These findings highlight BA circulation through the gut-liver axis as an important regulatory component of the liver regeneration program. Taken together, both the injurious and proliferative effects of BAs on hepatocytes emphasize the importance of appropriately maintaining BA homeostasis to facilitate liver repair. The role of BA signaling during liver regeneration has been reviewed. For the thoroughness of this review, we briefly cover the role of FXR-associated pathways in regulating liver regeneration. In addition to regulating BA homeostasis, FXR controls lipid and glucose metabolism. FXR whole body KO mice exhibited a delayed liver regeneration due to dysregulated BA synthesis. Intestinal FXR was also found to facilitate liver regeneration through up-regulation of FGF15 in mice. FGF15 is an ileal-secreted enterokine that is induced by FXR to inhibit BA overproduction. Additionally, intestinal FXR KO impeded liver regeneration as a result of insufficient FGF15 activity which was rescued by administration of exogenous FGF15. As such, FGF15 KO mice suffered significantly higher lethality rates after liver resection due to hepatic failure relative to wild type mice. Furthermore, hepatocytespecific FXR KO mice also show delayed liver regeneration from inactivation of CYCLIN D and suppressed HGF-mediated signaling. In addition to the vital role of BA circulation through the gut-liver axis, cytokine and paracrine signaling molecules generated from the liver and intestine including tumor necrosis factor α , IL-6, and FGF15/19, and HGF impact liver regeneration as well. HGF treatment reduces inflammation and promotes colonic epithelial regeneration, plastic round plant pots potentially preventing translocation of harmful microbes and metabolites across the intestinal mucosa.

Taken together, liver regeneration is regulated by the enterohepatic circulation of BAs as well as cytokines and growth factors.Hepatic as well as microbial enzymes are responsible for the synthesis of various BAs . There is a species difference in BA profiles. In human, cholic acid and chenodeoxycholic acid are primary BAs . However, in mice, α-muricholic acid and β-MCA are the major primary BAs. These primary BAs are sterol compounds synthesized from cholesterol and conjugated with mainly glycine in human or taurine in mice. Primary BAs enter the intestinal lumen and undergo deconjugation, dehydroxylation, epimerization, and oxidation using bacterial enzymes. Conjugation increases the aqueous solubility of BAs and renders them largely impermeable to the intestinal epithelium, thus preventing them from exiting the intestinal lumen. The conversion of primary to secondary BAs deoxycholic acid and lithocholic acid is also mediated via bacterial enzyme 7α-dehydroxylase. Therefore, the composition of BAs in germ-free and conventional rats is drastically different; specifically, germ-free rats have elevated taurine-conjugated BAs and reduced secondary and glycine-conjugated BAs. Among BAs, CDCA has the highest binding affinity to FXR. In mice, tauro-β-MCA is an inhibitor of FXR. These findings point to the possibility that intestinal bacteria not only regulate BA deconjugation, but also BA synthesis through FXR. A cross-sectional study of patients with cirrhosis showed elevated primary BAs and Enterobacteriaceae and diminished 7α-dehydroxylating bacteria including Lachonospiraceae, Ruminococcaceae, and Blautia. Mice treated with antibiotics consisting of bacitracin, neomycin, and streptomycin had increased tauro-CA and T- β-MCA and reduced secondary BAs, which indicated the diminished intestinal 7α- dehydroxylating bacteria. In addition, antibiotic treatment also suppressed Fgf15 expression and increased Cyp7a1 expression, which indicated the regulation of microbiota on BA synthesis .

This modulation of intestinal FXR and BA synthesis carries many potential implications for liver regeneration, and requires further investigation. Additionally, total and fecal secondary BA levels were diminished in patients with cirrhotic livers with Enterobacteriaceae and Ruminococcaceae growth positively correlating with CDCA and DCA levels, respectively. Moreover, in cirrhotic patients who consumed alcohol, analysis of fecal and serum BA levels, serum endotoxin and stool microbiota revealed increased mRNA levels of inflammatory cytokines as well as secondary hydrophobic BAs. Such elevation in cytotoxic secondary BAs may compromise intestinal epithelial integrity and contribute to dysbiosis, which in turn impairs liver regeneration. Taken together, these findings implicate the gut microbiota in modulating the production and composition of BAs.While intestinal bacteria modulate BA synthesis, BAs can mutually influence the gut microbial population. In a FXR-dependent manner, conjugated BAs can exert antimicrobial effects in the digestive tract. Consequently, FXR KO mice exhibited higher densities of ileal bacteria and compromised epithelial barrier integrity. This effect was also observed in mice with biliary obstruction and reversible by administration of a FXR agonist. Conversely, hydrophobic, taurine-conjugated BAs enhanced the growth of sulfate reducing gut bacteria, leading to a “leaky gut” with increased antigen and bacterial translocation, cholelithiasis, carcinoma, inflammatory bowel disease, and colorectal cancer. Moreover, a low-fat diet supplemented with TCA, promoted changes in mouse host BA composition, which can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis and disrupted immune homeostasis. However, an increase in intestinal T-β-MCA caused by tempol, an antioxidant, reduced the colonic population of Lactobacillus, decreased bile salt hydrolase activity in the feces, and inhibited the intestinal FXR signaling.

This evidence suggests that the gut microbiota, as an “organ”, is capable of adapting to dynamic changes in intestinal environment. Exogenous administration of CA up-regulated bacterial 7α-dehydroxylation-mediated DCA production and altered the gut microbiota population with increased abundance of Firmicutes over Bacteroidetes in rat. In addition, exogenous CA increased pathogenic Clostridia and Erysipelotrichi populations, which can lead to colitis and cirrhosis. Overall, it appears that factors influencing either the BA composition or gut microbial diversity may also significantly impact on liver function and regeneration.Intestinal pathologies are linked to factors involved in liver injury or regeneration. For example, small bowel resection in piglets caused gut microbiota dysbiosis, which resulted in significant BA dysregulation and harmful clinical outcomes including steatorrhoea, persistent diarrhea, liver injury, and impaired regeneration. Small bowel resection also interrupted FXR-mediated signaling pathways, which are essential for liver regeneration. Increased intestinal permeability in alcoholic patients was positively correlated with severity of cirrhosis in alcoholic patients. A “leaky gut” caused endotoxemia in rats and humans and contributed to alcohol-induced hepatic cirrhosis and dysfunction. Furthermore, nonalcoholic fatty liver disease in rats was associated with compromised intestinal barrier integrity and elevated LP. Knockout toll-like receptor 4, an important modulator of innate immune response to LPS, resulted in aggressive onset of colitis and subsequent bacterial translocation to mesenchymal lymph nodes. Sepsis-induced liver and colonic epithelial damage could be ameliorated by probiotic VSL#3, which restored the diversity of the intestinal microbiota. This study showed that administration of a peroxisome proliferator-activated receptor gamma inhibitor completely abolished the anticipated probiotic benefits, suggesting that VSL#3 treatment may promote liver regeneration through a PPARγ-mediated pathway. Interestingly, liver regeneration was found to be accelerated in liver-specific PPARγ-null mice on a normal diet, but impaired when mutant mice suffered diet-induced fatty liver, suggesting that PPARγ inhibition may be detrimental in a state of intestinal dysbiosis. Bioactive peptide factors from Bifidobacterium infantis were also shown to improve epithelial cell barrier function and reduce inflammation, implying a potential pathway through which certain beneficial bacteria may enhance liver regeneration by protecting against hepatic damage. Metabolic pathways may also exert a hepatoprotective effect following liver injury. Parenteral administration of glutamine after liver resection dramatically increased liver regeneration by promoting hepatic alanine uptake and intestinal glutamine metabolism. Protein synthesis in colonic epithelium was increased, whereas bacterial translocation and endotoxin levels were greatly reduced. This improvement in intestinal epithelial barrier function may shield the liver from excessive endotoxemia after liver resection.Hepatic diseases have been linked to altered microbial diversity in the intestines that may create a positive feedback cycle that exacerbates hepatic injury and impede liver regeneration. Alcoholic liver disease patients generally had contracted Bacteroides species and expanded Proteobacteria species. This gut dysbiosis was also correlated with elevated serum endotoxin, likely from excessive bacterial translocation. The presence of endotoxemia along with reduction in Bacteroides density is expected to negatively impact liver regeneration. The study of liver steatosis, alcoholic and non-alcoholic, has proven valuable to illuminating the downstream consequences of gut microbiota alterations. Nonalcoholic steatohepatitis provokes an innate immune response, which stimulates hepatic inflammation through cytokines such as TNFα. Obesity-induced nonalcoholic steatohepatitis also perturbed gut microbiota composition by decreasing total microbial diversity, nft hydroponic most likely by Bacteroidetes species contraction. Hepatic lipid contents in patients with choline deficiency have also been shown to affect gut microbial diversity. Treatment with a combination of five Chinese herbs was found to promote growth of short chain fatty acid producer Collinsella while improving steatosis in rats. This altered gut microbiota associated with steatosis, particularly diminished Bacteroidetes abundance, may indicate gut dysbiosis and propagation of further hepatic injury.

Other etiologies, such as GI diseases, can also influence hepatic injury through modulation of the gut microbiota. In a rat model of irritable bowel syndrome, administration of Lactobacillus casei and Bifidobacterium lactis either before or after irritable bowel syndrome induction alleviated inflammation and apoptosis in both the colon and liver. Together, there is an intimate relationship between hepatic metabolism, microbiota, and liver injury as well as regeneration.It is well recognized that diet and nutrition play a significant role in the etiology of metabolic diseases and that affects tissue injury and repair. However, the precise mechanisms by which diets affect our health status and outcomes, particularly in the GI system, are poorly understood. Despite the exponential growth in marketing of synbiotics and probiotic products, there is a lack of established mechanistic links between gut microbiota alterations and physiological responses from the host. The current summary provides promising evidence, which indicates intestinal bacteria and BAs cross talk within the gut-liver axis and jointly regulate nutrient absorption, liver metabolism, and inflammatory processes. Thus, BA and bacteria-mediated signaling within the gut-liver axis is crucial for proper execution of injury response and repair, such relationship is summarized in Figure 3. It is critical to gain insights into how nutrient-host and microbiota-host interactions influence an individual’s predisposition to injury and tissue repair. Due to the intricate networks of implicated pathways as well as scarcity of available information, it seems that nutrigenomic, metabolomics, and microbiota profiling approaches are warranted to provide a better understanding regarding the impact of the aforementioned factors in influencing liver function and healing.Elderberry is a part of the Viburnaceae family and grows all over the world, including Europe, North America, and Asia. Due to the vast geographic and morphological variety within Sambucus, there have historically been many species within the genus. However, a reorganization by Bolli reclassified some of the most common species under Sambucus into subspecies of S. nigra. More recently, elderberry was moved out of the Adoxoaceae family, which had already been changed before when elderberry was taken out of the Caprifoliaceae family. These changes have impacted the three subspecies most of interest in this work: the European elderberry S. nigra ssp. nigra; the American elderberry S. nigra ssp. canadensis; and the blue elderberry S. nigra ssp. cerulea . However, due to wide acceptance of this naming scheme for the subspecies, it will be used through this work to align with the current naming, but previous works cited may use the former species names. Furthermore, some sources refer to the entire plant as an “elder”, while others refer to the plant as “elderberry”, which is also used to denote the fruit of the plant. In this work, “elderberry” is used to discuss the plant as well as the fruit. “Elderflower” is used to refer to the blossoms of the plant. European elderberry is the most well-studied and widely used subspecies of elderberry in the market. This subspecies grows throughout the European continent, including countries such as Slovenia, Portugal, and Austria. The fruit and flower have been studied for decades for their composition and bioactivity, and while elderberry and elderflower are not new ingredients to the market, they have garnered more attention in the last several years as consumers look for more natural remedies and supplements to support their health. This has been especially true during the COVID-19 pandemic, in which elderberry became a popular ingredient in immunity-supporting supplements. Thus, investigating other elderberry subspecies like the blue elderberry, the focus of future chapters, allows for farmers in the United States to capitalize on this demand, but more information is needed on this particular plant if it is going to be used in consumer products.There is a long, rich history of the use of different parts of the elderberry plant by many cultures. For example, the wood has been used for kindling and musical instruments. Indeed, the name of the plant is derived from various ancient words related to instruments. The flowers and berries have been used in a variety of beverages, foods, and other herbal supplements.