Infusion of donor feces affects the gut-brain axis in humans with metabolic syndrome.

OBJECTIVE: Increasing evidence indicates that intestinal microbiota play a role in diverse metabolic processes via intestinal butyrate production. Human bariatric surgery data suggest that the gut-brain axis is also involved in this process, but the underlying mechanisms remain unknown. METHODS: We compared the effect of fecal microbiota transfer (FMT) from post-Roux-en-Y gastric bypass (RYGB) donors vs oral butyrate supplementation on (123I-FP-CIT-determined) brain dopamine transporter (DAT) and serotonin transporter (SERT) binding as well as stable isotope-determined insulin sensitivity at baseline and after 4 weeks in 24 male and female treatment-naïve metabolic syndrome subjects. Plasma metabolites and fecal microbiota were also determined at these time points. RESULTS: We observed an increase in brain DAT after donor FMT compared to oral butyrate that reduced this binding. However, no effect on body weight and insulin sensitivity was demonstrated after post-RYGB donor feces transfer in humans with metabolic syndrome. Increases in fecal levels of Bacteroides uniformis were significantly associated with an increase in DAT, whereas increases in Prevotella spp. showed an inverse association. Changes in the plasma metabolites glycine, betaine, methionine, and lysine (associated with the S-adenosylmethionine cycle) were also associated with altered striatal DAT expression. CONCLUSIONS: Although more and larger studies are needed, our data suggest a potential gut microbiota-driven modulation of brain dopamine and serotonin transporters in human subjects with obese metabolic syndrome. These data also suggest the presence of a gut-brain axis in humans that can be modulated. NTR REGISTRATION: 4488.

The Potential Role of the Dipeptidyl Peptidase-4-Like Activity From the Gut Microbiota on the Host Health.

The Dipeptidyl peptidase-4 (DPP-4) activity influences metabolic, behavioral and intestinal disorders through the cleavage of key hormones and peptides. Some studies describe the existence of human DPP-4 homologs in commensal bacteria, for instance in Prevotella or Lactobacillus. However, the role of the gut microbiota as a source of DPP-4-like activity has never been investigated. Through the comparison of the DPP-4 activity in the cecal content of germ-free mice (GFM) and gnotobiotic mice colonized with the gut microbiota of a healthy subject, we bring the proof of concept that a significant DPP-4-like activity occurs in the microbiota. By analyzing the existing literature, we propose that DPP-4-like activity encoded by the intestinal microbiome could constitute a novel mechanism to modulate protein digestion as well as host metabolism and behavior.

Dietary fat and gut microbiota interactions determine diet-induced obesity in mice.

OBJECTIVE: Gut microbiota may promote positive energy balance; however, germfree mice can be either resistant or susceptible to diet-induced obesity (DIO) depending on the type of dietary intervention. We here sought to identify the dietary constituents that determine the susceptibility to body fat accretion in germfree (GF) mice. METHODS: GF and specific pathogen free (SPF) male C57BL/6N mice were fed high-fat diets either based on lard or palm oil for 4 wks. Mice were metabolically characterized at the end of the feeding trial. FT-ICR-MS and UPLC-TOF-MS were used for cecal as well as hepatic metabolite profiling and cecal bile acids quantification, respectively. Hepatic gene expression was examined by qRT-PCR and cecal gut microbiota of SPF mice was analyzed by high-throughput 16S rRNA gene sequencing. RESULTS: GF mice, but not SPF mice, were completely DIO resistant when fed a cholesterol-rich lard-based high-fat diet, whereas on a cholesterol-free palm oil-based high-fat diet, DIO was independent of gut microbiota. In GF lard-fed mice, DIO resistance was conveyed by increased energy expenditure, preferential carbohydrate oxidation, and increased fecal fat and energy excretion. Cecal metabolite profiling revealed a shift in bile acid and steroid metabolites in these lean mice, with a significant rise in 17ß-estradiol, which is known to stimulate energy expenditure and interfere with bile acid metabolism. Decreased cecal bile acid levels were associated with decreased hepatic expression of genes involved in bile acid synthesis. These metabolic adaptations were largely attenuated in GF mice fed the palm-oil based high-fat diet. We propose that an interaction of gut microbiota and cholesterol metabolism is essential for fat accretion in normal SPF mice fed cholesterol-rich lard as the main dietary fat source. This is supported by a positive correlation between bile acid levels and specific bacteria of the order Clostridiales (phylum Firmicutes) as a characteristic feature of normal SPF mice fed lard. CONCLUSIONS: In conclusion, our study identified dietary cholesterol as a candidate ingredient affecting the crosstalk between gut microbiota and host metabolism.

Maternal High-fat Diet Accelerates Development of Crohn's Disease-like Ileitis in TNFΔARE/WT Offspring.

BACKGROUND: Maternal high-fat diet (HFD) and obesity increases the risk of the offspring to develop inflammatory processes in various organs including the gut. We hypothesized that maternal diet-induced obesity programs the fetal gut towards inflammation in a mouse model of genetically-driven Crohn's disease (CD)-like ileitis. METHODS: TNF(WT/WT) and TNF(ΔARE/WT) dams were fed an experimental control diet (CTRLD; 13 kJ% fat) or HFD (48 kJ%). Offspring mice were fed CTRLD or HFD at 4 weeks of age. Metabolic characteristics and severity of CD-like ileitis was assessed in 8- and 12-week old WT and ARE offspring measuring tissue histopathology and markers of inflammation in the distal ileum as well as plasma cytokine and LPS levels. To study prenatal effects, we laser microdissected fetal intestinal epithelial cells at 17.5 days postconception and performed microarray-based global gene expression analysis. RESULTS: Maternal HFD significantly accelerated the severity of CD-like ileitis in HFD-fed ARE mice at early life stages associated with increased mucosal neutrophil infiltration, Il12p40 expression, and portal vein LPS levels. In contrast to WT mice, metabolic characteristics of ARE offspring were not affected by maternal HFD. Gene expression patterns in fetal intestinal epithelial cells of ARE mice remained largely unchanged under conditions of maternal diet-induced obesity suggesting that the positive association of intestinal inflammation, portal vein endotoxemia, and plasma TNF levels is independent of prenatal conditioning of the gut epithelium. CONCLUSIONS: Maternal HFD promotes the early onset of severe CD-like ileitis in genetically susceptible offspring independent of metabolic alterations.

Diet-induced obesity causes metabolic impairment independent of alterations in gut barrier integrity.

SCOPE: The causal relationship between diet-induced obesity and metabolic disorders is not clear yet. One hypothesis is whether the obese state or high-fat diet per se affects intestinal barrier function provoking metabolic comorbidities. METHODS AND RESULTS: In three independent experiments with AKR/J, SWR/J, or BL/6J mice, we addressed the impact of genetic background, excess body fat storage, duration of high-fat feeding, and quality/quantity of dietary fat on glucose tolerance and gut barrier integrity in vivo and ex vivo. Impaired glucose tolerance in diet-induced obese BL/6J and AKR/J mice was not accompanied by an altered intestinal barrier function. Enforced dietary challenge by prolonged feeding and increasing fat quantity in BL/6J mice still failed to aggravate metabolic and intestinal deterioration. Despite a low-grade inflammatory status in adipose tissue, barrier function of BL/6J mice fed lard high-fat diet revealed no evidence for a diet-induced loss in barrier integrity. CONCLUSION: None of our results provided any evidence that gut barrier function is a subject to dietary regulation and obesity per se seems not to cause gut barrier impairment.

New insights into the interplay between the lysine transporter LysP and the pH sensor CadC in Escherichia coli.

The coordination of signal transduction and substrate transport represents a sophisticated way to integrate information on metabolite fluxes into transcriptional regulation. This widely distributed process involves protein-protein interactions between two integral membrane proteins. Here we report new insights into the molecular mechanism of the regulatory interplay between the lysine-specific permease LysP and the membrane-integrated pH sensor CadC, which together induce lysine-dependent adaptation of E. coli under acidic stress. In vivo analyses revealed that, in the absence of either stimulus, the two proteins form a stable association, which is modulated by lysine and low pH. In addition to its transmembrane helix, the periplasmic domain of CadC also participated in the interaction. Site-directed mutagenesis pinpointed Arg265 and Arg268 in CadC as well as Asp275 and Asp278 in LysP as potential periplasmic interaction sites. Moreover, a systematic analysis of 100 LysP variants with single-site replacements indicated that the lysine signal is transduced from co-sensor to sensor via lysine-dependent conformational changes (upon substrate binding and/or transport) of LysP. Our results suggest a scenario in which CadC is inhibited by LysP via intramembrane and periplasmic contacts under non-inducing conditions. Upon induction, lysine-dependent conformational changes in LysP transduce the lysine signal via a direct conformational coupling to CadC without resolving the interaction completely. Moreover, concomitant pH-dependent protonation of periplasmic amino acids in both proteins dissolves their electrostatic connections resulting in further destabilization of the CadC/LysP interaction.