Limosilactobacillus reuteri DSM 17938 supplementation and SARS-CoV-2 specific antibody response in healthy adults: a randomized, triple-blinded, placebo-controlled trial.

Studies have shown that probiotics can decrease the symptoms of respiratory tract infections as well as increase antibody responses following certain vaccinations. We examined the effect of probiotic supplementation on anti-SARS-CoV-2 specific antibody responses upon SARS-CoV-2 infection as well as after COVID-19 vaccination. In this randomized, triple-blinded, placebo-controlled intervention study with a parallel design, 159 healthy adults without prior SARS-CoV-2 infection or COVID-19 vaccination and any known risk factors for severe COVID-19 were randomly allocated into two study arms. The active treatment arm consumed a probiotic product containing a minimum of 1 × 108 colony-forming units of Limosilactobacillus reuteri DSM 17938 + 10 µg vitamin D3 twice daily for 6 months. The placebo arm consumed identical tablets containing only 10 µg vitamin D3. Anti-SARS-CoV-2 specific antibodies and virus neutralizing antibody titers were analyzed from blood samples collected at baseline, after 3 months, and after 6 months. Differences in serum antibody titers between the two study arms were tested with independent t-test using log-transformed values. In the intention-to-treat (ITT) analysis, SARS-CoV-2 infected individuals in the active treatment arm (n = 6) tended to have higher serum anti-spike IgG (609 [168-1480] BAU/ml vs 111 [36.1-1210] BAU/ml, p = 0.080) and anti-receptor binding domain (RBD) IgG (928 [212-3449] BAU/ml vs (83.7 [22.8-2094] BAU/ml, p = 0.066) levels than individuals in the placebo arm (n = 6). Considering individuals who were fully vaccinated with mRNA-based COVID-19 vaccines, the active treatment arm (n = 10) exhibited significantly higher serum levels of anti-RBD IgA (135 [32.9-976] BAU/ml vs 61.3 [26.7-97.1] BAU/ml, p = 0.036) than the placebo arm (n = 7) >28 days postvaccination. Supplementation with specific probiotics might improve the long-term efficacy of mRNA-based COVID-19 vaccines via enhanced IgA response.

Lactose digestion in humans: intestinal lactase appears to be constitutive whereas the colonic microbiome is adaptable.

Globally, ∼70% of adults are deficient in intestinal lactase, the enzyme required for the digestion of lactose. In these individuals, the consumption of lactose-containing milk and dairy products can lead to the development of various gastrointestinal (GI) symptoms. The primary solution to lactose intolerance is withdrawing lactose from the diet either by eliminating dairy products altogether or substituting lactose-free alternatives. However, studies have shown that certain individuals erroneously attribute their GI symptoms to lactose and thus prefer to consume lactose-free products. This has raised the question whether consuming lactose-free products reduces an individual's ability to absorb dietary lactose and if lactose-absorbers should thus avoid these products. This review summarizes the current knowledge regarding the acclimatization of lactose processing in humans. Human studies that have attempted to induce intestinal lactase expression with different lactose feeding protocols have consistently shown lack of enzyme induction. Similarly, withdrawing lactose from the diet does not reduce intestinal lactase expression. Evidence from cross-sectional studies shows that milk or dairy consumption is a poor indicator of lactase status, corroborating the results of intervention studies. However, in lactase-deficient individuals, lactose feeding supports the growth of lactose-digesting bacteria in the colon, which enhances colonic lactose processing and possibly results in the reduction of intolerance symptoms. This process is referred to as colonic adaptation. In conclusion, endogenous lactase expression does not depend on the presence of dietary lactose, but in susceptible individuals, dietary lactose might improve intolerance symptoms via colonic adaptation. For these individuals, lactose withdrawal results in the loss of colonic adaptation, which might lower the threshold for intolerance symptoms if lactose is reintroduced into the diet.

Two-Week Aflibercept or Erlotinib Administration Does Not Induce Changes in Intestinal Morphology in Male Sprague-Dawley Rats But Aflibercept Affects Serum and Urine Metabolic Profiles.

Gastrointestinal toxicity is a frequently observed adverse event during cancer treatment with traditional chemotherapeutics. Currently, traditional chemotherapeutics are often combined with targeted biologic agents. These biologics, however, possess a distinct toxicity profile, and they may also exacerbate the adverse effects of traditional chemotherapeutics. In this study, we aimed to characterize the gastrointestinal and metabolic changes after a 2-week treatment period with aflibercept, an antiangiogenic VEGFR decoy, and with erlotinib, a tyrosine-kinase inhibitor. Male rats were treated either with aflibercept or erlotinib for 2 weeks. During the 2-week treatment period, the animals in the aflibercept group received two subcutaneous doses of 25 mg/kg aflibercept. The erlotinib group got 10 mg/kg of erlotinib by oral gavage every other day. The control groups were treated similarly but received either saline injections or oral gavage of water. Intestinal toxicity was assessed by measuring intestinal permeability and by histological analyses of intestinal tissues. Metabolic changes were measured with 1H nuclear magnetic resonance in serum and urine. Neither aflibercept nor erlotinib induced changes in intestinal permeability or intestinal tissue morphology. However, aflibercept treatment resulted in stunted body weight gain and altered choline, amino acid, and lipid metabolism. Two-week treatment with aflibercept or erlotinib alone does not induce observable changes in gastrointestinal morphology and function. However, observed aflibercept-treatment related metabolic changes suggest alterations in intestinal microbiota, nutrient intake, and adipose tissue function. The metabolic changes are also interesting in respect to the systemic effects of aflibercept and their possible associations with adverse events caused by aflibercept administration.

The use of unlicensed bone marrow-derived platelet lysate-expanded mesenchymal stromal cells in colitis: a pre-clinical study.

BACKGROUND: Mesenchymal stromal cells (MSCs) are a promising candidate for treatment of inflammatory disorders, but their efficacy in human inflammatory bowel diseases (IBDs) has been inconsistent. Comparing the results from various pre-clinical and clinical IBD studies is also challenging due to a large variation in study designs. METHODS: In this comparative pre-clinical study, we compared two administration routes and investigated the safety and feasibility of both fresh and cryopreserved platelet-lysate-expanded human bone marrow-derived MSCs without additional licensing in a dextran sodium sulfate (DSS) colitis mouse model both in the acute and regenerative phases of colitis. Body weight, macroscopic score for inflammation and colonic interleukin (IL)-1ß and tumor necrosis factor (TNF)α concentrations were determined in both phases of colitis. Additionally, histopathology was assessed and Il-1ß and Agtr1a messenger RNA (mRNA) levels and angiotensin-converting enzyme (ACE) protein levels were measured in the colon in the regenerative phase of colitis. RESULTS: Intravenously administered MSCs exhibited modest anti-inflammatory capacity in the acute phase of colitis by reducing IL-1ß protein levels in the inflamed colon. There were no clear improvements in mice treated with fresh or cryopreserved unlicensed MSCs according to weight monitoring results, histopathology and macroscopic score results. Pro-inflammatory ACE protein expression and shedding were reduced by cryopreserved MSCs in the colon. CONCLUSIONS: In conclusion, we observed a good safety profile for bone marrow-derived platelet lysate-expanded MSCs in a mouse pre-clinical colitis model, but the therapeutic effect of MSCs prepared without additional licensing (i.e. such as MSCs are administered in graft-versus-host disease) was modest in the chosen in vivo model system and limited to biochemical improvements in cytokines without a clear benefit in histopathology or body weight development.

Exercise and gastrointestinal symptoms: running-induced changes in intestinal permeability and markers of gastrointestinal function in asymptomatic and symptomatic runners.

PURPOSE: Athletes frequently experience gastrointestinal (GI) symptoms during training and competition. Although the prevalence of exercise-induced GI symptoms is high, the mechanisms leading to GI distress during exercise are not fully understood. The aim of this study was to identify running-induced changes in intestinal permeability and markers of GI function and investigate their association with gastrointestinal symptoms. METHODS: We recruited 17 active runners who we allocated as either asymptomatic or symptomatic based on their history of experiencing GI symptoms during running. The participants took part in a running test where they were asked to run for 90 min at 80% of their best 10 km race speed. Intestinal permeability was measured at baseline and after the running test. Levels of serum intestinal fatty acid-binding protein (I-FABP), zonulin, bacterial lipopolysaccharide (LPS), and fecal calprotectin were also measured at baseline and after the running test. RESULTS: Running induced a significant increase in intestinal permeability and serum I-FABP concentration but there were no differences between asymptomatic and symptomatic runners. Serum LPS activity did not change from baseline following the running test but the symptomatic group exhibited higher LPS activity at baseline compared to the asymptomatic runners. CONCLUSIONS: Running for 90 min at a challenging pace causes small intestinal damage and increases intestinal permeability. However, these alterations in GI function do not appear to correlate with the development of GI symptoms during running.

Chemotherapy-induced gastrointestinal toxicity is associated with changes in serum and urine metabolome and fecal microbiota in male Sprague-Dawley rats.

PURPOSE: Chemotherapy-induced gastrointestinal toxicity (CIGT) is a complex process that involves multiple pathophysiological mechanisms. We have previously shown that commonly used chemotherapeutics 5-fluorouracil, oxaliplatin, and irinotecan damage the intestinal mucosa and increase intestinal permeability to iohexol. We hypothesized that CIGT is associated with alterations in fecal microbiota and metabolome. Our aim was to characterize these changes and examine how they relate to the severity of CIGT. METHODS: A total of 48 male Sprague-Dawley rats were injected intraperitoneally either with 5-fluorouracil (150 mg/kg), oxaliplatin (15 mg/kg), or irinotecan (200 mg/kg). Body weight change was measured daily after drug administration and the animals were euthanized after 72 h. Blood, urine, and fecal samples were collected at baseline and at the end of the experiment. The changes in the composition of fecal microbiota were analyzed with 16S rRNA gene sequencing. Metabolic changes in serum and urine metabolome were measured with 1 mm proton nuclear magnetic resonance (1H-NMR). RESULTS: Irinotecan increased the relative abundance of Fusobacteria and Proteobacteria, while 5-FU and oxaliplatin caused only minor changes in the composition of fecal microbiota. All chemotherapeutics increased the levels of serum fatty acids and N(CH3)3 moieties and decreased the levels of Krebs cycle metabolites and free amino acids. CONCLUSIONS: Chemotherapeutic drugs, 5-fluorouracil, oxaliplatin, and irinotecan, induce several microbial and metabolic changes which may play a role in the pathophysiology of CIGT. The observed changes in intestinal permeability, fecal microbiota, and metabolome suggest the activation of inflammatory processes.

Intestinal permeability to iohexol as an in vivo marker of chemotherapy-induced gastrointestinal toxicity in Sprague-Dawley rats.

PURPOSE: Gastrointestinal toxicity is the most common adverse effect of chemotherapy. Chemotherapeutic drugs damage the intestinal mucosa and increase intestinal permeability. Intestinal permeability is one of the key markers of gastrointestinal function and measuring intestinal permeability could serve as a useful tool for assessing the severity of chemotherapy-induced gastrointestinal toxicity. METHODS: Male Sprague-Dawley rats were injected intraperitoneally either with 5-fluorouracil (150 mg/kg), oxaliplatin (15 mg/kg) or irinotecan (200 mg/kg). Clinical signs of gastrointestinal toxicity were assessed daily by weighing the animals and by checking for diarrhea. After 48 h, intestinal permeability to iohexol was measured in vivo by giving the animals 1 ml of 647 mg/ml iohexol solution by oral gavage and collecting all the excreted urine for 24 h. All of the animals were euthanized 72 h after drug administration and tissue samples were harvested from the jejunum and colon. RESULTS: All chemotherapeutics caused significant body weight loss and diarrhea. Intestinal permeability to iohexol was also increased in all treatment groups and histological analysis revealed significant intestinal damage in both jejunum and colon. Iohexol permeability correlated with the severity of clinical signs of gastrointestinal toxicity and with acute colonic injury. CONCLUSIONS: Chemotherapeutic drugs, such as 5-fluorouracil, oxaliplatin, and irinotecan, increase intestinal permeability to iohexol. Measuring intestinal permeability to iohexol could provide a simple marker for assessing chemotherapy-induced gastrointestinal toxicity.