The gut microbiome is altered after bariatric surgery and is associated with weight loss. However, the commensal bacteria involved and the underlying mechanism remain to be determined. We performed shotgun metagenomic sequencing in obese subjects before and longitudinally after sleeve gastrectomy (SG), and found a significant enrichment in microbial species in Clostridia and bile acid metabolizing genes after SG treatment. Bile acid profiling further revealed decreased primary bile acids (PBAs) and increased conjugated secondary bile acids (C-SBAs) after SG. Specifically, glycodeoxycholic acid (GDCA) and taurodeoxycholic acid (TDCA) were increased at different follow-ups after SG, and were associated with the increased abundance of Clostridia and body weight reduction. Fecal microbiome transplantation with post-SG feces increased SBA levels, and alleviated body weight gain in the recipient mice. Furthermore, both Clostridia-enriched spore-forming bacteria and GDCA supplementation increased the expression of genes responsible for lipolysis and fatty acid oxidation in adipose tissue and reduced adiposity via Takeda G-protein-coupled receptor 5 (TGR5) signaling. Our findings reveal post-SG gut microbiome and C-SBAs as contributory to SG-induced weight loss, in part via TGR5 signaling, and suggest SBA-producing gut microbes as a potential therapeutic target for obesity intervention.

Bile acid diarrhea is a common but underdiagnosed condition. Because the gold standard test (75SeHCAT) is time-consuming and not widely available, fecal bile acid excretion is typically assessed by chromatography and mass spectrometry. Although enzymatic cycling assays are well established for the rapid and cost-effective analysis of total bile acids (TBA) in serum or plasma, their full potential has yet not been extended to stool samples in clinical routine.

The performance of the 'Total bile acids 21 FS' reagent (DiaSys) was evaluated in fecal matrix according to CLSI guidelines and EU-IVD Regulations (2017/745), and compared to an established microplate-based kit (IDK®) by measuring patient stool samples (n=122). Method agreement was assessed by Passing-Bablok and Bland-Altman analysis. The quantification of eight individual BAs was assessed using HPLC-MS/MS as reference method.

The DiaSys assay showed linearity between 3.5 and 130 μmol/L, good repeatability, total precision, and reproducibility with CVs of 1.7 %, 3.5 %, and 3.0 %. Limit of blank (LoB), detection (LoD), and quantitation (LoQ) were ≤0.17, ≤0.3, and 3.5 μmol/L, respectively. No significant interference from endogenous substances was observed. The methods showed good correlation up to 140 μmol/L (r=0.988), despite differences in the quantification of individual BAs, with mean deviations of 7 % (DiaSys) and 31 % (IDK®), respectively.

The advantages of enzymatic TBA analysis on fully automated clinical chemistry platforms can be exploited for the routine analysis of stool samples. However, cycling assays may benefit from reference standards that take into account the composition of the fecal BA pool.

Cholestatic liver disease(CLD) is caused by impaired bile flow due to obstruction of the biliary tract, and long-term exposure to bile acids in the liver triggers inflammation, eventually leading to liver toxicity and liver fibrosis. Emodin-8-O-β-D-glucopyranoside(EG) is anthraquinone compound that is widely found in traditional Chinese medicine. It possessed antioxidative and anti-inflammatory activities. However, the effect of EG on cholestatic liver injury(CLI) has not been explored. In this study, Alpha-naphthyl isothiocyanate(ANIT)-induced CLI mice were used to investigate the anti-cholestasis and hepatoprotective effects of EG through serum biochemical index detection, non-targeted metabolomics, lipidomics, and intestinal flora 16S rRNA sequencing. The results suggested that EG restores homeostasis of the gut microbiome while regulating bile acids metabolism and lipid-related metabolic pathways to reduce liver damage in ANIT-induced cholestasis. This study provides a new perspective on the mechanism of EG, and help offer a more natural approach to managing liver damage.

A high-fat/cholesterol/cholate-based (iHFC) diet induces pathological changes in Tsumura-Suzuki non-obese (TSNO) mice, resembling human metabolic dysfunction associated steatohepatitis (MASH), along with advanced liver fibrosis. In this study, we investigated the role of cholic acid (CA) in the development of iHFC diet-induced MASH development. In mice receiving an iHFC diet without CA (CA(-) iHFC diet), both lobular inflammation and fibrosis progression in the liver were attenuated compared to those on the standard iHFC diet. Notably, hepatocyte ballooning was significantly improved in the CA(-) iHFC diet group. The expression levels of genes associated with inflammation and fibrosis were lower in the livers of CA(-) iHFC diet-fed mice compared to those fed the iHFC diet. Furthermore, there were no significant changes in the proportion and number of monocyte-derived macrophages in the livers of CA(-) iHFC diet-fed mice relative to those in the ND (normal diet)-fed group. The co-localization of CD11c+ macrophages with collagen fibers in the livers of CA(-) iHFC diet-fed mice did not significantly differ from that of the ND-fed group. Moreover, the CA(-) iHFC-fed mice exhibited a distinct microbial composition relative to both ND- and iHFC-fed mice. Finally, the increase in deoxycholic acid in fecal samples and the reduced hepatic expression of Cyp27a1 and Cyp7a1 induced by the iHFC diet were less in the CA(-) iHFC-fed group. These results suggest that CA modulates iHFC diet-induced MASH development by influencing the accumulation of monocyte-derived macrophages in the liver and shaping the gut microbiota composition and bile acid profile.

Levilactobacillus brevis KU15006, isolated from kimchi, exhibits pathogen-antagonistic and anti-diabetic activities; however, the safety of this strain has not been assessed. In the present study, L. brevis KU15006 was evaluated to elucidate its safety as a probiotic strain using phenotypic and genotypic analyses. Its safety was assessed using a minimum inhibitory concentration test comprising nine antibiotics, 26 antibiotic resistance genes, a single conjugative element, virulence gene analysis, hemolysis, cell cytotoxicity, mucin degradation, and toxic metabolite production. L. brevis KU15006 exhibited equal or lower minimum inhibitory concentration for the nine antibiotics than the cut-off value established by the European Food Safety Authority. It did not harbor antibiotic resistance and virulence genes. L. brevis KU15006 lacked β-hemolysis, mucin degradation, cytotoxicity against Caco-2 cells, gelatin liquefaction, bile salt deconjugation, and toxic metabolite production abilities. Based on the results, L. brevis KU15006, which has antagonistic and anti-diabetic effects, could be marketed as a probiotic in the future.

Recent studies suggest that secondary bile acids (SBAs) play a role in energy metabolism and feed intake regulation, but their effects in fish remain largely unknown. This study evaluates the impact of intragastric administration of the main SBAs [500 µM lithocholic acid (LCA), 1,500 µM deoxycholic acid (DCA), and their taurine conjugates: 1,000 µM T-LCA and 600 µM T-DCA] on feed intake, regulatory pathways, and bile acid-related elements in rainbow trout. Results show that all tested SBAs influenced bile acid transporters [apical sodium-dependent bile acid transporter (Asbt), Na+ taurocholate co-transporting polypeptide (Ntcp), organic solute transporter α and β (Ostα, and Ostβ)] and receptors [farnesoid X receptor like-α and β (Fxrα, Fxrβ), and Takeda G protein-coupled receptor 5 (Tgr5)], with DCA and T-DCA mainly affecting the gastrointestinal tract and LCA modulating hypothalamic pathways, suggesting a putative orexigenic role. Plasma analysis confirmed SBA absorption from the gastrointestinal tract into the bloodstream. This study provides the first evidence in fish of SBAs modulating gene and protein expression linked to appetite regulation, underscoring their role in gut-brain communication. Although all SBAs influenced fxr expression, gpbar1 remained unaffected, differing from mammals where BAs suppress appetite. Notably, despite taurine-conjugated SBAs being the most abundant in rainbow trout, only nonconjugated LCA showed significant effects. Taken together, these results provide new information on the emerging importance of SBA in feed intake regulation and bile acid mechanisms.NEW & NOTEWORTHY This study determined for the first time in teleost fish (specifically in rainbow trout): 1) the role of secondary bile acids in the regulation of feed intake and associated signaling pathways, highlighting a putative orexigenic role of lithocholic acid (LCA); 2) the response of Asbt and Ostα transporters and Tgr5 receptor in hypothalamus after LCA administration; and 3) the reabsorption of LCA, DCA, and their taurine conjugates from the gastrointestinal tract into the bloodstream.

Feeding increases plasma bile acid levels while the nucleus of the solitary tract (NTS) and area postrema (AP) of the brain detect changes in hormones to regulate feeding. However, whether an increase in bile acids activates Takeda G protein-coupled receptor 5 (TGR5) in the NTS and/or AP to lower feeding through a negative feedback pathway is unknown. Here, we discover that infusion of TGR5 agonist CCDC in the NTS of male rats lowered food intake without causing conditional taste avoidance in short-term high fat (HF) fed male rats in association with HF-induced increase in TGR5 expression in the NTS. In contrast, CCDC infusion into the AP failed to lower food intake in HF rats with a reduction in TGR5 expression in the AP. CCDC infusion in the NTS activates TGR5 to reverse HF-induced leptin resistance by enhancing a leptin-leptin receptor-STAT3 signaling axis selectively in the NTS to lower feeding. Finally, metabolomic analysis indicated that HF impaired a refeeding-induced rise of endogenous TGR5 ligand deoxycholic acid in the plasma and subsequently in the NTS in association with hyperphagia, while direct infusion of deoxycholic acid in the NTS of HF rats activated TGR5 to lower feeding and enhanced leptin-STAT3 signaling, thereby altogether demonstrating physiological and pharmacological activation of TGR5 in the NTS regulates food intake. In summary, we discover that an activation of TGR5 in the NTS enhances leptin-STAT3 signaling to lower food intake. Our findings highlight the potential of targeting TGR5 to reverse leptin resistance in the NTS.

Metabolic dysfunction associated steatotic liver disease (MASLD) is the predominant cause of chronic liver disease, with dysregulation of bile acid (BA) metabolism and intestinal microbiota being intricately associated with MASLD progression. In this study, we investigated the role of ileal FXR in MASLD progression and BA metabolism in portal blood.

Sprague-Dawley rats were fed a typical western diet for 20 weeks, followed by local perfusion of AAV2-shNr1h4 to downregulate Nr1h4 expression in ileum tissue. To investigate the effect of ileal FXR on BA reabsorption and gut microbiota, portal blood and cecal fecal samples were collected from MASLD rats injected with AAV2-Ctrl or AAV2-shNr1h4 for metabolomics targeting BAs and 16S rRNA sequencing analysis.

Our results showed that hepatic steatosis and inflammation were alleviated, whereas the reabsorption of secondary BAs and unconjugated BAs into the portal blood was enhanced when ileal FXR was knocked down. Furthermore, knockdown of ileal FXR resulted in a significant alteration in composition of the cecal microbiota, characterized by an increasing abundance of microbes involved in secondary BA production, including Escherichia, Adlercreutzia, Eubacterium, and Clostridium.

These findings suggest that downregulation of ileal FXR ameliorates the progression of MASLD in rats by modulating BA metabolism mediated by the gut microbiota, indicating that ileal FXR might be a potential therapeutic target for the treatment of MASLD.

The specific influence of whole gut transit time (WGTT) on microbiome dynamics and bile acid metabolism remains unclear, despite links between changes in WGTT and certain gastrointestinal disorders. Our investigation aimed to determine the impact of WGTT changes on the composition of the fecal microbiome and bile acid profile.

Healthy volunteers (n = 18) received loperamide, to decrease bowel movement frequency, and senna, a laxative, each over a 6-day period, in a randomized sequence, with a minimum 16-day interval between each treatment. Stool samples were analyzed for microbiome by shotgun sequencing and bile acid composition determined with high-performance liquid chromatography coupled to tandem mass spectrometry. Sera were examined for markers of bile acid synthesis.

Senna or loperamide decreased or increased WGTT, respectively. Treatment altered stool characteristics, bowel movement frequency, and stool weight. The senna-treated group had increased primary and secondary fecal bile acids; serum levels of fibroblast growth factor 19 were significantly reduced. Increasing WGTT with loperamide led to an increase in bile salt hydrolase genes, along with elevated bacterial species richness (p = 0.04). Thirty-six species exhibiting significant differences were identified, several of which have notable implications for gut health. WGTT displayed negative correlations with total primary (particularly chenodeoxycholic acid) and secondary bile acids (ursodeoxycholic acid and glycochenodeoxycholic acid). Treatment-induced changes in microbiome composition and bile acid metabolism reverted back to baseline within 16 days.

Whole gut transit time changes significantly affect fecal microbiome composition and function, as well as bile acid composition and synthesis in healthy subjects. This consideration is likely to have long-term implications.

The roles of gut microbiota and microbially modified bile acids in human health have become widely recognized. In the last five years, various microbially modified bile acids (e.g., proteinogenic amino-conjugated bile acids, polyamine-conjugated bile acids, neuroactive amine-conjugated bile acids, methylcysteamine-conjugated bile acids, acylated bile acids, dicarboxylic acid-conjugated bile acids, lithocholic acid (LCA) derivatives) were identified and evaluated, which greatly enriched the mammalian bile acid pool and the bioactivity of bile acids. The structure, enzyme, function, clinical reports of these bile acids, and the bacteria to produce these bile acids were summarized in this review. These novel bile acids had various functions including immunoregulation, receptor regulator, antimicrobial activity, and microbial communities regulating effect. 70, 4, 1, 11, 19, 41, 43, 9, 10 species were observed to produce proteinogenic amino-conjugated bile acids, neuroactive amine-conjugated bile acids, methylcysteamine-conjugated bile acids, acylated bile acids, dicarboxylic acid-conjugated bile acids, 3-oxoLCA, isoLCA, 3-oxoalloLCA, and isoalloLCA, respectively. The current review has shed new light on discovering new bile acid derivatives as drug candidates. These microbially modified bile acids may play important roles in disease such as sleeve gastrectomy, fatty liver, inflammatory bowel disease, cystic fibrosis, and type 2 diabetes, which may also participate in normal physiological processes such as growth of infants, longevity, and dietary habits.

Bile acids, derived from cholesterol in the liver, consist a steroidal core. Primary bile acids and secondary bile acids metabolized by the gut microbiota make up the bile acid pool, which modulate nuclear hormone receptors to regulate immunity. Disruptions in the crosstalk between bile acids and the gut flora are intimately associated with the development and course of gastrointestinal inflammation.

This review provides an extensive summary of bile acid production, transport and metabolism. It also delves into the impact of bile acid metabolism on the body and explores the involvement of bile acid-microbiota interactions in various disease states. Furthermore, the potential of targeting bile acid signaling as a means to prevent and treat inflammatory bowel disease is proposed.

In this review, we primarily address the functions of bile acid-microbiota crosstalk in diseases. Firstly, we summarize bile acid signalling and the factors influencing bile acid metabolism, with highlighting the immune function of microbially conjugated bile acids and the unique roles of different receptors. Subsequently, we emphasize the vital role of bile acids in maintaining a healthy gut microbiota and regulating the intestinal barrier function, energy metabolism and immunity. Finally, we explore differences of bile acid metabolism in different disease states, offering new perspectives on restoring the host's health and the gastrointestinal ecosystem by targeting the gut microbiota-bile acid-bile acid receptor axis.

Bile salts are steroids with distinctive hydroxylation patterns that are produced and excreted by vertebrates. In contrast to common human bile salts, ursodeoxycholate (UDCA) has a 7-hydroxy group in β-configuration and is used in large amounts for the treatment of diverse gastrointestinal diseases. We isolated the 7β-hydroxysteroid dehydratase Hsh3 that is involved in UDCA degradation by Sphingobium sp. strain Chol11. Hsh3 eliminates the 7β-hydroxy group as water, leading to a double bond in the B-ring. This is similar to 7α-hydroxysteroid dehydratases in this and other strains, but Hsh3 is evolutionarily different from these. Purified Hsh3 accepted steroids with and without side chains as substrates and had minor activity with 7α-hydroxy groups. The deletion mutant strain Chol11 Δhsh3 had impacted growth with UDCA and accumulated a novel compound. The compound was identified as 3',5-dihydroxy-H-methyl-hexahydro-5-indene-1-one-propanoate, consisting of steroid rings C and D with a C3-side chain carrying the former 7β-hydroxy group, indicating that Hsh3 activity is important especially for the later stages of bile salt degradation. Hsh3 homologs were found in other sphingomonads that were also able to degrade UDCA as well as in environmental metagenomes. Thus, Hsh3 adds to the bacterial enzyme repertoire for degrading a variety of differently hydroxylated bile salts.IMPORTANCEThe bacterial degradation of different bile salts is not only important for the removal of these steroidal compounds from the environment but also harbors interesting enzymes for steroid biotechnology. The 7β-hydroxy bile salt ursodeoxycholate (UDCA) naturally occurs in high concentration in the feces of black bears and has important pharmaceutical relevance for the treatment of different liver-related diseases, for which it is administered in high and increasing amounts. Additionally, it is present in the bile salt pool of humans in trace amounts. While UDCA degradation is environmentally important, the enzyme Hsh3 modifies the hydroxy group that confers the medically relevant properties and thus might be interesting for microbiome analyses and biotechnological applications.

Bile acids (BAs) are cholesterol derivatives synthesized by the liver, exhibit variation between different species. Researchers have long appreciated that microbiota play the roles in the biotransformation of BAs. However, relatively few studies have been reported on microbial-mediated production and transformation of BAs in amphibians. Our focus here is principally on difference of intestinal microbial diversity and BAs profiles between two common amphibians, Bufo gargarizans (B. gargarizans) and Rana chensinensis (R. chensinensis) tadpoles, through intestinal targeted BAs metabolomics and fecal metagenomic sequencing. The results demonstrated that B. gargarizans possessed higher levels of total BAs and higher ratio of unconjugated / conjugated BAs. In addition, the relative abundance of microbiota with bile salt hydrolase (BSH) activity in B. gargarizans was significantly higher than that of R. chensinensis, which may facilitate the conversion of conjugated to unconjugated BAs. Meanwhile the higher prevalence of bile-acid-induced (BAI) gene encoding microbiota in R. chensinensis may promote the synthesis of deoxycholic acid (DCA). Furthermore, discrepancies in virulence factors (VFs) and energy metabolism were observed between the two species, which may be linked to differences in the microbiota. This study revealed substantial differences in intestinal microbes and BAs across amphibian species, emphasizing the significant impact of intestinal microbes on BAs metabolism.

This study aimed to characterize plasma bile acid changes from birth to first calving and evaluate the effects of early transition milk (TM) feeding versus milk replacer (MR) during key stages. Fecal bile acids in TM-fed calves were also analyzed, offering insights into bile acid metabolism. Thirty female Holstein calves were fed TM or MR for the first 5 d, followed by 12 L/d MR. From d 14, calves were fed MR and starter with gradual weaning between wk 8 and 14. Blood samples were collected at 7 time points: 30 min and 12 h after birth, preweaning (wk 2, 6), weaning (wk 14), 8 mo, 13 mo, 3 wk before calving, at calving, and 3 wk after calving. Fecal samples were collected from a subset of TM-fed calves (n = 10) at birth, wk 6, wk 14, 8 mo, and calving. Samples were analyzed for bile acids using the Biocrates MxP Quant 500 kit. Cholic acid (CA) in plasma showed significant time-treatment interactions, with higher levels in TM-fed calves at weaning. Taurine- and glycine-conjugated bile acids had no treatment or time-treatment interactions, but all plasma bile acids showed significant time effects. Principal component analysis revealed that bile acid profiles at birth and after colostrum intake were tightly clustered. Plasma bile acid profiles showed greater dispersion during milk feeding and weaning, with tighter clustering observed postweaning, particularly at 13 mo, and in the transition period. Significant effects were observed for CA, deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA), with CA showing a notable interaction and being higher in TM-fed calves at weaning than in MR-fed calves. Bile acid levels increased toward weaning, peaked at wk 14, and decreased after weaning. Glycine-conjugated bile acids changed over time, with glycocholic acid (GCA) and glycodeoxycholic acid (GDCA) peaking at weaning, and glycochenodeoxycholic acid (GCDCA) being elevated before weaning, decreasing thereafter, and increasing again at calving. Taurine-conjugated bile acids also showed temporal changes, peaking at wk 6. The shifts in bile acid composition from birth to postcalving, with taurolithocholic acid (TLCA), GDCA, and taurocholic acid (TCA) initially dominating, CA increasing at weaning, and GDCA and DCA dominating at calving, with CA increasing again postcalving. During the transition to calving, CA decreased whereas glycine-conjugated bile acids increased relative to taurine-conjugated bile acids in plasma, irrespective of treatment. Fecal bile acid profiles in TM-fed calves clustered distinctly at birth, evolving through pre- to postweaning and calving, with increasing profile overlap over time. Most fecal bile acids, except DCA and CA, were abundant at birth but declined over time. Both DCA and CA increased postweaning, mirroring plasma trends. From wk 6 to calving, DCA was the dominant bile acid, accounting for the highest percentage of total bile acids excreted in feces. Spearman's correlation analysis was performed to assess the relationship between plasma and fecal bile acids in TN-fed calves. A significant positive correlation was observed only for GCDCA (Spearman's rank correlation coefficient [rho] = 0.35), whereas all other bile acids were not correlated. These results illustrate the complex dynamics of bile acid profiles during calf development.

Host-microbiome communication is frequently perturbed in gut pathologies due to microbiome dysbiosis, leading to altered production of bacterial metabolites. Among these, 7α-dehydroxylated bile acids are notably diminished in inflammatory bowel disease patients. Herein, we investigated whether restoration of 7α-dehydroxylated bile acids levels by Clostridium scindens, a human-derived 7α-dehydroxylating bacterium, can reestablish intestinal epithelium homeostasis following colon injury. Gnotobiotic and conventional mice were subjected to chemically-induced experimental colitis following administration of Clostridium scindens. Colonization enhanced the production of 7α-dehydroxylated bile acids and conferred prophylactic and therapeutic protection against colon injury through epithelial regeneration and specification. Computational analysis of human datasets confirmed defects in intestinal cell renewal and differentiation in ulcerative colitis patients while expression of genes involved in those pathways showed a robust positive correlation with 7α-dehydroxylated bile acid levels. Clostridium scindens administration could therefore be a promising biotherapeutic strategy to foster mucosal healing following colon injury by restoring bile acid homeostasis.

Interactions between the gut microbiome and bile acids are complex and are linked to outcomes in pediatric liver disease by mechanisms that are incompletely understood. In adults, primary bile acids are synthesized in the liver and secreted into the intestine, where complex communities of gut microbes deconjugate, oxidize, epimerize, and 7α-dehydroxylate bile acids into a diverse array of unconjugated, secondary, allo-, iso-, and oxo-bile acids. In contrast, the infant gut microbiota contains a simple, Bifidobacterium-dominant community that transitions to a more diverse, adult-like community as additional microbes colonize the gut. This microbial succession gradually confers deconjugation, oxidation, epimerization, and 7α-dehydroxylation activities that mature the bile acid pool from a profile dominated by primary bile acids early in life to a more diverse, adult-like bile acid profile in later childhood. Altered bile acid profiles in pediatric cholestatic disorders have the potential to change the developmental trajectory of the microbiome. Conversely, alterations in the gut microbiome may re-shape the bile acid pool and hepatic bile acid metabolism. Understanding the mechanisms underlying these interactions will increase our understanding of liver pathophysiology and will motivate new therapeutic strategies for pediatric hepatic disorders. This review aims to highlight differences between the pediatric and adult intestinal microbiome and bile acid pool, and to discuss interactions between gut microbes and bile acids that are critical in early life and that may impact outcomes in infants and children with cholestatic liver disease, including biliary atresia.

Hyperlipidemia, characterized by abnormally elevated levels of lipids such as cholesterol, is a significant risk factor for cardiovascular diseases (CVD), contributing to increased oxidative stress, inflammation, and disruption of gut immunity. Dysbiosis, or imbalance in the gut microbiome, plays a critical role in the pathogenesis of hyperlipidemia. Probiotics, as key components of the gut microbiome, have been shown to positively impact health. This study aimed to evaluate the effects of Limosilactobacillus reuteri MSMC64 on lipid profiles, blood glucose levels, hepatic steatosis, antioxidant capacity, inflammatory biomarkers, and colon barrier immunity in hyperlipidemic rats induced by a high-cholesterol diet. The results demonstrated that the administration of L. reuteri MSMC64 may improve lipid profiles and blood glucose levels, reduce hepatic steatosis and oxidative stress, and lower inflammatory biomarkers while maintaining colon barrier integrity. These findings suggest that L. reuteri MSMC64 has the potential to be developed as a probiotic supplement for mitigating risk factors associated with hyperlipidemia and CVD.

The fecal metabolome comprises metabolites that are excreted or not absorbed by the animal. This study examined the changes in the fecal metabolome of dairy cows from the end of one lactation period, through the dry period, and into the subsequent lactation. Twelve Holstein cows (BW = 745 ± 71 kg, BCS = 3.43 ± 0.66) were housed in a tiestall barn from 7 wk before to 15 wk after parturition, with dry-off occurring approximately 6 wk before the expected calving date (mean dry-off time = 42 d). Fecal samples were taken at wk -7, -5, -1, +1, +5, +10, and +15 relative to calving. Targeted metabolomics identified a total of 93 metabolites, including AA, biogenic amines, bile acids (BA), acylcarnitines (AcylCN), and some phospholipids. Principal component analysis (PCA) revealed clear metabolic shifts that showed a clear separation between the samples from the dry period and the samples from the end, early, and middle of lactation, indicating significant changes in the metabolic profiles in the feces. The transition from the dry period (wk -5, -1 relative to calving) to lactation (wk +1, +5, +10, +15, and -7 relative to calving) is characterized by an increase in fecal AA and metabolites, such as Glu, Met, β-alanine, and methionine sulfoxide, reflecting a shift in nitrogen metabolism to support increased protein metabolism for milk production. Higher concentrations of polyamines, such as spermidine and putrescine, were observed postpartum, indicating increased cell growth and improved tissue regeneration. Elevated gamma-aminobutyric acid levels during lactation indicate increased microbial activity driven by a nutrient-rich diet. Results showed significant adjustments in BA profiles as cows transitioned into lactation. Deoxycholic acid remained the predominant BA in feces, reflecting ongoing microbial transformation, whereas glycine- and taurine-conjugated BA increased postpartum, suggesting improved enterohepatic circulation and lipid absorption. Fecal AcylCN showed dynamic shifts with elevated levels during late gestation, a decrease in the dry period, and an increase postpartum, indicating increased fatty acid oxidation to meet energy demands. Results showed that phosphatidylcholines decreased prepartum but increased after calving. This indicates shifts in lipid metabolism reflecting energy requirements in lactation and suggests that fecal lipid composition is an indicator of metabolic adaptations in dairy cows. In particular, PCA revealed considerable overlap in the fecal metabolite profiles of multiparous and primiparous cows, indicating similar metabolic profiles. This was also confirmed by volcano plots, which showed no significant differences in fecal metabolism between the 2 groups across different weeks relative to calving (wk -7, -5, -1, +1, +5, +10, and +15). Overall, these results emphasize the complex interactions between dietary factors, liver and gastrointestinal function, and the gut microbiome in shaping the fecal metabolite profile of dairy cows. These results underscore the value of this data set in advancing the application of fecal metabolome profiling to investigate metabolic changes during critical transitions in the lactation cycle of dairy cows.

The human gut hosts a diverse microbial community, essential for maintaining overall health. However, antibiotics, commonly prescribed for infections, can disrupt this delicate balance, leading to antibiotic-associated diarrhea, inflammatory bowel disease, obesity, and even neurological disorders. Recognizing this, probiotics have emerged as a promising strategy to counteract these adverse effects.

This review aims to offer a comprehensive overview of the latest evidence concerning the utilization of probiotics in managing antibiotic-associated side effects.

Probiotics play a crucial role in preserving gut homeostasis, regulating intestinal function and metabolism, and modulating the host immune system. These mechanisms serve to effectively alleviate antibiotic-associated adverse effects and enhance overall well-being.

Conjugated lithocholic acid (LCA) plays a critical role in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). In this process, hepatocyte inflammation-caused upregulation of its receptor, Takeda G protein-coupled receptor 5 (TGR5) is a crucial factor. Serum bile acid profiling shows an increase in conjugated LCA, which correlates with disease severity. Depletion of Gpbar1 in hepatocytes significantly protects against the progression from MASLD to metabolic dysfunction-associated steatohepatitis (MASH) that is related to conjugated LCA. In vivo and in vitro experiments indicate that TGR5 activation in hepatocytes promotes lipotoxicity-induced cell death and inflammation by suppressing de novo carnitine biosynthesis. Mechanistically, TGR5 binding to CD36 facilitates E3 ubiquitin ligase TRIM21 recruitment, leading to the degradation of BBOX1, a crucial enzyme in de novo carnitine biosynthesis. Targeting TGR5 therapeutically can restore carnitine biosynthesis, which may offer a potent strategy to prevent or reverse the transition from MASLD to MASH.

This study explored the impact of Bacteroides uniformis (B. uniformis) on fatty liver hemorrhagic syndrome (FLHS) induced by a high-energy and low-protein (HELP) diet in laying hens, mainly focusing on hepatic lipid metabolism, gut microbiota, and arachidonic acid (AA) metabolism. A total of 120 Dawu Golden Phoenix laying hens (210-day-old) were randomly divided into four groups. The control group (CON) was fed a standard diet and received a daily gavage of PBS, while the other groups were fed with a HELP diet to induce FLHS and received a daily gavage of PBS (MOD), 1 × 109 CFU/ml B. uniformis (BUL), and 1 × 1011 CFU/ml B. uniformis (BUH) for 70 days. All hens were administered 1 ml daily by gavage. Each group had 6 replications with 5 hens per replication. The results showed that B. uniformis increased the egg production rate and feed conversion ratio and decreased body weight, liver index, and abdominal fat rate (p < 0.05). B. uniformis treatment reduced liver lipid accumulation by reducing the levels of Triglyceride (TG), Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), alanine transaminases (ALT), and aspartate transaminases (AST) in serum and significantly elevated high-density lipoprotein cholesterol (HDL-C) (p < 0.05). The results indicated that B. uniformis altered the gut microbiota. Specifically, the abundance of Bacteroides was higher, and the relative abundances of Treponema, Helicobacter, and Spirochaetota were lower than those of the MOD group (p < 0.05). Moreover, targeted metabolomic analysis showed that supplementation of B. uniformis significantly elevated 6-keto-PGF1α and AA levels, along with significantly reduced levels of thromboxane B2 (TXB2), leukotriene D4 (LTD4), 8-isoprostaglandin F2α (8-iso-PGF2α), 12S-hydroxyeicosatetraenoic acid (12S-HETE), 15S-hydroxyeicosatetraenoic acid (15S-HETE), 9-S-hydroxy-octadecadienoic acid (9S-HODE), and 13-S-hydroxy-octadecadienoic acid (13S-HODE) (p < 0.05). In conclusion, the oral intake of B. uniformis can improve liver function, gut microbiota, and AA metabolism, thereby helping to ameliorate FLHS in Dawu Golden Phoenix laying hens.

Bile acids play vital roles in control of lipid, glucose, and energy metabolism by activating Takeda G protein-coupled receptor 5 and Farnesoid X receptor, the latter promoting production of the endocrine-acting fibroblast growth factor 19 (FGF19). Short-term administration of single bile acids has been reported to enhance plasma levels of GLP-1 and to enhance energy expenditure. However, prolonged bile acid supplementation (eg, of chenodeoxycholic acid for gallstone dissolution) has been reported to have adverse effects.

In this proof-of-concept study, we assessed the safety and metabolic effects of oral glycine-conjugated deoxycholic acid (GDCA) administration at 10 mg/kg/day using regular and slow-release capsules (mimicking physiological bile acid release) over 30 days in 2 groups of each 10 healthy lean men, respectively.

GDCA increased postprandial total bile acid and FGF19 concentrations while suppressing those of the primary bile acids chenodeoxycholic acid and cholic acid. Plasma levels of 7α-hydroxy-4-cholesten-3-one were reduced, indicating repressed hepatic bile acid synthesis. There were minimal effects on indices of lipid, glucose, and energy metabolism. No serious adverse events were reported during GDCA administration in either capsule types, although 50% of participants showed mild increases in plasma levels of liver transaminases and 80% (regular capsules) and 50% (slow-release capsules) of participants experienced gastrointestinal adverse events.

GDCA administration leads to elevated FGF19 levels and effectively inhibits primary bile acid synthesis, supporting therapy compliance and its effectiveness. However, effects on lipid, glucose, and energy metabolism were minimal, indicating that expanding the pool of this relatively hydrophobic bile acid does not impact energy metabolism in healthy subjects.

Trillions of microorganisms play a pivotal role in maintaining health and preventing disease in humans. Their presence influences daily life, habits, energy levels, and pathologies. The present narrative review synthesized recent studies of microbial diversity across organ systems. The composition of the microbiota regulates the intestinal barrier, modulates the immune response, influences metabolism, and produces essential compounds such as short-chain fatty acids and neurotransmitters. Dysbiosis is associated with numerous pathologies, including metabolic, autoimmune, neurodegenerative, and cardiovascular diseases. The microbiota is key to maintaining physiological balance and reducing disease risk. Therapeutic interventions, such as probiotics, prebiotics, postbiotics, and microbiome transplantation, offer promising perspectives in restoring microbial homeostasis and preventing chronic diseases.

The effects of dietary supplementation with epigallocatechin-3-gallate (EGCG) on growth performance, antioxidant capacity, immune function, and gut microbiota in geese were investigated. Seventy-two healthy 35-day-old male geese were randomly divided into a control group (basal diet) or an EGCG group (basal diet + 200 mg/kg EGCG), with 36 geese per group, which was further subdivided into 6 replicates (6 geese per replicate). The experiment lasted 21 days. Geese in the EGCG group exhibited significantly higher final body weight (2.93 kg vs. 2.28 kg, P < 0.01) and average daily gain (72.38 g/d vs. 41.4 g/d, P < 0.01) along with a 42.8 % reduction in the feed conversion ratio (3.95 vs. 6.91, P < 0.01) versus the control. Liver weights in the EGCG group were significantly elevated compared to the CON group on days 14 and 21 (P < 0.05) and a strong correlation between liver weight and body weight. EGCG significantly increased catalase, glutathione peroxidase, and superoxide dismutase activities, and the total antioxidant capacity in serum and jejunum while decreasing malondialdehyde (MDA) levels (P < 0.05). Immunological analyses revealed elevated serum immunoglobulin (Ig)A, IgG, and IgM and lysozyme in the EGCG group (P < 0.05), accompanied by a decrease in the pro-inflammatory cytokines interleukin-6 and interferon-γ. Intestinal morphology demonstrated increased villus height-to-crypt depth ratios in the duodenum and ileum (P < 0.05). 16S rRNA sequencing indicated that EGCG increased the relative abundance of Akkermansia and Verrucomicrobiota (P < 0.05) in the cecal content and enriched microbial functions related to inorganic ion transport and metabolism. Correlation analysis revealed positive associations between Akkermansia and IgA, and between Firmicutes and oxidative damage markers (MDA). Overall, dietary supplementation with 200 mg/kg EGCG could improve growth performance, antioxidant capacity, immune response, and gut microbiota structure in geese, supporting its potential as a plant-based feed additive.

The gut microbiome, a complex community of microorganisms residing in the intestinal tract, plays a dual role in colorectal cancer (CRC) development, acting both as a contributing risk factor and as a protective element. This review explores the mechanisms by which gut microbiota contribute to CRC, emphasizing inflammation, oxidative stress, immune evasion, and the production of genotoxins and microbial metabolites. Fusobacterium nucleatum, Escherichia coli (pks+), and Bacteroides fragilis promote tumorigenesis by inducing chronic inflammation, generating reactive oxygen species, and producing virulence factors that damage host DNA. These microorganisms can also evade the antitumor immune response by suppressing cytotoxic T cell activity and increasing regulatory T cell populations. Additionally, microbial-derived metabolites such as secondary bile acids and trimethylamine-N-oxide (TMAO) have been linked to carcinogenic processes. Conversely, protective microbiota, including Lactobacillus, Bifidobacterium, and Faecalibacterium prausnitzii, contribute to intestinal homeostasis by producing short-chain fatty acids (SCFAs) like butyrate, which exhibit anti-inflammatory and anti-carcinogenic properties. These beneficial microbes enhance gut barrier integrity, modulate immune responses, and inhibit tumor cell proliferation. Understanding the dynamic interplay between pathogenic and protective microbiota is essential for developing microbiome-based interventions, such as probiotics, prebiotics, and fecal microbiota transplantation, to prevent or treat CRC. Future research should focus on identifying microbial biomarkers for early CRC detection and exploring personalized microbiome-targeted therapies. A deeper understanding of host-microbiota interactions may lead to innovative strategies for CRC management and improved patient outcomes.

The commensal gut microbiota has a role in the pathogenesis of extra-intestinal autoimmune diseases such as multiple sclerosis (MS) with unknown mechanisms. Deoxycholic acid (DCA) and lithocholic acid (LCA) are secondary bile acid metabolites (BAMs) produced from primary bile acids by gut microbiota that play key immune regulatory functions by promoting FOXP3+ regulatory T (Treg) cell differentiation at the expense of Th17 cells. Here, we show that bacteria releasing enzymes responsible for secondary BAMs production are under-represented in the gut of MS patients, resulting in significantly reduced intestinal concentration of DCA and immune dysregulation with increased percentage of Th17 cells. We validated our human findings in a preclinical model of MS by showing that DCA/LCA administration prevents experimental autoimmune encephalomyelitis (EAE) by dampening Th17 cell differentiation and the effector phenotype of myelin-reactive T cells. Our data highlight the key role of immune regulatory BAMs for the prevention of central nervous system (CNS) autoimmunity.

The current definition of a postbiotic is a "preparation of inanimate microorganisms and/or their components that confers a health benefit on the host". Postbiotics can be mainly classified as metabolites, derived from intestinal bacterial fermentation, or structural components, as intrinsic constituents of the microbial cell. Secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) are bacterial metabolites generated by the enzymatic modifications of primary bile acids by microbial enzymes. Secondary bile acids function as receptor ligands modulating the activity of a family of bile-acid-regulated receptors (BARRs), including GPBAR1, Vitamin D (VDR) receptor and RORγT expressed by various cell types within the entire human body. Secondary bile acids integrate the definition of postbiotics, exerting potential beneficial effects on human health given their ability to regulate multiple biological processes such as glucose metabolism, energy expenditure and inflammation/immunity. Although there is evidence that bile acids might be harmful to the intestine, most of this evidence does not account for intestinal dysbiosis. This review examines this novel conceptual framework of secondary bile acids as postbiotics and how these mediators participate in maintaining host health.

Distiller's grains (DG) are a potential source of animal feeds, and many studies have indicated positive regulatory roles of feeding DG diets in animal breeding. However, there is currently a dearth of research on the actions and underlying mechanisms of probiotics-fermented distiller's grains (FDG)-based diets in cattle breeding. This study aimed to assess the impact of integrating FDG into the diet of finishing cattle on their fecal microbial community and metabolites. Thirty Simmental crossbred cattle (local yellow cattle × Simmental cattle, 8.5 months old, 420.38 ± 68.11 kg) were selected and randomly divided into three dietary treatments, including the basal diet group (CON group), the FDG replacing 10% concentrate (FDG-10%) group, and the FDG replacing 20% concentrate (FDG-20%) group. 16S and ITS sequencing of fecal samples collected from each group on the 30th day of the formal feeding suggested that feeding FDG diets had little effect on the composition and diversity of fecal bacterial and fungal communities in finishing cattle. However, the relative abundance of cellulose-degrading bacteria, including the Christensenellaceae R-7 group and Ruminococcaceae family was significantly higher in both the FDG-20% vs CON comparison and the FDG-20% vs FDG-10% comparison. Besides, the FDG-10% group had a significant drop in the relative abundance of Aspergillus and a noteworthy increase in the relative abundance of Candida when compared to the CON group. Non-targeted metabolomics analysis showed that the addition of FDG modified the levels of organoheterocyclic compounds, lipids and lipid-like molecules, and benzenoids in the feces of finishing cattle and significantly enhanced the metabolic pathway of bile secretion. Further correlation analyses suggested a close association between the significantly differential fecal microbiota and metabolites. In conclusion, these results suggest that FDG supplementation has little effect on the structure and diversity of the fecal microbiota in finishing cattle, but alters intestinal metabolite profiles and influences bile secretion pathways by modulating the relative abundance of genera of fecal bacteria and fungi Christensenellaceae R-7 group, Lachnospiraceae_NK3A20_group, Mucor, and Candida. These findings provide a scientific theoretical basis for the use of FDG in animal feeds.

Probiotics-fermented distiller's grains (FDG) are potential feed sources for livestock. Here, we investigated the effects of partially replacing concentrates with FDG on fecal bacterial and fungal community structure and metabolic profiles in finishing cattle. The results reveal that feeding FDG-based diets alters intestinal metabolite profiles and up-regulates bile secretion pathways through the regulation of relative abundance of certain fecal genera. These findings provide some new insights into clarifying the role and potential mechanisms of FDG diets and also offer a scientific basis for the development of FDG into functional feed resources.

Clostridium scindens is a commensal gut bacterium capable of forming the secondary bile acids as well as converting glucocorticoids to androgens. Historically, only two strains, C. scindens ATCC 35704 and C. scindens VPI 12708, have been characterized to any significant extent. The formation of secondary bile acids is important in the etiology of cancers of the GI tract and in the prevention of Clostridioides difficile infection. We determined the presence and absence of bile acid inducible (bai) and steroid-17,20-desmolase (des) genes among C. scindens strains and the features of the pangenome of 34 cultured strains of C. scindens and a set of 200 metagenome-assembled genomes (MAGs) to understand the variability among strains. The results indicate that the C. scindens cultivars have an open pangenome with 12,720 orthologous gene groups and a core genome with 1630 gene families, in addition to 7051 and 4039 gene families in the accessory and unique (i.e., strain-exclusive) genomes, respectively. The pangenome profile including the MAGs also proved to be open. Our analyses reveal that C. scindens strains are distributed into two clades, indicating the possible onset of C. scindens separation into two species, as suggested by gene content, phylogenomic, and average nucleotide identity (ANI) analyses. This study provides insight into the structure and function of the C. scindens pangenome, offering a genetic foundation of significance for many aspects of research on the intestinal microbiota and bile acid metabolism.

Background/Objectives: The gut microbiota plays a pivotal role in host physiology through metabolite production, with lipids serving as essential biomolecules for cellular structure, metabolism, and signaling. This review aims to elucidate the interactions between gut microbiota and lipid metabolism and their implications for enhancing swine production. Methods: We systematically analyzed current literature on microbial lipid metabolism, focusing on mechanistic studies on microbiota-lipid interactions, key regulatory pathways in microbial lipid metabolism, and multi-omics evidence (metagenomic/metabolomic) from swine models. Results: This review outlines the structural and functional roles of lipids in bacterial membranes and examines the influence of gut microbiota on the metabolism of key lipid classes, including cholesterol, bile acids, choline, sphingolipids, and fatty acids. Additionally, we explore the potential applications of microbial lipid metabolism in enhancing swine production performance. Conclusions: Our analysis establishes a scientific framework for microbiota-based strategies to optimize lipid metabolism. The findings highlight potential interventions to improve livestock productivity through targeted manipulation of gut microbial communities.

Whether a gut-joint axis exists to regulate osteoarthritis is unknown. In two independent cohorts, we identified altered microbial bile acid metabolism with reduced glycoursodeoxycholic acid (GUDCA) in osteoarthritis. Suppressing farnesoid X receptor (FXR)-the receptor of GUDCA-alleviated osteoarthritis through intestine-secreted glucagon-like peptide 1 (GLP-1) in mice. GLP-1 receptor blockade attenuated these effects, whereas GLP-1 receptor activation mitigated osteoarthritis. Osteoarthritis patients exhibited a lower relative abundance of Clostridium bolteae, which promoted the formation of ursodeoxycholic acid (UDCA), a precursor of GUDCA. Treatment with C. bolteae and Food and Drug Administration-approved UDCA alleviated osteoarthritis through the gut FXR-joint GLP-1 axis in mice. UDCA use was associated with lower risk of osteoarthritis-related joint replacement in humans. These findings suggest that orchestrating the gut microbiota-GUDCA-intestinal FXR-GLP-1-joint pathway offers a potential strategy for osteoarthritis treatment.

Dysbiosis in gut microbiota and abnormalities in bile acids have been linked to neurodegenerative diseases. While many studies have focused on the relationship between colonic bacteria and Alzheimer's disease (AD), this study propose that alterations in the small intestine microbiota may play a more critical role. This is because the small intestine is pivotal in recycling bile acids through enterohepatic circulation. This study uses amyloid precursor protein knock-in (APPNL-G-F/NL-G-F) transgenic mice to investigate the association between intestinal microbiota and bile acid metabolism. The results showed that the accumulation of beta-amyloid (Aβ) leads to a significant decrease in Lactobacillus johnsonii and a notable increase in bacteria of the genus Clostridium in the small intestine, which are important microorganisms for producing toxic bile acids. Extracellular vesicles (EVs) involved in bacterial interactions and bacteria-host interactions are currently a focus of research. Treatment with L. johnsonii-derived EVs at concentrations of 1010 and 1012/mL) inhibited the growth of Clostridium scindens and suppressed the production of toxic secondary lithocholic acid (TLA) at non-cytotoxic concentrations (108/mL). Furthermore, the removal of small RNA from L. johnsonii-derived EVs resulted in the loss of their ability to suppress TLA production. These results suggest that the small intestine microbiota may play a more critical role than the colonic microbiota in AD. Deterioration of small intestine microbiota led to the metabolism disruption of certain secondary bile acids, which have been reported to exacerbate AD pathology. The EVs released by L. johnsonii, which is abundant in the small intestine, can suppress toxic TLA and have the potential to be developed into health-promoting probiotics.

Abnormal bile acid (BA) metabolism is involved in liver fibrosis. In a previous study, we discovered that the hydrophobic BA glycochenodeoxycholate (GCDCA) induced liver fibrosis and that GW4064, an agonist of farnesoid X receptor (FXR), alleviated liver fibrosis caused by GCDCA. However, the impacts of GCDCA on liver BAs, gut BAs, the intestinal barrier, and the gut microbiota are unclear, and obtaining this information would provide additional information into the role of GCDCA in the development of liver fibrosis. In the present study, ultra-performance liquid chromatography‒tandem mass spectrometry revealed that mice administered GCDCA by gavage had higher levels of total and primary liver BAs than those in the control group, and a significant reduction in primary liver BAs was observed in the GCDCA + GW4064 group compared with those in the GCDCA group. Compared with those in the control group, the mice administered GCDCA by gavage had greater levels of total and primary BAs in the gut, especially T-alpha-MCA and T-beta-MCA, and no significant differences in the terminal ileum were observed between the GCDCA and GCDCA + GW4064 groups. Immunohistochemistry indicated that GCDCA administration inhibited gut FXR and FGF15 expression, whereas GW4064 activated gut FXR and promoted FGF15 expression. Moreover, immunohistochemistry revealed that GCDCA administration decreased mucin2, claudin-1, occludin, and ZO-1 expression, whereas GW4064 restored their expression. 16S rDNA sequencing revealed that the alpha diversity of the microbiota did not significantly differ among the three groups, but differences in the beta diversity of the microbiota were observed among the three groups. At the phylum level, GCDCA significantly disturbed the gut microbiota, as indicated by reductions in Desulfobacterota, Bacteroidota, and Actinobacteria in the GCDCA group compared with those in the control group. However, significantly increased abundances of Proteobacteria, Cyanobacteria, and Patescibacteria were noted in the GCDCA group compared with the control group. GW4064 administration significantly improved the microbiota structure at the phylum level. The efficacy of GW4064 was also observed at the genus level. Correlation analyses revealed fewer relationships between the gut microbiota and gut BAs, whereas the gut microbiota was more closely related to liver BAs in the GCDCA and GW4064 intervention groups. Together, GCDCA induced cholestasis and disturbed BA metabolism in the gut and liver, as well as the intestinal barrier and structure of the gut microbiota. Activation of gut FXR improved intestinal barrier injury and alleviated BA metabolism dysfunction and dysbacteriosis caused by GCDCA under cholestatic conditions.

Glycochenodeoxycholate (GCDCA) is a hydrophobic bile acid (BA) in humans and is highly increased in the serum and stool of liver fibrosis patients. However, the effects of GCDCA were not comprehensively investigated in the process of liver bile acid metabolism, gut microbiota, and intestinal barrier. It was reported that GCDCA can promote liver fibrosis via the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway in mice, and gut farnesoid X receptor activation alleviated the fibrosis caused by GCDCA in our previous study. Gut microbiota is also responsible for BA metabolism; meanwhile, BA metabolism may also exert an effect on the intestinal barrier. Nowadays, the comprehensive understanding of gut microbiota and intestinal barrier in relation to BA disorder was still insufficient. Current study further investigated the role of GCDCA in BA metabolism, gut microbiota, and intestinal barrier to help understand the effects of GCDCA in liver fibrosis, which may provide intervention methods for liver fibrosis caused by dysregulation of BA metabolism.

Gut microbiome-associated metabolites and white matter hyperintensities (WMH) are independently associated with cognitive impairment. However, it is unclear if gut metabolites and WMH interact to influence dementia.

To examine the association between gut microbial metabolites and cognitive outcomes and assess whether the severity of baseline WMH would impact associations between gut microbial metabolites and cognitive outcomes.

Cross-sectional design.

Cohort of individuals who are clinically normal, mild cognitive impairment, or Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI).

A total of 578 participants with available baseline 3.0T 2D-Fluid Attenuation Inversion Recovery (FLAIR) Magnetic Resonance Imaging (MRI) scans and baseline gut microbial metabolite measurement were included in the analysis.

Gut metabolite measurements and automated WMH volume estimations were obtained from FLAIR MRI and were used to assess the association and interaction with cognitive impairment.

Of 104 metabolites studied, glycodeoxycholic acid (GDCA) surpassed the false discovery rate and was associated the Alzheimer's Disease Assessment Scale-Cognitive Subscale version 13 (ADAS-Cog13) score (β = 0.12, 95 % CI = 0.05-0.20, p = 0.001) and cognitive impairment determined by mini-mental status exam (MMSE) (OR = 2.11, 95 % CI = 1.41-3.15, p < 0.001). GDCA was associated with higher ADAS-Cog13 in participants with low WMH burden (β = 0.21, 95% CI = 0.10-0.32, p < 0.001) but not in participants with high WMH burden (β = 0.04, 95 % CI = -0.07 to 0.14, p = 0.48; interaction p = 0.02).

An elevated level of GDCA was associated with worse cognition. WMH severity modified the association between GDCA and cognitive outcomes.