Colonocyte Metabolism Research Articles

Campylobacter infection of young children in Colombia and its impact on the gastrointestinal environment.

Campylobacter infections are a leading cause of bacterial-derived gastroenteritis worldwide with particularly profound impacts on pediatric patients in low- and middle-income countries. It remains unclear how Campylobacter impacts these hosts, though it is becoming increasingly evident that it is a multifactorial process that depends on the host immune response, the gastrointestinal microbiota, various bacterial factors, and host nutritional status. Since these factors likely vary between adult and pediatric patients in different regions of the world, it is important that studies define these attributes in well-characterized clinical cohorts in diverse settings. In this study, we analyzed the fecal microbiota and the metabolomic and micronutrient profiles of asymptomatic and symptomatic pediatric patients in Colombia who were either infected or uninfected with Campylobacter during a case-controlled study on acute diarrheal disease. Here, we report that the microbiome of Campylobacter-infected children only changed in their abundance of Campylobacter spp. despite the inclusion of children with or without diarrhea. In addition to increased Campylobacter, computational models were used to identify fecal metabolites that were associated with Campylobacter infection and found that glucose-6-phosphate and homovanillic acid were the strongest predictors of infection in these pediatric patients, which suggests that colonocyte metabolism is impacted during infection. Despite changes to the fecal metabolome, the concentrations of intestinal minerals and trace elements were not significantly impacted by Campylobacter infection but were elevated in uninfected children with diarrhea.IMPORTANCEGastrointestinal infection with pathogenic Campylobacter species has long been recognized as a significant cause of human morbidity. Recently, it has been observed that pediatric populations in low- and middle-income countries are uniquely impacted by these organisms in that infected children can be persistently colonized, develop enteric dysfunction, and exhibit reduced development and growth. While the association of Campylobacter species with these long-term effects continues to emerge, the impact of infection on the gastrointestinal environment of these children remains uncharacterized. To address this knowledge gap, our group leveraged clinical samples collected during a previous study on gastrointestinal infections in pediatric patients to examine the fecal microbiota, metabolome, and micronutrient profiles of those infected with Campylobacter species and found that the metabolome was impacted in a way that suggests gastrointestinal cell metabolism is affected during infection, which is some of the first data indicating how gastrointestinal health in these patients may be affected.

The epithelial C15ORF48/miR-147-NDUFA4 axis is an essential regulator of gut inflammation, energy metabolism, and the microbiome

Chronic inflammation is epidemiologically linked to the pathogenesis of gastrointestinal diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, our understanding of the molecular mechanisms controlling gut inflammation remains insufficient, hindering the development of targeted therapies for IBD and CRC. In this study, we uncovered C15ORF48/miR-147 as a negative regulator of gut inflammation, operating through the modulation of epithelial cell metabolism. C15ORF48/miR-147 encodes two molecular products, C15ORF48 protein and miR-147-3p microRNA, which are predominantly expressed in the intestinal epithelium. C15ORF48/miR-147 ablation leads to gut dysbiosis and exacerbates chemically induced colitis in mice. C15ORF48 and miR-147-3p work together to suppress colonocyte metabolism and inflammation by silencing NDUFA4, a subunit of mitochondrial complex IV (CIV). Interestingly, the C15ORF48 protein, a structural paralog of NDUFA4, contains a unique C-terminal α-helical domain crucial for displacing NDUFA4 from CIV and its subsequent degradation. NDUFA4 silencing hinders NF-κB signaling activation and consequently attenuates inflammatory responses. Collectively, our findings have established the C15ORF48/miR-147-NDUFA4 molecular axis as an indispensable regulator of gut homeostasis, bridging mitochondrial metabolism and inflammation.

Mitochondrial remodeling and energy metabolism adaptations in colonic crypts during spontaneous epithelial repair after colitis induction in mice

Mucosal healing has emerged as a therapeutic goal to achieve lasting clinical remission in ulcerative colitis. Intestinal repair in response to inflammation presumably requires higher energy supplies for the restoration of intestinal barrier and physiological functions. However, epithelial energy metabolism during intestinal mucosal healing has been little studied, whereas inflammation-induced alterations have been reported in the main energy production site, the mitochondria. The aim of the present work was to assess the involvement of mitochondrial activity and the events influencing their function during spontaneous epithelial repair after colitis induction in mouse colonic crypts. The results obtained show adaptations of colonocyte metabolism during colitis to ensure maximal ATP production for supporting energetic demand by both oxidative phosphorylation and glycolysis in a context of decreased mitochondrial biogenesis and through mitochondrial function restoration during colon epithelial repair. In parallel, colitis-induced mitochondrial ROS production in colonic epithelial cells was rapidly associated with transient expression of GSH-related enzymes. Mitochondrial respiration in colonic crypts was markedly increased during both inflammatory and recovery phases despite decreased expression of several mitochondrial respiratory chain complex subunits after colitis induction. Rapid induction of mitochondrial fusion was associated with mitochondrial function restoration. Finally, in contrast with the kinetics expression of genes involved in mitochondrial oxidative metabolism and in glycolysis, the expression of glutaminase was markedly reduced in the colonic crypts both during colitis and repair phases. Overall, our data suggest that the epithelial repair after colitis induction is characterized by a rapid and transient increased capacity for mitochondrial ATP production in a context of apparent restoration of mitochondrial biogenesis and metabolic reorientation of energy production. The potential implication of energy production adaptations within colonic crypts to sustain mucosal healing in a context of altered fuel supply is discussed.

FADS1-arachidonic acid axis enhances arachidonic acid metabolism by altering intestinal microecology in colorectal cancer

Colonocyte metabolism shapes the microbiome. Metabolites are the main mediators of information exchange between intestine and microbial communities. Arachidonic acid (AA) is an essential polyunsaturated fatty acid and its role in colorectal cancer (CRC) remains unexplored. In this study, we show that AA feeding promotes tumor growth in AOM/DSS and intestinal specific Apc−/− mice via modulating the intestinal microecology of increased gram-negative bacteria. Delta-5 desaturase (FADS1), a rate-limiting enzyme, is upregulated in CRC and effectively mediates AA synthesis. Functionally, FADS1 regulates CRC tumor growth via high AA microenvironment-induced enriched gram-negative microbes. Elimination of gram-negative microbe abolishes FADS1 effect. Mechanistically, gram-negative microbes activate TLR4/MYD88 pathway in CRC cells that contributes FADS1-AA axis to metabolize to prostaglandin E2 (PGE2). Cumulatively, we report a potential cancer-promoting mechanism of FADS1-AA axis in CRC that converts raising synthesized AA to PGE2 via modulating the intestinal microecology of gram-negative.

Excess Dietary Sugar Alters Colonocyte Metabolism and Impairs the Proliferative Response to Damage

The colonic epithelium requires continuous renewal by crypt resident intestinal stem cells (ISCs) and transit-amplifying (TA) cells to maintain barrier integrity, especially after inflammatory damage. The diet of high-income countries contains increasing amounts of sugar, such as sucrose. ISCs and TA cells are sensitive to dietary metabolites, but whether excess sugar affects their function directly is unknown. Here, we used a combination of 3-dimensional colonoids and a mouse model of colon damage/repair (dextran sodium sulfate colitis) to show the direct effect of sugar on the transcriptional, metabolic, and regenerative functions of crypt ISCs and TA cells. We show that high-sugar conditions directly limit murine and human colonoid development, which is associated with a reduction in the expression of proliferative genes, adenosine triphosphate levels, and the accumulation of pyruvate. Treatment of colonoids with dichloroacetate, which forces pyruvate into the tricarboxylic acid cycle, restored their growth. In concert, dextran sodium sulfate treatment of mice fed a high-sugar diet led to massive irreparable damage that was independent of the colonic microbiota and its metabolites. Analyses on crypt cells from high-sucrose-fed mice showed a reduction in the expression of ISC genes, impeded proliferative potential, and increased glycolytic potential without a commensurate increase in aerobic respiration. Taken together, our results indicate that short-term, excess dietary sucrose can directly modulate intestinal crypt cell metabolism and inhibit ISC/TA cell regenerative proliferation. This knowledge may inform diets that better support the treatment of acute intestinal injury.

Ghrelin Alleviates Experimental Ulcerative Colitis in Old Mice and Modulates Colonocyte Metabolism via PPARγ Pathway.

There is a growing prevalence of inflammatory bowel disease (IBD), a chronic inflammatory condition of the gastrointestinal tract, among the aging population. Ghrelin is a gut hormone that, in addition to controlling feeding and energy metabolism, has been shown to exert anti-inflammatory effects; however, the effect of ghrelin in protecting against colitis in old mice has not been assessed. Here, we subjected old female C57BL/6J mice to dextran sulfate sodium (DSS) in drinking water for six days, then switched back to normal drinking water, administered acyl-ghrelin or vehicle control from day 3 to 13, and monitored disease activities throughout the disease course. Our results showed that treatment of old mice with acyl-ghrelin attenuated DSS-induced colitis. Compared to the DSS group, ghrelin treatment decreased levels of the inflammation marker S100A9 in the colons collected on day 14 but not on day 8, suggesting that the anti-inflammatory effect was more prominent in the recovery phase. Ghrelin treatment also significantly reduced F4/80 and interleukin-17A on day 14. Moreover, acyl-ghrelin increased mitochondrial respiration and activated transcriptional activity of the peroxisome proliferator-activated receptor gamma (PPARγ) in Caco-2 cells. Together, our data show that ghrelin alleviated DSS-induced colitis, suggesting that ghrelin may promote tissue repair in part through regulating epithelial metabolism via PPARγ mediated signaling.

Wogonin regulates colonocyte metabolism via PPARγ to inhibit Enterobacteriaceae against dextran sulfate sodium-induced colitis in mice.

To investigate the potential effects and mechanism of wogonin on dextran sulfate sodium (DSS)-induced colitis, 70 male mice were administered wogonin (12.5, 25, 50 mg·kg-1 ·d-1 , i.g.) for 10 days, meanwhile, in order to induce colitis, the mice were free to drink 3% DSS for 6 days. We found that wogonin could obviously ameliorate DSS-induced colitis, including preventing colon shortening and inhibiting pathological damage. In addition, wogonin could increase the expression of PPARγ, which not only restores intestinal epithelial hypoxia but also inhibits iNOS protein to reduce intestinal nitrite levels. All these effects facilitated a reduction in the abundance of Enterobacteriaceae in DSS-induced colitis mice. Therefore, compared with the DSS group, the number of Enterobacteriaceae in the intestinal flora was significantly reduced after administration of wogonin or rosiglitazone by 16s rDNA technology. We also verified that wogonin could promote the expression of PPARγ mRNA and protein in Caco-2 cells, and this effect disappeared when PPARγ signal was inhibited. In conclusion, our study suggested that wogonin can activate the PPARγ signal of the Intestinal epithelium to ameliorate the Intestinal inflammation caused by Enterobacteriaceae bacteria expansion.

Functional metabolic capacity of pig colonocytes is differentially modulated by fermentable fibre and poorly digestible protein

The intestine is a highly metabolic organ that relies on energy production within the intestinal cells to sustain its functions. In the colon, intestinal cell metabolic function could be affected positively and negatively by microbiota-derived metabolites. Protein fermentation metabolites are known to negatively impact intestinal metabolic function, while fibre fermentation metabolites are generally thought beneficial. We aimed to investigate whether proteins of different digestibility in the absence and presence of fibres impact the energy metabolism of colonocytes, with potentially adverse health effects. We fed 32, 9-week-old boars one of four experimental diets for 14 days in a 2 × 2 factorial arrangement. Whey and collagen were added as a well and a poorly digestible protein source, respectively, and fibre was either included at 5% or 23%. We examined the effects of the diets on the flux of fermentation metabolites in colon digesta and assessed the impact of the diets on functional metabolic capacity of isolated colonocytes using the Seahorse XF analyzer. Feeding the poorly digestible protein source collagen indeed increased nitrogen flow into the colon by 135% compared to the well-digestible whey-protein source. Feeding high fermentable fibre increased colonic fluxes of both fibre-derived metabolites acetate, propionate, butyrate and caproate, but also increased flux of protein-derived metabolites ammonia, isobutyrate, isovalerate, valerate and isocaproate. To analyse the impact of the diets and the induced differential metabolic composition of the intestinal lumen on functional metabolic capacity of the intestine, we used extracellular flux analysis on freshly isolated pig colonocytes. Colonocytes isolated from high fermentable fibre-fed pigs in the whey-protein diet, but not in the collagen-protein diet, had a reduced mitochondrial capacity, as indicated by a 35% reduction of maximal respiration (interaction P < 0.05) and a 20% reduction of spare respiratory capacity (interaction P < 0.05). Colonocytes from high fermentable fibre-fed pigs had a 37% decreased glycolytic activity compared to the colonocytes isolated from the low fermentable fibre-fed pigs (P < 0.001). This indicated that different diets, and in particular different protein sources and fibre levels, differentially affect colonic epithelial cell metabolism in pigs. Especially, high fermentable fibre lowered both colonocyte mitochondrial and glycolytic metabolism, indicating that high-fibre intake in pigs could lower colonocyte energetic status. Because the metabolic capacity of colonocytes is tightly linked with their functionality, assessment of intestinal cell metabolic capacity may be a valuable tool for future research.

Pyruvate kinase M1 regulates butyrate metabolism in cancerous colonocytes

Colorectal cancer (CRC) cells shift metabolism toward aerobic glycolysis and away from using oxidative substrates such as butyrate. Pyruvate kinase M1/2 (PKM) is an enzyme that catalyzes the last step in glycolysis, which converts phosphoenolpyruvate to pyruvate. M1 and M2 are alternatively spliced isoforms of the Pkm gene. The PKM1 isoform promotes oxidative metabolism, whereas PKM2 enhances aerobic glycolysis. We hypothesize that the PKM isoforms are involved in the shift away from butyrate oxidation towards glycolysis in CRC cells. Here, we find that PKM2 is increased and PKM1 is decreased in human colorectal carcinomas as compared to non-cancerous tissue. To test whether PKM1/2 alter colonocyte metabolism, we created a knockdown of PKM2 and PKM1 in CRC cells to analyze how butyrate oxidation and glycolysis would be impacted. We report that butyrate oxidation in CRC cells is regulated by PKM1 levels, not PKM2. Decreased butyrate oxidation observed through knockdown of PKM1 and PKM2 is rescued through re-addition of PKM1. Diminished PKM1 lowered mitochondrial basal respiration and decreased mitochondrial spare capacity. We demonstrate that PKM1 suppresses glycolysis and inhibits hypoxia-inducible factor-1 alpha. These data suggest that reduced PKM1 is, in part, responsible for increased glycolysis and diminished butyrate oxidation in CRC cells.

Pyruvate kinase M1 regulates butyrate metabolism in cancerous colonocytes

Colorectal cancer (CRC) cells shift metabolism toward aerobic glycolysis and away from using oxidative substrates such as butyrate. Butyrate is a short‐chain fatty acid produced by resident bacteria in the colon and serves as the primary energy source for non‐cancerous colonocytes. Pyruvate kinase M1/2 (PKM) is an enzyme that catalyzes the last step in glycolysis, which converts phosphoenolpyruvate to pyruvate, and produces ATP. M1 and M2 are alternatively spliced isoforms of the Pkm gene. The PKM1 isoform promotes oxidative metabolism, whereas PKM2 enhances aerobic glycolysis. We hypothesize that the PKM isoforms are involved in the shift away from butyrate oxidation towards glycolysis in CRC cells. Here, we find that PKM2 is increased and PKM1 is decreased in human colorectal carcinomas as compared to non‐cancerous tissue. To test whether PKM1/2 alter colonocyte metabolism, we created a knockdown of PKM2 and PKM1 in CRC cells to analyze how butyrate oxidation and glycolysis would be impacted. We report that butyrate oxidation in CRC cells is regulated by PKM1 levels, not by PKM2. Decreased butyrate oxidation observed through knockdown of PKM1 and PKM2 is rescued through re‐addition of PKM1. Diminished PKM1 lowered mitochondrial basal respiration and decreased mitochondrial spare capacity. We demonstrate that PKM1 inhibits hypoxia‐inducible factor‐1 alpha (HIF1α) and suppresses glycolysis. These data suggest that reduced PKM1 is, in part, responsible for increased glycolysis and diminished butyrate oxidation in CRC cells.

Microbial hydrogen economy alleviates colitis by reprogramming colonocyte metabolism and reinforcing intestinal barrier

ABSTRACT With the rapid development and high therapeutic efficiency and biosafety of gas-involving theranostics, hydrogen medicine has been particularly outstanding because hydrogen gas (H2), a microbial-derived gas, has potent anti-oxidative, anti-apoptotic, and anti-inflammatory activities in many disease models. Studies have suggested that H2-enriched saline/water alleviates colitis in murine models; however, the underlying mechanism remains poorly understood. Despite evidence demonstrating the importance of the microbial hydrogen economy, which reflects the balance between H2-producing (hydrogenogenic) and H2-utilizing (hydrogenotrophic) microbes in maintaining colonic mucosal ecosystems, minimal efforts have been exerted to manipulate relevant H2–microbe interactions for colonic health. Consistent with previous studies, we found that administration of hydrogen-rich saline (HS) ameliorated dextran sulfate sodium–induced acute colitis in a mouse model. Furthermore, we demonstrated that HS administration can increase the abundance of intestinal-specific short-chain fatty acid (SCFA)–producing bacteria and SCFA production, thereby activating the intracellular butyrate sensor peroxisome proliferator–activated receptor γ signaling and decreasing the epithelial expression of Nos2, consequently promoting the recovery of the colonic anaerobic environment. Our results also indicated that HS administration ameliorated disrupted intestinal barrier functions by modulating specific mucosa-associated mucolytic bacteria, leading to substantial inhibition of opportunistic pathogenic Escherichia coli expansion as well as a significant increase in the expression of interepithelial tight junction proteins and a decrease in intestinal barrier permeability in mice with colitis. Exogenous H2 reprograms colonocyte metabolism by regulating the H2–gut microbiota–SCFAs axis and strengthens the intestinal barrier by modulating specific mucosa-associated mucolytic bacteria, wherein improved microbial hydrogen economy alleviates colitis.

Butyrate Suppresses Glucose Metabolism of Colorectal Cancer Cells via GPR109a-AKT Signaling Pathway and Enhances Chemotherapy.

Glycolysis inhibitors are promising therapeutic drugs for tumor treatment, which target the uniquely elevated glucose metabolism of cancer cells. Butyrate is a critical product of beneficial microbes in the colon, which exerts extraordinary anti-cancer activities. In particular, butyrate shows biased inhibitory effects on the cell growth of cancerous colonocytes, whereas it is the major energy source for normal colonocytes. Besides its roles as the histone deacetylases (HDACs) inhibitor and the ligand for G-protein coupled receptor (GPR) 109a, the influence of butyrate on the glucose metabolism of cancerous colonocytes and the underlying molecular mechanism are not fully understood. Here, we show that butyrate markedly inhibited glucose transport and glycolysis of colorectal cancer cells, through reducing the abundance of membrane GLUT1 and cytoplasmic G6PD, which was regulated by the GPR109a-AKT signaling pathway. Moreover, butyrate significantly promoted the chemotherapeutical efficacy of 5-fluorouracil (5-FU) on cancerous colonocytes, with exacerbated impairment of DNA synthesis efficiency. Our findings provide useful information to better understand the molecular basis for the impact of butyrate on the glucose metabolism of colorectal cancer cells, which would promote the development of beneficial metabolites of gut microbiota as therapeutical or adjuvant anti-cancer drugs.

PPARγ: The Central Mucus Barrier Coordinator in Ulcerative Colitis.

Ulcerative colitis (UC) is an idiopathic, long-term inflammatory disorder of the colon, characterized by a continuous remitting and relapsing course. The intestinal mucus barrier is the first line at the interface between the host and microbiota and acts to protect intestinal epithelial cells from invasion. Data from patients and animal studies have shown that an impaired mucus barrier is closely related to the severity of UC. Depletion of the mucus barrier is not just the strongest but is also the only independent risk factor predicting relapse in patients with UC. Peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear transcription regulator, is involved in the regulation of inflammatory cytokine expression. It is also known to promote mucus secretion under pathological conditions to expel pathogenic bacteria or toxins. More important, PPARγ has been shown to affect host-microbiota interactions by modulating the energy metabolism of colonocytes and the oxygen availability of the intestinal microbiome. It is well known that gut microbiota homeostasis is essential for butyrate generation by the commensal bacteria to supply energy resources for colonocytes. Therefore, it can be speculated that PPARγ, as a central coordinator of the mucus barrier, may be a promising target for the development of effective agents to combat UC.

Microbial management.

Colonocyte metabolism plays an essential role in balancing the gut microbiota

Microbial hydrogen economy alleviates colitis by reprogramming colonocyte metabolism and reinforcing intestinal epithelial barrier

Abstract Several studies have found exogenous H2 treatment can alleviate inflammatory damage in inflammatory bowel disease (IBD) animal models, but the mechanisms behind it are less clearly understood. The present study aimed to investigate whether hydrogen-rich saline (HS) attenuates IBD in mice model and the underlying mechanisms. The results showed that HS administration significantly inhibit weight loss and reduce inflammatory damage in dextran sulfate sodium (DSS)-induced acute ulcerative colitis (UC) mice model. We observed that H2 regulates the composition of microbiota by up-regulating the abundance of intestinal specific short chain fatty acids (SCFAs)-producing bacteria. Increased butyrate-producing microbes activated the intracellular butyrate sensor peroxisome proliferator–activated receptor γ (PPAR-γ) signaling pathway, meanwhile decreased the epithelial expression of Nos2, the gene encoding inducible nitric oxide synthase, and thus promoted the recovery of colonic anaerobic environment. Our results also indicated that HS administration reduce intestinal epithelial barrier permeability by decreasing the dextran concentrations in serum, inhibit dysbiotic Enterobacteriaceae expansion, increasing mucus secretion in the colonic lumen, and promoting the expression of intestinal interepithelial tight junction protein. Taken together, we identified the mechanism by which exogenous H2-improved “microbial hydrogen economy” regulates metabolic reprogramming of colonocyte through microbiota-activated PPAR-γ signaling pathway to provide colonic anaerobic environment, and reinforces intestinal epithelial barrier function, thereby promoting the recovery of intestinal homeostasis.

Implications for Ulcerative Colitis and Colorectal Cancer: Role of Pyruvate Kinase M2 in Regulating the Oxidation of Fiber-derived Butyrate in the Diseased Colonocyte (OR04-04-19)

ObjectivesDietary fiber has been proposed to protect against colorectal cancer. Butyrate, a fiber metabolite that is produced by bacteria in the colon, is known to inhibit cell proliferation and promote cell differentiation, while also inducing apoptotic cell death in colorectal cancer cells at physiologically relevant concentrations. Unlike the majority of cells in the human body that prefer utilizing glucose, non-cancerous colonocytes use butyrate as their primary energy source. However, colorectal cancer cells shift away from utilizing butyrate towards glucose (the Warburg effect). A decrease in butyrate utilization by the colonocyte has been reported in ulcerative colitis (UC) and colorectal cancer (CRC). In both of these diseases, the protein called Pyruvate Kinase Isoform M2 (PKM2) is a factor that has been found to be elevated in colonocytes and is known to catalyze a key step in glycolysis. We hypothesize that upregulation of PKM2 in ulcerative colitis and colorectal cancer results in diminished butyrate oxidation, and increased glucose utilization in colonocytes. MethodsMitochondrial function, substrate utilization will be analyzed in several colorectal cell lines, isolated colonocytes, or colonocytes grown in 3-D culture where PKM2 is knocked down, knocked-out, or overexpressed. An in vivo mouse model of colitis will be used to study the impact of PKM2 in the injury and repair process. ResultsKnockdown of PKM2 in cancerous colonocytes was associated with reduced proliferation and increased apoptosis. Butyrate oxidation was also increased in PKM2 knockdown cells. PKM2 regulated mitochondrial function and impacted the expression of uncoupling proteins (UCPs). Elevated PKM2 in primary colonocytes was associated with diminished butyrate utilization. Finally, conditional knockout of PKM2 in the colon resulted inhibited DSS-induced colitis. ConclusionsThese results show an important role for PKM2 in promoting ulcerative colitis and colorectal cancer through shifting colonocyte metabolism away from butyrate utilization. Funding SourcesUniversity of Tennessee - Start-up Funds.

Colonocyte metabolism shapes the gut microbiota.

An imbalance in the colonic microbiota might underlie many human diseases, but the mechanisms that maintain homeostasis remain elusive. Recent insights suggest that colonocyte metabolism functions as a control switch, mediating a shift between homeostatic and dysbiotic communities. During homeostasis, colonocyte metabolism is directed toward oxidative phosphorylation, resulting in high epithelial oxygen consumption. The consequent epithelial hypoxia helps to maintain a microbial community dominated by obligate anaerobic bacteria, which provide benefit by converting fiber into fermentation products absorbed by the host. Conditions that alter the metabolism of the colonic epithelium increase epithelial oxygenation, thereby driving an expansion of facultative anaerobic bacteria, a hallmark of dysbiosis in the colon. Enteric pathogens subvert colonocyte metabolism to escape niche protection conferred by the gut microbiota. The reverse strategy, a metabolic reprogramming to restore colonocyte hypoxia, represents a promising new therapeutic approach for rebalancing the colonic microbiota in a broad spectrum of human diseases.

Metabolic regulation of microbiota

Microbiota The gut microbiota affects human health, but we are only just beginning to develop a mechanistic understanding of some of the host-microbe interactions involved. Litvak et al. review how host colon epithelial cells mediate the symbiosis. Healthy colonocytes maintain anaerobic conditions in the gut lumen because their metabolism ensures rapid oxygen consumption. Such conditions select for obligate anaerobic organisms. These tend to be those that consume dietary fiber and produce short-chain fatty acids beneficial to the host. If there is a shift in colonocyte metabolism—because of disease, diet, or other damage—the epithelium becomes oxygenated. The presence of oxygen allows expansion of facultative aerobic organisms. Microbes in genera that include pathogens are often oxygen-tolerant, and dysbiosis can be the result. Science , this issue p. [eaat9076][1] [1]: /lookup/doi/10.1126/science.aat9076

Antibiotic-induced microbiome depletion alters metabolic homeostasis by affecting gut signaling and colonic metabolism

Antibiotic-induced microbiome depletion (AIMD) has been used frequently to study the role of the gut microbiome in pathological conditions. However, unlike germ-free mice, the effects of AIMD on host metabolism remain incompletely understood. Here we show the effects of AIMD to elucidate its effects on gut homeostasis, luminal signaling, and metabolism. We demonstrate that AIMD, which decreases luminal Firmicutes and Bacteroidetes species, decreases baseline serum glucose levels, reduces glucose surge in a tolerance test, and improves insulin sensitivity without altering adiposity. These changes occur in the setting of decreased luminal short-chain fatty acids (SCFAs), especially butyrate, and the secondary bile acid pool, which affects whole-body bile acid metabolism. In mice, AIMD alters cecal gene expression and gut glucagon-like peptide 1 signaling. Extensive tissue remodeling and decreased availability of SCFAs shift colonocyte metabolism toward glucose utilization. We suggest that AIMD alters glucose homeostasis by potentially shifting colonocyte energy utilization from SCFAs to glucose.

Functional imaging of the interaction between gut microbiota and the human host: A proof-of-concept clinical study evaluating novel use for 18F-FDG PET-CT.

Recent data comparing germ-free to conventionally-raised mice demonstrated that energy homeostasis of colonocytes is dependent on gut microbiota through regulation of short chain fatty acids (SCFA) production and glucose utilization. We sought to evaluate 18F-FDG PET-CT as a novel technique for functional imaging of alterations in glucose metabolism as a result of the interaction between the gut microbiota and the human host. We conducted a prospective study in healthy humans that underwent 18F-FDG PET-CT and sampling of the gut microbiota before and after orally administered broad-spectrum antibiotics. The primary outcomes were total and regional physiologic colonic 18F-FDG uptake (measured as the mean and max standardized uptake values [SUVmean and SUVmax]). The study demonstrated significant increases in physiologic colonic 18F-FDG uptake in all study participants following antibiotic treatment and a 4-5log reduction of gut bacterial load. The mean increase in SUVmax was 0.63±0.37 SD (p = 0.004) and the median increase was 0.42 with an IQR of 0.40–0.81. The mean increase in SUVmean was 0.31±0.24 SD (p = 0.01) and the median increase was 0.41 with an IQR of 0.06–0.55. A likely explanation for this phenomenon is a shift in colonocyte metabolism to glycolysis due to a shortage of SCFA.