Literature Review and Commentary

By Alan R. Gaby, MD

Probiotic During Pregnancy Prevents Allergic Disease in the Child

In a previous study, pregnant women in New Zealand who had or whose husband/partner had a history of allergic disease were randomly assigned to receive, in double-blind fashion, Lactobacillus rhamnosus HN001 (6 x 10⁹ colony-forming units per day) or placebo. Treatment was started at 35 weeks of gestation and was continued until delivery or, if breastfeeding, until the infants were age six months. The infants were randomly assigned to receive the same probiotic or placebo from birth until two years of age. Compared with placebo, L. rhamnosus HN001 reduced the cumulative incidence of eczema by 49% (p < 0.05).¹ The present study followed these children until 11 years of age. At age 11, compared with placebo, previous probiotic use was associated with a 54% reduction in the prevalence of eczema (p = 0.015) and a 27% reduction in the prevalence of hay fever (p < 0.05).

Comment: These results demonstrate that L. rhamnosus HN001 can reduce the prevalence of allergic disease in young children, and that the benefit persists at least until age 11. It cannot be assumed that other probiotic strains would have a similar effect. Indeed, in the original study, a different probiotic (Bifidobacterium animalis subsp lactis strain HN019) did not significantly decrease the cumulative incidence of eczema. In another study, L. rhamnosus GG administered during pregnancy and early infancy did not reduce the incidence of eczema in the children, and was associated with an increased rate of recurrent episodes of wheezing bronchitis.²

The mechanism of action of L. rhamnosus HN001 is not known, although it presumably works by altering the intestinal flora or certain aspects of immune function. This probiotic strain is commercially available in a number of products, either as a component of a multi-strain probiotic or as a component of a prenatal/perinatal multivitamin-multimineral.

Wickens K, et al. Effects of Lactobacillus rhamnosus HN001 in early life on the cumulative prevalence of allergic disease to 11 years. Pediatr Allergy Immunol. 2018;29:808-814.

Are Vitamin E Vaginal Suppositories Effective for Atrophic Vaginitis?

Fifty-two postmenopausal Iranian women (aged 40-65 years) with vaginal atrophy who had been referred to a gynecology clinic were randomly assigned to receive, in single-blind fashion, vitamin E vaginal suppositories (100 IU per suppository) or 0.625 mg of conjugated estrogens vaginal cream. The treatments were administered daily for 10 days, then twice a week for 10 weeks. Both groups demonstrated significant improvement in the Abbreviated Sexual Function Questionnaire, with no significant difference between groups.

Comment: Evan Shute, along with his brother, Wilfrid Shute, was a pioneer in the clinical use of vitamin E. In a 1973 lecture, Evan Shute stated that “senile vaginitis” (another term for atrophic vaginitis) responded well to topical application of vitamin E suppositories. As far as I am aware, that clinical observation was never followed up with randomized controlled trials, until now.

In an editorial in the July issue of the Townsend Letter, I provided evidence to suggest that a large proportion of the nutrition research coming from Iran may be fabricated. While intravaginal vitamin E may be useful for atrophic vaginitis, it is difficult to believe it is as effective as conjugated estrogens (which is what the present study reported). Confirmatory studies are therefore needed before vitamin E suppositories can be considered a proven treatment for atrophic vaginitis.

Golmakani N, et al. Vitamin E as alternative local treatment in genitourinary syndrome of menopause: a randomized controlled trial. Int Urogynecol J. 2019;30:831-837.

Vitamin D Prevents Migraines

Forty-eight patients (aged 18-65 years; mean, 44.6 years) in Denmark with migraines were randomly assigned to receive, in double-blind fashion, 4,000 IU per day of vitamin D₃ or placebo for 24 weeks. The mean serum 25-hydroxyvitamin D level at baseline was 33 ng/ml. The mean percent reduction in the number of migraine days during the last four weeks of the trial (compared with baseline) was significantly greater in the vitamin D group than in the placebo group (48% vs. 20%; p < 0.05). The proportion of patients who had a positive response (defined as a 50%-or-greater reduction in attack frequency) was significantly higher in the vitamin D group than in the placebo group (data not shown; p < 0.01). (According to a personal communication from Gazerani P, the response rate was 75% in the vitamin D group and 50% in the placebo group.) Compared with placebo, vitamin D had no effect on migraine severity.

Comment: In this randomized controlled trial, supplementation with 4,000 IU per day of vitamin D decreased the number of migraine days and the attack frequency in patients with recurrent migraines who were not vitamin D-deficient at baseline. The mechanism of action of vitamin D is not known. Other treatments that have been shown to prevent migraine recurrences include identifying and avoiding allergenic foods and supplementing with magnesium, riboflavin, or coenzyme Q10. Because the long-term safety of high-dose vitamin D (particularly in relation to the risk of kidney stones and atherosclerosis) has not been clearly demonstrated,³ its use for migraine prophylaxis should probably be reserved for people who do not respond adequately to these other interventions. Additional research should investigate whether lower doses of vitamin D are also effective for preventing migraines.

Gazerani P, et al. A randomized, double-blinded, placebo-controlled, parallel trial of vitamin D₃ supplementation in adult patients with migraine. Curr Med Res Opin. 2019;35:715-723.

Non-Celiac Gluten or Wheat Sensitivity: Intestinal Inflammation as an Underlying Mechanism

Markers of immune function were examined in 78 patients with non-celiac gluten or wheat sensitivity (NCGWS; documented by double-blind wheat challenge) and in a control group of patients with self-reported NCGWS but negative results from the wheat-challenge test. Duodenal and rectal biopsies were performed after the subjects had consumed a wheat-containing diet for at least four weeks. Duodenal tissue from patients with NCGWS, as compared with duodenal tissue from controls, had significantly higher numbers of intra-epithelial CD3+ T cells, lamina propria CD45+ cells, and eosinophils. In addition, rectal mucosa from patients with NCGWS had a larger number of enlarged lymphoid follicles, intra-epithelial CD3+ T cells, lamina propria CD45+ cells, and eosinophils than rectal mucosa from controls.

Comment: Many people who do not have celiac disease believe they are sensitive to wheat or to all gluten-containing foods. While the medical community was originally skeptical about whether NCGWS is real, in recent years it has become recognized by most authorities as a true clinical entity. In the present study, patients with NCGWS showed evidence of increased inflammation in duodenal and rectal mucosa. That finding suggests that inflammation of multiple areas of the intestinal tract plays a role in the pathogenesis of NCGWS.

Carroccio A, et al. Duodenal and rectal mucosa inflammation in patients with non-celiac wheat sensitivity. Clin Gastroenterol Hepatol. 2019;17:682-690.e3.

Do Dietary Advanced Glycation End Products Increase Fracture Risk?

Mice were fed a standard control diet or a diet high in advanced glycation end products (AGEs), which was produced by autoclaving the standard diet at 120° C for 15 minutes. The diets were identical in energy and nutrient content. After 18 months, among female mice, the high-AGE diet, as compared with the standard diet, resulted in inferior vertebral trabecular structure, decreased bone mineral density, and decreased resistance against fractures. The results in male mice were less clear.

Comment: AGEs are formed during cooking and processing, by the interaction of a reducing sugar (i.e., glucose, fructose, or lactose) and protein, or a reducing sugar and an amine-containing lipid. AGEs present in food are absorbed intact and persist in tissues, where they increase the inflammatory response. Because inflammation is thought to play a role in the pathogenesis of osteoporosis, consumption of a high-AGE diet might increase the risk of age-related bone loss and osteoporotic fractures. That possibility is supported by the results of the present study.

The AGE content of the diet can be decreased by cooking at lower temperatures and in the presence of water, as compared with cooking at higher temperatures and in the absence of water. Temperature and cooking method seem to be a more important factor for AGE formation than cooking time. Emphasizing boiling, poaching, and stewing over frying, broiling, and roasting may decrease daily AGE intake by up to 50%. Consuming more raw foods can further decrease AGE intake, because the AGE content of raw foods is very low.

Illien-Junger S, et al. Dietary advanced glycation end products have sex- and age-dependent effects on vertebral bone microstructure and mechanical function in mice. J Bone Miner Res. 2018;33:437-448.

Topical vitamin C for Senile Purpura

Eighteen patients (mean age, 88 years) with senile purpura were randomly assigned to apply, in double-blind fashion, a 5% vitamin C cream to affected areas on one limb and a placebo cream to affected areas on another limb twice a day for 12 weeks. The active treatment contained vitamin C in glycerol at pH 6.0, emulsified in a silicone base and prepared under one atmosphere of nitrogen. This product, which is available under the name Active C (La Roche Posay, France), is formulated in such a way as to minimize the oxidation of the vitamin C. Compared with placebo, active treatment was associated with a significant improvement in the overall clinical score. Improvements included a reduction of hemorrhage areas and an increase in dermal thickness and skin elasticity.

Comment: Senile purpura (also known as Bateman purpura) is a classical sign of skin aging. Manifestations include fragile skin due to atrophy of the dermis, purpuric lesions (petechiae or ecchymoses), and spontaneous stellar pseudocicatrices. These abnormalities occur primarily in sun-exposed areas. Vitamin C plays an important role in tissue integrity, including the integrity of skin tissue. Aging of the skin is associated with a decrease in the concentration of vitamin C in the dermis. Sun exposure is also known to decrease the concentration of vitamin C and other antioxidants in the skin. The results of the present study suggest that localized vitamin C deficiency plays a role in the pathogenesis of senile purpura, and that topical application of vitamin C may be beneficial for this condition.

Humbert P, et al. Bateman purpura (dermatoporosis): a localized scurvy treated by topical vitamin C – double-blind randomized placebo-controlled clinical trial. J Eur Acad Dermatol Venereol. 2018;32:323-328.

Probiotic for Patients with Celiac Disease Who Remain Symptomatic on a Gluten-Free Diet

One hundred nine patients (mean age, 44 years) with celiac disease who had irritable bowel syndrome (IBS)-type symptoms while on a gluten-free diet were randomly assigned to receive, in double-blind fashion, a multi-strain probiotic or placebo once a day for six weeks. The probiotic contained two lactobacillus strains and three bifidobacterium strains and was manufactured by Probioresearch, (Rome, Italy). The mean IBS Severity Scoring System score improved by 15.9% in the probiotic group and worsened by 8.2% in the placebo group (p < 0.001 for the difference in the change between groups). The mean Gastrointestinal Symptom Rating Scale score improved by 19.8% in the probiotic group and worsened by 12.9% in the placebo group (p < 0.001 for the difference in the change between groups). The proportion of patients who had at least a 50% improvement in the IBS Severity Scoring System score was significantly greater in the probiotic group than in the placebo group (15.3% vs. 3.8%; p < 0.04).

Comment: About 30% of patients with celiac disease experience (IBS)-type symptoms despite following a gluten-free diet. One possible cause of these symptoms is an imbalance of the intestinal flora. In the present study, treatment with a multi-strain probiotic improved symptoms to a modest degree in patients with celiac disease who had IBS-type symptoms while on a gluten-free diet.

Francavilla R, et al. Clinical and microbiological effect of a multispecies probiotic supplementation in celiac patients with persistent IBS-type symptoms: a randomized, double-blind, placebo-controlled, multicenter trial. J Clin Gastroenterol. 2019;53:e117-e125.

Mediterranean Diet Improves Pregnancy Outcomes

Six hundred ninety-seven pregnant Spanish women who did not have gestational diabetes were randomly assigned at 8-12 weeks of gestation to consume a low-fat control diet (no more than 30% of total calories as fat) or a Mediterranean diet enriched with extra-virgin olive oil (at least 40 ml per day) and pistachio nuts (25-30 g per day). The primary outcome measure was a composite of adverse maternal and fetal outcomes (emergency C-section, perineal trauma, pregnancy-induced hypertension and preeclampsia, prematurity, large-for-gestational-age, and small-for gestational-age). Compared with the low-fat diet, the Mediterranean diet resulted in a 52% reduction in the composite endpoint (p = 0.0001), with a number-needed-to-treat of five. Risk of urinary tract infection, emergency C-section, perineal trauma, large-for-gestational-age, and small-for gestational age were each significantly reduced by the Mediterranean diet.

Comment: The Mediterranean diet refers to the diet of olive-growing regions of the Mediterranean. In addition to olive oil, the diet emphasizes salads, legumes, wheat, fruit, nuts, and garlic. In Italy a lot of pasta is consumed, whereas in Spain fish consumption is high. Fat intake is around 30-40% of total energy. Consumption of a Mediterranean diet has been reported to improve cardiovascular disease risk factors, decrease the risk of major cardiovascular events, improve nonalcoholic fatty liver disease, and decrease inflammation. The results of the present study demonstrate that a Mediterranean diet enriched with extra-virgin olive oil and pistachios, as compared with a low-fat diet, resulted in a 52% reduction in adverse pregnancy outcomes in pregnant women who did not have gestational diabetes.

Assaf-Balut C, et al. A Mediterranean diet with an enhanced consumption of extra virgin olive oil and pistachios improves pregnancy outcomes in women without gestational diabetes mellitus: a sub-analysis of the St. Carlos Gestational Diabetes Mellitus Prevention Study. Ann Nutr Metab. 2019;74:69-79.

REFERENCES

1. Wickens K, et al. Effects of Lactobacillus rhamnosus HN001 in early life on the cumulative prevalence of allergic disease to 11 years. Pediatr Allergy Immunol. 2018;29:808-814.↩︎
2. . Kopp MV, et al. Randomized, double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical effects of Lactobacillus GG supplementation. Pediatrics. 2008;121:e850-e856.↩︎
3. . Gaby AR. Vitamin D. In Gaby AR. Nutritional Medicine, Second Edition. Concord, NH, 2017. https://doctorgaby.com, chapter 23.↩︎