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Exercise Training Reduces the Inflammatory Response and Promotes Intestinal Mucosa-Associated Immunity in Lynch Syndrome.
Deng, N, Reyes-Uribe, L, Fahrmann, JF, Thoman, WS, Munsell, MF, Dennison, JB, Murage, E, Wu, R, Hawk, ET, Thirumurthi, S, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023;29(21):4361-4372
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Lynch syndrome (LS) is a genetic disorder conferring a 60% lifetime risk of developing colorectal cancer (CRC). Exercise is associated with a reduction in CRC risk in the general population, potentially mediated via modulation of inflammation. The aim of this non-randomised, controlled trial was to test whether an intervention consisting of 3 x 45-minute cycling classes per week for 12 months affects inflammatory factors (prostaglandin E2, PGE2) in the colorectal mucosa and blood and whether this intervention is feasible in LS carriers. The control group received usual care with one session of exercise counselling. Of 60 patients invited to join the study, 21 (35%) agreed to take part. Of the 11 participants in the intervention group, 9 (81.2%) completed the study with an average adherence to the intervention of 51.3%, compared to 7/10 completing in the control group. VO2 peak (maximal aerobic capacity) increased significantly in the intervention group, compared to the control group over the 12 months. Patients in the intervention group also had a significant reduction in colonic and systemic PGE2 levels compared to controls following intervention. Changes in gene expression which may reflect an increased immune surveillance of the colon were also observed in the intervention group. The authors concluded that the study confirmed that exercise may modulate inflammation in the colonic mucosa in patients at high risk of CRC and that further randomised studies are necessary to confirm the potential benefits of exercise for patients with LS.
Abstract
PURPOSE Lynch syndrome (LS) is a hereditary condition with a high lifetime risk of colorectal and endometrial cancers. Exercise is a non-pharmacologic intervention to reduce cancer risk, though its impact on patients with LS has not been prospectively studied. Here, we evaluated the impact of a 12-month aerobic exercise cycling intervention in the biology of the immune system in LS carriers. PATIENTS AND METHODS To address this, we enrolled 21 patients with LS onto a non-randomized, sequential intervention assignation, clinical trial to assess the effect of a 12-month exercise program that included cycling classes 3 times weekly for 45 minutes versus usual care with a one-time exercise counseling session as control. We analyzed the effects of exercise on cardiorespiratory fitness, circulating, and colorectal-tissue biomarkers using metabolomics, gene expression by bulk mRNA sequencing, and spatial transcriptomics by NanoString GeoMx. RESULTS We observed a significant increase in oxygen consumption (VO2peak) as a primary outcome of the exercise and a decrease in inflammatory markers (prostaglandin E) in colon and blood as the secondary outcomes in the exercise versus usual care group. Gene expression profiling and spatial transcriptomics on available colon biopsies revealed an increase in the colonic mucosa levels of natural killer and CD8+ T cells in the exercise group that were further confirmed by IHC studies. CONCLUSIONS Together these data have important implications for cancer interception in LS, and document for the first-time biological effects of exercise in the immune system of a target organ in patients at-risk for cancer.
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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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Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT.
Suez, J, Zmora, N, Zilberman-Schapira, G, Mor, U, Dori-Bachash, M, Bashiardes, S, Zur, M, Regev-Lehavi, D, Ben-Zeev Brik, R, Federici, S, et al
Cell. 2018;174(6):1406-1423.e16
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Probiotics are commonly used to reduce the risk of antibiotic associated diarrhoea (AAD). This study, in both mice and humans, investigated the effects of an 11 strain probiotic supplement and autologous faecal microbiome transplantation (aFMT) after antibiotic treatment. (Autologous meaning the person’s own, pre-antibiotic stool was transplanted.) Gut mucosa samples along the digestive tract and stool samples were investigated for microbiome composition and activity (transcriptome). The investigators found that without antibiotics the probiotics did not colonise very well, suggesting that our native microbiome offers resistance. After antibiotics, which would kill off much of our gut bacteria,the probiotics colonise the gut mucosa much better. However, the probiotics appear to then prevent the microbiome to return to its native, pre-antibiotic state. Whilst in those with the aFMT and in those who did nothing (“watchful waiting”) the microbiome returned to pre-antibiotic state fairly quickly, in the probiotic group even after 5 months the microbiome had not returned to its native composition. In vitro experiments suggest that the delay in the probiotic group is due to substances secreted by the probiotic bacteria, in particular Lactobacilli. The authors conclude that the potential benefits in terms of reducing the risk of AAD with probiotics may be offset with a delay in reconstitution of the native microbiome, and call for more research into aFMT and a more personalised approach to probiotic therapy.
Abstract
Probiotics are widely prescribed for prevention of antibiotics-associated dysbiosis and related adverse effects. However, probiotic impact on post-antibiotic reconstitution of the gut mucosal host-microbiome niche remains elusive. We invasively examined the effects of multi-strain probiotics or autologous fecal microbiome transplantation (aFMT) on post-antibiotic reconstitution of the murine and human mucosal microbiome niche. Contrary to homeostasis, antibiotic perturbation enhanced probiotics colonization in the human mucosa but only mildly improved colonization in mice. Compared to spontaneous post-antibiotic recovery, probiotics induced a markedly delayed and persistently incomplete indigenous stool/mucosal microbiome reconstitution and host transcriptome recovery toward homeostatic configuration, while aFMT induced a rapid and near-complete recovery within days of administration. In vitro, Lactobacillus-secreted soluble factors contributed to probiotics-induced microbiome inhibition. Collectively, potential post-antibiotic probiotic benefits may be offset by a compromised gut mucosal recovery, highlighting a need of developing aFMT or personalized probiotic approaches achieving mucosal protection without compromising microbiome recolonization in the antibiotics-perturbed host.
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Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features.
Zmora, N, Zilberman-Schapira, G, Suez, J, Mor, U, Dori-Bachash, M, Bashiardes, S, Kotler, E, Zur, M, Regev-Lehavi, D, Brik, RB, et al
Cell. 2018;174(6):1388-1405.e21
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Evidence regarding the efficacy of probiotics in colonising the gut mucosa are sparse. The authors investigated whether probiotics colonise the gut mucosa in mice and humans, using both gut mucosa and stool samples. They found that, in both mice and humans, results from stool samples only partially correlate with colonisation of the gut mucosa as determined through gut mucosa samples. Whilst results were fairly uniform in mice, in humans a person-specific resistance to colonisation of the gut mucosa by probiotics was observed. Inter-person variation could be predicted by the composition of the pre-probiotic microbiome and host immune features.
Abstract
Empiric probiotics are commonly consumed by healthy individuals as means of life quality improvement and disease prevention. However, evidence of probiotic gut mucosal colonization efficacy remains sparse and controversial. We metagenomically characterized the murine and human mucosal-associated gastrointestinal microbiome and found it to only partially correlate with stool microbiome. A sequential invasive multi-omics measurement at baseline and during consumption of an 11-strain probiotic combination or placebo demonstrated that probiotics remain viable upon gastrointestinal passage. In colonized, but not germ-free mice, probiotics encountered a marked mucosal colonization resistance. In contrast, humans featured person-, region- and strain-specific mucosal colonization patterns, hallmarked by predictive baseline host and microbiome features, but indistinguishable by probiotics presence in stool. Consequently, probiotics induced a transient, individualized impact on mucosal community structure and gut transcriptome. Collectively, empiric probiotics supplementation may be limited in universally and persistently impacting the gut mucosa, meriting development of new personalized probiotic approaches.
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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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Cognitive impairment in coeliac disease improves on a gluten-free diet and correlates with histological and serological indices of disease severity.
Lichtwark, IT, Newnham, ED, Robinson, SR, Shepherd, SJ, Hosking, P, Gibson, PR, Yelland, GW
Alimentary pharmacology & therapeutics. 2014;40(2):160-70
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Coeliac disease (CD) is an inflammatory autoimmune disorder caused by the ingestion of gluten. While CD is known to primarily affect the bowel, there is reported evidence of potential neurological side effects. Cognition may be impaired in undiagnosed CD patients because of nutrient deficiencies, systemic inflammation and changes in the gut microbiome. CD patients often report a mild cognitive impairment, brain fog, characterised by difficulty concentrating, short-term memory and confusion. The aim of this study was to investigate the relationship between gut mucosal healing and cognitive function in eleven patients recently diagnosed with CD commencing a strict gluten-free diet. The findings of this study showed that in newly diagnosed CD patients, cognitive functioning improved with a gluten-free diet and was correlated with mucosal healing. Based on this study, the authors conclude that cognition is impaired in people with untreated coeliac disease and may affect the performance of everyday tasks. This finding also introduces the possibility of using cognitive tests to provide a marker of intestinal healing.
Abstract
BACKGROUND Mild impairments of cognition or 'Brain fog' are often reported by patients with coeliac disease but the nature of these impairments has not been systematically investigated. AIM: This longitudinal pilot study investigated relationships between cognitive function and mucosal healing in people with newly diagnosed coeliac disease commencing a gluten-free diet. METHODS Eleven patients (8 females, 3 males), mean age 30 (range 22-39) years, were tested with a battery of cognitive tests at weeks 0, 12 and 52. Information processing efficacy, memory, visuospatial ability, motoric function and attention were tested. Small bowel biopsies were collected via routine gastroscopy at weeks 12 and 52 and were compared to baseline Marsh scores. Cognitive performance was compared to serum concentrations of tissue transglutaminase antibodies, biopsy outcomes and other biological markers. RESULTS All patients had excellent adherence to the diet. Marsh scores improved significantly (P = 0.001, Friedman's test) and tissue transglutaminase antibody concentrations decreased from a mean of 58.4 at baseline to 16.8 U/mL at week 52 (P = 0.025). Four of the cognitive tests assessing verbal fluency, attention and motoric function showed significant improvement over the 12 months and strongly correlated with the Marsh scores and tissue transglutaminase antibody levels (r = 0.377-0.735; all P < 0.05). However, no meaningful patterns of correlations were found for nutritional or biochemical markers, or markers of intestinal permeability. CONCLUSIONS In newly diagnosed coeliac disease, cognitive performance improves with adherence to the gluten-free diet in parallel to mucosal healing. Suboptimal levels of cognition in untreated coeliac disease may affect the performance of everyday tasks.