Microbial degradation of complex carbohydrates in the gut

The Gut Microbiome in Health and Disease

Colorectal cancer, a common malignancy of the digestive system with high morbidity and mortality, is closely associated with the microbiota. Recent studies have revealed that the gut microbiota and intratumoral microbiota are not only anatomically connected but also functionally synergistic. Together, they shape the tumor microenvironment and profoundly influence CRC initiation, progression, immune evasion, metastasis, and therapeutic response. Centered on the concept of the "gut-tumor microbiota axis," this review summarizes the origins, dynamic alterations, and functional roles of both microbial communities in CRC. It highlights their metabolic outputs, regulatory effects on tumor cell behavior and the immune microenvironment, and their implications in chemotherapy, immunotherapy, and microbiota-based engineered therapies. Coordinated modulation of gut and intratumoral microbiota may offer novel avenues for precision interventions, providing new therapeutic strategies and enhancing the efficacy of current treatments for CRC.Colorectal cancer (CRC) is a prevalent malignancy of the digestive system characterized by high morbidity and mortality. Accumulating evidence indicates that both the gut microbiota and intratumoral microbiota are integral to CRC pathogenesis and therapeutic outcomes. Understanding their interactions provides new insights into tumor biology and treatment strategies.This review synthesizes recent findings on the composition, origin, and dynamic alterations of gut and intratumoral microbiota in CRC. It focuses on their metabolic outputs, immunoregulatory mechanisms, and their collective influence on tumor initiation, progression, immune evasion, metastasis, and therapeutic response. Publications related to microbiota-tumor interactions and microbiota-based interventions were systematically analyzed and summarized. The gut and intratumoral microbiota form an interconnected and functionally synergistic ecosystem, jointly shaping the tumor microenvironment. These microbial communities modulate metabolic pathways, immune signaling, and tumor cell behavior, thereby influencing the efficacy of chemotherapy, immunotherapy, and emerging microbiota-based engineered therapies. Recent studies highlight the translational potential of targeting the "gut-tumor microbiota axis" to enhance treatment precision and overcome therapeutic resistance.The bidirectional interplay between the gut and intratumoral microbiota represents a critical determinant of CRC development and treatment responsiveness. Coordinated modulation of both microbial compartments may enable precision medicine approaches, offering novel therapeutic avenues and improving clinical outcomes in CRC patients.

The Intestinal Metabolome: An Intersection Between Microbiota and Host

The microbial community of the human large intestine plays an important role in nutrition and health. Molecular analyses have revealed the diversity of gut bacteria; although some dominant species are abundant in most individuals, humans show considerable inter-individual variation in the strain composition of their intestinal microbiota. It is helpful therefore to define broad functional groups (‘clubs’) that share one or more characteristics of interest. This approach has been applied to the formation by microbial fermentation of short chain fatty acids that are actively absorbed by the host as energy sources. A combination of targeted molecular detection and information on cultured isolates is helping to reveal the impact of diet upon groups responsible for the fermentation of particular dietary carbohydrates and the formation of butyrate, and should provide the basis for theoretical modelling of this complex community.

The microbial degradation of lignocellulose biomass is not only an important biological process but is of increasing industrial significance in the bioenergy sector. The mechanism by which the plant cell wall, an insoluble composite structure, activates the extensive repertoire of microbial hydrolytic enzymes required to catalyze its degradation is poorly understood. Here we have used a transposon mutagenesis strategy to identify a genetic locus, consisting of two genes that modulate the expression of xylan side chain-degrading enzymes in the saprophytic bacterium Cellvibrio japonicus. Significantly, the locus encodes a two-component signaling system, designated AbfS (sensor histidine kinase) and AbfR (response regulator). The AbfR/S two-component system is required to activate the expression of the suite of enzymes that remove the numerous side chains from xylan, but not the xylanases that hydrolyze the beta1,4-linked xylose polymeric backbone of this polysaccharide. Studies on the recombinant sensor domain of AbfS (AbfS(SD)) showed that it bound to decorated xylans and arabinoxylo-oligosaccharides, but not to undecorated xylo-oligosaccharides or other plant structural polysaccharides/oligosaccharides. The crystal structure of AbfS(SD) was determined to a resolution of 2.6A(.) The overall fold of AbfS(SD) is that of a classical Per Arndt Sim domain with a central antiparallel four-stranded beta-sheet flanked by alpha-helices. Our data expand the number of molecules known to bind to the sensor domain of two-component histidine kinases to include complex carbohydrates. The biological rationale for a regulatory system that induces enzymes that remove the side chains of xylan, but not the hydrolases that cleave the backbone of the polysaccharide, is discussed.

Wild mammals often consume different food sources as they become geographical available. This change in diet composition is likely to influence the gut microbial community, yet it remains unclear what the relationship looks like—particularly in small herbivores—under natural conditions. We used DNA sequencing approaches to characterize the diet composition and gut microbial community of wild plateau pikas (Ochotona curzoniae) collected from three altitudes. We tested if diet and gut microbiota composition changes across altitudes, and the relationship between diet diversity and gut microbiota diversity. Our results showed that altitude significantly influences the composition of diet and gut microbial communities. Notably, the alpha diversity (Shannon diversity and observed OTUs) of individual diet was not significantly correlated with that of gut microbiota, whereas the beta diversity (Jaccard and Bray-Curtis dissimilarity) of diet was positively correlated with that of gut microbiota. Our study is the first time to highlight the relationship between diet and gut microbiota composition in wild pikas on the Qinghai-Tibet Plateau. It suggests that the species richness within individual gut microbiota does not linearly increase with diet diversity, whereas those individuals that are more similar in diet composition harbor more similar gut microbiota.

The rising prevalence of type 1 diabetes (T1D) over the past decades has been linked to lifestyle changes, but the underlying mechanisms are largely unknown. Recent findings point to gut-associated mechanisms in the control of T1D pathogenesis. In nonobese diabetic (NOD) mice, a model of T1D, diabetes development accelerates after deletion of the Toll-like receptor 4 (TLR4). We hypothesized that altered intestinal functions contribute to metabolic alterations, which favor accelerated diabetes development in TLR4-deficient (TLR4−/−) NOD mice. In 70–90-day-old normoglycemic (prediabetic) female NOD TLR4+/+ and NOD TLR4−/− mice, gut morphology and microbiome composition were analyzed. Parameters of lipid metabolism, glucose homeostasis, and mitochondrial respiratory activity were measured in vivo and ex vivo. Compared with NOD TLR4+/+ mice, NOD TLR4−/− animals showed lower muscle mass of the small intestine, higher abundance of Bacteroidetes, and lower Firmicutes in the large intestine, along with lower levels of circulating short-chain fatty acids (SCFA). These changes are associated with higher body weight, hyperlipidemia, and severe insulin and glucose intolerance, all occurring before the onset of diabetes. These mice also exhibited insulin resistance–related abnormalities of energy metabolism, such as lower total respiratory exchange rates and higher hepatic oxidative capacity. Distinct alterations of gut morphology and microbiota composition associated with reduction of circulating SCFA may contribute to metabolic disorders promoting the progression of insulin-deficient diabetes/T1D development. The rising prevalence of type 1 diabetes (T1D) over the past decades has been linked to lifestyle changes, but the underlying mechanisms are largely unknown. Recent findings point to gut-associated mechanisms in the control of T1D pathogenesis. In nonobese diabetic (NOD) mice, a model of T1D, diabetes development accelerates after deletion of the Toll-like receptor 4 (TLR4). We hypothesized that altered intestinal functions contribute to metabolic alterations, which favor accelerated diabetes development in TLR4-deficient (TLR4−/−) NOD mice. In 70–90-day-old normoglycemic (prediabetic) female NOD TLR4+/+ and NOD TLR4−/− mice, gut morphology and microbiome composition were analyzed. Parameters of lipid metabolism, glucose homeostasis, and mitochondrial respiratory activity were measured in vivo and ex vivo. Compared with NOD TLR4+/+ mice, NOD TLR4−/− animals showed lower muscle mass of the small intestine, higher abundance of Bacteroidetes, and lower Firmicutes in the large intestine, along with lower levels of circulating short-chain fatty acids (SCFA). These changes are associated with higher body weight, hyperlipidemia, and severe insulin and glucose intolerance, all occurring before the onset of diabetes. These mice also exhibited insulin resistance–related abnormalities of energy metabolism, such as lower total respiratory exchange rates and higher hepatic oxidative capacity. Distinct alterations of gut morphology and microbiota composition associated with reduction of circulating SCFA may contribute to metabolic disorders promoting the progression of insulin-deficient diabetes/T1D development.

Natural polysaccharides cellulose, hemicelluloses, inulin etc., galactooligosaccharides (GOS), and fructooligosaccharides (FOS) play a significant role in the improvement of gut microbiota balance and human health. These polysaccharides prevent pathogen adhesion that stimulates the immune system and gut barrier function by servicing as fermentable substrates for the gut microbiota. The gut microbiota plays a key role in the fermentation of non-digestible carbohydrates (NDCs) fibres. Moreover, the gut microbiota is responsible for the production of short-chain fatty acids (SCFAs) like acetate, propionate and butyrate. Acetate is the most abundant and it is used by many gut commensals to produce propionate and butyrate in a growth-promoting cross-feeding process. The dietary fibres affect the gut microbiome and play vital roles in signaling pathways. The SCFAs, acetate, butyrate, and propionate have been reported to affect on metabolic activities at the molecular level. Acetate affects the metabolic pathway through the G protein-coupled receptor (GPCR) and free fatty acid receptor 2 (FFAR2/GPR43) while butyrate and propionate transactivate the peroxisome proliferator-activated receptorsγ (PPARγ/NR1C3) and regulate the PPARγ target gene Angptl4 in colonic cells of the gut. The FFAR2 signaling pathway regulates the insulin-stimulated lipid accumulation in adipocytes and inflammation, however peptide tyrosine-tyrosine(PPY) and glucagon-like peptide 1 regulates appetite. The NDCs via gutmicrobiota dependent pathway regulate glucose homeostasis, gut integrity and hormone by GPCR, NF-kB, and AMPK-dependent processes.

AimThe aim of this study was to characterize the gut microbiome of adolescents with obesity.Material and MethodThe study sample consisted of 40 adolescents aged 11–17 years with obesity (n=18) and...

Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children

Fermentable Carbohydrate Restriction Reduces Luminal Bifidobacteria and Gastrointestinal Symptoms in Patients with Irritable Bowel Syndrome1–4

The effect of modifying dietary protein and carbohydrate in weight loss on arterial compliance and postprandial lipidemia in overweight women with polycystic ovary syndrome

Rapid climate warming is 'greening' the tundra, reflecting a higher plant biomass, particularly of deciduous shrubs and grasses. However, the consequences of these changes for herbivore nutrition are unclear. Although, the gut microbiome mediates nutrient metabolism, and hence herbivores' capacity to adapt to dietary change, few studies have investigated the effect of annual changes in the diet-gut microbiome nexus on fitness-related traits. In a model system, the Svalbard reindeer, a species experiencing the greatest rate of climate warming on Earth, we investigate how changes in diet and the gut microbiome impact reindeer body mass. Using high-resolution DNA metabarcoding, we assessed diet and gut microbiome bacterial composition in rumen samples from animals culled in October from 1998 to 2004 in four different valleys. Overall diet diversity and grass relative reads abundance (RRA) were significantly higher following warmer summers, while the RRA of the dwarf shrub Salix polaris increased with the maximum normalised difference vegetation index (NDVI), our measure of annual biomass. Autumn body mass, a strong proxy of fitness in Svalbard reindeer, was significantly, positively correlated with Salix RRA, most pronounced in females that had reproduced, and by that depleted body reserves. Multivariate analyses revealed a highly significant relationship between diet and microbiome composition at the individual level. This included a significant positive correlation between Salix and bacterial diversity. However, a structural equation model revealed that the direct path effect of Salix on reindeer body mass was stronger than the indirect path effect, mediated through the gut microbiome. Our results suggest that climate-driven Arctic greening may have implications for herbivore body mass, operating through a change in diet composition. These findings reveal some of the mechanistic underpinnings of Arctic warming on herbivore populations and highlight the importance of the diet-gut microbiome nexus in facilitating species resilience to rapid climate change.

Promote or Prevent? Gut Microbial Function and Immune Status May Determine the Effect of Fiber in Inflammatory Bowel Disease

Introduction Glucose is an important, if not the sole, source of energy metabolism in the fed state for brain and other nervous tissue, red blood cells, renal medulla, and retina. Assimilation of diet-derived glucose is necessary to provide glucose per se for these tissues, to serve as a source of nonprotein energy, and to stimulate normal rates of insulin secretion required to adequately suppress protein degradation and excessive lipolysis, and to stimulate protein synthesis. Carbohydrate contributes approximately 40% of the energy intake in infants ingesting human milk or cow milk-based formulas, and lactose provides perhaps the sole source of diet-derived glucose in human milk and about 50% of the diet-derived glucose in preterm formulas. Dietary carbohydrate is assimilated via the intestine and colon in humans of all ages, but in the preterm newborn or young infant with defective function of the small intestine, bacterial fermentation of dietary carbohydrate is an especially quantitatively important metabolic pathway for enteral carbohydrate assimilation. This process may have both beneficial and adverse effects on the infant. Figure 22.1 summarizes carbohydrate assimilation by the gut. Lactose, like other dietary sugars fed to newborn infants (such as glucose polymer), is digested in the small intestine but also may undergo some fermentation in the colon. Glucose and galactose, derived from lactose digestion, are absorbed in the small intestine, enter the portal vein, and then undergo uptake by the liver, where galactose is almost quantitatively removed by the combined processes of conversion to glucose or incorporation into glycogen.