Butyrate as a Potential Preventive Therapy for Obesity

Due to its grave pathological role of obesity, comprehensive research is being continued to find out the causative factors involved in it. Recent advances in this field are increasingly recognized that there is a connection between diet, gut microbiota, intestinal barrier function and the low-grade inflammation that characterize the progression from obesity to metabolic disturbances, making dietary strategies to modulate the intestinal environment is important. In this context, the ability of some Gram-positive anaerobic bacteria to produce the shortchain fatty acid butyrate is impressive. A lower abundance of butyrate-producing bacteria has been associated with metabolic risk in humans. Recent studies suggest that butyrate might have been linked with metabolic risk in humans, and recommend that butyrate might have an anti-inflammatory mediator in metabolic diseases, and the potential of butyrate can alleviate obesity-related metabolic complications, possibly due to its ability to enhance the intestinal barrier function. Endogenous butyrate synthesis, delivery, and absorption by colonocytes have been well studied. Butyrate exerts its function by serving as a histone deacetylase (HDAC) inhibitor or signaling through several G Protein-Coupled Receptors (GPCRs). Latterly butyrate has gained selective attention for its favorable effects on intestinal homeostasis and energy metabolism. With anti-inflammatory properties, butyrate improves intestinal barrier function and mucosal immunity. Growing proof has highlighted the influence of butyrate on obesity. In this review the current knowledge on the features of butyrate, especially its potential effects and mechanisms involved in intestinal health and obesity. Here we review and discuss the potentials of butyrate as an anti-inflammatory mediator in obesity and the potential for dietary interventions increasing intestinal availability of butyrate.

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The Potential of Gut Commensals in Reinforcing Intestinal Barrier Function and Alleviating Inflammation

Nutrients ◽

10.3390/nu10080988 ◽

2018 ◽

Vol 10 (8) ◽

pp. 988 ◽

Cited By ~ 97

Author(s):

Kaisa Hiippala ◽

Hanne Jouhten ◽

Aki Ronkainen ◽

Anna Hartikainen ◽

Veera Kainulainen ◽

...

Keyword(s):

Barrier Function ◽

Metabolic Diseases ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Intestinal Health ◽

Beneficial Effects ◽

Beneficial Action ◽

Anti Inflammatory ◽

Major Factors ◽

Extracellular Structures

The intestinal microbiota, composed of pro- and anti-inflammatory microbes, has an essential role in maintaining gut homeostasis and functionality. An overly hygienic lifestyle, consumption of processed and fiber-poor foods, or antibiotics are major factors modulating the microbiota and possibly leading to longstanding dysbiosis. Dysbiotic microbiota is characterized to have altered composition, reduced diversity and stability, as well as increased levels of lipopolysaccharide-containing, proinflammatory bacteria. Specific commensal species as novel probiotics, so-called next-generation probiotics, could restore the intestinal health by means of attenuating inflammation and strengthening the epithelial barrier. In this review we summarize the latest findings considering the beneficial effects of the promising commensals across all major intestinal phyla. These include the already well-known bifidobacteria, which use extracellular structures or secreted substances to promote intestinal health. Faecalibacterium prausnitzii, Roseburia intestinalis, and Eubacterium hallii metabolize dietary fibers as major short-chain fatty acid producers providing energy sources for enterocytes and achieving anti-inflammatory effects in the gut. Akkermansia muciniphila exerts beneficial action in metabolic diseases and fortifies the barrier function. The health-promoting effects of Bacteroides species are relatively recently discovered with the findings of excreted immunomodulatory molecules. These promising, unconventional probiotics could be a part of biotherapeutic strategies in the future.

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Current knowledge on non-steroidal anti-inflammatory drug-induced small-bowel damage: a comprehensive review

Journal of Gastroenterology ◽

10.1007/s00535-019-01657-8 ◽

2019 ◽

Vol 55 (5) ◽

pp. 481-495 ◽

Cited By ~ 9

Author(s):

Toshio Watanabe ◽

Yasuhiro Fujiwara ◽

Francis K. L. Chan

Keyword(s):

Small Bowel ◽

Current Knowledge ◽

Significant Proportion ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Drug Induced ◽

Anti Inflammatory ◽

Factor Α ◽

Small Bowel Endoscopy ◽

Intestinal Ulcers

AbstractRecent advances in small-bowel endoscopy such as capsule endoscopy have shown that non-steroidal anti-inflammatory drugs (NSAIDs) frequently damage the small intestine, with the prevalence rate of mucosal breaks of around 50% in chronic users. A significant proportion of patients with NSAIDs-induced enteropathy are asymptomatic, but some patients develop symptomatic or complicated ulcers that need therapeutic intervention. Both inhibition of prostaglandins due to the inhibition of cyclooxygenases and mitochondrial dysfunction secondary to the topical effect of NSAIDs play a crucial role in the early process of injury. As a result, the intestinal barrier function is impaired, which allows enterobacteria to invade the mucosa. Gram-negative bacteria and endogenous molecules coordinate to trigger inflammatory cascades via Toll-like receptor 4 to induce excessive expression of cytokines such as tumor necrosis factor-α and to activate NLRP3 inflammasome, a multiprotein complex that processes pro-interleukin-1β into its mature form. Finally, neutrophils accumulate in the mucosa, resulting in intestinal ulceration. Currently, misoprostol is the only drug that has a proven beneficial effect on bleeding small intestinal ulcers induced by NSAIDs or low-dose aspirin, but its protection is insufficient. Therefore, the efficacy of the combination of misoprostol with other drugs, especially those targeting the innate immune system, should be assessed in the next step.

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Intestinal Mucosal Barrier Function Restoration in Mice by Maize Diet Containing Enriched Flavan-4-Ols

Nutrients ◽

10.3390/nu12040896 ◽

2020 ◽

Vol 12 (4) ◽

pp. 896 ◽

Cited By ~ 1

Author(s):

Binning Wu ◽

Rohil Bhatnagar ◽

Vijaya V. Indukuri ◽

Shara Chopra ◽

Kylie March ◽

...

Keyword(s):

Barrier Function ◽

Control Diet ◽

Intestinal Barrier ◽

Mucosal Barrier ◽

Intestinal Barrier Function ◽

Low Grade ◽

Colonic Inflammation ◽

Mucosal Barrier Function ◽

Inflammatory Bowel ◽

Histology Score

Inflammatory bowel disease (IBD), a chronic intestinal inflammatory condition, awaits safe and effective preventive strategies. Naturally occurring flavonoid compounds are promising therapeutic candidates against IBD due to their great antioxidant potential and ability to reduce inflammation and improve immune signaling mediators in the gut. In this study, we utilized two maize near-isogenic lines flavan-4-ols-containing P1-rr (F+) and flavan-4-ols-lacking p1-ww (F−) to investigate the anti-inflammatory property of flavan-4-ols against carboxymethylcellulose (CMC)-induced low-grade colonic inflammation. C57BL/6 mice were exposed to either 1% CMC (w/v) or water for a total of 15 weeks. After week six, mice on CMC treatment were divided into four groups. One group continued on the control diet. The second and third groups were supplemented with F+ at 15% or 25% (w/w). The fourth group received diet supplemented with F− at 15%. Here we report that mice consuming F+(15) and F+(25) alleviated CMC-induced increase in epididymal fat-pad, colon histology score, pro-inflammatory cytokine interleukin 6 expression and intestinal permeability compared to mice fed with control diet and F−(15). F+(15) and F+(25) significantly enhanced mucus thickness in CMC exposed mice (p < 0.05). These data collectively demonstrated the protective effect of flavan-4-ol against colonic inflammation by restoring intestinal barrier function and provide a rationale to breed for flavan-4-ols enriched cultivars for better dietary benefits.

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Mechanisms Mediating Anti-Inflammatory Effects of Delta-Tocotrienol and Tart Cherry Anthocyanins in 3T3-L1 Adipocytes

Nutrients ◽

10.3390/nu12113356 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3356

Author(s):

Lexie Harlan ◽

London T. Mena ◽

Latha Ramalingam ◽

Shasika Jayarathne ◽

Chwan-Li Shen ◽

...

Keyword(s):

Metabolic Diseases ◽

Combined Treatment ◽

Low Grade ◽

Tart Cherry ◽

Metabolic Complications ◽

Inflammatory Protein ◽

Anti Inflammatory ◽

Low Grade Inflammation ◽

Macrophage Inflammatory Protein

Chronic low-grade inflammation is a primary characteristic of obesity and can lead to other metabolic complications including insulin resistance and type 2 diabetes (T2D). Several anti-inflammatory dietary bioactives decrease inflammation that accompanies metabolic diseases. We are specifically interested in delta-tocotrienol, (DT3) an isomer of vitamin E, and tart cherry anthocyanins (TCA), both of which possess individual anti-inflammatory properties. We have previously demonstrated that DT3 and TCA, individually, reduced systemic and adipose tissue inflammation in rodent models of obesity. However, whether these compounds have combinatorial effects has not been determined yet. Hence, we hypothesize that a combined treatment of DT3 and TCA will have great effects in reducing inflammation in adipocytes, and that these effects are mediated via the nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), a major inflammatory transcription factor. We used 3T3-L1 adipocytes and treated them with 1–5 µM doses of DT3 along with tart cherry containing 18–36 µg anthocyanin/mL, to assess effects on inflammation. Neither DT3 nor TCA, nor their combinations had toxic effects on adipocytes. Furthermore, pro-inflammatory markers interleukin-6 (IL-6) and p-65 (subunit of NFkB) were reduced at the protein level in media collected from adipocytes with both individual and combined treatments. Additionally, other downstream targets of NFkB including macrophage inflammatory protein 2 (Mip2), and Cyclooxygenase-2 (Cox2) were also significantly downregulated (p ≤ 0.05) when treated with individual and combined doses of DT3 and TCA with no additional combinatorial effects. In summary, DT3 and TCA individually, are beneficial in reducing inflammation with no additional combinatorial effects.

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Health-Promoting Properties of Proanthocyanidins for Intestinal Dysfunction

Nutrients ◽

10.3390/nu12010130 ◽

2020 ◽

Vol 12 (1) ◽

pp. 130 ◽

Cited By ~ 7

Author(s):

Carlos González-Quilen ◽

Esther Rodríguez-Gallego ◽

Raúl Beltrán-Debón ◽

Montserrat Pinent ◽

Anna Ardévol ◽

...

Keyword(s):

Barrier Function ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Intestinal Barrier ◽

Experimental Models ◽

Intestinal Barrier Function ◽

Grape Seeds ◽

Inflammatory Conditions ◽

Bacterial Endotoxins ◽

Health Promoting

The intestinal barrier is constantly exposed to potentially harmful environmental factors, including food components and bacterial endotoxins. When intestinal barrier function and immune homeostasis are compromised (intestinal dysfunction), inflammatory conditions may develop and impact overall health. Evidence from experimental animal and cell culture studies suggests that exposure of intestinal mucosa to proanthocyanidin (PAC)-rich plant products, such as grape seeds, may contribute to maintaining the barrier function and to ameliorating the pathological inflammation present in diet-induced obesity and inflammatory bowel disease. In this review, we aim to update the current knowledge on the bioactivity of PACs in experimental models of intestinal dysfunction and in humans, and to provide insights into the underlying biochemical and molecular mechanisms.

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Tolerogenic Dendritic Cells Shape a Transmissible Gut Microbiota that Protects from Metabolic Diseases

10.2337/figshare.14687523 ◽

2021 ◽

Author(s):

Emelyne Lécuyer ◽

Tiphaine Le Roy ◽

Aurélie Gestin ◽

Amélie Lacombe ◽

Catherine Philippe ◽

...

Keyword(s):

Dendritic Cells ◽

Metabolic Diseases ◽

Intestinal Inflammation ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Low Grade ◽

Obesity And Diabetes ◽

Tolerogenic Dendritic Cells ◽

Tolerogenic Function ◽

And Function

Excess of chronic contact between microbial motifs and intestinal immune cells are known to trigger a low-grade inflammation involved in many pathologies such as obesity and diabetes. The important skewing of intestinal adaptive immunity in the context of diet-induced obesity (DIO) is well described but how dendritic cells (DCs) participate to these changes is still poorly documented. To address this question, transgenic mice with enhanced DCs lifespan and immunogenicity (DChBcl-2 mice) are challenged with a high-fat diet. Those mice display resistance to DIO and metabolic alterations. The DIO-resistant phenotype is associated with healthier parameters of intestinal barrier function and lower intestinal inflammation. DChBcl-2 DIO-resistant mice demonstrate a particular increase in tolerogenic DC numbers and function which is associated with strong intestinal IgA, Th17 and T regulatory immune responses. Microbiota composition and function analyses reveal that the DChBcl-2 mice microbiota is characterized by lower immunogenicity and an enhanced butyrate production. Cohousing experiments and fecal microbial transplantations are sufficient to transfer the DIO resistance status to WT mice demonstrating that maintenance of DCs tolerogenic ability sustains a microbiota able to drive DIO resistance. DCs tolerogenic function is revealed as a new potent target in metabolic disease management.

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Tolerogenic Dendritic Cells Shape a Transmissible Gut Microbiota that Protects from Metabolic Diseases

10.1101/2020.10.22.350033 ◽

2020 ◽

Author(s):

Emelyne Lécuyer ◽

Tiphaine Le Roy ◽

Aurélie Gestin ◽

Amélie Lacombe ◽

Catherine Philippe ◽

...

Keyword(s):

Dendritic Cells ◽

Metabolic Diseases ◽

Intestinal Inflammation ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Low Grade ◽

Obesity And Diabetes ◽

Tolerogenic Dendritic Cells ◽

Tolerogenic Function ◽

And Function

ABSTRACTExcess of chronic contact between microbial motifs and intestinal immune cells are known to trigger a low-grade inflammation involved in many pathologies such as obesity and diabetes.The important skewing of intestinal adaptive immunity in the context of diet-induced obesity (DIO) is well described but how dendritic cells (DCs) participate to these changes is still poorly documented. To address this question, transgenic mice with enhanced DCs lifespan and immunogenicity (DChBcl-2 mice), are challenged with a high fat diet.Those mice display resistance to DIO and metabolic alterations. The DIO resistant phenotype is associated with healthier parameters of intestinal barrier function and lower intestinal inflammation. DChBcl-2 DIO-resistant mice demonstrate a particular increase in tolerogenic DC numbers and function which is associated with strong intestinal IgA, Th17 and T regulatory immune responses.Microbiota composition and function analyses reveal that the DChBcl-2 mice microbiota is characterized by a lower immunogenicity and an enhanced butyrate production. Cohousing experiments and fecal microbial transplantations are sufficient to transfer the DIO resistance status to WT mice demonstrating that maintenance of DCs tolerogenic ability sustains a microbiota able to drive DIO resistance. DCs tolerogenic function is revealed as a new potent target in metabolic diseases management.

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Intestinal Barrier Dysfunction, LPS Translocation, and Disease Development

Journal of the Endocrine Society ◽

10.1210/jendso/bvz039 ◽

2020 ◽

Vol 4 (2) ◽

Cited By ~ 20

Author(s):

Siddhartha S Ghosh ◽

Jing Wang ◽

Paul J Yannie ◽

Shobha Ghosh

Keyword(s):

Barrier Function ◽

Current Knowledge ◽

Intestinal Barrier ◽

Systemic Circulation ◽

Intestinal Barrier Function ◽

Disease Development ◽

Barrier Dysfunction ◽

Intestinal Alkaline Phosphatase ◽

Targeted Interventions ◽

Associated Diseases

Abstract The intestinal barrier is complex and consists of multiple layers, and it provides a physical and functional barrier to the transport of luminal contents to systemic circulation. While the epithelial cell layer and the outer/inner mucin layer constitute the physical barrier and are often referred to as the intestinal barrier, intestinal alkaline phosphatase (IAP) produced by epithelial cells and antibacterial proteins secreted by Panneth cells represent the functional barrier. While antibacterial proteins play an important role in the host defense against gut microbes, IAP detoxifies bacterial endotoxin lipopolysaccharide (LPS) by catalyzing the dephosphorylation of the active/toxic Lipid A moiety, preventing local inflammation as well as the translocation of active LPS into systemic circulation. The causal relationship between circulating LPS levels and the development of multiple diseases underscores the importance of detailed examination of changes in the “layers” of the intestinal barrier associated with disease development and how this dysfunction can be attenuated by targeted interventions. To develop targeted therapies for improving intestinal barrier function, it is imperative to have a deeper understanding of the intestinal barrier itself, the mechanisms underlying the development of diseases due to barrier dysfunction (eg, high circulating LPS levels), the assessment of intestinal barrier function under diseased conditions, and of how individual layers of the intestinal barrier can be beneficially modulated to potentially attenuate the development of associated diseases. This review summarizes the current knowledge of the composition of the intestinal barrier and its assessment and modulation for the development of potential therapies for barrier dysfunction-associated diseases.

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Curcumin improves intestinal barrier function: modulation of intracellular signaling, and organization of tight junctions

AJP Cell Physiology ◽

10.1152/ajpcell.00235.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. C438-C445 ◽

Cited By ~ 61

Author(s):

Jing Wang ◽

Siddhartha S. Ghosh ◽

Shobha Ghosh

Keyword(s):

Type 2 Diabetes ◽

Tight Junctions ◽

Barrier Function ◽

Intracellular Signaling ◽

Metabolic Diseases ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Barrier Dysfunction ◽

Oral Supplementation

Association between circulating lipopolysaccharide (LPS) and metabolic diseases (such as type 2 diabetes and atherosclerosis) has shifted the focus from high-fat high-cholesterol containing Western-type diet (WD)-induced changes in gut microbiota per se to release of gut bacteria-derived products (e.g., LPS) into circulation due to intestinal barrier dysfunction as the possible mechanism for the chronic inflammatory state underlying the development of these diseases. We demonstrated earlier that oral supplementation with curcumin attenuates WD-induced development of type 2 diabetes and atherosclerosis. Poor bioavailability of curcumin has precluded the establishment of a causal relationship between oral supplementation and it is in vivo effects. We hypothesized that curcumin attenuates WD-induced chronic inflammation and associated metabolic diseases by modulating the function of intestinal epithelial cells (IECs) and the intestinal barrier function. The objective of the present study was to delineate the underlying mechanisms. The human IEC lines Caco-2 and HT-29 were used for these studies and modulation of direct as well as indirect effects of LPS on intracellular signaling as well as tight junctions were examined. Pretreatment with curcumin significantly attenuated LPS-induced secretion of master cytokine IL-1β from IECs and macrophages. Furthermore, curcumin also reduced IL-1β-induced activation of p38 MAPK in IECs and subsequent increase in expression of myosin light chain kinase involved in the phosphorylation of tight junction proteins and ensuing disruption of their normal arrangement. The major site of action of curcumin is, therefore, likely the IECs and the intestinal barrier, and by reducing intestinal barrier dysfunction, curcumin modulates chronic inflammatory diseases despite poor bioavailability.

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Bioaccessibility and Bioactivity of Cereal Polyphenols: A Review

Foods ◽

10.3390/foods10071595 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1595

Author(s):

Borkwei Ed Nignpense ◽

Nidhish Francis ◽

Christopher Blanchard ◽

Abishek Bommannan Santhakumar

Keyword(s):

Barrier Function ◽

Plasma Concentrations ◽

Intestinal Barrier ◽

Inflammatory Activity ◽

Intestinal Barrier Function ◽

Mucin Production ◽

Therapeutic Benefits ◽

Wide Range ◽

Anti Inflammatory

Cereal bioactive compounds, especially polyphenols, are known to possess a wide range of disease preventive properties that are attributed to their antioxidant and anti-inflammatory activity. However, due to their low plasma concentrations after oral intake, there is controversy regarding their therapeutic benefits in vivo. Within the gastrointestinal tract, some cereal polyphenols are absorbed in the small intestine, with the majority accumulating and metabolised by the colonic microbiota. Chemical and enzymatic processes occurring during gastrointestinal digestion modulate the bioactivity and bioaccessibility of phenolic compounds. The interactions between the cereal polyphenols and the intestinal epithelium allow the modulation of intestinal barrier function through antioxidant, anti-inflammatory activity and mucin production thereby improving intestinal health. The intestinal microbiota is believed to have a reciprocal interaction with polyphenols, wherein the microbiome produces bioactive and bioaccessible phenolic metabolites and the phenolic compound, in turn, modifies the microbiome composition favourably. Thus, the microbiome presents a key link between polyphenol consumption and the health benefits observed in metabolic conditions in numerous studies. This review will explore the therapeutic value of cereal polyphenols in conjunction with their bioaccessibility, impact on intestinal barrier function and interaction with the microbiome coupled with plasma anti-inflammatory effects.

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