L. rhamnosus R0011 is a unique, high producer of polysaccharides, which facilitate colonization and stimulate intestinal immune response. Lactococcus and Pediococcus help reduce spoilage caused by undesirable bacteria in cultured dairy products.

Jarro-Dophilus enhanced probiotics system is ideal for traveling when refrigeration is not readily available. Capsule individually blister packed to help ensure shelf stability.

Supplement Facts:
Probiotics Bacteria 4.4 Billion
Organisms
L. rhamnosus R0011 (15.4%) 680 Million
L. casei R0256 (15.4%) 680 Million
L. plantarum R0202 (7.7%) 340 Million
Lactobacillus acidophilus R0052 (15.4%) 680 Million
Bifidobacterium longum BB536 (morinaga strain)(15.4%) 680 Million
Bifidobacterium breve R0070 (7.7%) 340 Million
Pediococcus (15.3%) 670 Million
acidilactici R1001
lactococcus (7.6%) 330 Million
diacetylactis R0100

Usage: Take 1 to 2 probiotics capsules per day, preferably on an empty stomach, though it may also be taken with food, or as directed by your qualified health consultant.

Benefit of prebiotics and probiotics supplements
Probiotics have been defined as live microorganisms that (when ingested) have a beneficial effect in the prevention and treatment of specific medical conditions. These microorganisms are believed to exert biological effects through a phenomenon known as colonization resistance, whereby the indigenous anaerobic flora limits the concentration of potentially harmful (mostly aerobic) germs in the digestive tract. Other modes of action, such as supplying enzymes or influencing enzyme activity in the gastrointestinal tract, may also account for some of the other functions that have been attributed to probiotics.
   Prebiotics are nondigestible food ingredients that benefit host health by selectively stimulating the growth and/or activity of bacteria in the colon. The prebiotic fructooligosaccharide (FOS), is found naturally in many foods, such as wheat, onions, bananas, honey, garlic, or leeks. They can also be isolated from chicory root or synthesized enzymatically from sucrose. Fermentation of FOS in the colon results in a large number of physiologic effects including increasing the numbers of bifidobacteria in the colon, increasing calcium absorption, increasing fecal weight, shortening of gastrointestinal transit time, and possibly lowering blood lipid levels. The increase in bifidobacteria has been assumed to benefit human health by producing compounds to inhibit potential pathogens, by reducing blood ammonia levels, and by producing vitamins and digestive enzymes.

Allergy
Immunotherapy. 2013. Understanding the role of probiotics and prebiotics in preventing allergic disease: evidence and methodological issues.

Colic in babies
A daily dose of "good" bacteria may help infants cry less. After three weeks of treatment with probiotic bacteria, babies cried for an average of about a half-hour a day, while infants who received a placebo were still crying for an hour and a half daily. At the study's outset, babies in both groups were crying for five to six hours a day. Pediatrics, September 2010.

Reduce the incidence of the common cold
A Chinese study found small children who drink a mixture of probiotic bacteria mixed in milk twice a day during the winter and spring had fewer common colds, needed fewer antibiotics, and missed fewer days of school. The study involved 326 children, ages 3 to 5 years, who were randomly assigned to three different groups: one given milk with a bacterium called Lactobacillus acidophilus mixed in, another that received the same organism along with a strain of another bacterium, Bifidobacterium animalis, and a third that received just milk with placebo. Compared to the placebo group, the Lactobacillus group had 53 percent fewer fevers. The Lactobacillus / Bifidobacterium group had even larger reductions in symptom rates. When children in the test groups did get fevers, coughs or runny noses, they recovered significantly faster. The combination probiotic product used in this study is now marketed as "HOWARU Protect" by Danisco in Madison, Wisconsin. Pediatrics, 2009.

Diarrhea prevention or treatment
Probiotic supplements may help remedy certain types of diarrhea caused by the use of antibiotics. Probiotics may be used preventively to prevent or reduce symptoms of "traveler's diarrhea."

Australian researchers have modified good bacteria -- that may be useful in preventing or treating travelers' diarrhea, an all too common problem during trips to certain countries. The probiotics work against a type of E. coli bacteria that causes diarrhea by producing a chemical that is toxic to intestinal cells. The probiotics carry a molecule that looks a lot like the toxin receptor found on intestinal cells. This mimicry causes the toxin to bind to the microbes instead of the intestinal cells. Lab tests showed that these probiotics could bind and neutralize a significant amount of enterotoxin, according to a report in the medical journal Gastroenterology. Moreover, treatment with these agents conferred significant intestinal protection in rabbits exposed to the toxin. The results suggest that these probiotics could be a useful treatment for traveler's diarrhea caused by E. coli, the researchers state.

Compared with standard formulas, those containing beneficial probiotics organisms seem to reduce the number and duration of diarrhea episodes in infants attending childcare centers. Of two types of probiotics tested -- Lactobacillus reuteri and Bifidobacterium lactis -- L. reuteri may be the better supplement. Dr. Zvi Weizman, from Soroka Medical Center in Beer-Sheva, Israel, assessed various infectious outcomes in 201 infants randomly given formula supplemented with L. reuteri, B. lactis, or no probiotics. In addition to having fewer and shorter diarrhea episodes, infants treated with the probiotic formulas also had fewer episodes of fever. Pediatrics, 2005.

Immune system
Probiotic bacteria such as Lactobacilli or Bifidobacteria are believed to positively affect the immune response by improving the intestinal microbial balance leading to enhanced antibody production and phagocytic (devouring or killing) activity of white blood cells. Bifidobacterium lactis could be an effective probiotic dietary supplement for enhancing some aspects of cellular immunity in the elderly.
  
Probiotics enhance systemic cellular immune responses and may be useful as a dietary supplement to boost natural immunity in otherwise healthy adults. Children who take probiotic containing milk often havefewer respiratory infections.

Effects of probiotic therapy in critically ill patients: a randomized, double-blind, placebo-controlled trial
American Journal of Clinical Nutrition 2007.
Multiple organ dysfunction syndrome (MODS) is a major cause of mortality in intensive care units. A breakdown in gut barrier function and immune dysfunction are associated with the onset of MODS. Probiotic bacteria have been shown to modulate intestinal barrier and immune function. This study assessed the efficacy of a probiotic compound in a viable and nonviable formulation in modulating intestinal permeability and immune function and preventing the onset of MODS in patients in the intensive care unit. A double-blind, randomized controlled trial was conducted in the intensive care unit of a tertiary care teaching hospital. Twenty-eight critically ill patients admitted to the intensive care unit were randomly assigned to receive 1 of 3 treatments daily for 7 d: 1) placebo, 2) viable probiotics, or 3) equivalent probiotic sonicates. MODS scores and systemic concentrations of immunoglobulin (Ig) A and IgG were measured on days 1, 4, and 7, and intestinal permeability measurements were taken daily. The patients responded to viable probiotics with a significantly larger increase in systemic IgA and IgG concentrations than in the patients who received placebo or sonicates. MODS scores were not significantly affected by probiotic treatment. Over the study period, intestinal permeability decreased in most patients. Patients receiving viable probiotics show a greater enhancement in immune activity than do patients receiving either placebo or probiotic bacterial sonicates.


Inflammatory bowel disease
Probiotics may be helpful in ulcerative colitis and Crohn's disease.
Taking a mixture of several probiotic bacteria reduces symptoms in patients with ulcerative colitis that doesn't respond to conventional medications. The probiotic mixture contained four strains of Lactobacillus, three strains of Bifidobacterium and one strain of Streptococcus salivarius -- all well-known species of good bacteria. Researchers from the University of Alberta in Edmonton, Canada enrolled 34 patients with active ulcerative colitis who were treated with the probiotic mixture twice daily for 6 weeks. A variety of standard treatments had been tried on the patients first, with no help. Remission occurred in 53 percent of the patients and an additional 24 percent experienced some degree of improvement in symptoms. A few patients experienced no improvement or worsening of their symptoms. The only apparent side effect from the probiotic mixture was increased bloating. Testing of sampled colonic tissue provided direct evidence that the probiotic bacteria had, in fact, reached the diseased sites of the colon.  American Journal of Gastroenterology, 2005.

A pilot trial of Saccharomyces boulardii in ulcerative colitis.
Eur J Gastroenterol Hepatol 2003.
Probiotics can be useful in the treatment of inflammatory bowel disease. In a previous report, the non-pathogenic yeast Saccharomyces boulardii was found to be beneficial in the maintenance treatment of Crohn's disease. The aim of this study was to assess the efficacy of S. boulardii in ulcerative colitis patients. A group of 25 patients with a mild to moderate clinical flare-up of ulcerative colitis received additional treatment with S. boulardii 250 mg three times a day for 4 weeks during maintenance treatment with mesalazine. These patients were unsuitable for steroid therapy. Before and after treatment, Rachmilewitz's clinical activity index was calculated. The probiotic treatment was considered a therapeutic success only when the final score was lower than 6. Of the 24 patients who completed the study, 17 attained clinical remission; this was confirmed endoscopically. Our preliminary results suggest that S. boulardii can be effective in the treatment of ulcerative colitis. Controlled studies with this probiotic agent are warranted.

Eczema
Probiotics given during pregnancy to the mother and then post-natally to the child substantially reduce the incidence of eczema in those children at 2 years of life.

Irritable bowel syndrome
Probiotic supplements may be helpful in IBS. A preparation containing the beneficial microbe Bifidobacterium infantis relieves symptoms of irritable bowel syndrome.

Post-infectious irritable bowel syndrome is a common disorder wherein symptoms of IBS begin after an episode of acute gastroenteritis. The causes of PIBS are not fully understood, but are believed to include persistent sub-clinical inflammation, changes in intestinal permeability and alteration of gut flora. Lactase deficiency can occur with difficulty in metabolizing lactose sugar.

Ter Arkh. 2013. The role of small bowel microflora in the development of secondary lactase deficiency and the possibilities of its treatment with probiotics. Patients with PIBS were randomized to 2 groups: 1) 41 patients received basic therapy (mesim forte as one tablet t.i.d., no-spa, 40 mg, t.i.d.) and combined probiotic bifiform (Ferrosan) containing Bifidobacterium longum 107, Enterococcus faecium 107 as one capsule t.i.d. for 14 days. Group 2 patients had basic therapy in combination with placebo. After a 14-day course of therapy with the combined probiotic bifiform, restoration of eubiosis in the small bowel lumen was achieved in 70% of the patients and by normalization of the lactase test.

Chemotherapy drugs
In cancer patients, treatment with the probiotic Lactobacillus reduces the frequency of severe diarrhea and abdominal pain that often comes with 5-fluorouracil (5-FU)-based chemotherapy.

Ulcer relief
Up until recently, peptic ulcer disease was thought to be caused by an imbalance between acid and pepsin secretion, as well as defensive factors such as bicarbonate secretion and gastric mucosal barrier. The isolation of Helicobacter pylori from patients with chronic gastritis and duodenal and gastric ulcers has revolutionized thinking about the causes of ulcers. Current data suggest that persistent infection with Helicobacter pylori may account for peptic ulcer disease. In this study, 59 adult volunteers infected with H. pylori were given Lactobacillus- and Bifidobacterium-containing yogurt (AB-yogurt) twice daily after a meal for 6 weeks. Eleven subjects positive for H. pylori infection were treated with milk placebo as control subjects. H. pylori bacterial loads were determined with use of a breath test, which was performed before and 4 and 8 weeks after the start of AB-yogurt supplementation. Results: Yogurt containing probiotics suppressed H. pylori infection.
     Dr. Sahelian says: When you purchase yogurt, makes sure the label says that it contains these organisms. Or, you may directly supplement with probiotics.

Probiotics and H. Pylori infection
Effects of ingesting Lactobacillus- and Bifidobacterium -containing yogurt in subjects with colonized Helicobacter pylori.
American Journal of Clinical Nutrition 2004
Evidence suggests that ingesting lactic acid bacteria exerts a suppressive effect on Helicobacter pylori infection in both animals and humans. Supplementing with the probiotics Lactobacillus- and Bifidobacterium-containing yogurt was shown to improve the rates of eradication of H. pylori in humans, a cause of ulcers. Objective: We administered probiotics to subjects with asymptomatic H. pylori to test whether the probiotics yogurt could inhibit H. pylori growth. Design: In an intervention study, 59 adult volunteers infected with H. pylori were given probioitics-yogurt twice daily after a meal for 6 weeks. Eleven subjects positive for H. pylori infection were treated with milk placebo as control subjects. H. pylori bacterial loads were determined with use of the 13C-urea breath test, which was performed before and 4 and 8 wk after the start of probioitics supplementation. Results: Bb12 exerted an in vitro inhibitory effect against H. pylori, whereas La5 did not show an effect. Administration of probioitcs-yogurt decreased the urease activity of H. pylori after 6 wk of therapy. Regular intake of yogurt containing these bacteria effectively suppressed H. pylori infection in humans.

Pretreatment with Lactobacillus- and Bifidobacterium containing yogurt can improve the efficacy of quadruple therapy in eradicating residual Helicobacter pylori infection after failed triple therapy
American Journal of Clinical Nutrition 2006
Lactobacillus and Bifidobacterium containing yogurt may suppress Helicobacter pylori. Improvement of the eradication rate by quadruple therapy of residual H. pylori after failed triple therapy is needed. We tested whether prior treatment with probiotics improved the efficacy of quadruple therapy in eradicating residual H. pylori after failed triple therapy. Design: One hundred thirty-eight patients in whom triple therapy failed were enrolled for a culture study of H. pylori to assess antimicrobial resistance. These patients were then randomly assigned in equal numbers to either a yogurt probiotics quadruple therapy group or a quadruple therapy-only group. The patients received 1 wk of quadruple therapy with or without a 4-wk pretreatment with probiotics yoghurt (400 mL/d). A 4-wk pretreatment with probiotics yogurt can decrease H. pylori loads despite antimicrobial resistance, thus improving the efficacy of quadruple therapy in eradicating residual H. pylori.

Secondary lactase deficiency restoration
Use can help those with lactose intolerance after a gastrointestinal infection.

STD or sexually transmitted disease prevention
The presence of lactobacilli and possibly other such beneficial organisms could potentially reduce the risk from trichomoniasis.

Vitamin D level increase
J Clin Endocrinol Metab. 2013. Oral supplementation with probiotic L. reuteri NCIMB 30242 increases mean circulating 25-hydroxyvitamin D: a post-hoc analysis of a randomized controlled trial.

Taking together with antibiotics
Should one take a probiotic while taking antibiotics or wait until the prescription treatment is over?
   I still need to see good research on this, but it seems for the time being that taking the probiotics the same day is okay, but they are better taken 2 or 3 hours after the antibiotic dose.  

Studies
World J Gastroenterol. 2013. Probiotic supplementation decreases intestinal transit time: meta-analysis of randomized controlled trials.

Dr. Py Tubelius and colleagues from Tetra Pak Occupational Health and Safety AB conducted the current study to determine if one probiotic, Lactobacillus reuteri, might help prevent sick leave due to respiratory or gastrointestinal infections. They randomly assigned 262 employees of the company to take a drink containing L. reuteri or a placebo drink every day for 80 days. Twenty-three of the 87 workers on placebo, or about 26%, took sick leave during the course of the study, compared to 10 of the workers taking the probiotic, or 11%. Among the subset of workers on the night shift, none of the 26 taking the probiotic called in sick, compared to 9 of their 27 colleagues, or 33%. Shift workers are known to be more prone to develop stomach ailments, colds and other types of short-term illness leading to sick leave. While the mechanism by which the probiotic might help prevent illnesses isn't clear, the researchers add, it's likely that it helped to strengthen immune function. Environmental Health, 2005.

Probiotics Displace Bad Bacteria in the Nose -- Even though the nose-- with its hairs-- is a filtering system that prevents many harmful bugs, dust, and other undesirable elements from entering the respiratory system, it is also, in some people, a reservoir for harmful bacteria including those that cause staph infections, ear infections, sinus infections, and pneumonia. In those carrying harmful bacteria in their nasal cavities, antiseptic regimens could be crucial for infection control after major operations on or injuries of the head, nasal sinuses, or lungs. Such regimens may also be important for diabetic patients and persons in intensive care units, or with impaired immunity due to various other causes. But, instead of just trying to kill these harmful bacteria with antiseptics or antibiotics, another option may be to displace them with healthy bacteria. Scientists at the Swiss National Accident Insurance Institute, Lucerne, Switzerland tested a possible effect of the ingestion of probiotics on the bacterial flora of the nose. Volunteers were randomly assigned to consume either a probiotic fermented milk drink that included beneficial bacteria such as lactobacilli and bifidobacteria or standard yogurt daily for 3 weeks. At the conclusion of the study, nasal microbial flora were analyzed. There was a 20 % reduction in the occurrence of harmful bacteria in the group who consumed the probiotic drink compared to the group who consumed yogurt.
     Dr Sahelian says: For those who do not wish to drink probiotic fermented milk, capsules of probiotics are available in health food stores. Look for a product that contains several billion bacteria per capsule, including lactobacilli and bifidobacteria. One to three capsules a day should be sufficient.

Probiotics supplements for children
Many infants and children may be lacking beneficial bacteria, and supplements could potentially help them get fewer infections. Compared with standard formulas, those containing beneficial "probiotic" organisms seem to reduce the number and duration of diarrhea episodes in infants attending childcare centers. Of two types of probiotic tested -- Lactobacillus reuteri and Bifidobacterium lactis -- Lactobacillus may be the better supplement, according to the report in the medical journal Pediatrics. Probiotic supplements affect the immune response by improving the intestinal microbial balance leading to enhanced antibody production. Another study indicates that children who take probiotic supplements suffer fewer respiratory infections.

Probiotics products
Some probiotics supplements sold over the counter may not contain enough live bacteria to be effective. "There's a chance that you may be buying dead bacteria unless you shop very carefully," says Dr. Tod Cooperman, president of ConsumerLab dot com. The analysis by ConsumerLab dot com included 13 brands. Consumer Lab found just 9 contained at least 1 billion viable organisms per dose, the amount considered necessary for effectiveness. Brands that fell short of the billion mark included DDS Acidophilus; Flora Source; Nature's Secret Ultimate Probiotic 4-Billion; and Rite Aid Acidophilus, Milk Free. Advocare Probiotic Restore did contain the 1 billion minimum, but claimed on its label to pack 30 billion per dose.

KeVita is a Ca;lifornia probiotic company that supplies these microorganisms in a liquid bottle, KeVita has six different bottles, some sweetened with stevia, that provide about 20 billion organisms. The liquid tastes good.

Questions
Are homeostatic soil organisms supplement preferable to probiotics for gastrointestinal disorders?
   Since I have not seen any independent published studies with homeostatic soil organisms, and none comparing homeostatic soil organisms to a probiotic supplement, it is not possible for me to say with any degree of certainty.

Can probiotics supplements be taken the same day as curcumin, turmeric, and serrapeptase?
   Probably but I have not seen any research regarding these combinations.

Is a daily dose of a probiotic supplement recommended for everyone or is it specifically for people who are taking anti-biotics or have intestinal issues?
   Each person is unique in their benefit from probiotic supplements. Some people may consume yogurt on a regular basis or have developed good intestinal flora throughout life. Others may have a shortage of good bacteria or have taken antibiotics in the past. Therefore, it is difficult to make a firm recommendation regarding wholesale advice on taking probiotics. As a general rule, it would seem prudent and reasonable for many people to take a probiotic supplement a few times a week or a few times a month.

My Mother got clostridium difficile toxin after a six week course of Ertapenum. She was taking Jarrow Dophilus probiotic during this course. Finished antibiotic, was without probiotic for 4 days and developed CDT. Does now want to take Flagyl. She is back on Jarrow Dophilus and then we added Saccharomyces boulardii. This seemed to be too much and she goes to the bathroom frequently. She does not have diarrhea but just goes often. Although it isn't watery it does not look normal. She has some stomach cramps. My question is - How long do we give the probiotic to get her back to normal before further steps need to be taken. I have read under the Mayo Clinic that it is possible to treat this with probiotics. When should she start to feel normal if this is actually working?
   It is impossible for me to know since I would have to review the whole medical history, lab results, and physical exam in order to have a better understanding of the situation.

There is so much conflicting information about probiotics that I thought I would ask you for clarification. Several years ago, I attended a lecture sponsored by Pharmax, with Dr. Nigel Plummer as the speaker. He said that probiotics would stay well in a freezer. Now I read that freezing could compromise the bacteria. What do you say? And second, at another seminar, Dr. Michael Wald shared that taking a probiotic at the same time as an antibiotic, the probiotic would enhance the efficiency of the drug. I have never been able to find any information to corroborate either of these two assertions. Whatever information you have about these two areas of confusion, would be greatly appreciated. Gina Liberti, MS, DTR, MS ED, Adjunct Professor, Functional Nutrition, SUNY Rockland Community College.
   As far as I know, freezing or more practically keeping the bottles in the non-freezer section of a refrigerator helps with the longevity of the bacteria. I have not seen much reliable research in regards to taking antibiotics with probiotics. There are dozens of different antibiotics and many types of beneficial bacteria, and it would seem that each combination has to be studied by itself in various dosages as a treatment of various conditions. Therefore, making a blanket statement that probiotics would enhance the efficacy or efficiency of the antibiotic seems simplistic. It is probably a lot more complicated than that.

I am a junior at Hartford Union High School in Wisconsin. I have been assigned a research project on a scientific topic of my choice and I chose probiotics. The topic has intrigued me and I hope you could help answer a couple questions of me and I would like to hear your opinion. What health benefits do they offer? If people start taking these supplements will it help reduce their chances of becoming infected my certain diseases? What illnesses can it help prevent? Are there any risks or side effects?
   There have not been any significant side effects or risks thus far associated with the use of these friendly bacteria supplements. They could help improve the immune system, reduce the incidence of diarrhea, provide benefits to those with inflammatory bowel disease, and possibly reduce the incidence of upper respiratory infections.

Is there any such thing as a probiotic suppository available for women to use to fight yeast infections. If so where can I get them and what are the ingredients?
   There are some products that are sold as being suppositories for women. However, we don't have any knowledge on how well they work. If you do a google search for " probiotic suppository " you will find them.

Do you know if any of the following supplements harm beneficial bacteria, I find so much conflicting data. I would be interested to know about the following and if they kill the good bacteria; Olive leaf Caprylic acid Oregano oil Peppermint oil. I have taken several of these for IBS, really helps but don't want to harm my good guys.
   A. I have not seen any studies yet that show taken these causes such harm.