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1.
Transforming Psoriasis Care: Probiotics and Prebiotics as Novel Therapeutic Approaches.
Buhaș, MC, Candrea, R, Gavrilaș, LI, Miere, D, Tătaru, A, Boca, A, Cătinean, A
International journal of molecular sciences. 2023;24(13)
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Psoriasis is a chronic inflammatory disease of the skin, characterised by dysfunctional proliferation and differentiation of keratinocytes (a type of skin cell). Previous research has shown that psoriasis is associated with gut dysbiosis and increased levels of inflammatory cytokines. The aim of this non-randomised, open-label clinical trial of 63 psoriasis patients was to evaluate the effectiveness of supplementation with a spore-based probiotic (containing 5 strains of Bacillus, taken for 12 weeks) in combination with 3 prebiotics (fructo-oligosaccharides, xylo-oligosaccharides and galacto-oligosaccharides, taken for 8 weeks) alongside standard topical treatment versus topical treatment alone. Outcome measure included Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), inflammatory cytokines, insulin, glucose, lipids, uric acid, body composition, BMI and skin analysis. 15 of the 42 patients in the supplementation group also had a microbiome analysis. Significant improvements were seen in the supplementation group for PASI, DLQI, inflammatory markers, blood lipids, BMI as well as skin analysis, compared to the control group. Favourable changes in microbiome analysis were also observed. It is noteworthy that there were several significant differences between groups at baseline, including severity of psoriasis which was worse in the supplemented group. The authors concluded that patients receiving a combination of a spore-based probiotics and prebiotics alongside standard topical treatment experienced multiple improvements but that further clinical trials are required to establish the most effective combinations and doses.
Abstract
Psoriasis is a chronic inflammatory skin disease with autoimmune pathological characteristics. Recent research has found a link between psoriasis, inflammation, and gut microbiota dysbiosis, and that probiotics and prebiotics provide benefits to patients. This 12-week open-label, single-center clinical trial evaluated the efficacy of probiotics (Bacillus indicus (HU36), Bacillus subtilis (HU58), Bacillus coagulans (SC208), Bacillus licheniformis (SL307), and Bacillus clausii (SC109)) and precision prebiotics (fructooligosaccharides, xylooligosaccharides, and galactooligosaccharides) in patients with psoriasis receiving topical therapy, with an emphasis on potential metabolic, immunological, and gut microbiota changes. In total, 63 patients were evaluated, with the first 42 enrolled patients assigned to the intervention group and the next 21 assigned to the control group (2:1 ratio; non-randomized). There were between-group differences in several patient characteristics at baseline, including age, psoriasis severity (the incidence of severe psoriasis was greater in the intervention group than in the control group), the presence of nail psoriasis, and psoriatic arthritis, though it is not clear whether or how these differences may have affected the study findings. Patients with psoriasis receiving anti-psoriatic local therapy and probiotic and prebiotic supplementation performed better in measures of disease activity, including Psoriasis Area and Severity Index, Dermatology Life Quality Index, inflammatory markers, and skin thickness compared with those not receiving supplementation. Furthermore, in the 15/42 patients in the intervention group who received gut microbiota analysis, the gut microbiota changed favorably following 12 weeks of probiotic and prebiotic supplementation, with a shift towards an anti-inflammatory profile.
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A Pilot Study To Investigate the Immune-Modulatory Effects of Fasting in Steroid-Naive Mild Asthmatics.
Han, K, Nguyen, A, Traba, J, Yao, X, Kaler, M, Huffstutler, RD, Levine, SJ, Sack, MN
Journal of immunology (Baltimore, Md. : 1950). 2018;201(5):1382-1388
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Previous studies have shown that caloric restriction and fasting may modulate immune function and have positive effects in asthmatics. The aim of this pilot study was to evaluate the effects of fasting on specific inflammatory markers that might mediate such benefits. 18 mild asthmatics, 5 of whom were not on steroid inhalers, fasted for 24 hours. Lung function and immune parameters were evaluated at baseline and 2.5 hours after the first meal following the fast. There were significant differences between subjects who were and were not on steroid inhalers. Whilst one day of fasting did not affect lung function, a number of inflammatory parameters were improved by fasting in those not taking steroid inhalers, but not in those who were taking steroids. The authors conclude that caloric restriction might be considered as a strategy to improve systemic and pulmonary inflammation in asthma.
Abstract
A fasting mimetic diet blunts inflammation, and intermittent fasting has shown ameliorative effects in obese asthmatics. To examine whether canonical inflammatory pathways linked with asthma are modulated by fasting, we designed a pilot study in mild asthmatic subjects to assess the effect of fasting on the NLRP3 inflammasome, Th2 cell activation, and airway epithelial cell cytokine production. Subjects with documented reversible airway obstruction and stable mild asthma were recruited into this study in which pulmonary function testing (PFT) and PBMCextraction was performed 24 h after fasting, with repeated PFT testing and blood draw 2.5 h after refeeding. PFTs were not changed by a prolonged fast. However, steroid-naive mild asthmatics showed fasting-dependent blunting of the NLRP3 inflammasome. Furthermore, PBMCs from these fasted asthmatics cocultured with human epithelial cells resulted in blunting of house dust mite-induced epithelial cell cytokine production and reduced CD4+ T cell Th2 activation compared with refed samples. This pilot study shows that prolonged fasting blunts the NLRP3 inflammasome and Th2 cell activation in steroid-naive asthmatics as well as diminishes airway epithelial cell cytokine production. This identifies a potential role for nutrient level-dependent regulation of inflammation in asthma. Our findings support the evaluation of this concept in a larger study as well as the potential development of caloric restriction interventions for the treatment of asthma.
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Spexin peptide is expressed in human endocrine and epithelial tissues and reduced after glucose load in type 2 diabetes.
Gu, L, Ma, Y, Gu, M, Zhang, Y, Yan, S, Li, N, Wang, Y, Ding, X, Yin, J, Fan, N, et al
Peptides. 2015;71:232-9
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Little is known about the functions of the peptide spexin. Recent studies have shown a relationship between spexin and body weight regulation. It is thought that spexin might be related to glucose control and fat metabolism in type 2 diabetes mellitus (T2DM). The aim of this study was to examine the location of spexin in human tissue and measure spexin levels after a glucose load in T2DM patients. First, the researchers examined human tissue samples. Blood samples were then collected from 121 adults with T2DM and 105 healthy individuals. Additionally, an oral glucose tolerance test (OGTT) was performed on 12 healthy volunteers. In human tissue samples, the levels of spexin were highest in the adrenal gland, skin, stomach, small intestine, liver, thyroid, pancreatic islets, visceral fat, lung, colon, and kidney, and lowest in muscle and connective tissue. Blood levels of spexin were significantly lower in T2DM patients compared to healthy controls. Spexin levels were found to be inversely related to fasting blood glucose and lipids. During the OGTT, spexin levels were also inversely correlated with blood glucose levels. The authors concluded that spexin is highly expressed among endocrine and epithelial tissues. Changes in the blood levels of spexin could represent an adaptation to the rise of glucose and lipids associated with T2DM. However, the exact role of spexin in endocrine diseases is still to be discovered.
Abstract
Spexin mRNA and protein are widely expressed in rat tissues and associate with weight loss in rodents of diet-induced obesity. Its location in endocrine and epithelial cells has also been suggested. Spexin is a novel peptide that involves weight loss in rodents of diet-induced obesity. Therefore, we aimed to examine its expression in human tissues and test whether spexin could have a role in glucose and lipid metabolism in type 2 diabetes mellitus (T2DM). The expression of the spexin gene and immunoreactivity in the adrenal gland, skin, stomach, small intestine, liver, thyroid, pancreatic islets, visceral fat, lung, colon, and kidney was higher than that in the muscle and connective tissue. Immunoreactive serum spexin levels were reduced in T2DM patients and correlated with fasting blood glucose (FBG, r=-0.686, P<0.001), hemoglobin A1c (HbA1c, r=-0.632, P<0.001), triglyceride (TG, r=-0.236, P<0.001) and low density lipoprotein-cholesterol (LDL-C, r=-0.382, P<0.001). A negative correlation of blood glucose with spexin was observed during oral glucose tolerance test (OGTT). Spexin is intensely expressed in normal human endocrine and epithelial tissues, indicating that spexin may be involved in physiological functions of endocrine and in several other tissues. Circulating spexin levels are low in T2DM patients and negatively related to blood glucose and lipids suggesting that the peptide may play a role in glucose and lipid metabolism in T2DM.
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Vitamin D supplementation for the prevention of type 2 diabetes in overweight adults: study protocol for a randomized controlled trial.
de Courten, B, Mousa, A, Naderpoor, N, Teede, H, de Courten, MP, Scragg, R
Trials. 2015;16:335
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With the rising rates of vitamin D deficiency, identifying cost-effective, preventative strategies are imperative. Vitamin D plays a well-known role in bone mineralisation, however its protective role against chronic diseases is not very well understood. The aim of this trial is to investigate whether vitamin D supplementation will increase insulin sensitivity and secretion, as well as to determine whether vitamin D deficiency underlies the inflammatory properties associated with obesity. 50 overweight adults between 18 and 60 years old were recruited and assigned to receive either 4,000 IU vitamin D daily or identical placebo capsules for 16 weeks. This study elucidates the potential role vitamin D supplementation could have on preventing diabetes and its associated co-morbidities. It also provides comprehensive insight into the potential mechanisms of action. The authors conclude that this trial can corroborate existing knowledge while expanding the understanding on the role of vitamin D in the inflammatory response and subsequent development of disease.
Abstract
BACKGROUND Despite Australia's sunny climate, low vitamin D levels are increasingly prevalent. Sun exposure is limited by long working hours, an increase in time spent indoors, and sun protection practices, and there is limited dietary vitamin D fortification. While the importance of vitamin D for bone mineralization is well known, its role as a protective agent against chronic diseases, such as type 2 diabetes and cardiovascular disease, is less understood. Observational and limited intervention studies suggest that vitamin D might improve insulin sensitivity and secretion, mainly via its anti-inflammatory properties, thereby decreasing the risk of development and progression of type 2 diabetes. The primary aim of this trial is to investigate whether improved plasma concentrations of 25-hydroxyvitamin D (25(OH)D), obtained through vitamin D supplementation, will increase insulin sensitivity and insulin secretion. A secondary aim is to determine whether these relationships are mediated by a reduction in underlying subclinical inflammation associated with obesity. METHODS/DESIGN Fifty overweight but otherwise healthy nondiabetic adults between 18 and 60 years old, with low vitamin D levels (25(OH)D < 50 nmol/l), will be randomly assigned to intervention or placebo. At baseline, participants will undergo a medical review and anthropometric measurements, including dual X-ray absorptiometry, an intravenous glucose tolerance test, muscle and fat biopsies, a hyperinsulinemic euglycemic clamp, and questionnaires assessing diet, physical activity, sun exposure, back and knee pain, and depression. The intervention group will receive a first dose of 100,000 IU followed by 4,000 IU vitamin D (cholecalciferol) daily, while the placebo group will receive apparently identical capsules, both for a period of 16 weeks. All measurements will be repeated at follow-up, with the primary outcome measure expressed as a change from baseline in insulin sensitivity and secretion for the intervention group compared with the placebo group. Secondary outcome measures will compare changes in anthropometry, cardiovascular risk factors, and inflammatory markers. DISCUSSION The trial will provide much needed clinical evidence on the impact of vitamin D supplementation on insulin resistance and secretion and its underlying mechanisms, which are relevant for the prevention and management of type 2 diabetes. TRIAL REGISTRATION Clinicaltrials.gov ID: NCT02112721 .
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Free radical damage to cerebral cortex in Alzheimer's disease, microvascular brain injury, and smoking.
Sonnen, JA, Larson, EB, Gray, SL, Wilson, A, Kohama, SG, Crane, PK, Breitner, JC, Montine, TJ
Annals of neurology. 2009;65(2):226-9
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Previous evidence supports a pathogenic role for increased free radical damage to brain regions in Alzheimer’s disease (AD). Adult Changes in Thought (ACT), a longitudinal study assessing brain aging and incident dementia among 3392 adults, has found that consumption of vitamin E, vitamin C or both was not associated with reduced risk of developing dementia over 5.5 years of follow up. The aim of this study was to determine whether this lack of therapeutic effect is associated with a measureable pharmacologic effect. This autopsy study examined 71 brains from ACT and found that increased free radical damage was associated with AD, microvascular brain injury and smoking, but not with antioxidant supplement usage. Based on the lack of therapeutic effect from the ACT and no apparent pharmacologic effect from this autopsy study, the authors conclude that future clinical trials for AD should consider dietary sources rather than supplements and investigate other antioxidants and various combinations.
Abstract
Evidence supports a pathogenic role for free radical injury to brain in Alzheimer's disease; however, clinical trial results are only mildly encouraging. Examining brains from The Adult Changes in Thought study offers a unique perspective. Selectively increased free radical damage to cerebral cortex was associated with Alzheimer's disease, microvascular brain injury, and current smoking, but not with antioxidant supplement usage. Our results support suppression of free radical injury to brain as a therapeutic target for Alzheimer's disease and microvascular brain injury; however, future clinical trials should consider other antioxidants or doses than those identified in our study.
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Dietary flaxseed alters tumor biological markers in postmenopausal breast cancer.
Thompson, LU, Chen, JM, Li, T, Strasser-Weippl, K, Goss, PE
Clinical cancer research : an official journal of the American Association for Cancer Research. 2005;11(10):3828-35
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High levels of the hormone oestrogen are linked with an increased risk of developing breast cancer. Plant lignans have similar chemical structures to oestrogen and may block the action of oestrogen in breast cancer cells. Flaxseed (also known as linseed) is a rich source of lignan precursors and has been shown to reduce tumour growth in rats. Therefore, it is thought that flaxseed might be effective in cancer treatment and prevention. This randomised, double-blind, placebo-controlled trial examined the effects of dietary flaxseed on tumour growth in postmenopausal women with newly diagnosed breast cancer. Patients were given either a muffin containing 25g of flaxseed or a control muffin, every day from the time of the initial biopsy until undergoing surgery to remove the tumours. They continued to eat their normal diet. The group that ate the flaxseed muffins experienced significant reductions of between 34 and 71% in various markers of tumour growth, and a significant increase in apoptosis of 30%. The control group did not experience any significant changes in these markers. The authors concluded that eating flaxseed has the potential to reduce tumour growth in patients with breast cancer.
Abstract
PURPOSE Flaxseed, the richest source of mammalian lignan precursors, has previously been shown to reduce the growth of tumors in rats. This study examined, in a randomized double-blind placebo-controlled clinical trial, the effects of dietary flaxseed on tumor biological markers and urinary lignan excretion in postmenopausal patients with newly diagnosed breast cancer. EXPERIMENTAL DESIGN Patients were randomized to daily intake of either a 25 g flaxseed-containing muffin (n = 19) or a control (placebo) muffin (n = 13). At the time of diagnosis and again at definitive surgery, tumor tissue was analyzed for the rate of tumor cell proliferation (Ki-67 labeling index, primary end point), apoptosis, c-erbB2 expression, and estrogen and progesterone receptor levels. Twenty-four-hour urine samples were analyzed for lignans, and 3-day diet records were evaluated for macronutrient and caloric intake. Mean treatment times were 39 and 32 days in the placebo and flaxseed groups, respectively. RESULTS Reductions in Ki-67 labeling index (34.2%; P = 0.001) and in c-erbB2 expression (71.0%; P = 0.003) and an increase in apoptosis (30.7%; P = 0.007) were observed in the flaxseed, but not in the placebo group. No significant differences in caloric and macronutrient intake were seen between groups and between pre- and posttreatment periods. A significant increase in mean urinary lignan excretion was observed in the flaxseed group (1,300%; P < 0.01) compared with placebo controls. The total intake of flaxseed was correlated with changes in c-erbB2 score (r = -0.373; P = 0.036) and apoptotic index (r = 0.495; P < 0.004). CONCLUSION Dietary flaxseed has the potential to reduce tumor growth in patients with breast cancer.
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The association of calcium and vitamin D with risk of colorectal adenomas.
Hartman, TJ, Albert, PS, Snyder, K, Slattery, ML, Caan, B, Paskett, E, Iber, F, Kikendall, JW, Marshall, J, Shike, M, et al
The Journal of nutrition. 2005;135(2):252-9
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Calcium and vitamin D may play a role in colorectal cancer incidence. One possible explanation is that they may act synergistically on a number of mechanisms to protect against recurrence of colonic adenomas. The aim of the study was to determine the effects of a high-fibre, high-fruit and vegetable, and low-fat diet on the recurrence of adenomatous polyps in the large bowel. For the present study, 1905 participants from the 2079 Polyp Prevention Trial participants who completed the full trial follow-up were evaluated. The participants’ diet was assessed at baseline and annually, and they also received full colonoscopies at baseline, their 1-year visit and at the end of the trial i.e. 4 years after randomization. Results show that there were no significant associations between any of the adenoma recurrence outcome variables and dietary or total calcium intake, consumption of low or high-fat dairy products or dietary vitamin D intake. However, total vitamin D intake was weakly inversely associated with adenoma recurrence. Calcium and vitamin D supplementation were also inversely associated with single and multiple adenoma recurrence. The study shows that calcium and vitamin D intake may provide weakly protective associations with the risk for recurrence of adenoma polyps.
Abstract
The Polyp Prevention Trial (PPT) was a multicenter randomized clinical trial designed to determine the effects of a high-fiber, high-fruit and vegetable, low-fat diet on the recurrence of adenomatous polyps in the large bowel. Detailed dietary intake and supplement use data were collected at baseline and at each of 4 annual study visits. Adenoma recurrence was ascertained by complete colonoscopy at baseline and after 1 and 4 y. Recurrence was found in 754 of the 1905 trial participants. We evaluated the association between calcium and vitamin D intake and adenomatous polyp recurrence after adjusting for intervention group, age, gender, nonsteroidal anti-inflammatory drug use, total energy intake, and the interaction of gender and intervention group. Vitamin D models were also adjusted for the location of the clinic site. Dietary variables were adjusted for total energy intake via the residual method. There were no overall significant associations between adenoma recurrence and dietary calcium intake [odds ratio (OR) for the 5th compared with the lowest quintile = 0.91; 95% CI = 0.67-1.23; P-trend = 0.68], total calcium intake (OR = 0.86; 95% CI = 0.62-1.18; P-trend = 0.20), or dietary vitamin D intake (OR = 0.93; 95% CI = 0.69-1.25; P-trend = 0.43) averaged over follow-up. Total vitamin D intake was weakly inversely associated with adenoma recurrence (OR = 0.84; 95% CI = 0.62-1.13; P-trend = 0.03). Supplemental calcium and vitamin D use during follow-up also were inversely associated with adenoma recurrence (OR for any compared with no use = 0.82; 95% CI = 0.68-0.99; and OR = 0.82; 95% CI = 0.68-0.99; for calcium and vitamin D, respectively). Slightly stronger associations were noted for the prevention of multiple recurrences. Our analyses did not suggest a significant effect modification between total calcium and total vitamin D intake (P = 0.14) on risk for adenoma recurrence. This trial cohort provides some evidence that calcium and vitamin D may be inversely associated with adenoma recurrence.
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Metabolism of phytanic acid and 3-methyl-adipic acid excretion in patients with adult Refsum disease.
Wierzbicki, AS, Mayne, PD, Lloyd, MD, Burston, D, Mei, G, Sidey, MC, Feher, MD, Gibberd, FB
Journal of lipid research. 2003;44(8):1481-8
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Phytanic acid (PA) is a branched-chain fatty acid, found in many animal products, that, unlike most fatty acids, cannot be metabolised by beta-oxidation. Instead, it undergoes alpha-oxidation in the peroxisome. Adult Refsum Disease is a genetic neurological disease, in which alpha-oxidation is impaired, resulting in the accumulation of PA in nerves and fat tissues. Other pathways for the metabolism of PA are not fully understood, such as omega-oxidation, which results in the production of 3-methyl-organic acids (3-MAA). This study assessed the contribution of the omega-oxidation pathway to the metabolism of PA by measuring 3-MAA excretion in patients with ARD. Eleven patients with ARD were put on a low-PA diet for 12 weeks. Blood, urine and tissue samples were taken at the start and end of the 12-week period to assess levels of PA and its metabolites. The low-PA diet led to an average 21% fall in blood PA levels over 12 weeks. The capacity of the omega-oxidation pathway was 6.9mg PA/day. The authors concluded that the omega-oxidation pathway can metabolise PA ingested by patients with ARD. Therefore, omega-oxidation is a potential target for therapeutic intervention to reduce PA levels in ARD patients.
Abstract
Adult Refsum disease (ARD) is associated with defective alpha-oxidation of phytanic acid (PA). omega-Oxidation of PA to 3-methyl-adipic acid (3-MAA) occurs although its clinical significance is unclear. In a 40 day study of a new ARD patient, where the plasma half-life of PA was 22.4 days, omega-oxidation accounted for 30% initially and later all PA excretion. Plasma and adipose tissue PA and 3-MAA excretion were measured in a cross-sectional study of 11 patients. The capacity of the omega-oxidation pathway was 6.9 (2.8-19.4) mg [20.4 (8.3-57.4) micromol] PA/day. 3-MAA excretion correlated with plasma PA levels (r = 0.61; P = 0.03) but not adipose tissue PA content. omega-Oxidation during a 56 h fast was studied in five patients. 3-MAA excretion increased by 208 +/- 58% in parallel with the 158 (125-603)% rise in plasma PA. Plasma PA doubled every 29 h, while 3-MAA excretion followed second-order kinetics. Acute sequelae of ARD were noted in three patients (60%) after fasting. The omega-oxidation pathway can metabolise PA ingested by patients with ARD, but this activity is dependent on plasma PA concentration. omega-Oxidation forms a functional reserve capacity that enables patients with ARD undergoing acute stress to cope with limited increases in plasma PA levels.