Ulcerative colitis (UC) and Crohn's disease (CD), collectively known as Inflammatory Bowel Diseases (IBD), are caused by a complex interplay between genetic, immunologic, microbial and environmental factors. Dysbiosis of the gut microbiome is increasingly considered to be causatively related to IBD and is strongly affected by components of a Western life style. Bacteria that ferment fibers and produce short chain fatty acids (SCFAs) are typically reduced in mucosa and feces of patients with IBD, as compared to healthy individuals. SCFAs, such as acetate, propionate and butyrate, are important metabolites in maintaining intestinal homeostasis. Several studies have indeed shown that fecal SCFAs levels are reduced in active IBD. SCFAs are an important fuel for intestinal epithelial cells and are known to strengthen the gut barrier function. Recent findings, however, show that SCFAs, and in particular butyrate, also have important immunomodulatory functions. Absorption of SCFAs is facilitated by substrate transporters like MCT1 and SMCT1 to promote cellular metabolism. Moreover, SCFAs may signal through cell surface G-protein coupled receptors (GPCRs), like GPR41, GPR43, and GPR109A, to activate signaling cascades that control immune functions. Transgenic mouse models support the key role of these GPCRs in controlling intestinal inflammation. Here, we present an overview of microbial SCFAs production and their effects on the intestinal mucosa with specific emphasis on their relevance for IBD. Moreover, we discuss the therapeutic potential of SCFAs for IBD, either applied directly or by stimulating SCFAs-producing bacteria through pre- or probiotic approaches.

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Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases.

Ana M Valdes and colleagues discuss strategies for modulating the gut microbiota through diet and probiotics

https://www.bmj.com/content/bmj/361/bmj.k2179.full.pdf

Role of the gut microbiota in nutrition and health

Short chain fatty acids (SCFAs) being produced during fermentation of non-digestible polysaccharides are regulatory compounds with the potential to influence inflammatory, as well as emotional state and cognition through the gut–brain axis. We analyzed the association between stool concentration of SCFAs (acetic acid (C 2:0), propionic acid (C 3:0), isobutyric acid (C 4:0 i), butyric acid (C 4:0 n), isovaleric acid (C 5:0 i) valeric acid (C 5:0 n), isocaproic acid (C 6:0 i), caproic acid, and (C 6:0 n) heptanoic acid (C 7:0)) and depressive symptoms among women and looked for the potential confounders of microbiota byproduct synthesis. We enrolled 116 women aged 52.0 ± 4.7 years and recognized depression in 47 (40.52%). To analyze the emotional state, Beck’s Depression Inventory (BDI) was used. We assessed SCFAs content by means of gas chromatography. Fiber intake was estimated using parts of food frequency questionnaire. The content of acetic acid was significantly lowered compared to non-depressed women (median {IQR}: 29.49 {20.81} vs. 34.99 {19.55}, p = 0.04). A tendency toward decreased level of propionic acid was noticed (median {IQR}: 16.88 {9.73} vs. 21.64 {12.17}, p = 0.07), while the concentration of isocaproic acid was significantly increased in (median {IQR}: 0.89 {1.15} vs. 0.56 {0.95}, p < 0.01) comparison to matched healthy subjects. We found negative correlations between acetate, propionate, and Beck’s score (r = −0.2, p = 0.03; r = −0.21, p = 0.02, respectively). Statistically significant correlations between acetate and propionate and BDI somatic score (r = −0.21, p = 0.01; r = −0.17, p = 0.03), as well as correlations regarding isocaproic and both cognitive/affective (r = 0.37, p = 0.0001) and somatic (r = 9.37, p < 0.001) scores were found. Women who declared current usage of lipid-lowering and thyroid drugs in the past, had higher content of C6:0-i (Users; median {IQR}: 1.91 {3.62} vs. non-users; 0.55 {0.67}; p = 0.0048).and lower of C2:0 (Users; median {IQR}: 23.07 {12.80} vs. non users 33.73 {21.44}; p = 0.041), respectively. No correlations regarding SCFAs concentration and fiber intake were found. We concluded that SCFAs may potentially contribute to depression phenotype, however, due to the small size of groups suffering from moderately heavy (n = 5) and severe (n = 7) depression, the conclusion should be treated with caution. Pharmacotherapy of hyperlipidemia and thyroid disease might affect SCFAs synthesis. Studies with more participants are required.

Faecal Short Chain Fatty Acids Profile is Changed in Polish Depressive Women

Over the last 10 years, there has been a growing interest in the relationship between gut microbiota, the brain, and neurologic-associated affections. As multiple preclinical and clinical research studies highlight gut microbiota’s potential to modulate the general state of health state, it goes without saying that gut microbiota plays a significant role in neurogenesis, mental and cognitive development, emotions, and behaviors, and in the progression of neuropsychiatric illnesses. Gut microbiota produces important biologic products that, through the gut-brain axis, are directly connected with the appearance and evolution of neurological and psychiatric disorders such as depression, anxiety, bipolar disorder, autism, schizophrenia, Parkinson’s disease, Alzheimer’s disease, dementia, multiple sclerosis, and epilepsy. This study reviews recent research on the link between gut microbiota and the brain, and microbiome’s role in shaping the development of the most common neurological and psychiatric illnesses. Moreover, special attention is paid to the use of probiotic formulations as a potential non-invasive therapeutic opportunity for prevention and management of neuropsychiatric-associated affections. Graphical Abstract

Guts Imbalance Imbalances the Brain: A Review of Gut Microbiota Association With Neurological and Psychiatric Disorders

We investigated the effect of α-cyclodextrin (α-CD) on the bacterial populations of gut microbiota, production of organic acids, and short-chain fatty acids (SCFAs), and lipid metabolism in obese mice induced by feeding a high-fat diet (HFD). Male C57BL/6J mice were assigned to three diet groups: normal diet (ND) (5% [w/w] fat), HFD (35% [w/w] fat), and HFD (35% [w/w] fat) + 5.5% (w/w) α-CD for 16 weeks. Increases in body and epididymal adipose tissue weights were observed in the HFD group compared with the ND group, which were attenuated in the HFD+α-CD group. The supplementation of α-CD increased the total number of bacteria, Bacteroides, Bifidobacterium, and Lactobacillus that were decreased in gut microbiota of mice by feeding the HFD. Importantly, α-CD administration increased the concentrations of lactic acid and SCFAs, such as acetic, propionic, and butyric acids, and decreased glucose concentrations in cecal contents. Furthermore, supplementation of α-CD upregulated the gene expression of peroxisome proliferator-activated receptor (PPAR)γ involved in adipocyte differentiation and PPARα involved in energy expenditure and downregulated that of sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase involved in fatty acid and triglyceride synthesis in adipose tissue. This study revealed that the alteration in gut microbiota and increased production of lactic acid and SCFAs by supplementation of α-CD have beneficial antiobesity effects via modulating the expression of genes related to lipid metabolism, indicating a prebiotic property of α-CD. © 2018 BioFactors, 2018.

Dietary α-cyclodextrin modifies gut microbiota and reduces fat accumulation in high-fat-diet-fed obese mice.

This study investigated the effect of various prebiotics (indigestible dextrin, α-cyclodextrin, and dextran) on human colonic microbiota at a dosage corresponding to a daily intake of 6 g of prebiotics per person (0.2% of dietary intake). We used an in vitro human colonic microbiota model based on batch fermentation starting from a faecal inoculum. Bacterial 16S rRNA gene sequence analysis showed that addition of 0.2% prebiotics did not change the diversity and composition of colonic microbiota. This finding coincided with results from a clinical study showing that the microbiota composition of human faecal samples remained unchanged following administration of 6 g of prebiotics over seven days. However, compared to absence of prebiotics, their addition reduced the pH and increased the generation of acetate and propionate in the in vitro system. Thus, even at such relatively low amounts, prebiotics appear capable of activating the metabolism of colonic microbiota.

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Low amounts of dietary fibre increase in vitro production of short-chain fatty acids without changing human colonic microbiota structure

Purpose Effective methods to ameliorate radiation enteropathy have not been developed. To address this issue, we investigated the reduced form of coenzyme Q10 (rCoQ10) as a potential radioprotector in a mouse model. Methods and Materials rCoQ10 was added to a standard laboratory mouse diet at a final concentration of 1.0% 9 days before irradiation and 30 days thereafter or dissolved in corn oil and administered transorally. Accumulated amounts of coenzyme Q10 (CoQ10) or coenzyme Q9 in the intestine were measured by high-performance liquid chromatography. Reactive oxygen species (ROS), apoptosis, and morphologic changes in the intestine were assessed by immunohistochemistry after administration of 13 Gy of x-ray to the mouse abdomen. Body weight and survival were monitored for 30 days after irradiation. Cytotoxicity using 3 human cancer cell lines and the tumor growth–inhibiting effect in a xenograft were investigated to determine whether rCoQ10 interferes with radiation-specific cytotoxic effects on tumor growth. Results CoQ10 was greatly accumulated in all sections of the intestine after both massive transoral dosing and dietary administration, whereas coenzyme Q9 was not. Administration of rCoQ10 suppressed ROS production and inhibited apoptosis in the crypts, resulting in preservation of villi structures after irradiation. Notably, 92% of mice fed the rCoQ10-supplemented diet were healthy and alive 30 days after irradiation, whereas 50% of control mice died (P  Conclusions Administration of rCoQ10 led to its accumulation in the intestine and induced radioprotective effects by inhibiting ROS-mediated apoptosis, thereby preserving intestinal structures. Our results indicated that rCoQ10 supplementation effectively ameliorated radiation enteropathy.

Amelioration of Radiation Enteropathy by Dietary Supplementation With Reduced Coenzyme Q10.

Optical frequency domain imaging (OFDI) is a high-resolution intracoronary imaging modality with fast automated longitudinal pullback. We aimed to evaluate the ability of performing OFDI from the superficial femoral artery (SFA) to the below-knee (BK) artery. This clinical trial was a multi-center, single-arm, open-label study. The primary endpoint was to obtain a clear image of the intra-vascular lumen from the SFA to the BK artery, specifically  > 270° visualization of the blood vessel lumen with  > 16/21 cross sections. The proportion of the clear image (≥ 85%) was regarded as confirmatory of the ability of OFDI to visualize the vessel lumen. Overall, 20 patients were enrolled. The proportion of the primary endpoint was 90% (18/20), and the pre-specified criterion was successfully attained. The proportion of the clear image assessed by the operator was 100% (20/20), and an additional statistical analysis for the proportion of the visualization,  > 270°, of the blood vessel lumen revealed a significantly higher cut-off value than that for the pre-specified criterion, 85% (p = 0.0315). There were three adverse events not related to OFDI. OFDI achieved acceptable visualization of the vessel lumen without any adverse event related to it. After regulatory approval based on the present study, OFDI will be available as a new option of endovascular imaging for peripheral artery diseases in daily practice Trial registration: This study was registered in the Japanese Registry of Clinical Trials (jRCT 2052190025, https://jrct.niph.go.jp/latest-detail/jRCT2052190025
 ).

Takahiro Yasuda

Papers

Low amounts of dietary fibre increase in vitro production of short-chain fatty acids without changing human colonic microbiota structure

Amelioration of Radiation Enteropathy by Dietary Supplementation With Reduced Coenzyme Q10.

Efficacy of optical frequency domain imaging in detecting peripheral artery disease: the result of a multi-center, open-label, single-arm study.