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Diet-induced metabolic endotoxemia is an important factor in the development of many chronic diseases in animals and man. The gut epithelium is an efficient barrier that prevents the absorption of liposaccharide (LPS). Structural changes to the intestinal epithelium in response to dietary alterations allow LPS to enter the bloodstream, resulting in an increase in the plasma levels of LPS (termed metabolic endotoxemia). LPS activates Toll-like receptor-4 (TLR4) leading to the production of numerous pro-inflammatory cytokines and, hence, low-grade systemic inflammation. Thus, metabolic endotoxemia can lead to several chronic inflammatory conditions. Obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD) can also cause an increase in gut permeability and potential pharmacological and dietary interventions could be used to reduce the chronic low-grade inflammation associated with endotoxemia.

Sepsis is defined as life-threatening organ dysfunction caused by the dysregulated host response to infection. Despite serious mortality and morbidity, no sepsis-specific drugs exist. Endotoxemia is often used to model the hyperinflammation associated with early sepsis. This model classically uses lipopolysaccharide (LPS) from Gram-negative pathogens to activate the immune system, leading to hyperinflammation, microcirculatory disturbances and death. Other toxins may also be used to activate the immune system including Gram-positive peptidoglycan (PG) and lipoteichoic acid (LTA). In addition to these standard toxins, other bacterial components can induce inflammation. These molecules activate different signaling pathways and produce different physiological responses which can be taken advantage of for sepsis modeling. Endotoxemia modeling can provide information on pathways to inflammation in sepsis and contribute to preclinical drug development.

Diet and dietary components have profound effects on the composition of the gut microbiota and are among the most important contributors to the alteration in bacterial flora. This review examines the effects the “Western”, “plant-based”, “high-fat”, “medical ketogenic”, and “Mediterranean” diets have on the composition of the gut microbiota in both mice and human subjects. We show that specific dietary components that are commonly found in the “plant-based” and “Mediterranean” diet play a role in shifting the microbial composition. This review further evaluates the bacterial metabolites that are associated with diet, and their role in systemic inflammation and metabolic endotoxemia. Furthermore, the associations between diet/dietary components and altering bacterial composition, may lead to potential therapeutic targets for type II diabetes, obesity, and inflammatory diseases.

Metabolic endotoxemia is a condition in which blood lipopolysaccharide (LPS) levels are elevated, regardless of the presence of obvious infection. It has been suggested to lead to chronic inflammation-related diseases such as obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease (NAFLD), pancreatitis, amyotrophic lateral sclerosis, and Alzheimer’s disease. In addition, it has attracted attention as a target for the prevention and treatment of these chronic diseases. As metabolic endotoxemia was first reported in mice that were fed a high-fat diet, research regarding its relationship with diets has been actively conducted in humans and animals. In this review, we summarize the relationship between fat intake and induction of metabolic endotoxemia, focusing on gut dysbiosis and the influx, kinetics, and metabolism of LPS. We also summarize the recent findings about dietary factors that attenuate metabolic endotoxemia, focusing on the regulation of gut microbiota. We hope that in the future, control of metabolic endotoxemia using dietary factors will help maintain human health.

Although periodontitis has been implicated as a risk factor for various systemic diseases, the precise mechanisms by which periodontitis induces systemic disease remain to be elucidated. We have previously revealed that repeated oral administration of Porphyromonas gingivalis elicits endotoxemia via changes in the gut microbiota of the ileum, and thereby induces systemic inflammation and insulin resistance. However, it is not clear to what extent a single administration of P. gingivalis could affect gut microbiota composition, gut barrier function, and subsequent influx of gut microbiota into the liver. Therefore, in the present study, C57BL/6 mice were orally administered P. gingivalis (strain W83) once and compared to sham-inoculated mice. The phylogenetic structure and diversity of microbial communities in the gut and liver were analyzed by pyrosequencing the 16S ribosomal RNA genes. Serum endotoxin activity was determined by a Limulus amebocyte lysate test. Gene expression in the intestine and expression of 16S rRNA genes in the blood and liver were examined by quantitative polymerase chain reaction. Administration of P. gingivalis significantly altered gut microbiota, with an increased proportion of phylum Bacteroidetes, a decreased proportion of phylum Firmicutes, and increased serum endotoxin levels. In the intestinal tissues, gene expression of tjp-1 and occludin, which are involved in intestinal permeability, were downregulated. Higher amounts of bacterial DNA were detected in the liver of infected mice. Importantly, changes in gut microbiota preceded systemic inflammatory changes. These results further support the idea that disturbance of the gut microbiota composition by orally derived periodontopathic bacteria may be a causal mechanism linking periodontitis and systemic disease.

Societal lifestyle changes, especially increased consumption of a high-fat diet lacking dietary fibers, lead to gut microbiota dysbiosis and enhance the incidence of adiposity and chronic inflammatory disease. We aimed to investigate the metabolic effects of inulin with different degrees of polymerization on high-fat diet-fed C57BL/6 J mice and to evaluate whether different health outcomes are related to regulation of the gut microbiota. Short-chain and long-chain inulins exert beneficial effects through alleviating endotoxemia and inflammation. Antiinflammation was associated with a proportional increase in short-chain fatty acid-producing bacteria and an increase in the concentration of short-chain fatty acids. Inulin might decrease endotoxemia by increasing the proportion of Bifidobacterium and Lactobacillus , and their inhibition of endotoxin secretion may also contribute to antiinflammation. Interestingly, the beneficial health effects of long-chain inulin were more pronounced than those of short-chain inulin. Long-chain inulin was more dependent than short-chain inulin on species capable of processing complex polysaccharides, such as Bacteroides . A good understanding of inulin-gut microbiota-host interactions helps to provide a dietary strategy that could target and prevent high-fat diet-induced endotoxemia and inflammation through a prebiotic effect.

Objective The increasing prevalence of obesity and type 2 diabetes (T2D) demonstrates the failure of conventional treatments to curb these diseases. The gut microbiota has been put forward as a key player in the pathophysiology of diet-induced T2D. Importantly, cranberry (Vaccinium macrocarpon Aiton) is associated with a number of beneficial health effects. We aimed to investigate the metabolic impact of a cranberry extract (CE) on high fat/high sucrose (HFHS)-fed mice and to determine whether its consequent antidiabetic effects are related to modulations in the gut microbiota. Design C57BL/6J mice were fed either a chow or a HFHS diet. HFHS-fed mice were gavaged daily either with vehicle (water) or CE (200 mg/kg) for 8 weeks. The composition of the gut microbiota was assessed by analysing 16S rRNA gene sequences with 454 pyrosequencing. Results CE treatment was found to reduce HFHS-induced weight gain and visceral obesity. CE treatment also decreased liver weight and triglyceride accumulation in association with blunted hepatic oxidative stress and inflammation. CE administration improved insulin sensitivity, as revealed by improved insulin tolerance, lower homeostasis model assessment of insulin resistance and decreased glucose-induced hyperinsulinaemia during an oral glucose tolerance test. CE treatment was found to lower intestinal triglyceride content and to alleviate intestinal inflammation and oxidative stress. Interestingly, CE treatment markedly increased the proportion of the mucin-degrading bacterium Akkermansia in our metagenomic samples. Conclusions CE exerts beneficial metabolic effects through improving HFHS diet-induced features of the metabolic syndrome, which is associated with a proportional increase in Akkermansia spp. population.

This study was aimed at determining potential effects of apple-derived pectin on weight gain, gut microbiota, gut barrier and metabolic endotoxemia in rat models of diet-induced obesity. The rats received a standard diet (control; Chow group; n = 8) or a high-fat diet (HFD; n = 32) for eight weeks to induce obesity. The top 50th percentile of weight-gainers were selected as diet induced obese rats. Thereafter, the Chow group continued on chow, and the diet induced obese rats were randomly divided into two groups and received HFD (HF group; n = 8) or pectin-supplemented HFD (HF-P group; n = 8) for six weeks. Compared to the HF group, the HF-P group showed attenuated weight gain (207.38 ± 7.96 g vs. 283.63 ± 10.17 g, p < 0.01) and serum total cholesterol level (1.46 ± 0.13 mmol/L vs. 2.06 ± 0.26 mmol/L, p < 0.01). Compared to the Chow group, the HF group showed a decrease in Bacteroidetes phylum and an increase in Firmicutes phylum, as well as subordinate categories (p < 0.01). These changes were restored to the normal levels in the HF-P group. Furthermore, compared to the HF group, the HF-P group displayed improved intestinal alkaline phosphatase (0.57 ± 0.20 vs. 0.30 ± 0.19, p < 0.05) and claudin 1 (0.76 ± 0.14 vs. 0.55 ± 0.18, p < 0.05) expression, and decreased Toll-like receptor 4 expression in ileal tissue (0.76 ± 0.58 vs. 2.04 ± 0.89, p < 0.01). The HF-P group also showed decreased inflammation (TNFα: 316.13 ± 7.62 EU/mL vs. 355.59 ± 8.10 EU/mL, p < 0.01; IL-6: 51.78 ± 2.35 EU/mL vs. 58.98 ± 2.59 EU/mL, p < 0.01) and metabolic endotoxemia (2.83 ± 0.42 EU/mL vs. 0.68 ± 0.14 EU/mL, p < 0.01). These results suggest that apple-derived pectin could modulate gut microbiota, attenuate metabolic endotoxemia and inflammation, and consequently suppress weight gain and fat accumulation in diet induced obese rats.

Sepsis is a dynamic state that progresses at variable rates and has life-threatening consequences. Staging patients along the sepsis timeline requires a thorough knowledge of the evolution of cellular and molecular events at the tissue level. Here, we investigated the kidney, an organ central to the pathophysiology of sepsis. Single-cell RNA-sequencing in a murine endotoxemia model revealed the involvement of various cell populations to be temporally organized and highly orchestrated. Endothelial and stromal cells were the first responders. At later time points, epithelial cells upregulated immune-related pathways while concomitantly downregulating physiological functions such as solute homeostasis. Sixteen hours after endotoxin, there was global cell–cell communication failure and organ shutdown. Despite this apparent organ paralysis, upstream regulatory analysis showed significant activity in pathways involved in healing and recovery. This rigorous spatial and temporal definition of murine endotoxemia will uncover precise biomarkers and targets that can help stage and treat human sepsis.

(1) Background: Nutrition is a major lifestyle factor that can prevent the risk of cognitive impairment and dementia. Diet-induced metabolic endotoxemia has been proposed as a major root cause of inflammation and these pathways emerge as detrimental factors of healthy ageing. The aim of this paper was to update research focusing on the relationship between a fat-rich diet and endotoxemia, and to discuss the potential role of endotoxemia in cognitive performances. (2) Methods: We conducted a non-systematic literature review based on the PubMed database related to fat-rich meals, metabolic endotoxemia and cognitive disorders including dementia in humans. A total of 40 articles out of 942 in the first screening met the inclusion criteria. (3) Results: Evidence suggested that a fat-rich diet, depending on its quality, quantity and concomitant healthy food components, could influence metabolic endotoxemia. Since only heterogeneous cross-sectional studies are available, it remains unclear to what extent endotoxemia could be associated or not with cognitive disorders and dementia. (4) Conclusions: A fat-rich diet has the capability to provide significant increases in circulating endotoxins, which highlights nutritional strategies as a promising area for future research on inflammatory-associated diseases. The role of endotoxemia in cognitive disorders and dementia remains unclear and deserves further investigation.