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.

Probiotics and Commensal Bacteria Metabolites Trigger Epigenetic Changes in the Gut and Influence Beneficial Mood Dispositions.

The effect of the intestinal microbiome on the gut-brain axis has received considerable attention, strengthening the evidence that intestinal bacteria influence emotions and behavior. The colonic microbiome is important to health and the pattern of composition and concentration varies extensively in complexity from birth to adulthood. That is, host genetics and environmental factors are complicit in shaping the development of the intestinal microbiome to achieve immunological tolerance and metabolic homeostasis from birth. Given that the intestinal microbiome perseveres to maintain gut homeostasis throughout the life cycle, epigenetic actions may determine the effect on the gut-brain axis and the beneficial outcomes on mood. Probiotics are postulated to exhibit a range of positive health benefits including immunomodulating capabilities. Lactobacillus and Bifidobacterium are genera of bacteria found in the intestines and so far, the benefits afforded by ingesting bacteria such as these as probiotics to people with mood disorders have varied in efficacy. Most likely, the efficacy of probiotic bacteria at improving mood has a multifactorial dependency, relying namely on several factors that include the agents used, the dose, the pattern of dosing, the pharmacotherapy used, the characteristics of the host and the underlying luminal microbial environment (e.g., gut dysbiosis). Clarifying the pathways linking probiotics with improvements in mood may help identify the factors that efficacy is dependent upon. Adjunctive therapies with probiotics for mood disorders could, through DNA methylation molecular mechanisms, augment the intestinal microbial active cohort and endow its mammalian host with important and critical co-evolutionary redox signaling metabolic interactions, that are embedded in bacterial genomes, and that in turn can enhance beneficial mood dispositions.

Letter on "Role of gut microbiome in immune regulation and immune checkpoint therapy of colorectal cancer".

Investigations that decipher the human microbiome have reformed the way medicine is focusing on bacteria. An interesting research review recently published in the journal of Digestive Diseases and Sciences conceivably linked adjunctive commensal intestinal bacteria with the capacity to modulate the immune microenvironment towards immune checkpoint inhibitor (ICIs) efficacy of cancer immunotherapy. Evidence has emerged that the intestinal microbiome can modulate outcomes to ICIs therapies via two major mechanisms, namely mechanisms that are antigen-specific (i.e., epitopes are shared between microbial and tumour antigens that can enhance or reduce anti-tumour immune responses) and those mechanisms that are antigen-independent (i.e., modulation of responses to ICIs by engaging innate and/or adaptive immune cells).

Is miR-223 Upregulation in Inflammatory Bowel Diseases a Protective Response?

Inflammatory bowel diseases (IBD) are characterized by chronic inflammation and damage of colonocytes with etiology of genetic, epigenetic and environmental factors. MicroRNA-223 (miR-223) has been found to be increased in both IBD patients and animal colitis models. However, contentious opinions relevant to the roles of miR-223 in IBD have been reported. Notwithstading that most studies have described that miR-223 has anti-inflammatory effects, several reports have progressed a pro-inflammatory view. In this review, we summarise both the anti-inflammatory and pro-inflammatory effects of miR-223 on key molecules in inflammatory responses in both animal models and in patients diagnosed with IBD and objectively discuss the possible basis for the discrepancies.

An exploratory study of the gut microbiota in major depression with anxious distress.

OBJECTIVES: To explore differences in the diversity and composition of the gut microbiome between major depressive disorder (MDD) with and without anxious distress. METHODS: The study comprised 117 participants (79 female, 36 male, 2 other, mean age 38.2 ± 13.4 years) with a current major depressive episode (MDE) with (n = 63) and without (n = 54) the anxious distress specifier. A clinical psychologist administered the structured clinical interview for the DSM-5-RV to confirm a diagnosis of depression. Participants provided stool samples which were immediately frozen and stored at -80 °C. These samples were analysed using the Illumina 16S Metagenomics sequencing protocol in which the sequencing primers target the V3 and V4 regions of the 16S rRNA gene. Participants also completed mental health questionnaires to assess severity of depression (BDI-II), generalized anxiety (GAD-7), and stress (PSS). RESULTS: There were no significant group differences in α-diversity (Shannon's diversity Index; Simpson Index), richness (ACE; Chao1), (Pielou's) evenness, or beta diversity (Bray-Curtis dissimilarity index and weighted UniFrac distance) of gut bacteria. Significant group differences in the relative abundance of gut microbiota however were observed at each taxonomical level, including across 15 genera and 18 species. LIMITATIONS: This was an exploratory study that needs to be replicated across larger samples and compared with a healthy control group. CONCLUSIONS: The research contributes to knowledge of the depressive gut microbial profile unique to the anxious distress subtype of MDD.

Pilot clinical and pharmacokinetic study of Δ9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain.

This pilot study aimed to assess the safety, tolerability, pharmacokinetics and exploratory analgesic effect of a novel water-soluble oro-buccal nanoparticle spray of a cannabis-based medicine (MDCNS-01) in patients with advanced incurable malignancy with unrelieved pain from opioid analgesic. The study was a non-blinded single arm 2 stage study. Stage I was a single escalating dose (n = 5) [2.5 mg Δ9-THC and 2.5 mg CBD) versus a 3-fold escalated dose. Stage II was an up-titrated dose in patients with advanced cancers and intractable pain (n = 25). During Stage I with an increased cannabis-based medicine dose, maximum observed plasma concentrations of cannabinoids were dose dependant. The water-soluble formulation in the current study resulted in a higher median (min, max) systemic exposure of Δ9-THC than CBD (AUC from 2.5 mg each of Δ9-THC and CBD, was 1.71 ng mL.h-1 (1.1, 6.6) and 0.65 ng mL.h-1 (0.49, 4.1), respectively). During stage II a subgroup of patients diagnosed with breast and prostate cancers with bone metastases, had the highest mean pain score improvement from baseline of 40% (unadjusted) and 33% (adjusted for rescue medication use). For all patients the most reported adverse events were mild or moderate drowsiness affecting 11 (44%) and 4 (6%) patients, respectively, and nausea and vomiting that affected 18 (72%) patients. The water-soluble cannabis-based medicine provided acceptable bioavailability for Δ9-THC/CBD, appeared safe and tolerable in advanced incurable cancers with uncontrolled pain with preliminary evidence of analgesic efficacy.

The vermiform cecal appendix, expendable or essential? A narrative review.

PURPOSE OF REVIEW: The vermiform cecal appendix is a small thin pouch-like tube of intestinal tissue situated in the lower right abdomen. It is attached at the junction of the large intestine between the ascending colon and small intestine. Historically, the appendix has been labeled redundant with no significant function, a remnant of evolution. This idea was thought to represent a function that may have been critical for survival that became nonsignificant over time. Evolutionary biologists deemed it to be a vestigial organ that early in human evolution was a dedicated organ that was useful and exploited by herbivorous ancestors. RECENT FINDINGS: Currently, the vermiform cecal appendix has generated significant renewed research interest. As such it has been reported to present a site with a high concentration of lymphoid tissue and a biofilm microbiome that approximately mirrors that which is found in the large bowel. SUMMARY: Research suggests that the vermiform cecal appendix may be the site of a safe-house biofilm that could re-inoculate the large bowel. Given that the appendix has no known role in digestion, the network of lymphoid tissue and microbiome could constitute an initial site of bacterial translocations that can influence early life ontology and immunological tolerance. A dysbiotic microbiome in the appendix is posited to trigger inflammatory sequelae.

A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide for treating diabetic-related peripheral neuropathic pain.

BACKGROUND: Peripheral neuropathy is a common complication of diabetes. The management of the associated neuropathic pain remains difficult to treat. OBJECTIVE: This study explored the safety, tolerability and efficacy of a palmitoylethanolamide (PEA) formulation in treating diabetic-related peripheral neuropathic pain (PNP). Secondary outcomes included systemic inflammation, sleep and mood changes in patients diagnosed with type 1 and type 2 diabetes and PNP. DESIGN: This study was a single-centre, quadruple-blinded, placebo-controlled trial with 70 participants receiving 600 mg of PEA or placebo daily, for 8 weeks, with a 94% rate of study participation completion. Primary outcomes were neuropathic pain and specific pain types (the BPI-DPN and NPSI). The secondary outcomes were sleep quality (MOS sleep scale), mood (DASS-21), glucose metabolism and inflammation. RESULTS: There was a significant reduction (P ≤ 0.001) in BPI-DPN total pain and pain interference, NPSI total score and sub-scores, except for evoked pain (P = 0.09) in the PEA group compared with the placebo group. The MOS sleep problem index and sub-scores significantly improved (P ≤ 0.001). DASS-21 depression scores significantly reduced (P = 0.03), but not anxiety or stress scores. Interleukin-6 and elevated C-reactive protein levels significantly reduced in the PEA group (P = 0.05), with no differences in fibrinogen between groups (P = 0.78) at treatment completion. There were no changes in safety pathology parameters, and the treatment was well tolerated. CONCLUSIONS: The study demonstrated that the PEA formulation reduced diabetic peripheral neuropathic pain and inflammation along with improving mood and sleep. Further studies on the mechanistic effectiveness of PEA as an adjunct medicine and as a monotherapy pain analgesic are warranted. CLINICAL TRIAL REGISTRATION: Registry name: Australian New Zealand Clinical Trials Registry (ANZCTR), Registration number: ACTRN12620001302943, Registration link: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380826 , Actual study start date: 20 November 2020.

The Role of the Gut-Lung Axis in COVID-19 Infections and Its Modulation to Improve Clinical Outcomes.

The main entry point of SARS-CoV-2 is the respiratory tract and as such immune defence in this site determines if the virus will spill-over to the systemic circulation and circulate and infect other major organs. The first line of mucosal immune defence is composed of mucins, an epithelial barrier, and immune cells in the nasal cavity. The lung immune defence is carried out by numerous alveoli. The lung microbiota is a key factor in determining the efficacy of lung mucosal immunity protection. The intestinal microbiota has been demonstrated to affect the severity of COVID-19. Gut dysbiosis is involved in hyperinflammation and multiple organ failure through communications with multiple organs. The gut lung axis could be the earliest axis affected in COVID-19. Through the gut-lung axis, gut dysbiosis can affect the pathogenesis of the lung in COVID-19. In this review, we summarise the effects that gut dysbiosis can progress on the lung, and the lung microbiota. The possible mechanisms and approaches for modulation are discussed.

Tetrahydrocannabinol and cannabidiol medicines for chronic pain and mental health conditions.

Combination tetrahydrocannabinol (THC)/cannabidiol (CBD) medicines or CBD-only medicines are prospective treatments for chronic pain, stress, anxiety, depression, and insomnia. THC and CBD increase signaling from cannabinoid receptors, which reduces synaptic transmission in parts of the central and peripheral nervous systems and reduces the secretion of inflammatory factors from immune and glial cells. The overall effect of adding CBD to THC medicines is to enhance the analgesic effect but counteract some of the adverse effects. There is substantial evidence for the effectiveness of THC/CBD combination medicines for chronic pain, especially neuropathic and nociplastic pain or pain with an inflammatory component. For CBD-only medication, there is substantial evidence for stress, moderate evidence for anxiety and insomnia, and minimal evidence for depression and pain. THC/CBD combination medicines have a good tolerability and safety profile relative to opioid analgesics and have negligible dependence and abuse potential; however, should be avoided in patients predisposed to depression, psychosis and suicide as these conditions appear to be exacerbated. Non-serious adverse events are usually dose-proportional, subject to tachyphylaxis and are rarely dose limiting when patients are commenced on a low dose with gradual up-titration. THC and CBD inhibit several Phase I and II metabolism enzymes, which increases the exposure to a wide range of drugs and appropriate care needs to be taken. Low-dose CBD that appears effective for chronic pain and mental health has good tolerability and safety, with few adverse effects and is appropriate as an initial treatment.

Intestinal Dysbiosis, the Tryptophan Pathway and Nonalcoholic Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH), which may then progress to the development of cirrhosis and hepatocarcinoma. NASH is characterized by both steatosis and inflammation. Control of inflammation in NASH is a key step for the prevention of disease progression to severe sequalae. Intestinal dysbiosis has been recognized to be an important causal factor in the pathogenesis of NASH, involving both the accumulation of lipids and aggravation of inflammation. The effects of gut dysbiosis are mediated by adverse shifts of various intestinal commensal bacterial genera and their associated metabolites such as butyrate, tryptophan, and bile acids. In this review, we focus on the roles of tryptophan and its metabolites in NASH in association with intestinal dysbiosis and discuss possible therapeutic implications.

Effects of olives and their constituents on the expression of ulcerative colitis: a systematic review of randomised controlled trials.

Extra virgin olive oil is often associated with anti-inflammatory and antioxidant properties. Its effects on inflammatory conditions such as ulcerative colitis (UC), however, have yet to be defined. As such, we aimed to conduct a systematic review and meta-analysis of studies investigating olive-based interventions in UC. A comprehensive database search for randomised controlled trials was performed between 9 July 2018 and 16 August 2018. Studies identified from search alerts were included up to 22 June 2020. Both individuals living with UC at any disease stage and murine models of UC were included in this review. No human trials meeting the eligibility criteria were identified, while nineteen animal studies comprised 849 murine models of UC were included in this review. Pooling of the data could not be performed due to heterogeneous outcomes; however, general trends favouring olive-based interventions were identified. Milder disease expression including weight maintenance, reduced rectal bleeding and well-formed stools favouring olive-based interventions was statistically significant in 16/19 studies, with moderate-to-large effect sizes (-0·66 (95 % CI -1·56, 0·24) to -12·70 (95 % CI -16·8, -8·7)). Olive-based interventions did not prevent the development of colitis-like pathologies in any study. In conclusion, effects of olive-based interventions on murine models of UC appear promising, with milder disease outcomes favouring the intervention in most trials and effect sizes suggesting potential clinical relevance. However, the lack of published randomised controlled human trials warrants further investigation to determine if these effects would translate to individuals living with UC.

Enhancing Endocannabinoid Control of Stress with Cannabidiol.

The stress response is a well-defined physiological function activated frequently by life events. However, sometimes the stress response can be inappropriate, excessive, or prolonged; in which case, it can hinder rather than help in coping with the stressor, impair normal functioning, and increase the risk of somatic and mental health disorders. There is a need for a more effective and safe pharmacological treatment that can dampen maladaptive stress responses. The endocannabinoid system is one of the main regulators of the stress response. A basal endocannabinoid tone inhibits the stress response, modulation of this tone permits/curtails an active stress response, and chronic deficiency in the endocannabinoid tone is associated with the pathological complications of chronic stress. Cannabidiol is a safe exogenous cannabinoid enhancer of the endocannabinoid system that could be a useful treatment for stress. There have been seven double-blind placebo controlled clinical trials of CBD for stress on a combined total of 232 participants and one partially controlled study on 120 participants. All showed that CBD was effective in significantly reducing the stress response and was non-inferior to pharmaceutical comparators, when included. The clinical trial results are supported by the established mechanisms of action of CBD (including increased N-arachidonylethanolamine levels) and extensive real-world and preclinical evidence of the effectiveness of CBD for treating stress.

The intestinal microbiota and improving the efficacy of COVID-19 vaccinations.

Most COVID-19 cases are mild or asymptomatic and recover well, suggesting that effective immune responses ensue, which successfully eliminate SARS-CoV-2 viruses. However, a small proportion of patients develop severe COVID-19 with pathological immune responses. This indicates that a strong immune system balanced with anti-inflammatory mechanisms is critical for the recovery from SARS-CoV-2 infections. Many vaccines against SARS-CoV-2 have now been developed for eliciting effective immune responses to protect from SARS-CoV-2 infections or reduce the severity of the disease if infected. Although uncommon, serious morbidity and mortality have resulted from both COVID-19 vaccine adverse reactions and lack of efficacy, and further improvement of efficacy and prevention of adverse effects are urgently warranted. Many factors could affect efficacy of these vaccines to achieve optimal immune responses. Dysregulation of the gut microbiota (gut dysbiosis) could be an important risk factor as the gut microbiota is associated with the development and maintenance of an effective immune system response. In this narrative review, we discuss the immune responses to SARS-CoV-2, how COVID-19 vaccines elicit protective immune responses, gut dysbiosis involvement in inefficacy and adverse effects of COVID-19 vaccines and the modulation of the gut microbiota by functional foods to improve COVID-19 vaccine immunisations.