A Mediterranean-like fat blend protects against the development of severe colitis in the mucin-2 deficient murine model
2022; 14 (1): 2055441
There is a growing appreciation that the interaction between diet, the gut microbiota and the immune system contribute to the development and progression of inflammatory bowel disease (IBD). A mounting body of scientific evidence suggests that high-fat diets exacerbate IBD; however, there is a lack of information on how specific types of fat impact colitis. The Mediterranean diet (MD) is considered a health-promoting diet containing approximately 40% total fat. It is not known if the blend of fats found in the MD contributes to its beneficial protective effects.Mice deficient in the mucin 2 gene (Muc 2-/-) were weaned to 40% fat, isocaloric, isonitrogenous diets. We compared the MD fat blend (high monounsaturated, 2:1 n-6:n-3 polyunsaturated and moderate saturated fat) to diets composed of corn oil (CO, n-6 polyunsaturated-rich), olive oil (monounsaturated-rich) or milk fat (MF, saturated-rich) on spontaneous colitis development in Muc2-/- mice. The MD resulted in lower clinical and histopathological scores and induced tolerogenic CD103+ CD11b+ dendritic, Th22 and IL-17+ IL-22+ cells necessary for intestinal barrier repair. The MD was associated with beneficial microbes and associated with higher cecal acetic acid levels negatively correlated with colitogenic microbes like Akkermansia muciniphila. In contrast, CO showed a higher prevalence of mucin-degraders including A. muciniphila and Enterobacteriaceae, which have been associated with colitis.A dietary blend of fats mimicking the MD, reduces disease activity, inflammation-related biomarkers and improves metabolic parameters in the Muc2-/- mouse model. Our findings suggest that the MD fat blend could be incorporated into a maintenance diet for colitis.
View details for DOI 10.1080/19490976.2022.2055441
View details for Web of Science ID 000787577900001
View details for PubMedID 35471119
View details for PubMedCentralID PMC9045830
Metabolomics-Guided Hypothesis Generation for Mechanisms of Intestinal Protection by Live Biotherapeutic Products
2021; 11 (5)
The use of live biotherapeutic products (LBPs), including single strains of beneficial probiotic bacteria or consortiums, is gaining traction as a viable option to treat inflammatory-mediated diseases like inflammatory bowel disease (IBD). However, LBPs' persistence in the intestine is heterogeneous since many beneficial bacteria lack mechanisms to tolerate the inflammation and the oxidative stress associated with IBD. We rationalized that optimizing LBPs with enhanced colonization and persistence in the inflamed intestine would help beneficial bacteria increase their bioavailability and sustain their beneficial responses. Our lab developed two bioengineered LBPs (SBT001/BioPersist and SBT002/BioColoniz) modified to enhance colonization or persistence in the inflamed intestine. In this study, we examined colon-derived metabolites via ultra-high performance liquid chromatography-mass spectrometry in colitic mice treated with either BioPersist or BioColoniz as compared to their unmodified parent strains (Escherichia coli Nissle 1917 [EcN] and Lactobacillus reuteri, respectively) or to each other. BioPersist administration resulted in lowered concentrations of inflammatory prostaglandins, decreased stress hormones such as adrenaline and corticosterone, increased serotonin, and decreased bile acid in comparison to EcN. In comparison to BioColoniz, BioPersist increased serotonin and antioxidant production, limited bile acid accumulation, and enhanced tissue restoration via activated purine and pyrimidine metabolism. These data generated several novel hypotheses for the beneficial roles that LBPs may play during colitis.
View details for DOI 10.3390/biom11050738
View details for Web of Science ID 000653446700001
View details for PubMedID 34063522
View details for PubMedCentralID PMC8156236
Deletion of mucin 2 induces colitis with concomitant metabolic abnormalities in mice
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
2021; 320 (5): G791-G803
Patients with inflammatory bowel disease (IBD) are at increased risk of under-recognized metabolic comorbidities. Chronic intestinal inflammation in IBD along with changes to the gut microbiome leads to broader systemic effects. Despite the existence of multiple animal models to study colitis, limited studies have examined the metabolic abnormalities associated with these models. In this study, a spontaneous model of colitis (mucin 2 knock-out mouse, Muc2-/-) was used to investigate the impact of intestinal disease on metabolic dysfunction. Before the onset of severe colitis, such as rectal prolapse, Muc2-/- mice exhibited impaired glucose clearance. Defects were noted in the insulin signaling pathway corresponding with upregulated genes in lipid utilization pathways, increased mitochondrial number, and peroxisome proliferator-activated coactivator 1α (PGC-1α), a transcription factor central to energy metabolism regulation. Parallel to these metabolic alterations, Muc2-/- mice exhibited systemic inflammation and bacteremia. We further characterized the dysbiotic microbiome's predicted functional categories given its contributing role to the colitic phenotype in the Muc2-/- mice. In addition to less butyrate levels, we show an increased predisposition to lipid metabolism and lipid biosynthesis pathways in the microbiome associated with the host's altered metabolic state. This study establishes the Muc2-/- mouse model that develops spontaneous colitis, as an ideal model for studying early comorbid metabolic dysfunction. Clarification of the underlying etiology of two phenotypes in this model could unravel important clues regarding the treatment of metabolic comorbidities during colitis.NEW & NOTEWORTHY This study discloses the impaired systemic energy metabolism in a classic colitis murine model (Muc2-/- knock-out model). Investigating the interaction between colitis and metabolic disorders helps to extend our knowledge on deciphering inflammatory bowel disease-associated comorbidities and provides new insight into clinical treatment.
View details for DOI 10.1152/ajpgi.00277.2020
View details for Web of Science ID 000687916600009
View details for PubMedID 33728986
Connecting the Dots Between Inflammatory Bowel Disease and Metabolic Syndrome: A Focus on Gut-Derived Metabolites
2020; 12 (5)
The role of the microbiome in health and disease has gained considerable attention and shed light on the etiology of complex diseases like inflammatory bowel disease (IBD) and metabolic syndrome (MetS). Since the microorganisms inhabiting the gut can confer either protective or harmful signals, understanding the functional network between the gut microbes and the host provides a comprehensive picture of health and disease status. In IBD, disruption of the gut barrier enhances microbe infiltration into the submucosae, which enhances the probability that gut-derived metabolites are translocated from the gut to the liver and pancreas. Considering inflammation and the gut microbiome can trigger intestinal barrier dysfunction, risk factors of metabolic diseases such as insulin resistance may have common roots with IBD. In this review, we focus on the overlap between IBD and MetS, and we explore the role of common metabolites in each disease in an attempt to connect a common origin, the gut microbiome and derived metabolites that affect the gut, liver and pancreas.
View details for DOI 10.3390/nu12051434
View details for Web of Science ID 000542272700238
View details for PubMedID 32429195
View details for PubMedCentralID PMC7285036
Egg white consumption increases GSH and lowers oxidative damage in 110-week-old geriatric mice hearts
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
2020; 76: 108252
The number of geriatrics with an advanced age is rising worldwide, with attendant cardiovascular disorders, characterized by elevated oxidative stress. Such oxidative stress is accelerated by an age-related loss of critical antioxidants like glutathione (GSH) and dietary solutions to combat this loss does not exist. While egg white is rich in sulphur amino acids (AAs), precursors for GSH biosynthesis, whether they can increase sulphur AA in vivo and augment GSH in the aged myocardium remain unclear. We hypothesized that egg white consumption increases GSH and reduces oxidative damage and inflammation in the geriatric heart. To this end, 101-102 week-old mice were given a AIN 76A diet supplemented with either 9% w/w egg white powder or casein for 8 weeks. Subsequent analysis revealed that egg white increased serum sulphur AA and cardiac GSH, while reducing the cysteine carrying transporter SNAT-2 and elevating glutamine transporter ASCT2 in the heart. Increased GSH was accompanied by elevated expression of GSH biosynthesis enzyme glutathione synthase as well as mitochondrial antioxidants like superoxide dismutase 2 and glutathione peroxidase 1 in egg white-fed hearts. These hearts also demonstrated lower oxidative damage of lipids (4-hydroxynonenal) and proteins [nitrotyrosine] with elevated anti-inflammatory IL-10 gene expression. These data demonstrate that even at the end of lifespan, egg whites remain effective in promoting serum sulphur AAs and preserve cardiac GSH with potent anti-oxidant and mild anti-inflammatory effects in the geriatric myocardium. We conclude that egg white intake may be an effective dietary strategy to attenuate oxidative damage in the senescent heart.
View details for DOI 10.1016/j.jnutbio.2019.108252
View details for Web of Science ID 000512211200013
View details for PubMedID 31816560
- Omega-3 PUFA vs. NSAIDs for Preventing Cardiac Inflammation FRONTIERS IN CARDIOVASCULAR MEDICINE 2018; 5: 146
Excess Linoleic Acid Increases Collagen I/III Ratio and "Stiffens" the Heart Muscle Following High Fat Diets
JOURNAL OF BIOLOGICAL CHEMISTRY
2015; 290 (38): 23371-23384
Controversy exists on the benefits versus harms of n-6 polyunsaturated fatty acids (n-6 PUFA). Although n-6 PUFA demonstrates anti-atherosclerotic properties, survival following cardiac remodeling may be compromised. We hypothesized that n-6 PUFA like linoleic acid (LA) or other downstream PUFAs like γ-linolenic acid or arachidonic acid alter the transforming growth factor-β (TGFβ)-collagen axis in the heart. Excess dietary LA increased the collagen I/III ratio in the mouse myocardium, leading to cardiac "stiffening" characterized by impaired transmitral flow indicative of early diastolic dysfunction within 5 weeks. In vitro, LA under TGFβ1 stimulation increased collagen I and lysyl oxidase (LOX), the enzyme that cross-links soluble collagen resulting in deposited collagen. Overexpression of fatty acid desaturase 2 (fads2), which metabolizes LA to downstream PUFAs, reduced collagen deposits, LOX maturation, and activity with LA, whereas overexpressing fads1, unrelated to LA desaturation, did not. Furthermore, fads2 knockdown by RNAi elevated LOX activity and collagen deposits in fibroblasts with LA but not oleic acid, implying a buildup of LA for aggravating such pro-fibrotic effects. As direct incubation with γ-linolenic acid or arachidonic acid also attenuated collagen deposits and LOX activity, we concluded that LA itself, independent of other downstream PUFAs, promotes the pro-fibrotic effects of n-6 PUFA. Overall, these results attempt to reconcile opposing views of n-6 PUFA on the cardiovascular system and present evidence supporting a cardiac muscle-specific effect of n-6 PUFAs. Therefore, aggravation of the collagen I/III ratio and cardiac stiffening by excess n-6 PUFA represent a novel pathway of cardiac lipotoxicity caused by high n-6 PUFA diets.
View details for DOI 10.1074/jbc.M115.682195
View details for Web of Science ID 000361685500043
View details for PubMedID 26240151
View details for PubMedCentralID PMC4645600