Eat broccoli sprouts for your gut

July 4, 2022August 1, 2022 gettingwell4 5+ stars Premium, Epigenetics, Immune system, Stress Control group, Genetic factors

Two 2022 papers, starting with a review of sulforaphane’s effects on intestinal inflammation:

“This review summarizes characteristics of intestinal inflammation, the anti-inflammatory mechanism of sulforaphane (SFN) and its various protective effects on intestinal inflammation, and possible future applications of SFN for promoting intestinal health.

SFN is an effective agonist of Nrf2, and it is also able to inhibit expression of inflammation-related genes by activating Nrf2. This kind of anti-inflammatory mechanism has already been confirmed in treatment of intestinal mucositis using SFN.

The main absorption site of SFN after oral administration is the small intestine, and its achievable dose for the hind intestine may be lower than the expected dose. Although absorbed SFN can reach the large intestine through intestinal blood and other transportation routes, its therapeutic effect on target tissues may not be as efficient as it would be when the expected dose is directly absorbed by hindgut cells.

Considering that there are several predisposing factors that lead to intestinal inflammation, more research on the effect of SFN on intestinal inflammation with different causes and characteristics should be carried out. Appropriate carriers should be selected according to the onset site and related physiological environment, and a scientific and effective intestinal targeted delivery system for SFN needs to be developed.”

https://pubs.rsc.org/en/content/articlelanding/2022/FO/D1FO03398K “The functional role of sulforaphane in intestinal inflammation: a review” (not freely available). Thanks to Professor Lei Zheng for providing a copy.

Reference 89 – Sulforaphane Normalizes Intestinal Flora and Enhances Gut Barrier in Mice with BBN-Induced Bladder Cancer (not freely available) – in the above graphic was cited for:

“The effect of SFN intervention on intestinal injury in mice with bladder cancer was investigated. It was found that SFN significantly reduced tissue damage in the colon and cecum of mice and normalized the imbalance in intestinal flora caused by BBN, which manifested as an increase in Bacteroides fragilis and Clostridium cluster 1, thus promoting SCFA production.

SFN administration upregulated expression of tight junction proteins including ZO-1, occludin, claudin-1 and glucagon-like peptide 2 (GLP2) to repair damage of mucosal epithelium of the colon and caecum, while reducing release of IL-6 and the secreted immunoglobulin A (SIgA). This study showed for the first time SFN’s alleviating effect on intestinal inflammation may be produced by regulating intestinal flora structure, suggesting that the protective effect of SFN on intestinal health could be multidirectional.”

That study’s 2022 follow-on rodent study also used oral sulforaphane doses:

“This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate underlying mechanisms.

Male C57BL/6 mice were treated with various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment.

5, 10, and 20 mg/kg/day of SFN treatment significantly ameliorated inflammatory damage in mice colon tissue when compared to the colitis group.

5, 10, and 20 mg/kg/day of SFN remarkably mitigated morphological alterations and protected colonic tissue integrity.

Nrf2 expression was increased significantly by 5, 10, and 20 mg/kg/day of SFN treatment.

SFN partially restored perturbed gut microbiota composition, and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.

The contents of butyric acid, iso-butyric acid, valeric acid, and iso-valeric acid were all decreased in DSS-induced colitis mice and in 2.5 mg/kg/day of the SFN treatment group, whereas this decreased tendency was reversed by 10 and 20 mg/kg/day of SFN.

A proposed mechanism by which SFN protects against colitis:

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Signal Transducer and Activator of Transcription 3 (STAT3), and Phase II enzyme UDP-glucuronosyltransferase (UGT) were involved in the protective effect of SFN against DSS-induced colitis.

Nrf2 activation followed by STAT3 signaling pathway play a pivotal role in the protective effect of SFN on colitis. SFN can be considered a potential candidate in the treatment of IBD.”

https://www.frontiersin.org/articles/10.3389/fnut.2022.893344/full “The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism”

A human equivalent dose of the second paper’s oral dose of 20 mg sulforaphane / kg body weight is (.081 x 20 mg) x 70 kg = 113 mg. Per Estimating daily consumption of broccoli sprout compounds, I ate about half that every day by microwaving 3-day-old broccoli sprouts through Week 56, when I cut back to about 35 mg a day. I dialed that back in Week 87 to about 17 mg a day (100 μmol), which is used in a plethora of studies.

I’ve never had ulcerative colitis or inflammatory bowel disease. If I would be diagnosed with either, it would take about five minutes to get back to this study’s equivalent of 10 mg / kg body weight with broccoli seeds and sprouts.

Doubling that to 20 mg may involve taking supplements, though. Haven’t checked for commercial availability lately, but I’ve read a dozen or so studies on encapsulating sulforaphane so that it could reach the colon.

The soluble receptor for AGEs

July 3, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress Control group, Genetic factors

Two 2022 human studies on sRAGE, starting with one of hypoxia-related diseases:

“The receptor for advanced glycation end products is found on endothelial and inflammatory cell surfaces. It binds to circulating advanced glycation end products, activating a proinflammatory protein cascade that contributes to systemic oxidative stress and inflammation.

sRAGE is the soluble isoform of RAGE and acts as a protective decoy by buffering inflammatory ligands, decreasing inflammatory injury. Therefore, low levels of sRAGE are a biomarker of deficient inflammatory control.

We show that plasma concentrations of the anti-inflammatory molecule sRAGE are reduced in patients with chronic obstructive pulmonary disease (COPD) and in patients with obstructive sleep apnoea (OSA). Overlap of COPD and OSA does not lead to an additive effect.

Effective treatment by continuous positive airway pressure (CPAP) of subjects with obstructive apnoeas (with or without associated COPD) increases the level of sRAGE, while in healthy subjects and COPD without OSA, these levels do not change over time. This is the first study to investigate the effect of CPAP on plasma levels of sRAGE.”

https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-022-02092-9 “Soluble RAGE in COPD, with or without coexisting obstructive sleep apnoea”

A second study introduced sRAGE isoforms:

“We explored associations of circulating levels of soluble RAGE, its endogenous secretory (esRAGE) and cleaved (cRAGE) isoforms, AGEs, and their respective ratios with 15-year all-cause mortality in type 2 diabetes. The potential prognostic value of sRAGE as a marker of disease and occurrence of adverse events seems to be suitable for individuals with chronic disease or multimorbidity, and not for the general population.

Baseline AGEs and sRAGE isoforms concentration were measured by ELISA in 362 patients with type 2 diabetes and in 125 age- and gender-matched healthy control subjects. At an average follow-up of 15 years, 130 deaths [in T2D subjects] were observed.

A nomogram based on age, sex, HbA1c, systolic blood pressure, and the AGEs/cRAGE ratio was built to predict 5-, 10- and 15-year survival in type 2 diabetes. Kaplan-Meier survival function for patients with type 2 diabetes grouped according to quartiles of the nomogram-based mortality risk score:

An increase in the AGEs/cRAGE ratio was accompanied by a higher risk of all-cause mortality in patients with type 2 diabetes. The AGEs/cRAGE ratio led to a significant, albeit modest, improvement in the already established RECODe model of predicting 10-year all-cause mortality in type 2 diabetes based on age, sex, ethnicity, smoking, systolic blood pressure, history of major adverse cardiovascular events (MACE), HbA1c, total cholesterol, HDL-C, serum creatinine, and urinary albumin-to-creatinine ratio.

While none of the parameters was significantly associated with development of any complication in patients without complications at the time of enrollment, sRAGE was associated with the development of MACE over a 15-year follow-up in patients with type 2 diabetes who had no history of MACE at recruitment.”

https://cardiab.biomedcentral.com/articles/10.1186/s12933-022-01535-3 “Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study”

Gut microbiota therapy

June 25, 2022 gettingwell4 4-5 stars Advanced knowledge, Brainstem, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Serotonin, Stress Control group, Genetic factors, Neural plasticity, Neurodegenerative disease

This June 2022 review cited twenty 2022 papers for relationships between Parkinson’s disease and gut microbiota:

“Clinical diagnosis of PD is based on typical motor symptoms, and novel diagnostic biomarkers have been developed such as imaging markers, and α-synuclein fluid and tissue markers. Multimorbidity of non-motor disorders heighten the risk of adverse outcomes for patients with PD, which usually appear 20 years before onset of motor symptoms.

The gut microbiota is intimately connected to occurrence, development, and progression of PD, especially in early stages. A better understanding of the microbiota–gut–brain axis in PD can provide an opportunity to monitor an individual’s health by manipulating gut microbiota composition.

Several approaches like administration of probiotics, psychobiotics, prebiotics, synbiotics, postbiotics, FMT, and dietary modifications have been tried to mitigate dysbiosis-induced ill effects and alleviate PD progression.

Epidemiological studies have reported that diet affects (positively or negatively) onset of neurodegenerative disorders. Evidence suggests that diet composition’s effects on brain health is not due to diet-induced inflammatory response, but because of its effects on the gut microbiome.

Dysbiotic gut microbiota (including altered microbial metabolites) may play crucial roles in PD via various mechanisms, such as:

Increased intestinal permeability;

Aggravated intestinal inflammation and neuroinflammation;

Abnormal aggregation of α-synuclein fibrils;

Imbalanced oxidative stress; and

Decreased neurotransmitters production.

Future studies are essential to further elucidate cause-effect relationships between gut microbiota and PD, improved PD therapeutic and diagnostic options, disease progression tracking, and patient stratification capabilities to deliver personalized treatment and optimize clinical trial designs.”

https://www.frontiersin.org/articles/10.3389/fimmu.2022.937555/full “Gut Microbiota: A Novel Therapeutic Target for Parkinson’s Disease”

Taurine week #7: Brain

June 18, 2022January 19, 2025 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Amygdala, Anterior cingulate cortex, Brain development, Cerebellum, Cerebrum, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress, Thalamus Brain neurons, Control group, Embryo development, Genetic factors, Neurodegenerative disease, Prefrontal cortex

Finishing a week’s worth of 2022 taurine research with two reviews of taurine’s brain effects:

“We provide a overview of brain taurine homeostasis, and review mechanisms by which taurine can afford neuroprotection in individuals with obesity and diabetes. Alterations to taurine homeostasis can impact a number of biological processes such as osmolarity control, calcium homeostasis, and inhibitory neurotransmission, and have been reported in both metabolic and neurodegenerative disorders.

Models of neurodegenerative disorders show reduced brain taurine concentrations. On the other hand, models of insulin-dependent diabetes, insulin resistance, and diet-induced obesity display taurine accumulation in the hippocampus. Given cytoprotective actions of taurine, such accumulation of taurine might constitute a compensatory mechanism that attempts to prevent neurodegeneration.

Taurine release is mainly mediated by volume-regulated anion channels (VRAC) that are activated by hypo-osmotic conditions and electrical activity. They can be stimulated via glutamate metabotropic (mGluR) and ionotropic receptors (mainly NMDA and AMPA), adenosine A₁ receptors (A₁R), and metabotropic ATP receptors (P2Y).

Taurine mediates its neuromodulatory effects by binding to GABA_A, GABA_B, and glycine receptors. While taurine binding to GABA_A and GABA_B is weaker than to GABA, taurine is a rather potent ligand of the glycine receptor. Reuptake of taurine occurs via taurine transporter TauT.

Cytoprotective actions of taurine contribute to brain health improvements in subjects with obesity and diabetes through various mechanisms that improve neuronal function, such as:

Modulating inhibitory neurotransmission, which promotes an excitatory–inhibitory balance;

Stimulating antioxidant systems; and

Stabilizing mitochondria energy production and Ca²⁺ homeostasis.”

https://www.mdpi.com/2072-6643/14/6/1292/htm “Taurine Supplementation as a Neuroprotective Strategy upon Brain Dysfunction in Metabolic Syndrome and Diabetes”

A second review focused on taurine’s secondary bile acids produced by gut microbiota:

“Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. Hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases.

Biliary acids may influence each of the following three mechanisms through which interactions within the brain-gut-microbiota axis take place: neurological, immunological, and neuroendocrine. These microbial metabolites can act as direct neurotransmitters or neuromodulators, serving as key modulators of the brain-gut interactions.

The gut microbial community, through their capacity to produce bile acid metabolites distinct from the liver, can be thought of as an endocrine organ with potential to alter host physiology, perhaps to their own favour. Hydrophilic bile acids, currently regarded as important hormones, exert modulatory effects on gut microbiota composition to produce secondary bile acids which seem to bind a number of receptors with a higher affinity than primary biliary acids, expressed on many different cells.

TUDCA regulates expression of genes involved in cell cycle regulation and apoptotic pathways, promoting neuronal survival. TUDCA:

Improves protein folding capacity through its chaperoning activity, in turn reducing protein aggregation and deposition;

Reduces reactive oxygen species production, leading to protection against mitochondrial dysfunction;

Ameliorates endoplasmic reticulum stress; and

Inhibits expression of pro-inflammatory cytokines, exerting an anti-neuroinflammatory effect.

Although Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and cerebral ischemia have different disease progressions, they share similar pathways which can be targeted by TUDCA. This makes this bile acid a potentially strong therapeutic option to be tested in human diseases. Clinical evidence collected so far has reported comprehensive data on ALS only.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166453/ “Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases”

Taurine week #6: Stress

June 17, 2022August 8, 2022 gettingwell4 4-5 stars Advanced knowledge, Cerebellum, Cerebrum, Cortisol, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Lower brain, Neurochemicals, Serotonin, Stress Antidepressants, Brain neurons, Control group, Genetic factors, Neural plasticity, Prefrontal cortex

Two 2022 rodent studies of taurine’s associations with long-term stress, starting with a chronic restraint stress model:

“We show that chronic restraint stress can lead to hyperalgesia accompanied by changes in gut microbiota that have significant gender differences. Corresponding changes of bacteria can further induce hyperalgesia and affect different serum metabolism in mice of the corresponding sex.

Different serum metabolites between pseudo-germ-free mice receiving fecal microbiota transplantation from the chronic restraint stress group and those from the control group were mainly involved in bile secretion and steroid hormone biosynthesis for male mice, and in taurine and hypotaurine metabolism and tryptophan metabolism for female mice.

Effects of gut microbiota transplantation on serum metabolomics of female host: Taurine and hypotaurine metabolism, tryptophan metabolism, serotonergic synapse, arachidonic acid metabolism, and choline metabolism in cancer were the five identified pathways in which these different metabolites were enriched.

Taurine and hypotaurine play essential roles in anti-inflammation, anti-hypertension, anti-hyperglycemia, and analgesia. Taurine can be used as a diagnostic index for fibromyalgia syndrome and neuropathic pain.

These findings improve our understanding of sexual dimorphism in gut microbiota in stress-induced hyperalgesia and the effect of gut microbiota on blood metabolic traits. Follow-up research will investigate causal relationships between them.”

https://www.sciencedirect.com/science/article/pii/S1043661822000743 “Gut microbiota and its role in stress-induced hyperalgesia: Gender-specific responses linked to different changes in serum metabolites”

Human equivalents:

A 7-8 month-old mouse would be a 38-42 year-old human.
A 14-day stress period is about two years for humans.

A second study used a chronic social defeat stress model:

“The level of taurine in extracellular fluid of the cerebral medial prefrontal cortex (mPFC) was significantly reduced in mice with chronic social defeat stress (CSDS)-induced depression. We found that taurine supplementation effectively rescued immobility time during a tail suspension assay and improved social avoidance behaviors in CSDS mice.

Male C57BL/6 J mice (∼ 23 g) and male CD-1 mice aged 7–8 months (∼ 45 g) were used. CD-1 mice were screened for aggressive behavior during social interactions for three consecutive days before the start of the social defeat sessions. Experimental C57BL/6 J mice were subjected to physical interactions with a novel CD-1 mouse for 10 min once per day over 10 consecutive days.

We found significant reductions in taurine and betaine levels in mPFC interstitial fluid of CSDS mice compared with control mice.

We additionally investigated levels of interstitial taurine in chronic restraint stress (CRS) mice, another depressive animal model. After 14 days of CRS treatment, mice showed typical depression-like behaviors, including decreased sucrose preference and increased immobility time. mPFC levels of interstitial taurine were also significantly decreased in CRS mice.

Taurine treatment protected CSDS mice from impairments in dendritic complexity, spine density, and proportions of different types of spines. Expression of N-methyl D-aspartate receptor subunit 2A, an important synaptic receptor, was largely restored in the mPFC of these mice after taurine supplementation.

These results demonstrated that taurine exerted an antidepressive effect by protecting cortical neurons from dendritic spine loss and synaptic protein deficits.”

https://link.springer.com/article/10.1007/s10571-022-01218-3 “Taurine Alleviates Chronic Social Defeat Stress-Induced Depression by Protecting Cortical Neurons from Dendritic Spine Loss”

Human equivalents:

A 7-8 month-old mouse would be a 38-42 year-old human.
A 500 mg/kg taurine dose injected intraperitoneally is (.081 x 500 mg) x 70KG = 2.835 g.
A 10-day stress period is about a year and a half for humans.

Don’t think aggressive humans would have to be twice as large to stress those around them. There may be choices other than enduring a year and a half of that.

Taurine week #3: Organs

June 15, 2022January 19, 2025 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress Control group, Genetic factors

Three 2022 papers investigated taurine’s effects on organs, starting with a rodent study of sepsis:

“Sepsis usually causes multiple organ dysfunctions and high mortality. Pathogenesis of sepsis is thought to be driven by hyperactive inflammation following pathogen invasion. If the immune system fails to eradicate pathogens, immune homeostasis is disturbed, leading to an overwhelming inflammation accompanied by immunosuppression.

Metabolomic analysis showed large amounts of taurine in neutrophils and monocytes and a dramatic decrease in taurine levels after lipopolysaccharides (LPS) exposure:

Cecal ligation and puncture (CLP) model mice and CLP plus taurine mice were injected intraperitoneally with saline (200 μl) or taurine (200 mg/kg, in 200 μl) respectively at 6, 24, and 48 h after the operation. Taurine protected septic mice from death, improving tissue injuries in the lung, liver, and kidney by reducing neutrophil infiltration and TNF-α production.

Our data indicate that a supplement with taurine might be a promising therapeutic strategy for sepsis to reduce hyperactive inflammation and improve multiple organ dysfunctions.”

https://www.sciencedirect.com/science/article/abs/pii/S0008874922000272 “Mechanism of taurine reducing inflammation and organ injury in sepsis mice” (not freely available) Thanks to Dr. Liuluan Zhu for providing a copy.

Taurine demonstrated the only decrease in 17 amino acids measured in monocytes above. It was the same story for those amino acids and neutrophils.

A human equivalent to each of three mouse taurine doses administered over two days was (.081 x 200 mg) x 70 kg = 1.134 g. A second dose given at the 12-hour point may have improved treated subjects’ survival, as half of them died before the study’s 24-hour point of a second dose.

A second rodent study was on liver injury:

“We investigated the beneficial effects of taurine on fatty liver injury in vivo induced by tunicamycin, a chemical endoplasmic reticulum (ER) stressor.

The unfolded protein response (UPR) is a protein homeostasis-maintaining system that monitors ER conditions by sensing inadequacy in ER protein folding capacity. The ER is both a protein homeostasis-maintaining system and the primary site of lipid metabolism. The UPR plays vital roles in maintaining metabolic and lipid homeostasis.

Glutathione (GSH), a final byproduct of sulfur-containing amino acid metabolism, is not only a powerful antioxidant, but also a principal redox buffer in the ER. Depletion of reduced glutathione can cause additional oxidative stress.

Cysteine, the metabolic precursor of GSH, is also an essential substrate for taurine synthesis. Utilization of cysteine to generate GSH and taurine is competitive.

In this study, availability of cysteine is favored for GSH synthesis due to sufficient taurine supply. Taurine supplementation restored GSH levels, which were attenuated by tunicamycin treatment, by increasing expression of GCLC, an enzyme mediating GSH synthesis.

The protective effect of taurine on tunicamycin-induced hepatic injury results from its concurrent mitigation of both ER and oxidative stress.”

https://www.mdpi.com/2075-1729/12/3/354/htm “Taurine Ameliorates Tunicamycin-Induced Liver Injury by Disrupting the Vicious Cycle between Oxidative Stress and Endoplasmic Reticulum Stress”

This study provided further evidence for an idea in Treating psychopathological symptoms will somehow resolve causes? that:

“Such positive effects of taurine on glutathione levels may be explained by the fact that cysteine is the essential precursor to both metabolites, whereby taurine supplementation may drive metabolism of cysteine towards GSH synthesis.”

A third rodent study investigated lung pneumonia:

“We evaluated anti-inflammatory effects of taurine derivative N-chlorotaurine (also known as taurine chloramine; TauCl) against LPS-induced pneumonia in obese mice maintained on a high fat diet.

Taurine is present in immune system cells such as macrophages and neutrophils. When an organism is infected by pathogens, immune cells produce hypochlorous acid to kill pathogens. Taurine reacts with excessive hypochlorous acid to produce TauCl, which reduces high levels of hypochlorous acid and its toxicity to surrounding host cells.

Intraperitoneal TauCl suppressed excessive immune response in lungs. TauCl treatment attenuates acute pneumonia-related pulmonary and systemic inflammation, including muscle wasting.”

https://www.mdpi.com/2218-1989/12/4/349/htm “N-Chlorotaurine Reduces the Lung and Systemic Inflammation in LPS-Induced Pneumonia in High Fat Diet-Induced Obese Mice”

Taurine week #2: Bile acids

June 14, 2022January 19, 2025 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Glutamate, Hypothalamus, Immune system, Limbic system, Neurochemicals, Testosterone Brain neurons, Control group, Genetic factors, Neurodegenerative disease

Two papers investigated taurine’s integration into bile acids, starting with a review:

“Bile acids (BAs) are produced from cholesterol in the liver and are termed primary BAs. Primary BAs are conjugated with glycine and taurine in the liver, and stored in the gallbladder. BAs are released from the gallbladder into the small intestine via food intake to facilitate digestion and absorption of lipids and lipophilic vitamins by forming micelles in the small intestine.

After deconjugation by the gut microbiome, primary BAs are converted into secondary BAs. Most BAs in the intestine are reabsorbed and transported to the liver, where both primary and secondary BAs are conjugated with glycine or taurine and rereleased into the intestine.

Some BAs reabsorbed from the intestine spill into systemic circulation, where they bind to a variety of nuclear and cell-surface receptors in tissues. Some BAs are not reabsorbed and bind to receptors in the terminal ileum.

BAs can affect cell-surface and intracellular membranes, including those of mitochondria and the endoplasmic reticulum. BAs are also hormones or signaling molecules, and can regulate BA, glucose, and lipid metabolism in various tissues, including the liver, pancreas, and both brown and white adipose tissue. BAs also affect the immune system.

BAs can affect the nervous system. More than 20 BAs have been detected in the brain of humans and rodents. The brain communicates with the gut and gut microbiome through BAs.”

https://www.mdpi.com/2076-2607/10/1/68/htm “Physiological Role of Bile Acids Modified by the Gut Microbiome”

Reference 56 was a human study:

“Centenarians (individuals aged 100 years and older) have a decreased susceptibility to ageing-associated illnesses, chronic inflammation, and infectious diseases. Centenarians have a distinct gut microbiome enriched in microorganisms that are capable of generating unique secondary bile acids.

We identified centenarian-specific gut microbiota signatures and defined bacterial species as well as genes and/or pathways that promote generation of isoLCA, 3-oxoLCA, 3-oxoalloLCA, and isoalloLCA. To our knowledge, isoalloLCA is one of the most potent antimicrobial agents that is selective against Gram-positive microorganisms, including multidrug-resistant pathogens, suggesting that it may contribute to maintenance of intestinal homeostasis by enhancing colonization-resistance mechanisms.”

https://www.nature.com/articles/s41586-021-03832-5 “Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians” (not freely available)

A few more papers will be coming on taurine and bile acids. I haven’t seen one investigate both taurine and glycine treatments to aid bile acid in achieving therapeutic results.

Betaine and diabetes

June 5, 2022January 19, 2025 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Stress Control group, DNA methylation, Genetic factors, Neurodegenerative disease

Two 2022 papers on betaine’s effects, starting with a review:

“Rodent studies provide evidence that betaine effectively limits many diabetes-related disturbances.

Betaine therapy improves glucose tolerance and insulin action, which is strongly associated with changes in insulin-sensitive tissues, such as skeletal muscle, adipose tissue, and liver.

Betaine supplementation positively affects multiple genes, which expression is dysregulated in diabetes.

AMP-activated protein kinase is thought to play a central role in the mechanism underlying anti-diabetic betaine action.

Studies with animal models of type 2 diabetes have shown that betaine exerts anti-inflammatory and anti-oxidant effects, and also alleviates endoplasmic reticulum stress.

These changes contribute to improved insulin sensitivity and better blood glucose clearance. Results of animal studies encourage exploration of therapeutic betaine efficacy in humans with type 2 diabetes.”

https://www.sciencedirect.com/science/article/pii/S0753332222003353 “The anti-diabetic potential of betaine. Mechanisms of action in rodent models of type 2 diabetes”

Reference 31 was a human study:

“Few studies on humans have comprehensively evaluated intake composition of methyl-donor nutrients choline, betaine, and folate in relation to visceral obesity (VOB)-related hepatic steatosis (HS), the hallmark of non-alcoholic fatty liver diseases.

Total choline intake was the most significant dietary determinant of HS in patients with VOB.

Combined high intake of choline and betaine, but not folate, was associated with an 81% reduction in VOB-related HS.

High betaine supplementation could substitute for choline and folate to normalize homocysteine levels under methyl donor methionine-restriction conditions.

Preformed betaine intake from whole-grain foods and vegetables can lower obesity-increased choline and folate requirements by sparing choline oxidation for betaine synthesis and folate for methyl donor conversion in one-carbon metabolism.

Our data suggest that combined dietary intake of choline and betaine reduces the VOB-related HS risk in a threshold-dependent manner.”

https://www.mdpi.com/2072-6643/14/2/261/htm “Optimal Dietary Intake Composition of Choline and Betaine Is Associated with Minimized Visceral Obesity-Related Hepatic Steatosis in a Case-Control Study”

Increasing betaine intake to lower choline and folate requirements was similar to an idea in Treating psychopathological symptoms will somehow resolve causes? that:

“Such positive effects of taurine on glutathione levels may be explained by the fact that cysteine is the essential precursor to both metabolites, whereby taurine supplementation may drive metabolism of cysteine towards GSH synthesis.”

I came across this first paper by it citing All about the betaine, Part 2:

“This review focuses on biological and beneficial effects of dietary betaine (trimethylglycine), a naturally occurring and crucial methyl donor that restores methionine homeostasis in cells. Betaine is endogenously synthesized through metabolism of choline, or exogenously consumed through dietary intake.

Human intervention studies showed no adverse effects with 4 g/day supplemental administration of betaine in healthy subjects. However, overweight subjects with metabolic syndrome showed a significant increase in total and LDL-cholesterol concentrations. These effects were not observed with 3 g/day of betaine administration.

Betaine exerts significant therapeutic and biological effects that are potentially beneficial for alleviating a diverse number of human diseases and conditions.”

https://www.mdpi.com/2079-7737/10/6/456/htm “Beneficial Effects of Betaine: A Comprehensive Review”

The oligosaccharide stachyose

June 4, 2022 gettingwell4 4-5 stars Advanced knowledge, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Stress Brain neurons, Control group, Genetic factors, Neural plasticity

Two 2022 stachyose papers to follow on to Don’t take Beano if you’re stressed, which studied raffinose. Stachyose is in the raffinose oligosaccharide group with similar characteristics, and its content is usually larger in legumes. First is a rodent study:

“Stress can activate the hypothalamic–pituitary–adrenal (HPA) axis and elevate glucocorticoids in the body (cortisol in humans and corticosterone in rodents). Glucocorticoid receptors are abundant in the hippocampus, and play an important role in stress-induced cognition alteration.

Corticosterone is often used to model cognitive impairment induced by stress. Long-term potentiation (LTP) deficit and cognitive impairment always coexist in stress models, and LTP impairment is often considered as one mechanism for stress-induced cognitive deficits.

N-methyl-D-aspartate (NMDA) receptors play critical roles both in normal synaptic functions and excitotoxicity in the central nervous system. D-serine, a coactivator of NMDA receptors, plays an important role in brain function.

In this study, we focused on effects of stachyose, on LTP impairment by corticosterone, gut flora, and the D-serine pathway.

Data in this study showed that 7-consecutive-day intragastric (i.g.) administration of stachyose had protective effect. There was little effect via intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration.

To disturb gut flora, a combination of non-absorbable antibiotics (ATB) were applied. Results showed that ATB canceled the protective effect of stachyose without affecting LTP in control and corticosterone-treated mice, suggesting that stachyose may display its protective effects against LTP impairment by corticosterone via gut flora.

Further study is needed to uncover the relation between gut flora and the D-serine metabolic pathway.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.799244/full “Stachyose Alleviates Corticosterone-Induced Long-Term Potentiation Impairment via the Gut–Brain Axis”

One of this study’s references was Eat oats and regain cognitive normalcy.

A stachyose clinical trial is expected to complete this month:

“In the stachyose intervention group, each person took 5 g of stachyose daily before breakfast. Administration method was 100 ml of drinking water dissolved and taken orally for two months. Each person in the placebo control group took the same amount of maltodextrin daily. Stool samples of the 36 subjects were collected weekly.

Primary outcome measures:

Expression of microRNA; and

Structure of gut microbiota.”

https://clinicaltrials.gov/ct2/show/NCT05392348 “Regulatory Effect of Stachyose on Gut Microbiota and microRNA Expression in Human”

The misnomer of nonessential amino acids

June 4, 2022June 4, 2022 gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Brainstem, Cerebellum, Cerebrum, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress Control group, Embryo development, Neural plasticity, Neurodegenerative disease, Prefrontal cortex

Three papers, starting with a 2022 review:

“Ideal diets must provide all physiologically and nutritionally essential amino acids (AAs).

Proposed optimal ratios and amounts of true digestible AAs in diets during different phases of growth and production. Because dynamic requirements of animals for dietary AAs are influenced by a plethora of factors, data below as well as the literature serve only as references to guide feeding practices and nutritional research.

Nutritionists should move beyond the ‘ideal protein’ concept to consider optimum ratios and amounts of all proteinogenic AAs in diets for mammals, birds, and aquatic animals, and, in the case of carnivores, also taurine. This will help formulate effectively low-protein diets for livestock (including swine and high-producing dairy cattle), poultry, fish, and crustaceans, as well as zoo and companion animals.”

https://journals.sagepub.com/doi/10.1177/15353702221082658 “The ‘ideal protein’ concept is not ideal in animal nutrition”

A second 2022 review focused on serine:

“The main dietary source of L-serine is protein, in which L-serine content ranges between 2 and 5%. At the daily intake of ~1 g protein per kg of body weight, the amount of serine obtained from food ranges between 1.4 and 3.5 g (13.2–33.0 mmol) per day in an adult.

Mechanisms of potential benefits of supplementing L-serine include increased synthesis of sphingolipids, decreased synthesis of 1-deoxysphingolipids, decrease in homocysteine levels, and increased synthesis of cysteine and its metabolites, including glutathione. L-serine supplementation has been suggested as a rational therapeutic approach in several disorders, particularly primary disorders of L-serine synthesis, neurodegenerative disorders, and diabetic neuropathy.

Unfortunately, the number of clinical studies evaluating dietary supplementation of L-serine as a possible therapy is small. Studies examining therapeutic effects of L-serine in CNS injury and chronic renal diseases, in which it is supposed that L-serine weakens glutamate neurotoxicity and lowers homocysteine levels, respectively, are missing.”

https://www.mdpi.com/2072-6643/14/9/1987/htm “Serine Metabolism in Health and Disease and as a Conditionally Essential Amino Acid”

A 2021 review subject was D-serine, L-serine’s D-isoform:

“The N-methyl-D-aspartate glutamate receptor (NMDAR) and its co-agonist D-serine are currently of great interest as potential important contributors to cognitive function in normal aging and dementia. D-serine is necessary for activation of NMDAR and in maintenance of long-term potentiation, and is involved in brain development, neuronal connectivity, synaptic plasticity, and regulation of learning and memory.

The source of D-amino acids in mammals was historically attributed to diet or intestinal bacteria until racemization of L-serine by serine racemase was identified as the endogenous source of D-serine. The enzyme responsible for catabolism (breakdown) of D-serine is D-amino acid oxidase; this enzyme is most abundant in cerebellum and brainstem, areas with low levels of D-serine.

Activation of the NMDAR co-agonist-binding site by D-serine and glycine is mandatory for induction of synaptic plasticity. D-serine acts primarily at synaptic NMDARs whereas glycine acts primarily at extrasynaptic NMDARs.

In normal aging there is decreased expression of serine racemase and decreased levels of D-serine and down-regulation of NMDARs, resulting in impaired synaptic plasticity and deficits in learning and memory. In contrast, in AD there appears to be activation of serine racemase, increased levels of D-serine and overstimulation of NMDARs, resulting in cytotoxicity, synaptic deficits, and dementia.”

https://www.frontiersin.org/articles/10.3389/fpsyt.2021.754032/full “An Overview of the Involvement of D-Serine in Cognitive Impairment in Normal Aging and Dementia”

Fueling a gut fire

June 1, 2022June 25, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system Control group, Genetic factors

This 2022 article commented on a human / rodent study of gut dysbiosis:

“Crohn’s disease (CD) is a chronic disease that causes inflammation in the gastrointestinal track. Together with ulcerative colitis, another major type of inflammatory bowel disease (IBD), these intestinal disorders affect millions of people in the U.S. and worldwide.

Excessive T helper 1 (Th1) and Th17 cell responses have been documented to act as important mediators of CD pathogenesis. An imbalance between regulatory T (Treg) cells and effector T cells in the intestinal tissue microenvironment is crucial to promote gut inflammation in CD.

Lysophosphatidylserine (LysoPS) exaggerates intestinal inflammation by fueling IFNγ-producing Th1 cells via metabolic reprogramming and chromatin modification (panel A). While this work has provided novel functional insights into dysbiotic microbiota–derived LysoPS in CD pathogenesis (panel B), it also raises several questions.

By employing multiple animal colitis models, the authors have shown that administration of LysoPS was detrimental in T cell–driven colitis, while having no significant impact on pathogenesis of T cell–independent dextran sodium sulfate–induced colitis.

Considering the complex nature of LysoPS in regulating responses of different immune cell types in a given tissue environment under a particular physiological or pathological condition, more research is needed to elucidate the precise role of LysoPS in CD before targeting these multifunctional bioactive lipids to treat human gastrointestinal disorders becomes a reality.”

https://doi.org/10.1084/jem.20220723 “Fueling the fire in the gut”

The referenced study:

“We identified key metabolites derived from dysbiotic microbiota that induce enhanced Th1 responses and exaggerate colitis in mouse models.

Patients with CD showed elevated LysoPS concentration in their feces, accompanied by a higher relative abundance of microbiota possessing a gene encoding the phospholipid-hydrolyzing enzyme phospholipase A.

Our findings elaborate on the mechanism by which metabolites elevated in patients with CD harboring dysbiotic microbiota promote Th1-mediated intestinal pathology.”

https://doi.org/10.1084/jem.20211291 “Lysophosphatidylserines derived from microbiota in Crohn’s disease elicit pathological Th1 response”

When standard DSS and TNBS models of colitis don’t account for observed effects, other avenues need to be investigated. Relationships with our gut microbiota are complicated.

Take β-glucan for new blood vessels

May 23, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system Control group, Embryo development, Genetic factors

This 2022 cell study investigated yeast cell wall β-glucan’s effects on angiogenesis:

“Angiogenesis, the formation of new blood vessels, is essential for embryonic development and physiological damage repair, such as wound healing and post-ischemic tissue restoration. It is also essential for pathological processes, such as diabetic retinopathy, rheumatoid arthritis, and atherosclerosis.

We evaluated physical and functional interactions of β-glucan with HDAC5, including the scratched wound, tube formation, and rat aortic ring assays. β-glucan-induced HDAC5 pathway mediates cell migration and formation of tubes and microvessels in vitro and ex vivo.

Our findings demonstrate that β-glucan-induced HDAC5 phosphorylation is important in endothelial cell angiogenesis. Further investigations into how β-glucan phosphorylates HDAC5 are required. There is also a need to identify a receptor that specifically binds to β-glucan in vascular endothelial cells.

β-glucan could be useful in developing new strategies in therapeutic angiogenesis for conditions such as cardiovascular disease and diabetes.”

https://www.sciencedirect.com/science/article/abs/pii/S0141813022010273 “Yeast beta-glucan mediates histone deacetylase 5-induced angiogenesis in vascular endothelial cells” (not freely available). Thanks to Dr. Chan-Gi Pack for providing a copy.

Young gut, young eyes

May 17, 2022May 17, 2022 gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Stress Brain neurons, Control group, Corpus callosum, Genetic factors, Neural plasticity, Neurodegenerative disease

I’ll highlight this 2022 rodent study findings of effects on eye health:

“We tested the hypothesis that manipulating intestinal microbiota influences development of major comorbidities associated with aging and, in particular, inflammation affecting the brain and retina. Using fecal microbiota transplantation, we exchanged intestinal microbiota of young (3 months), old (18 months), and aged (24 months) mice.

Transfer of aged donor microbiota into young mice accelerates age-associated central nervous system inflammation, retinal inflammation, and cytokine signaling. It promotes loss of key functional protein in the eye, effects which are coincident with increased intestinal barrier permeability.

These detrimental effects can be reversed by transfer of young donor microbiota.

We provide the first direct evidence that aged intestinal microbiota drives retinal inflammation, and regulates expression of the functional visual protein RPE65. RPE65 is vital for maintaining normal photoceptor function via trans-retinol conversion. Mutations or loss of function are associated with retinitis pigmentosa, and are implicated in age-related macular degeneration.

Our finding that age-associated decline in host retinal RPE65 expression is induced by an aged donor microbiota, and conversely is rescued by young donor microbiota transfer, suggests age-associated gut microbiota functions or products regulate visual function.”

https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-022-01243-w “Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain”

Exercise substitutes?

May 16, 2022September 11, 2022 gettingwell4 2-3 stars Required further work, Cerebrum, Epigenetics, Hippocampus, Immune system, Limbic system, Memory, Stress Brain neurons, Control group, Genetic factors, Infants, Neurodegenerative disease

Two papers, starting with a 2022 abstract of an ongoing in vitro study with rodent cells:

“Exercise mimetics may target and activate the same mechanisms that are upregulated with exercise administration alone. This is particularly useful under conditions where contractile activity is compromised due to muscle disuse, disease, or aging.

Sulforaphane and Urolithin A represent our preliminary candidates for antioxidation and mitophagy, respectively, for maintaining mitochondrial turnover and homeostasis. Preliminary results suggest that these agents may be suitable candidates as exercise mimetics, and set the stage for an examination of synergistic effects.”

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.R3745 “Exercise mimicry: Characterization of nutraceutical agents that may contribute to mitochondrial homeostasis in skeletal muscle” (study not available)

A second 2022 paper reviewed what’s known todate regarding urolithins:

“Urolithins (Uros) are metabolites produced by gut microbiota from the polyphenols ellagitannins (ETs) and ellagic acid (EA). ETs are one of the main groups of hydrolyzable tannins. They can occur in different plant foods, including pomegranates, berries (strawberries, raspberries, blackberries, etc.), walnuts, many tropical fruits, medicinal plants, and herbal teas, including green and black teas.

Bioavailability of ETs and EA is very low. Absorption of these metabolites could be increased by co-ingestion with dietary fructooligosaccharides (FOS).

Effects of other experimental factors: post-intake time, duration of administration, diet type (standard and high-fat), and ET dosage (without, low, and high ET intake) in ETs metabolism were evaluated in blood serum and urine of rats consuming strawberry phenolics. Highest concentrations were obtained after 2–4 days of administration.

Various crucial issues need further research despite significant evolution of urolithin research. Overall, whether in vivo biological activity endorsed to Uros is due to each specific metabolite and(or) physiological circulating mixture of metabolites and(or) gut microbial ecology associated with their production is still poorly understood.

Ability of Uros to cross the blood-brain barrier and the nature of metabolites and concentrations reached in brain tissues need to be clarified.

Specific in vivo activity for each free and conjugated Uro metabolite is unknown. Studies on different Uro metabolites and their phase-II conjugates are needed to understand their role in human health.

Evidence on safety and impact of Uros on human health is still scarce and only partially available for Uro-A.

It is unknown whether there are potential common links between gut microbial ecologies of the two unambiguously described metabotypes so far, i.e., equol (isoflavones) and Uros (ellagitannins).

Gut microbes responsible for producing different Uros still need to be better identified and characterized, and biochemical pathways and enzymes involved.”

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.202101019 “Urolithins: a Comprehensive Update on their Metabolism, Bioactivity, and Associated Gut Microbiota”

Coffee improves information’s signal-to-noise ratio

May 14, 2022May 16, 2022 gettingwell4 4-5 stars Advanced knowledge, Anterior cingulate cortex, Cerebrum, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals Brain neurons, Control group, Genetic factors, Neural plasticity, Neurodegenerative disease

This 2022 rodent study investigated caffeine’s effects:

“A majority of molecular and neurophysiological studies explored the impact of acute rather than repeated exposure to caffeine. We show that, in bulk tissue analysis, chronic caffeine treatment reduced metabolic processes related to lipids, mitochondria, and translation in mouse hippocampus. In sharp contrast to what was observed in bulk tissue, we found that caffeine induced a neuronal autonomous epigenomic response related to synaptic plasticity activation.

Regular caffeine intake exerts a long-term effect on neuronal activity/plasticity in the adult brain, lowering metabolic-related processes, and simultaneously finely tuning activity-dependent regulations. In non-neuronal cells, caffeine decreases activities under basal conditions, and improves signal-to-noise ratio during information encoding in brain circuits, contributing to bolster salience of information.

Overall, our data prompt the novel concept that regular caffeine intake promotes a more efficient ability of the brain to encode experience-related events. By coordinating epigenomic changes in neuronal and non-neuronal cells, regular caffeine intake promotes a fine-tuning of metabolism in resting conditions.”

https://www.jci.org/articles/view/149371 “Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription”