AG1® Induces a Favorable Impact on Gut Microbial Structure and Functionality in the Simulator of Human Intestinal Microbial Ecosystem® Model.

Modulation of the human gut microbiome has become an area of interest in the nutraceutical space. We explored the effect of the novel foundational nutrition supplement AG1® on the composition of human microbiota in an in vitro experimental design. Employing the Simulator of Human Intestinal Microbial Ecosystem (SHIME®) model, AG1® underwent digestion, absorption, and subsequent colonic microenvironment simulation under physiologically relevant conditions in healthy human fecal inocula. Following 48 h of colonic simulation, the gut microbiota were described using shallow shotgun, whole genome sequencing. Metagenomic data were used to describe changes in community structure (alpha diversity, beta diversity, and changes in specific taxa) and community function (functional heterogeneity and changes in specific bacterial metabolic pathways). Results showed no significant change in alpha diversity, but a significant effect of treatment and donor and an interaction between the treatment and donor effect on structural heterogeneity likely stemming from the differential enrichment of eight bacterial taxa. Similar findings were observed for community functional heterogeneity likely stemming from the enrichment of 20 metabolic pathways characterized in the gene ontology term database. It is logical to conclude that an acute dose of AG1 has significant effects on gut microbial composition that may translate into favorable effects in humans.

Farnesol induces protection against murine CNS inflammatory demyelination and modifies gut microbiome.

Farnesol is a 15­carbon organic isoprenol synthesized by plants and mammals with anti-oxidant, anti-inflammatory, and neuroprotective activities. We sought to determine whether farnesol treatment would result in protection against murine experimental autoimmune encephalomyelitis (EAE), a well-established model of multiple sclerosis (MS). We compared disease progression and severity in C57BL/6 mice treated orally with 100 mg/kg/day farnesol solubilized in corn oil to corn-oil treated and untreated EAE mice. Farnesol significantly delayed the onset of EAE (by ~2 days) and dramatically decreased disease severity (~80%) compared to controls. Disease protection by farnesol was associated with a significant reduction in spinal cord infiltration by monocytes-macrophages, dendritic cells, CD4+ T cells, and a significant change in gut microbiota composition, including a decrease in the Firmicutes:Bacteroidetes ratio. The study suggests FOL could protect MS patients against CNS inflammatory demyelination by partially modulating the gut microbiome composition.

Intestinal Dysbiosis as a component of pathophysiology in succinic semialdehyde dehydrogenase deficiency (SSADHD).

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited inborn error of the γ-aminobutyric acid (GABA) metabolism pathway. It results from mutations in the ALDH5A1 gene leading to elevated GABA, γ-hydroxybutyric acid (GHB), succinic semialdehyde (SSA), decreased glutamine and alterations in several other metabolites. The phenotype includes developmental and cognitive delays, hypotonia, seizures, neuropsychiatric morbidity and other nervous system pathologies. The composition of the intestinal flora of patients with SSADHD has not been characterized, and dysbiosis of the gut microbiome may unveil novel treatment paradigms. We investigated the gut microbiome in SSADHD using 16S ribosomal DNA sequencing and unmasked evidence of dysbiosis in both aldh5a1-deficient mice and patients with SSADHD. In the murine model, there was a reduction in α-diversity measurements, and there were 4 phyla, 3 classes, 5 orders, 9 families, and 15 genera that differed, with a total of 17 predicted metabolic pathways altered. In patients, there were changes in Fusobacterium, 3 classes, 4 orders, 11 families, and a predicted alteration in genes associated with the digestive system. We believe this is the first evaluation of microbiome structure in an IEM with a neurometabolic phenotype that is not treated dietarily.

Dysbiosis of the intestinal microbiome as a component of pathophysiology in the inborn errors of metabolism.

Inborn errors of metabolism (IEMs) represent monogenic disorders in which specific enzyme deficiencies, or a group of enzyme deficiencies (e.g., peroxisomal biogenesis disorders) result in either toxic accumulation of metabolic intermediates or deficiency in the production of key end-products (e.g., low cholesterol in Smith-Lemli-Opitz syndrome (Gedam et al., 2012 [1]); low creatine in guanidinoacetic acid methyltransferase deficiency (Stromberger, 2003 [2])). Some IEMs can be effectively treated by dietary restrictions (e.g., phenylketonuria (PKU), maple syrup urine disease (MSUD)), and/or dietary intervention to remove offending compounds (e.g., acylcarnitine excretion with the oral intake of l-carnitine in the disorders of fatty acid oxidation). While the IEMs are predominantly monogenic disorders, their phenotypic presentation is complex and pleiotropic, impacting multiple physiological systems (hepatic and neurological function, renal and musculoskeletal impairment, cardiovascular and pulmonary activity, etc.). The metabolic dysfunction induced by the IEMs, as well as the dietary interventions used to treat them, are predicted to impact the gut microbiome in patients, and it is highly likely that microbiome dysbiosis leads to further exacerbation of the clinical phenotype. That said, only recently has the gut microbiome been considered as a potential pathomechanistic consideration in the IEMs. In this review, we overview the function of the gut-brain axis, the crosstalk between these compartments, and the expanding reports of dysbiosis in the IEMs recently reported. The potential use of pre- and probiotics to improve clinical outcomes in IEMs is also highlighted.

Foundational Nutrition: Implications for Human Health.

Human nutrition, and what can be considered "ideal" nutrition, is a complex, multi-faceted topic which many researchers and practitioners deliberate. While some attest that basic human nutrition is relatively understood, it is undeniable that a global nutritional problem persists. Many countries struggle with malnutrition or caloric deficits, while others encounter difficulties with caloric overconsumption and micronutrient deficiencies. A multitude of factors contribute to this global problem. Limitations to the current scope of the recommended daily allowances (RDAs) and dietary reference intakes (DRIs), changes in soil quality, and reductions in nutrient density are just a few of these factors. In this article, we propose a new, working approach towards human nutrition designated "Foundational Nutrition". This nutritional lens combines a whole food approach in conjunction with micronutrients and other nutrients critical for optimal human health with special consideration given to the human gut microbiome and overall gut health. Together, this a synergistic approach which addresses vital components in nutrition that enhances the bioavailability of nutrients and to potentiate a bioactive effect.

Nutrient synergy: definition, evidence, and future directions.

Nutrient synergy refers to the concept that the combined effects of two or more nutrients working together have a greater physiological impact on the body than when each nutrient is consumed individually. While nutrition science traditionally focuses on isolating single nutrients to study their effects, it is recognized that nutrients interact in complex ways, and their combined consumption can lead to additive effects. Additionally, the Dietary Reference Intakes (DRIs) provide guidelines to prevent nutrient deficiencies and excessive intake but are not designed to assess the potential synergistic effects of consuming nutrients together. Even the term synergy is often applied in different manners depending on the scientific discipline. Considering these issues, the aim of this narrative review is to investigate the potential health benefits of consuming different nutrients and nutrient supplements in combination, a concept we define as nutrient synergy, which has gained considerable attention for its impact on overall well-being. We will examine how nutrient synergy affects major bodily systems, influencing systemic health. Additionally, we will address the challenges associated with promoting and conducting research on this topic, while proposing potential solutions to enhance the quality and quantity of scientific literature on nutrient synergy.

Co-consuming green tea with raloxifene decreases raloxifene systemic exposure in healthy adult participants.

Green tea is a popular beverage worldwide. The abundant green tea catechin (-)-epigallocatechin gallate (EGCG) is a potent in vitro inhibitor of intestinal UDP-glucuronosyltransferase (UGT) activity (Ki ~2 µM). Co-consuming green tea with intestinal UGT drug substrates, including raloxifene, could increase systemic drug exposure. The effects of a well-characterized green tea on the pharmacokinetics of raloxifene, raloxifene 4'-glucuronide, and raloxifene 6-glucuronide were evaluated in 16 healthy adults via a three-arm crossover, fixed-sequence study. Raloxifene (60 mg) was administered orally with water (baseline), with green tea for 1 day (acute), and on the fifth day after daily green tea administration for 4 days (chronic). Unexpectedly, green tea decreased the geometric mean green tea/baseline raloxifene AUC0-96h ratio to ~0.60 after both acute and chronic administration, which is below the predefined no-effect range (0.75-1.33). Lack of change in terminal half-life and glucuronide-to-raloxifene ratios indicated the predominant mechanism was not inhibition of intestinal UGT. One potential mechanism includes inhibition of intestinal transport. Using established transfected cell systems, a green tea extract normalized to EGCG inhibited 10 of 16 transporters tested (IC50 , 0.37-12 µM). Another potential mechanism, interruption by green tea of gut microbe-mediated raloxifene reabsorption, prompted a follow-up exploratory clinical study to evaluate the potential for a green tea-gut microbiota-drug interaction. No clear mechanisms were identified. Overall, results highlight that improvements in current models and methods used to predict UGT-mediated drug interactions are needed. Informing patients about the risk of co-consuming green tea with raloxifene may be considered.

Microbiome Methods in Experimental Autoimmune Encephalomyelitis.

Microbiome composition studies are increasingly shedding light on animal models of disease. This paper describes a protocol for analyzing the gut microbiome composition prior to and after the induction of mice to experimental autoimmune encephalomyelitis (EAE), the principal animal model of the human neuroinflammatory demyelinating disease multiple sclerosis (MS). We also address and provide data assessing the impact of mice reared in different animal facilities on EAE induction. Furthermore, we discuss potential regulators of the gut-microbiome-brain axis (GMBA) in relation to neuroinflammation and implications on demyelinating disease states. Our results suggest that mice reared in different animal facilities produce different levels of EAE induction. These results highlight the importance of accounting for consistent environmental conditions when inducing EAE and other animal models of disease. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Study of the composition of the gut microbiome in the neuroinflammatory model of experimental autoimmune encephalomyelitis Basic Protocol 2: Experimental procedures for DNA extraction and microbiome analysis.

The Gut Microbiome in Multiple Sclerosis: A Potential Therapeutic Avenue.

Recently, there has been a substantial increase in the number of studies focused upon connecting the gut microbiome with cases of central nervous system (CNS) autoimmunity. Multiple sclerosis (MS) is a neurodegenerative autoimmune disorder of the CNS. Recent experimental and clinical evidence suggests the presence of microbial imbalances in the gut of MS sufferers. The gut microbiome is defined as the summation of all the microbial entities as well as their genes, proteins, and metabolic products in a given space and time. Studies show the MS gut microbiome as having general alterations in specific taxa, some associated with the promotion of inflammatory cytokines and overall inflammation. In conjunction with these findings, experimental models of the disease have reported that T regulatory (Treg) cells have deficits in their function as a result of the aberrant gut microbiota composition. The findings suggest that the interactions between the host and the microbiota are reciprocal, although more extensive work is required to confirm this. Moreover, evidence indicates that changes in microbiota composition may result in imbalances that could result in disease, with the gut as a potential novel therapeutic avenue. By understanding the biological effects of aberrant gut microbiome composition, it is possible to contemplate current therapeutic options and their efficacy. Ultimately, more research is necessary in this field, but targeting the gut microbiota may lead to the development of novel therapeutic strategies.

The Gut Microbiome and Multiple Sclerosis.

The microbiome can be defined as the sum of the microbial and host's genome. Recent information regarding this complex organ suggests that in animal models of multiple sclerosis (MS), the composition of the gut microbiome can be altered, giving rise to both the effector and regulatory phases of central nervous system (CNS) demyelination. Experimental findings during the past decade in animal models of MS have provided clear evidence for the significant role of gut microbes in both the effector and regulatory phase of this condition. There is mounting evidence in preliminary human studies suggesting that a dysbiotic MS gut microbiome could affect disease progression. We propose considering the gut microbiome as a key organ for the regulation of tolerance mechanisms and speculate that the gut microbiome is the major environmental risk factor for CNS demyelinating disease. Accordingly, we hypothesize that intervention of the gut microbiome could result in safer novel therapeutic strategies to treat MS.