Prebiotics Progress Shifts in the Intestinal Microbiome That Benefits Patients with Type 2 Diabetes Mellitus.

Hypoglycemic medications that could be co-administered with prebiotics and functional foods can potentially reduce the burden of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM). The efficacy of drugs such as metformin and sulfonylureas can be enhanced by the activity of the intestinal microbiome elaborated metabolites. Functional foods such as prebiotics (e.g., oligofructose) and dietary fibers can treat a dysbiotic gut microbiome by enhancing the diversity of microbial niches in the gut. These beneficial shifts in intestinal microbiome profiles include an increased abundance of bacteria such as Faecalibacterium prauznitzii, Akkermancia muciniphila, Roseburia species, and Bifidobacterium species. An important net effect is an increase in the levels of luminal SCFAs (e.g., butyrate) that provide energy carbon sources for the intestinal microbiome in cross-feeding activities, with concomitant improvement in intestinal dysbiosis with attenuation of inflammatory sequalae and improved intestinal gut barrier integrity, which alleviates the morbidity of T2DM. Oligosaccharides administered adjunctively with pharmacotherapy to ameliorate T2DM represent current plausible treatment modalities.

A Double-Blind Randomized Placebo-Controlled Study Assessing the Safety, Tolerability and Efficacy of a Herbal Medicine Containing Pycnogenol Combined with Papain and Aloe vera in the Prevention and Management of Pre-Diabetes.

Background: Herbal medicines present attractive options to patients with chronic diseases. Undertaking clinical studies with patients presenting with symptomless pre-T2D can lead to significant limitations. Methods: A 12-week randomized double-blind placebo-controlled clinical study was conducted that investigated the safety and efficacy of an herbal formulation administered orally for the treatment of pre-type 2 diabetes (pre-T2D). Results: A numerically greater proportion of subjects in the interventional arm had impaired fasting glucose (IFG) at week 12 compared to the control arm (71.0% vs. 69.0%, p = 0.75). Fewer participants had impaired glucose tolerance (IGT) at 12 weeks in the intervention arm compared to the control arm (unadjusted 58.3% vs. 66.7%, p = 0.65; adjusting for baseline IGT, p = 0.266). In a subgroup analysis, subjects with a baseline fasting plasma glucose (FPG) level in the range of 6.1-6.9 mmol/L demonstrated a non-significant lower proportion of IFG at week 12 in the intervention arm compared to the control arm (60.0% vs. 41.7% p = 0.343). Total blood cholesterol and triglyceride levels remained unchanged from baseline to week 12 in both treatment groups. Conclusions: This study suggests that a polyherbal medicine was not effective for reducing the metabolic markers associated with pre-T2D over a 12-week period. Therefore, larger studies with well-defined endpoints and of longer duration are warranted.

A double-blind randomized placebo controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee osteoarthritis.

BACKGROUND: The aim of the study was to assess the safety, tolerability and efficacy of palmitoylethanolamide (PEA) when dosed at 300 mg and 600 mg per day on symptoms of knee osteoarthritis. METHODS: This was a single site, comparative, double-blind placebo controlled study in adults with mild to moderate knee osteoarthritis with 111 participants randomized to receive 300 mg PEA, 600 mg PEA or placebo each day, in divided doses b.i.d, for 8 weeks. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The secondary outcomes were the Numerical Rating Scales (NRS) for pain, the Depression Anxiety Stress Scale (DASS), the Perceived Stress Scale (PSS), the Pittsburg Sleep Quality Index (PSQI), the Short Form Health Survey (SF-36), the use of rescue pain medication and clinical safety assessment. RESULTS: There was a significant reduction in the total WOMAC score in the 300 mg PEA (p = 0.0372) and the 600 mg PEA (p = 0.0012) groups, the WOMAC pain score (300 mg PEA, p = 0.0074; 600 mg PEA, p = < 0.001), the WOMAC stiffness score (PEA 300 mg, p < 0.0490; 600 mg PEA, p = 0.001) and in the WOMAC function score in the 600 mg PEA group (p = 0.033) compared to placebo. The NRS pain evaluations for "worst pain" and "least pain" were significantly reduced in the 300 mg PEA group (p < 0.001, p = 0.005) and the 600 mg PEA group (p < 0.001, p < 0.001) compared to placebo. There was a significant reduction in anxiety (DASS) in both active treatment groups (300 mg PEA, p = 0.042; 600 mg PEA group (p = 0.043) compared to placebo. There were no changes in the clinical markers and the product was well tolerated. CONCLUSIONS: The study demonstrated that palmitoylethanolamide may be a novel treatment for attenuating pain and reducing other associated symptoms of knee osteoarthritis. Further studies on the pharmacological basis of this anti-inflammatory effect are now required.

Immunological Tolerance and Function: Associations Between Intestinal Bacteria, Probiotics, Prebiotics, and Phages.

Post-birth there is a bacterial assault on all mucosal surfaces. The intestinal microbiome is an important participant in health and disease. The pattern of composition and concentration of the intestinal microbiome varies greatly. Therefore, achieving immunological tolerance in the first 3-4 years of life is critical for maintaining health throughout a lifetime. Probiotic bacteria are organisms that afford beneficial health effects to the host and in certain instances may protect against the development of disease. The potential benefits of modifying the composition of the intestinal microbial cohort for therapeutic benefit is evident in the use in high risks groups such as premature infants, children receiving antibiotics, rotavirus infections in non-vaccinated children and traveler's diarrhea in adults. Probiotics and prebiotics are postulated to have immunomodulating capabilities by influencing the intestinal microbial cohort and dampening the activity of pathobiont intestinal microbes, such as Klebsiella pneumonia and Clostridia perfringens. Lactobacilli and Bifidobacteria are examples of probiotics found in the large intestine and so far, the benefits afforded to probiotics have varied in efficacy. Most likely the efficacy of probiotic bacteria has a multifactorial dependency, namely on a number of factors that include agents used, the dose, the pattern of dosing, and the characteristics of the host and the underlying luminal microbial environment and the activity of bacteriophages. Bacteriophages, are small viruses that infect and lyse intestinal bacteria. As such it can be posited that these viruses display an effective local protective control mechanism for the intestinal barrier against commensal pathobionts that indirectly may assist the host in controlling bacterial concentrations in the gut. A co-operative activity may be envisaged between the intestinal epithelia, mucosal immunity and the activity of bacteriophages to eliminate pathobiots, highlighting the potential role of bacteriophages in assisting with maintaining intestinal homeostasis. Hence bacteriophage local control of inflammation and immune responses may be an additional immunological defense mechanism that exploits bacteriophage-mucin glycoprotein interactions that controls bacterial diversity and abundance in the mucin layers of the gut. Moreover, and importantly the efficacy of probiotics may be dependent on the symbiotic incorporation of prebiotics, and the abundance and diversity of the intestinal microbiome encountered. The virome may be an important factor that determines the efficacy of some probiotic formulations.

The Brain-Intestinal Mucosa-Appendix- Microbiome-Brain Loop.

The brain and the gut are connected from early fetal life. The mother's exposure to microbial molecules is thought to exert in utero developmental effects on the fetus. These effects could importantly underpin the groundwork for subsequent pathophysiological mechanisms for achieving immunological tolerance and metabolic equilibrium post birth, events that continue through to 3-4 years of age. Furthermore, it is understood that the microbiome promotes cues that instruct the neonate's mucosal tissues and skin in the language of molecular and cellular biology. Post birth mucosal lymphoid tissue formation and maturation (most probably including the vermiform appendix) is microbiota-encouraged co-establishing the intestinal microbiome with a developing immune system. Intestinal mucosal tissue maturation loops the brain-gut-brain and is postulated to influence mood dispositions via shifts in the intestinal microbiome phyla. A plausible appreciation is that dysregulated pro-inflammatory signals from intestinal resident macrophages could breach the loop by providing adverse mood signals via vagus nerve afferents to the brain. In this commentary, we further suggest that the intestinal resident macrophages act as an upstream traffic controller of translocated microbes and metabolites in order to maintain local neuro-endocrine-immunological equilibrium. When macrophages are overwhelmed through intestinal microbiome and intestinal epithelial cell dysbiosis, pro-inflammatory signals are sustained, which may then lead to mood disorders. The administration of probiotics as an adjunctive medicine co-administered with antidepressant medications in improving depressed mood may have biological and clinical standing.