Gut Microbiota Metabolism and Interaction with Food Components.

The human gut contains trillions of microbes that play a central role in host biology, including the provision of key nutrients from the diet. Food is a major source of precursors for metabolite production; in fact, diet modulates the gut microbiota (GM) as the nutrients, derived from dietary intake, reach the GM, affecting both the ecosystem and microbial metabolic profile. GM metabolic ability has an impact on human nutritional status from childhood. However, there is a wide variability of dietary patterns that exist among individuals. The study of interactions with the host via GM metabolic pathways is an interesting field of research in medicine, as microbiota members produce myriads of molecules with many bioactive properties. Indeed, much evidence has demonstrated the importance of metabolites produced by the bacterial metabolism from foods at the gut level that dynamically participate in various biochemical mechanisms of a cell as a reaction to environmental stimuli. Hence, the GM modulate homeostasis at the gut level, and the alteration in their composition can concur in disease onset or progression, including immunological, inflammatory, and metabolic disorders, as well as cancer. Understanding the gut microbe-nutrient interactions will increase our knowledge of how diet affects host health and disease, thus enabling personalized therapeutics and nutrition.

Identification of avaC from Human Gut Microbial Isolates that Converts 5AVA to 2-Piperidone.

2-piperidone is a crucial industrial raw material of high-value nylon-5 and nylon-6,5. Currently, a major bottleneck in the biosynthesis of 2-piperidone is the identification of highly efficient 2-piperidone synthases. In this study, we aimed to identify specific strains among 51 human gut bacterial strains capable of producing 2-piperidone and to elucidate its synthetic mechanism. Our findings revealed that four gut bacterial strains, namely Collinsella aerofaciens LFYP39, Collinsella intestinalis LFYP54, Clostridium bolteae LFYP116, and Clostridium hathewayi LFYP18, could produce 2-piperidone from 5-aminovaleric acid (5AVA). Additionally, we observed that 2-piperidone could be synthesized from proline through cross-feeding between Clostridium difficile LFYP43 and one of the four 2-piperidone producing strains, respectively. To identify the enzyme responsible for catalyzing the conversion of 5AVA to 2-piperidone, we utilized a gain-of-function library and identified avaC (5-aminovaleric acid cyclase) in C. intestinalis LFYP54. Moreover, homologous genes of avaC were validated in the other three bacterial strains. Notably, avaC were found to be widely distributed among environmental bacteria. Overall, our research delineated the gut bacterial strains and genes involved in 2-piperidone production, holding promise for enhancing the efficiency of industrial biosynthesis of this compound.

Oral Propolis Nanoemulsions Modulate Gut Microbiota to Balance Bone Remodeling for Enhanced Osteoporosis Therapy.

The discovery of the bone-gut axis linking bone metabolism to gut microbiota (GM) dysbiosis has revolutionized our understanding of managing degenerative skeletal diseases. Targeting GM regulation has emerged as a promising approach to osteoporosis treatment. Herein, we develop propolis nanoemulsions (PNEs) with enhanced gastrointestinal stability and oral bioavailability for GM-based osteoporosis therapy. Orally administered PNEs exhibit superior antiosteoporosis efficacy in an ovariectomized (OVX) mouse model by modulating the GM structure and metabolites and restoring the intestinal barrier function. Multiomics analysis reveals that a reduction in Streptococcus abundance and an increase in the GM metabolite l-arginine are key factors in osteoporosis management. These changes suppress osteoclast activity and enhance osteoblast function, leading to balanced bone remodeling and, thus, significant antiosteoporotic effects via the gut-bone axis. Our results deepen insights into the intricate relationship between GM and bone remodeling, suggesting a promising strategy that maintains the homeostasis of the GM structure and metabolite for osteoporosis treatment.

Banxia Xiexin decoction modulates gut microbiota and gut microbiota metabolism to alleviate DSS-induced ulcerative colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Banxia Xiexin decoction (BXD) is a classic traditional Chinese medicine prescription for treating ulcerative colitis (UC). However, its potential mechanism of action is still unclear. AIM OF THE STUDY: Reveal the correlation between the beneficial impacts of BXD on UC and the composition of the gut microbiota. MATERIALS AND METHODS: The major constituents of BXD were identified using the HPLC-DAD technique. An experimental model of UC was induced in male C57BL/6 mice by administering dextran sodium sulfate (DSS). A total of 48 mice were divided into different groups, including control, model, high-dose BXD treatment, medium-dose BXD treatment, low-dose BXD treatment, and a group treated with 5-amino acid salicylic acid (5-ASA). Body weight changes and disease activity index (DAI) scores were documented; colon length, colon index, spleen index, and thymus index scores were determined; myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) activities were assessed; and histological staining with hematoxylin-eosin and alcian blue/phosphate Schiff was performed. The immunofluorescence technique was employed to examine the presence of ZO-1 and occludin in the colon tissue. 16S rRNA sequencing was employed to assess the gut microbiota's diversity and metabolomics was utilized to examine alterations in metabolites within the gut microbiota. The impact of BXD on the gut microbiota was confirmed through fecal microbiota transplantation (FMT). RESULTS: BXD exhibited a positive impact on UC mice, particularly in the high-dose BXD treatment group. The BXD group experienced weight recovery, decreased DAI scores, improved colon length, and restored of spleen and thymus index scores compared to the DSS group. Additionally, BXD alleviated colon damage and the inflammatory response while restoring intestinal barrier function. FMT in BXD-treated mice also showed therapeutic effects in UC mice. At the phylum level, the relative abundance of Desulfobacterota, Deferribacterota and Actinobacteriota increased; at the genus level, g__norank__f__Muribaculaceae, Dubosiella, Akkermansia, and Lactobacillus increased, whereas Faecalibaculum, Alloprevotella, Turicibacter, and g_Paraprevotella decreased. g__norank_f__Muribaculaceae was positively correlated with body weight and colon length and negatively with colon index scores, splenic index scores, and MPO levels; Alloprevotella was positively correlated with splenic index scores, histological scores, and TNF-α levels and negatively with thymus index scores and thymus index scores. Faecalibaculum was positively correlated with colon index scores and MPO levels. Metabolic investigations revealed 58 potential indicators, primarily associated with the metabolism of amino acids, purines, and lipids. Alloprevotella, g_Paraprevotella, and Bifidobacterium were strongly associated with metabolic pathways. CONCLUSION: BXD showed beneficial therapeutic effects in UC mice. The mechanism may be by promoting the balance and variety of gut microbiota, as well as regulating the metabolism of amino acids, purines, and lipids.

Exendin-4-enriched exosomes from hUCMSCs alleviate diabetic nephropathy via gut microbiota and immune modulation.

Introduction: Diabetic nephropathy (DN) presents a significant therapeutic challenge, compounded by complex pathophysiological mechanisms. Recent studies suggest Exendin-4 (Ex-4) as a potential ameliorative agent for DN, albeit with unclear mechanisms. This research investigates the effects and underlying mechanisms of Ex-4-enriched exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs) on DN, focusing on their renoprotective properties and interactions with gut microbiota. Method: Exosomes from hUCMSCs (hUCMSCs-Exo) were loaded with Ex-4 via electroporation. A streptozotocin (STZ) -induced DN mouse model was employed to assess the therapeutic impact of these engineered exosomes. The study further explored immune cell dynamics, mainly CD4+ regulatory T (Treg) cells, using bioinformatics, flow cytometry, and the influence of gut microbiota through antibiotic treatment and specific bacterial reintroduction. Results: Treatment with hUCMSCs-Exo@Ex-4 significantly improved key DN markers, including blood glucose and proteinuria, alleviating kidney damage. A notable decrease in natural Treg cell infiltration in DN was observed, while Ex-4-loaded exosomes promoted CD4+ Treg cell induction. The therapeutic benefits of hUCMSCs-Exo@Ex-4 were diminished upon CD4+ Treg cell depletion, underscoring their role in this context. Notably, CD4+ Treg cell induction correlated with the presence of Prevotella species, and disruption of gut microbiota adversely affected these cells and the therapeutic efficacy of the treatment. However, the reintroduction of Prevotella strains counteracted these adverse effects. Discussion: This study elucidates a novel therapeutic mechanism of Ex-4-loaded hUCMSCs exosomes in DN, highlighting the induction of CD4+ Treg cells mediated by specific gut microbiota components. These findings underscore the potential of leveraging gut microbiota and immune cell interplay in developing effective DN treatments.

Hypoglycemic Effect of Nobiletin via Gut Microbiota-Metabolism Axis on Hyperglycemic Mice.

SCOPE: Prediabetes and diabetes are major public health problems worldwide without specific cure currently. Gut microbes have been recognized as one of the vital therapeutic targets for diabetes. The exploration that nobiletin (NOB) whether affects gut microbes provides a scientific basis for its application. METHODS AND RESULTS: A hyperglycemia animal model is established using high-fat-fed ApoE-/- mice. After 24 weeks of NOB intervention, the level of fasting blood glucose (FBG), glucose tolerance, insulin resistance, and glycosylated serum protein (GSP) are measured. Pancreas integrity is observed by hematoxylin-eosin (HE) staining and transmission electron microscopy. 16s RNA sequencing and untargeted metabolomics are to determine the changes of intestinal microbial composition and metabolic pathways. The levels of FBG and GSP in hyperglycemic mice are effectively reduced. The secretory function of pancreas is improved. Meanwhile, NOB treatment restored the gut microbial composition and affected metabolic function. Furthermore, NOB treatment regulates the metabolic disorder mainly through lipid metabolism, amino acid metabolism, and Secondary bile acid metabolism, etc. In addition, it is possibly existed mutual promotion between microbe and metabolites. CONCLUSION: NOB probably plays a vital role in the hypoglycemic effect and pancreatic islets protection by improving microbiota composition and gut metabolism.

Melatonin and probiotics ameliorate nanoplastics-induced hematopoietic injury by modulating the gut microbiota-metabolism.

Plastic pollution has become a non-negligible global pollution problem. Nanoplastics (NP) can reach the bone marrow with blood circulation and develop hematotoxicity, but potential mechanisms and prevention strategies are lacking. Here, we report the biological distribution of NP particles in the bone marrow of mice and hematopoietic toxicity after exposure to 60 µg of 80 nm NP for 42 days. NP exposure inhibited the capability of bone marrow hematopoietic stem cells to renew and differentiate. Notably, probiotics and melatonin supplementation significantly ameliorated NP-induced hematopoietic damage, and the former was superior to the latter. And interestingly, melatonin and probiotic interventions may involve different microbes and metabolites. After melatonin intervention, creatine showed a stronger correlation with NP-induced gut microbiota disorders. In contrast, probiotic intervention reversed the levels of more gut microbes and plasma metabolites. Of these, threonine, malonylcarnitine, and 3-hydroxybutyric acid might be potential performers in the regulation of hematopoietic toxicity by gut microbes, as they had a more significant relationship with the identified microbes. In conclusion, supplementation with melatonin or probiotics may be two candidates to prevent hematopoietic toxicity attributable to NP exposure. Also, the multi-omics results may lay the foundation for future investigations into in-depth mechanisms.

A Critical Role for CARD9 in Intestinal Microbiota Modulation and Colorectal Malignancies.

The adaptor protein Caspase Recruitment Domain Family Member 9 (CARD9) plays an indispensable role in innate immunity. Recent studies indicate that dysregulated CARD9 is a critical risk factor in the progression of colorectal cancer (CRC). This review provides novel insights into the functions of CARD9 in CRC, particularly in delineating its role in disrupting the host microbe balance, fueling gut microbiota metabolism and inducing systemic immunoglobulin G (IgG) antifungal antibodies. These pathways provide important information that can potentially be used for therapeutic innovation in developing potential vaccines for CRC.

Probiotics: Protecting Our Health from the Gut.

The gut microbiota (GM) comprises billions of microorganisms in the human gastrointestinal tract. This microbial community exerts numerous physiological functions. Prominent among these functions is the effect on host immunity through the uptake of nutrients that strengthen intestinal cells and cells involved in the immune response. The physiological functions of the GM are not limited to the gut, but bidirectional interactions between the gut microbiota and various extraintestinal organs have been identified. These interactions have been termed interorganic axes by several authors, among which the gut-brain, gut-skin, gut-lung, gut-heart, and gut-metabolism axes stand out. It has been shown that an organism is healthy or in homeostasis when the GM is in balance. However, altered GM or dysbiosis represents a critical factor in the pathogenesis of many local and systemic diseases. Therefore, probiotics intervene in this context, which, according to various published studies, allows balance to be maintained in the GM, leading to an individual's good health.

5-Aminolevulinic Acid as a Novel Therapeutic for Inflammatory Bowel Disease.

5-Aminolevulinic acid (5-ALA) is a naturally occurring nonprotein amino acid licensed as an optical imaging agent for the treatment of gliomas. In recent years, 5-ALA has been shown to possess anti-inflammatory and immunoregulatory properties through upregulation of heme oxygenase-1 via enhancement of porphyrin, indicating that it may be beneficial for the treatment of inflammatory conditions. This study systematically examines 5-ALA for use in inflammatory bowel disease (IBD). Firstly, the ex vivo colonic stability and permeability of 5-ALA was assessed using human and mouse fluid and tissue. Secondly, the in vivo efficacy of 5-ALA, in the presence of sodium ferrous citrate, was investigated via the oral and intracolonic route in an acute DSS colitis mouse model of IBD. Results showed that 5-ALA was stable in mouse and human colon fluid, as well as in colon tissue. 5-ALA showed more tissue restricted pharmacokinetics when exposed to human colonic tissue. In vivo dosing demonstrated significantly improved colonic inflammation, increased local heme oxygenase-1 levels, and decreased concentrations of proinflammatory cytokines TNF-α, IL-6, and IL-1ß in both plasma and colonic tissue. These effects were superior to that measured concurrently with established anti-inflammatory treatments, ciclosporin and 5-aminosalicylic acid (mesalazine). As such, 5-ALA represents a promising addition to the IBD armamentarium, with potential for targeted colonic delivery.

Human Gut Microbiota Metabolism of Dietary Sesquiterpene Lactones: Untargeted Metabolomics Study of Lactucopicrin and Lactucin Conversion In Vitro and In Vivo.

SCOPE: Gut microbiota converts dietary phytochemicals into metabolites and modulates their health effects. The microbial metabolism of dietary terpenoids, as the sesquiterpene lactones of leafy vegetables, is unknown. METHODS AND RESULTS: In vitro fermentation of lactucopicrin, lactucin, and romaine lettuce with gut microbiota from independent donors, show their extensive metabolism through untargeted metabolomics of the fecal incubations. Dehydroxylations and double bond hydrogenations are the main catabolic reactions. Isomers of dihydrolactucopicrin, tetrahydrolactucopicrin, and deoxylactucin, are observed after lactucopicrin metabolism. Tetrahydrolactucin and hexahydrolactucin are also found after lactucin metabolism. Lettuce fermentation shows similar metabolic conversions. Phase II conjugates of most of these metabolites are detected in the urine of healthy volunteers after escarole salad intake. Glucuronides, and sulfates, of dihydrolactucopicrin, tetrahydrolactucopicrin, dihydrolactucin, and deoxylactucin, are detected in the urine although with large inter-subject variability. CONCLUSION: This is the first report on the gut microbiota metabolism of sesquiterpene lactones in humans, and one of the first reports to describe that dietary terpenoids of widely consumed leafy vegetables are extensively catabolized by human gut microbiota. A large inter-subject variation in the metabolism of sesquiterpene lactones also reflects differences in gut microbiota composition. It suggests that inter-individual differences in their health effects should be expected.

Interactions of Dihydromyricetin, a Flavonoid from Vine Tea (Ampelopsis grossedentata) with Gut Microbiota.

Dihydromyricetin (DMY) is the main bioactive constituent in vine tea (Ampelopsis grossedentata), which was predominantly distributed in the gastrointestinal tract and showed poor oral bioavailability. Our aim was to systematically investigate the interactions of DMY with gut microbiota. Through the metabolism study of DMY by fecal microflora in vitro, it was found that DMY could be metabolized into three metabolites by fecal microflora via reduction and dehydroxylation pathways, and the dehydroxylation metabolite was the dominant one. Meanwhile, in order to consider the influence of gut microbiota metabolism on the pharmacokinetics of DMY, the pharmacokinetics of DMY in control and pseudo-germ-free rats were compared. It was shown that area under the curve (AUC) could only slightly increase, however, peak concentration (Cmax ) could significantly increase in the pseudo-germ-free rats compared with the control rats, which indicated the gut microbiota metabolism played an important role in the pharmacokinetics of DMY. In addition, the long-term influence of DMY on gut microbiota composition by using 16S rRNA pyrosequencing was further investigated. And it was found that DMY could markedly alter the richness and diversity of the gut microbiota and modulate the gut microbiota composition. The present findings will be helpful for the future development and clinical application of DMY. PRACTICAL APPLICATION: The gut microbiota plays an important role in the pharmacokinetics of flavonoids. As well, the long-term supplements of flavonoids could alter the gut microbiota composition in turn. The study aims to clarify the mutual interaction of DMY with gut microbiota, which may lead to new information with respect to the mechanism study and clinical application of DMY.