Metastatic Colon Cancer in an Individual Following Prolonged Daily Inulin Consumption.

Studies in rodents suggest that inulin supplements may be carcinogenic. We present a case implicating that this risk extends to humans. A healthy male from a family lacking history of cancer had his first cancer-screening colonoscopy at age 56.

Hypertension Increases Susceptibility to Experimental Malaria in Mice.

Global prevalence of hypertension is on the rise, burdening healthcare, especially in developing countries where infectious diseases, such as malaria, are also rampant. Whether hypertension could predispose or increase susceptibility to malaria, however, has not been extensively explored. Previously, we reported that hypertension is associated with abnormal red blood cell (RBC) physiology and anemia.

Sex Dimorphic Effects of Bile Acid Metabolism in Liver Cancer in Mice.

Background & Aims: Hepatocellular carcinoma (HCC) is a male-dominant disease, but targeted sex hormone therapies have not been successful. Bile acids are a potential liver carcinogen and are biomolecules with hormone-like effects. A few studies highlight their potential sex dimorphism in physiology and disease.

Genetically engineered Lactobacillus paracasei rescues colonic angiotensin converting enzyme 2 (ACE2) and attenuates hypertension in female Ace2 knock out rats.

Engineered gut microbiota represents a new frontier in medicine, in part serving as a vehicle for the delivery of therapeutic biologics to treat a range of host conditions. The gut microbiota plays a significant role in blood pressure regulation; thus, manipulation of gut microbiota is a promising avenue for hypertension treatment. In this study, we tested the potential of Lactobacillus paracasei, genetically engineered to produce and deliver human angiotensin converting enzyme 2 (Lacto-hACE2), to regulate blood pressure in a rat model of hypertension with genetic ablation of endogenous Ace2 (Ace2 and Ace2).

Urine-based Detection of Congenital Portosystemic Shunt in C57BL/6 Mice.

Sporadic occurrence of congenital portosystemic shunt (PSS) at a rate of ∼1 out of 10 among C57BL/6 J mice, which are widely used in biomedical research, results in aberrancies in serologic, metabolic, and physiologic parameters. Therefore, mice with PSS should be identified as outliers in research. Accordingly, we sought methods to, reliably and efficiently, identify PSS mice.

Psyllium fiber protects mice against western diet-induced metabolic syndrome via the gut microbiota-dependent mechanism.

Impacts of dietary fiber on intestinal inflammation are complex, but some specific semi-purified fibers, particularly psyllium, can protect humans and rodents against colitis. Mechanisms underlying such protection are not fully understood but may involve activation of the FXR bile acid receptor. Obesity and its associated consequences, referred to as metabolic syndrome, are associated with, and promoted by, low-grade inflammation in a variety of tissues including the intestine.

Loss of toll-like receptor 5 potentiates spontaneous hepatocarcinogenesis in farnesoid X receptor-deficient mice.

Background: HCC is the most common primary liver cancer and a leading cause of cancer-related mortality. Gut microbiota is a large collection of microbes, predominately bacteria, that harbor the gastrointestinal tract. Changes in gut microbiota that deviate from the native composition, that is, "dysbiosis," is proposed as a probable diagnostic biomarker and a risk factor for HCC.

Conjugated bile acids are nutritionally re-programmable antihypertensive metabolites.

Background: Hypertension is the largest risk factor affecting global mortality. Despite available medications, uncontrolled hypertension is on the rise, whereby there is an urgent need to develop novel and sustainable therapeutics. Because gut microbiota is now recognized as an important entity in blood pressure regulation, one such new avenue is to target the gut-liver axis wherein metabolites are transacted via host-microbiota interactions.

Bacterial flagellin is a dominant, stable innate immune activator in the gastrointestinal contents of mice and rats.

Intestinal contents comprise the largest repository of immunogenic ligands of microbial origin. We undertook this study to assess the predominant microbe-associated molecular patterns (MAMPs) present therein and the receptors) that mediate the innate immune responses to them. Here, we demonstrated that intestinal contents from conventional, but not germ-free, mice and rats triggered robust innate immune responses and .

Crosstalk between Gut Microbiota and Host Immunity: Impact on Inflammation and Immunotherapy.

Gut microbes and their metabolites are actively involved in the development and regulation of host immunity, which can influence disease susceptibility. Herein, we review the most recent research advancements in the gut microbiota-immune axis. We discuss in detail how the gut microbiota is a tipping point for neonatal immune development as indicated by newly uncovered phenomenon, such as maternal imprinting, in utero intestinal metabolome, and weaning reaction.

Psyllium Fiber Protects Against Colitis Via Activation of Bile Acid Sensor Farnesoid X Receptor.

Background & Aims: Fiber-rich foods promote health, but mechanisms by which they do so remain poorly defined. Screening fiber types, in mice, revealed psyllium had unique ability to ameliorate 2 chronic inflammatory states, namely, metabolic syndrome and colitis. We sought to determine the mechanism of action of the latter.

Enterohepatic Shunt-Driven Cholemia Predisposes to Liver Cancer.

Background & Aims: Pathogenesis of hepatocellular carcinoma (HCC), which kills millions annually, is poorly understood. Identification of risk factors and modifiable determinants and mechanistic understanding of how they impact HCC are urgently needed.

Methods: We sought early prognostic indicators of HCC in C57BL/6 mice, which we found were prone to developing this disease when fed a fermentable fiber-enriched diet.

Selective IgA Deficiency in Spontaneously Hypertensive Rats With Gut Dysbiosis.

Background: The spontaneously hypertensive rat (SHR) is extensively used to study hypertension. Gut microbiota dysbiosis is a notable feature in SHR for reasons unknown. Immunoglobulin A (IgA) is a major host factor required for gut microbiota homeostasis.

Activation of CD81 skin ILC2s by cold-sensing TRPM8 neuron-derived signals maintains cutaneous thermal homeostasis.

As the outermost barrier tissue of the body, the skin harbors a large number of innate lymphoid cells (ILCs) that help maintain local homeostasis in the face of changing environments. How skin-resident ILCs are regulated and function in local homeostatic maintenance is poorly understood. We here report the discovery of a cold-sensing neuron-initiated pathway that activates skin group 2 ILCs (ILC2s) to help maintain thermal homeostasis.

Low-dose 1,3-butanediol reverses age-associated vascular dysfunction independent of ketone body β-hydroxybutyrate.

With an aging global population, identifying novel therapeutics are necessary to increase longevity and decrease the deterioration of essential end organs such as the vasculature. Secondary alcohol, 1,3-butanediol (1,3-BD), is commonly administered to stimulate the biosynthesis of the most abundant ketone body β-hydroxybutyrate (βHB), in lieu of nutrient deprivation. However, suprapharmacological concentrations of 1,3-BD are necessary to significantly increase systemic βHB, and 1,3-BD per se can cause vasodilation at nanomolar concentrations.

Immunoglobulin A, an Active Liaison for Host-Microbiota Homeostasis.

Mucosal surfaces in the gastrointestinal tract are continually exposed to native, commensal antigens and susceptible to foreign, infectious antigens. Immunoglobulin A (IgA) provides dual humoral responses that create a symbiotic environment for the resident gut microbiota and prevent the invasion of enteric pathogens. This review features recent immunological and microbial studies that elucidate the underlying IgA and microbiota-dependent mechanisms for mutualism at physiological conditions.

Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator.

Autophagy has long been associated with longevity, and it is well established that autophagy reverts and prevents vascular deterioration associated with aging and cardiovascular diseases. Currently, our understanding of how autophagy benefits the vasculature is centered on the premise that reduced autophagy leads to the accumulation of cellular debris, resulting in inflammation and oxidative stress, which are then reversed by reconstitution or upregulation of autophagic activity. Evolutionarily, autophagy also functions to mobilize endogenous nutrients in response to starvation.

IL-10 Receptor Neutralization-Induced Colitis in Mice: A Comprehensive Guide.

Interleukin-10 (IL-10) and its receptor (IL-10R) have been foremost targets to understand inflammatory bowel disease (IBD) pathogenesis. For the past several decades, IL-10-deficient (Il10 ) mice were considered one of the best models to study immune-mediated colitis. Several physiologic limitations with this model, e.

Bacterial Swarmers Enriched During Intestinal Stress Ameliorate Damage.

Background And Aims: Bacterial swarming, a collective movement on a surface, has rarely been associated with human pathophysiology. This study aims to define a role for bacterial swarmers in amelioration of intestinal stress.

Methods: We developed a polymicrobial plate agar assay to detect swarming and screened mice and humans with intestinal stress and inflammation.

Enterobactin induces the chemokine, interleukin-8, from intestinal epithelia by chelating intracellular iron.

Iron is an indispensable nutrient for both mammals and microbes. Bacteria synthesize siderophores to sequester host iron, whereas lipocalin 2 (Lcn2) is the host defense protein that prevent this iron thievery. Enterobactin (Ent) is a catecholate-type siderophore that has one of the strongest known affinities for iron.

Microbiota Introduced to Germ-Free Rats Restores Vascular Contractility and Blood Pressure.

Commensal gut microbiota are strongly correlated with host hemodynamic homeostasis but only broadly associated with cardiovascular health. This includes a general correspondence of quantitative and qualitative shifts in intestinal microbial communities found in hypertensive rat models and human patients. However, the mechanisms by which gut microbes contribute to the function of organs important for blood pressure (BP) control remain unanswered.

Fermentable fiber-induced hepatocellular carcinoma in mice recapitulates gene signatures found in human liver cancer.

Hepatocellular carcinoma (HCC), the most malignant form of primary liver cancer, is the fourth most prevalent cause of cancer mortality globally. It was recently discovered that the dietary fermentable fiber, inulin, can reprogram the murine liver to favor HCC development in a gut microbiota-dependent manner. Determining the molecular pathways that are either over expressed or repressed during inulin-induced HCC would provide a platform of potential therapeutic targets.