Dietary Short-chain Fatty Acids Research Articles

Effect of Dietary Short-Chain Fatty Acids on the Immune Status and Disease Resistance of European Seabass Juveniles

(1) Background: This study aimed to evaluate the potential of short-chain fatty acids as functional ingredients to improve the immune status and disease resistance of European seabass (Dicentrarchus labrax) juveniles. (2) Methods: For that purpose, triplicate groups of fish with an initial body weight of 15.2 ± 0.03 g were fed isoproteic (43% crude protein) and isolipidic (18% crude lipids) diets supplemented with sodium acetate (SA), sodium propionate (SP), and sodium butyrate (SB) at two inclusion levels: 0.25% and 0.50%. An unsupplemented diet was used as a control. After 56 days of feeding with the experimental diets, fish were intraperitoneally (i.p.) injected with 100 µL of Vibrio anguillarum (1.2 × 107 Colony Forming Units (CFU)/mL) and mortality was recorded for 3 weeks. At the end of the trial, there were no differences in survival between the treatment groups and the control, but survival was higher in fish fed the diet supplemented with SB 0.50 than SP 0.25 (93.3 vs. 66.7%). Compared to the pre-challenge values, and regardless of diet composition, all hematological parameters (hemoglobin, hematocrit, red blood cells, white blood cells) measured decreased after 4 h of bacterial challenge, except for neutrophils which were increased. Independently of diet composition, lysozyme and nitric oxide decreased at 4 and 24 h post infection. Compared to the control, diets supplemented with SA and SP promoted an up-regulation of both pro- and anti-inflammatory cytokines at 4 h after the challenge, while the diets supplemented with SB promoted an up-regulation of pro- and anti-inflammatory cytokines at 24 h after the challenge. (3) Conclusions: Overall, present results suggest that SA and SP provide a fast response to a bacterial challenge in European sea bass juveniles, while SB provides increased survival.

Microbial intestinal dysbiosis drives long-term allergic susceptibility by sculpting an ILC2–B1 cell–innate IgE axis

BackgroundThe abundance and diversity of intestinal commensal bacteria influence systemic immunity with impact on disease susceptibility and severity. For example, loss of short chain fatty acid (SCFA)-fermenting bacteria in early life (humans and mice) is associated with enhanced type 2 immune responses in peripheral tissues including the lung. ObjectiveOur goal was to reveal the microbiome-dependent cellular and molecular mechanisms driving enhanced susceptibility to type 2 allergic lung disease. MethodsWe used low-dose vancomycin to selectively deplete SCFA-fermenting bacteria in wild type mice (Vanc-dys mice). We then examined the frequency and activation status of innate and adaptive immune cell lineages with and without SCFA supplementation. Finally, we used ILC2-deficient and signal transducer and activator of transcription 6 (STAT6)-deficient transgenic mouse strains to delineate the cellular and cytokine pathways leading to enhanced allergic disease susceptibility. ResultsVanc-dys mice exhibit a 2-fold increase in lung ILC2 primed to produce elevated levels of interleukin (IL)-2, -5 and -13. In addition, upon IL-33 treatment, Vanc-dys lung ILC2 display a novel ability to produce high levels of IL-4. These expanded and primed ILC2 drive B1 cell expansion and IL-4-dependent production of IgE that, in turn, leads to exacerbated allergic inflammation. Importantly, these enhanced lung inflammatory phenotypes in Vanc-dys mice were reversed by administration of dietary SCFA (specifically butyrate). ConclusionSCFA regulate an ILC2-B1cell-IgE axis. Early-life administration of vancomycin, an antibiotic known to deplete SCFA-fermenting gut bacteria, primes and amplifies this axis and leads to a lifelong enhanced susceptibility to type 2 allergic lung disease.

Diet effects on colonic health influence the efficacy of Bin1 mAb immunotherapy for ulcerative colitis

Ulcerative colitis (UC) is an idiopathic disease of the large intestine linked to high fat-high protein diets, a dysbiotic microbiome, and a metabolome linked to diet and/or aberrant circadian rhythms associated with poor sleeping patterns. Understanding diet-affected factors that negatively influence colonic health may offer new insights into how to prevent UC and enhance the efficacy of UC immunotherapy. In this preclinical study, we found that standard or high fiber diets in mice positively influenced their colonic health, whereas a high fat-high protein diet negatively influenced colonic health, consistent with clinical findings. Animals fed a high fat/high protein diet experienced obesity and a reduced colon length, illustrating a phenotype we suggest calling peinosis [hunger-like-condition; Greek, peina: hunger; osis: condition], as marked by a lack of nutrient energy remaining in fecal pellets. Notably, a high fat/high protein diet also led to signs of muscle weakness that could not be explained fully by weight gain. In contrast, mice on a high fiber diet ranked highest compared to other diets in terms of colon length and lack of muscle weakness. That said, mice on a high fiber diet were more prone to UC and toxic responses to immunotherapy, consistent with clinical observations. Recent studies have suggested that a standard diet may be needed to support the efficacy of immunotherapeutic drugs used to prevent and treat UC. Here we observed that protection against UC by Bin1 mAb, a passive UC immunotherapy that acts by coordinately enforcing intestinal barrier function, protecting enteric neurons, and normalizing the microbiome, was associated with increased colonic levels of healthful short-chain fatty acids (SCFA), particularly butyric acid and propionic acid, which help enforce intestinal barrier function. This work offers a preclinical platform to investigate how diet affects UC immunotherapy and the potential of dietary SCFA supplements to enhance it. Further, it suggests that the beneficial effects of passive immunotherapy by Bin1 mAb in UC treatment may be mediated to some extent by promoting increased levels of healthful SCFA.

Promotion of astrocyte-neuron glutamate-glutamine shuttle by SCFA contributes to the alleviation of Alzheimer's disease

The brain is particularly susceptible to oxidative damage which is a key feature of several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease. The shuttling of glutathione (GSH) precursors from astrocytes to neurons has been shown to be instrumental for the neuroprotective activity. Here, we revealed that short chain fatty acids (SCFA), which have been related to AD and PD, could promote glutamate-glutamine shuttle to potentially resist oxidative damage in neurons at cellular level. Furthermore, we performed nine-month-long dietary SCFA supplementations in APPswe/PS1dE9 (APP/PS1) mice, and showed that it reshaped the homeostasis of microbiota and alleviated the cognitive impairment by reducing Aβ deposition and tau hyperphosphorylation. Single-cell RNA sequencing analysis of the hippocampus revealed SCFA can enhance astrocyte-neuron communication including glutamate-glutamine shuttle, mainly by acting on astrocyte in vivo. Collectively, our findings indicate that long-term dietary SCFA supplementations at early aging stage can regulate the neuroenergetics to alleviate AD, providing a promising direction for the development of new AD drug.

SCFAs improve disease resistance via modulate gut microbiota, enhance immune response and increase antioxidative capacity in the host

To evaluate the effects of dietary short chain fatty acids (SCFAs) on the intestinal health and innate immunity in crucian carp, a six-week feeding trial was carried out with following treatments: basal diet (BD), basal diet supplementation with 1% sodium acetate (BDSA), basal diet supplementation with 1% sodium propionate (BDSP) and basal diet supplementation with 1% sodium butyrate (BDSB). The results showed dietary BDSA, BDSP and BDSB could protect the host against oxidative stress by improving the activity of certain antioxidative enzymes (T-SOD, GSH-Px and CAT). Additionally, dietary SCFAs could enhance mucosal and humoral immune responses by improving certain innate immune parameters in serum and skin mucus productions (IgM, ACH50 and T-SOD). Furthermore, dietary BDSA and BDSP could up-regulate the expression of immune related genes (TNF-α, TGF-β and IL-8) and tight junction protein genes (occludin and ZO-1). Dietary BDSB could also elevate the expression of IL-8, TGF-β, ZO-1 and Occludin in the midgut. Although dietary differences of SCFAs didn't alter the α-diversity of the intestinal flora, they altered the core microbiota. Finally, the challenge trial showed that dietary basal diet supplementation with SCFAs could protect zebrafish against Aeromonas hydrophila. These results suggest that dietary SCFAs could improve innate immunity, modulate gut microbiota and increase disease resistance in the host, which indicated the potential of SCFAs as immunostimulants in aquaculture.

Effects of dietary short‐chain fatty acid salts on the growth performance, digestive, antioxidant and immune enzyme activities, immune‐related gene expression and resistance to Vibro parahaemolytics infection in juvenile ridgetail white prawn ( Exopalaemon carinicauda )

An 8-week feeding trial was conducted to study the effects of dietary short-chain fatty acid salts, sodium acetate (SA), sodium propionate (SP) and sodium butyrate (SB), on the growth performance, digestive ability, immune parameters and disease resistance of juvenile Exopalaemon carinicauda. Shrimps (14.60 ± 1.48 mg) were fed with 10 experimental diets containing 0.0 (control), 0.25%, 0.5% and 1% of SA, SB and SP in triplicate. The highest survival rate was observed in the SP (0.5%) group (p < 0.05). The final weight, specific growth rate and feed efficiency was highest in the SP (0.25%) group (p < 0.05). Shrimps that were fed SP (0.25%) had greater intestinal digestive enzyme (chymotrypsin) activity. Shrimps in the SA (0.5%) group had the highest activities of glutathione peroxidase, catalase, lysozyme, acid phosphatase and alkaline phosphatase, which was accompanied by the highest relative percent survival after a Vibro parahaemolyticus challenge (p < 0.05). The expression of immune-related genes (prophenoloxidase, C-type lectin and mannose binding lectin) in the hepatopancreas of shrimps fed SA (0.5%) and SP (0.25%) was higher than that of the control group (p < 0.05). These data suggest that SA (0.5%) and SP (0.25%) are beneficial to the growth performance and health of E. carinicauda.

The microbiota is dispensable for the early stages of peripheral regulatory T cell induction within mesenteric lymph nodes

Intestinal Foxp3+ regulatory T cell (Treg) subsets are crucial players in tolerance to microbiota-derived and food-borne antigens, and compelling evidence suggests that the intestinal microbiota modulates their generation, functional specialization, and maintenance. Selected bacterial species and microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), have been reported to promote Treg homeostasis in the intestinal lamina propria. Furthermore, gut-draining mesenteric lymph nodes (mLNs) are particularly efficient sites for the generation of peripherally induced Tregs (pTregs). Despite this knowledge, the direct role of the microbiota and their metabolites in the early stages of pTreg induction within mLNs is not fully elucidated. Here, using an adoptive transfer-based pTreg induction system, we demonstrate that neither transfer of a dysbiotic microbiota nor dietary SCFA supplementation modulated the pTreg induction capacity of mLNs. Even mice housed under germ-free (GF) conditions displayed equivalent pTreg induction within mLNs. Further molecular characterization of these de novo induced pTregs from mLNs by dissection of their transcriptomes and accessible chromatin regions revealed that the microbiota indeed has a limited impact and does not contribute to the initialization of the Treg-specific epigenetic landscape. Overall, our data suggest that the microbiota is dispensable for the early stages of pTreg induction within mLNs.

Examining the non-spatial pretraining effect on a water maze spatial learning task in rats treated with multiple intracerebroventricular (ICV) infusions of propionic acid: Contributions to a rodent model of ASD

Propionic acid (PPA) is produced by enteric gut bacteria and is a dietary short chain fatty acid. Intracerebroventricular (ICV) infusions of PPA in rodents have been shown to produce behavioural changes, including adverse effects on cognition, similar to those seen in autism spectrum disorders (ASD). Previous research has shown that repeated ICV infusions of PPA result in impaired spatial learning in a Morris water maze (MWM) as evidenced by increased search latencies, fewer direct and circle swims, and more time spent in the periphery of the maze than control rats. In the current study rats were first given non-spatial pretraining (NSP) in the water maze in order to familiarize the animals with the general requirements of the non-spatial aspects of the task before spatial training was begun. Then the effects of ICV infusions of PPA on acquisition of spatial learning were examined. PPA treated rats failed to show the positive effects of the non-spatial pretraining procedure, relative to controls, as evidenced by increased search latencies, longer distances travelled, fewer direct and circle swims, and more time spent in the periphery of the maze than PBS controls. Thus, PPA treatment blocked the effects of the pretraining procedure, likely by impairing sensorimotor components or memory of the pretraining.

Targeting the gut microbiota by Asian and Western dietary constituents: a new avenue for diabetes.

Increasing numerous diabetes annually is a great concern in public health globally. Gut microbiota recently has been suggested to be an emerging organ acting as a critical regulator in diabetes. Notably, gut microbiota is closely affected through an individual's nutrient intake and dietary pattern. Moreover, the metabolites of diets through gut microbiota are closely associated with the development of diabetes. Increasing evidence has established the association of different dietary pattern with alterations of the gut microbiota profile, in particular, the Asian diet and Western diet are typically as essential components linked to the interactions between gut microbiota and induction of obesity which is a significant risk factor for diabetes. In addition, some bacteria-related therapeutic methods including probiotics, dietary short-chain fatty acids immunotherapy, and gut microbiome transfer would be applied in the clinical prevention and control diabetes. Taken together, based on current published observations, the gut microbiota may serve as regulator or targets by the Asian diet and Western diet, contributing to the prevention or induction of diabetes eventually. In general, in the upcoming future, one of the emerging strategies for the prevention and control of diabetes may modulate gut microbiota through precise dietary strategies.

Dietary SCFAs Immunotherapy: Reshaping the Gut Microbiota in Diabetes.

Diet-microbiota related inflammatory conditions such as obesity, autoimmune type 1 diabetes (T1D), type 2 diabetes (T2D), cardiovascular disease (CVD) and gut infections have become a stigma in Western societies and developing nations. This book chapter examines the most relevant pre-clinical and clinical studies about diet-gut microbiota approaches as an alternative therapy for diabetes. We also discuss what we and others have extensively investigated- the power of dietary short-chain fatty acids (SCFAs) technology that naturally targets the gut microbiota as an alternative method to prevent and treat diabetes and its related complications.

Dietary short-chain fatty acid intake improves the hepatic metabolic condition via FFAR3

Fermented foods represent a significant portion of human diets with several beneficial effects. Foods produced by bacterial fermentation are enriched in short-chain fatty acids (SCFAs), which are functional products of dietary fibers via gut microbial fermentation. In addition to energy sources, SCFAs also act as signaling molecules via G-protein coupled receptors such as FFAR2 and FFAR3. Hence, dietary SCFAs in fermented foods may have a direct influence on metabolic functions. However, the detailed mechanism by dietary SCFAs remains unclear. Here, we show that dietary SCFAs protected against high-fat diet-induced obesity in mice in parallel with increased plasma SCFAs without changing cecal SCFA or gut microbial composition. Dietary SCFAs suppressed hepatic weight and lipid synthesis. These effects were abolished in FFAR3-deficient mice but not FFAR2-deficient. Thus, SCFAs supplementation improved hepatic metabolic functions via FFAR3 without influencing intestinal environment. These findings could help to promote the development of functional foods using SCFAs.

Dietary SCFAs, IL-22, and GFAP: The Three Musketeers in the Gut-Neuro-Immune Network in Type 1 Diabetes.

Microbial metabolites have a profound effect on the development of type 1 diabetes (T1D). The cross-talk between the gut microbiota, the nervous system, and immune system is necessary to establish and maintain immune and gut tolerance. As quoted by Hippocrates, “All disease begins in the gut.” Although this has been recognized for 2,000 years, the connection between the gut and autoimmune T1D is not yet well-understood. Here, we outline new advances supported by our research and others that have contributed to elucidate the impact of microbial metabolites on the physiology of the pancreas and the gut through their remarkable effect on the immune and nervous system. Among many of the mechanisms involved in the gut–beta-cell–immune cross-talk, glial fibrillary acidic protein (GFAP)-expressing cells are critical players in the development of invasive insulitis. Besides, this review reveals a novel mechanism for microbial metabolites by stimulating IL-22, an essential cytokine for gut homeostasis and beta-cell survival. The close connections between the gut and the pancreas are highlighted through our review as microbial metabolites recirculate through the whole body and intimately react with the nervous system, which controls essential disorders associated with diabetes. As such, we discuss the mechanisms of action of microbial metabolites or short-chain fatty acids (SCFAs), IL-22, and GFAP on beta-cells, gut epithelial cells, neurons, and glial cells via metabolite sensing receptors or through epigenetic effects. The fine-tuned gut–neuro–immune network may be profoundly affected by SCFA deficiency related to dysbiosis and diet alterations at very early stages of the initiation of the disease. Thus, dampening the initial immune response or preventing the perpetuation of the immune response by maintaining the integrity of the gut is among the alternative approaches to prevent T1D.

Impaired Spatial Cognition in Adult Rats Treated with Multiple Intracerebroventricular (ICV) Infusions of the Enteric Bacterial Metabolite, Propionic Acid, and Return to Baseline After 1Week of No Treatment: Contribution to a Rodent Model of ASD.

Propionic acid (PPA) is a dietary short chain fatty acid and an enteric bacterial metabolite. Intracerebroventricular (ICV) infusions of PPA in rodents have been shown to produce behavioral changes similar to those seen in autism spectrum disorders (ASD), including perseveration. The effects of ICV infusions of PPA on spatial cognition were examined by giving rats infusions of either PPA (0.26M, pH 7.4, 4μl/infusion) or phosphate-buffered saline (PBS, 0.1M) twice a day for 7days. The rats were then tested in the Morris water maze (MWM) for acquisition of spatial learning. After a recovery period of 1week of no treatment, the rats were then tested for reversal of spatial learning in the MWM. PPA-treated rats showed impaired spatial learning in the maze, relative to controls, as demonstrated by increased search latencies, fewer direct and circle swims, and more time spent in the periphery of the maze than PBS controls. After a recovery period of 1week of no treatment, these animals exhibited normal spatial reversal learning indicating that the behavioral cognitive deficits caused by PPA seem to be reversible.

High ambient temperature dampens adaptive immune responses to influenza A virus infection

Although climate change may expand the geographical distribution of several vector-borne diseases, the effects of environmental temperature in host defense to viral infection in vivo are unknown. Here, we demonstrate that exposure of mice to the high ambient temperature of 36 °C impaired adaptive immune responses against infection with viral pathogens, influenza, Zika, and severe fever with thrombocytopenia syndrome phlebovirus. Following influenza virus infection, the high heat-exposed mice failed to stimulate inflammasome-dependent cytokine secretion and respiratory dendritic cell migration to lymph nodes. Although commensal microbiota composition remained intact, the high heat-exposed mice decreased their food intake and increased autophagy in lung tissue. Induction of autophagy in room temperature-exposed mice severely impaired virus-specific CD8 T cells and antibody responses following respiratory influenza virus infection. In addition, we found that administration of glucose or dietary short-chain fatty acids restored influenza virus-specific adaptive immune responses in high heat-exposed mice. These findings uncover an unexpected mechanism by which ambient temperature and nutritional status control virus-specific adaptive immune responses.

Loss of Gut Microbiota Alters Immune System Composition and Cripples Postinfarction Cardiac Repair.

The impact of gut microbiota on the regulation of host physiology has recently garnered considerable attention, particularly in key areas such as the immune system and metabolism. These areas are also crucial for the pathophysiology of and repair after myocardial infarction (MI). However, the role of the gut microbiota in the context of MI remains to be fully elucidated. To investigate the effects of gut microbiota on cardiac repair after MI, C57BL/6J mice were treated with antibiotics 7 days before MI to deplete mouse gut microbiota. Flow cytometry was applied to examine the changes in immune cell composition in the heart. 16S rDNA sequencing was conducted as a readout for changes in gut microbial composition. Short-chain fatty acid (SCFA) species altered after antibiotic treatment were identified by high-performance liquid chromatography. Fecal reconstitution, transplantation of monocytes, or dietary SCFA or Lactobacillus probiotic supplementation was conducted to evaluate the cardioprotective effects of microbiota on the mice after MI. Antibiotic-treated mice displayed drastic, dose-dependent mortality after MI. We observed an association between the gut microbiota depletion and significant reductions in the proportion of myeloid cells and SCFAs, more specifically acetate, butyrate, and propionate. Infiltration of CX3CR1+ monocytes to the peri-infarct zone after MI was also reduced, suggesting impairment of repair after MI. Accordingly, the physiological status and survival of mice were significantly improved after fecal reconstitution, transplantation of monocytes, or dietary SCFA supplementation. MI was associated with a reorganization of the gut microbial community such as a reduction in Lactobacillus. Supplementing antibiotic-treated mice with a Lactobacillus probiotic before MI restored myeloid cell proportions, yielded cardioprotective effects, and shifted the balance of SCFAs toward propionate. Gut microbiota-derived SCFAs play an important role in maintaining host immune composition and repair capacity after MI. This suggests that manipulation of these elements may provide opportunities to modulate pathological outcome after MI and indeed human health and disease as a whole.

Effect of a specific composition of short- and medium-chain fatty acid 1-Monoglycerides on growth performances and gut microbiota of gilthead sea bream (Sparus aurata).

In aquaculture research, one important aim of gut microbiota studies is to provide the scientific basis for developing effective strategies to manipulate gut microbial communities through the diet, promoting fish health and improving productivity. Currently, there is an increasing commercial and research interest towards the use of organic acids in aquafeeds, due to several beneficial effects they have on growth performance and intestinal tract’s health of farmed fish. Among organic acids, monoglycerides of short-chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs) have attracted particular research attention also for their bacteriostatic and bactericidal properties. Accordingly, the present study aimed to evaluate the potential beneficial effects of SCFA and MCFA monoglycerides, used as a feed additive, on fish growth performance, and intestinal microbiota composition. For this purpose, a specific combination of short- and medium-chain 1-monoglycerides (SILOhealth 108Z) was tested in 600 juvenile gilthead sea bream (Sparus aurata) of about 60 g mean initial weight that were fed for 90 days with plant-based diets. Two isoproteic and isolipidic diets were formulated. The control fish group received a plant-based diet, whereas the other group received the same control feed, but supplemented with 0.5% of SILOhealth 108Z. The Illumina MiSeq platform for high-throughput amplicon sequencing of 16S rRNA gene and QIIME pipeline were used to analyse and characterize the whole microbiome associated both to feeds and S. aurata intestine. The number of reads taxonomically classified according to the Greengenes database was 394,611. We identified 259 OTUs at 97% identity in sea bream fecal samples; 90 OTUs constituted the core gut microbiota. Firmicutes, Proteobacteria and Actinobacteria represented the dominant phyla in both experimental groups. Among them, relative abundance of Firmicutes and Proteobacteria were positively and negatively affected by dietary SCFA monoglycerides supplementation, respectively. In summary, our findings clearly indicated that SILOhealth 108Z positively modulated the fish intestinal microbiota by increasing the number of beneficial lactic acid bacteria, namely, Lactobacillus, and reducing Gammaproteobacteria, which include several potential pathogenic bacteria. The specific composition of 1-monoglycerides of short- and medium-chain fatty acids contained in SILOhealth 108Z could thus have a great potential as a feed additive in aquaculture.

Dietary fatty acids and susceptibility to multiple sclerosis

Background: The gut microbiome as well as dietary habits have recently been established as environmental contributors to the pathogenesis of multiple sclerosis (MS), a T-cell-mediated autoimmune disease of the central nervous system (CNS). Objective: To summarize recent findings on the Janus-faced effects of dietary short-chain fatty acids (SCFAs) and long-chain fatty acids (LCFAs) on T-cell immunity with a special focus on the gut and the microbiome as an interface linking diet and T-cell responses during MS. Methods: Review article. Results: The autoimmune basis of MS most likely stems from an imbalance between pro-inflammatory T helper cell (Th)1 and Th17 cells and anti-inflammatory or regulatory mechanisms including regulatory T cells (Treg). Hence, the rationale of currently available therapeutic interventions is to either suppress pathogenic Th1/Th17 and/or to foster Treg responses. Dietary fatty acids are often discussed for their detrimental role in MS. However, recent studies investigating saturated fatty acids in animal models of MS revealed harmful as well as beneficial effects depending on their aliphatic chain length. Conclusion: Dietary SCFAs constitute interesting candidates as safe and potent add-on therapy in the immunomodulatory treatment armamentarium for relapsing-remitting MS.

Dietary short-chain fatty acids protect against type 1 diabetes.

The short-chain fatty acids (SCFAs) acetate and butyrate, which are released from specialized diets by gut microbes, protect non-obese diabetic (NOD) mice against insulitis and slow the progression of diabetes.

Short Chain Fatty Acids Prevent High-fat-diet-induced Obesity in Mice by Regulating G Protein-coupled Receptors and Gut Microbiota.

Elucidating the mechanisms by which short chain fatty acids (SCFA) reduce body weight may assist in the development of an effective weight control strategy. Dietary supplementation of acetate, propionate, butyrate or their admixture was shown to significantly inhibit the body weight gain induced by high-fat diet feeding. Supplementation of SCFAs caused significant changes in the expressions of G-protein coupled receptor 43 (GPR43) and GPR41 characterized by increases in the adipose tissue and reductions in the colon. Additionally, they influenced the bacterial community structure in feces, with a reduction in the proportion of Firmicutes and an increase in the proportion of Bacteroidetes. The effects of dietary SCFAs on the GPR expression and gut microbiota composition may further result in body weight reduction by enhancing triglyceride hydrolysis and FFA oxidation in the adipose tissue, promoting beige adipogenesis and mitochondrial biogenesis, and inhibiting chronic inflammation.

Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice

The gut microbiota plays a key role in host metabolism. Toll-like receptor 5 (TLR5), a flagellin receptor, is required for gut microbiota homeostasis. Accordingly, TLR5-deficient (T5KO) mice are prone to develop microbiota-dependent metabolic syndrome. Here we observed that T5KO mice display elevated neutral lipids with a compositional increaseof oleate [C18:1 (n9)] relative to wild-type littermates. Increased oleate contribution to hepatic lipids and liver SCD1 expression were both microbiota dependent. Analysis of short-chain fatty acids (SCFAs) and (13)C-acetate label incorporation revealed elevated SCFA in ceca and hepatic portal blood and increased liver de novo lipogenesis in T5KO mice. Dietary SCFAs further aggravated metabolic syndrome in T5KO mice. Deletion of hepatic SCD1 not only prevented hepatic neutral lipid oleate enrichment but also ameliorated metabolic syndrome in T5KO mice. Collectively, these results underscore the key role of the gut microbiota-liver axis in the pathogenesis of metabolic diseases.