Obesity-Driven Alterations in Gut Microbiota

The human body contains huge numbers of microbes, including thousands of bacterial species, in addition to many eukaryotes, Achaea, protists, and viruses, which collectively contain an estimated 5 million genes that have profound metabolic and immunomodulatory effects on their mammalian hosts. The community of microbes is termed the microbiota, whereas their collective genes are called the microbiome. Both the state of obesity and westernized diets are associated with microbial dysbiosis, which is a deviation from microbial organization that would otherwise promote optimal metabolic homeostasis. Dysbiotic microbiota in obesity is characterized by decreased diversity in the microbial community and by an increased ratio of the phylum Firmicutes to the phylum Bacteroidetes. The change in the Firmicutes/Bacteroidetes ratio occurs in both mice and humans, and weight loss restores microbial composition. Note that 3 genera of bacteria are often overrepresented in obesity in humans: Bacteroides and Prevotella (both Bacteroidetes) and Ruminococcus (Firmicutes). In addition to composition, major functional differences are observed in metabolic capacity of the microbial community. For instance, decreases in short-chain fatty acid (SCFA) producers, such as from the phylum Actinobacteria and blooms in pathogenic bacteria from the phylum Proteobacteria, occur in obesity. In addition to bacteria, recent work shows that the microbiota metabolic networks include yeast and archaea, which synergistically produce and use metabolites collectively with bacteria. Although this area is still underexplored, recent work suggests that yeast species abundance is lower in obesity, and supplementation with Saccharomyces cerevisiae improves metabolic parameters and adiposity.

When dysbiotic communities of bacteria are transferred to naive germ-free (GF) mice, the recipient mice develop increased adiposity, showing a direct impact of the microbes on advancing fat storage in the mammalian host. Although some bacteria are associated with excess adiposity, others have been directly implicated in improving metabolic syndrome and atherosclerosis, such as Akkermansia muciniphila , and are often found to be underrepresented in obesity. Administration of A muciniphila during obesity was shown to improve glucose tolerance. Schneeberger and colleagues found that among 27 genes that regulate inflammation and metabolism in white adipose tissue under high-fat feeding, 20 genes negatively correlate with the relative abundance of A muciniphila . In addition, Bifidobacterium spp also negatively correlated with 6 of 27 genes. Positive correlations were observed with Bilophila wadsworthia in 14 of 27 genes, and this microbe is known to expand under high-milk-fat diets and subsequently stimulate inflammatory responses. Together these observations suggest that certain microbes might regulate aspects of peripheral metabolism related to obesity and metabolism, but further investigations to determine strong proof of causality are required.

Another line of evidence that supports the notion that microbes might closely regulate host metabolism and body weight is found through the study of acute malnutrition in childhood. In contrast with overfed and obese individuals, work by Subramanian and colleagues followed severely malnourished children for 2 years. Through compositional modeling, they showed that the microbiota normally develop with growing children, but, with malnutrition, the microbiota maturity remains stunted and lags behind host development. Even after common therapeutic food interventions, the immaturity of the microbiota persisted. Note that the microbiota remains immature even under less severe malnourished states and that microbiota maturity correlated with anthropometric measurements of the children. These findings strongly support the notion of the gut microbiota functioning as a vital organ, and its development and growth throughout life may have important unknown implications for human health. Understanding the role of microbial development under states of hyperalimentation may provide insights into dysfunctional microbial-host metabolic interactions that lead to excessive fat storage.

Dietary Impact on the Gut Microbiota

Although host phenotype influences the composition of the microbial communities, diet also notably has an immediate and dramatic impact on microbial structure that mimics communities seen in obese individuals. For instance, David and colleagues observed in humans that a diet rich in animal-derived fat and protein resulted in significant changes in the gut microbiota in as little as a day, and, of particular note, blooms in hydrogen sulfide–producing bacteria such as B wadsworthia were also observed. Later, his group found that diet has a greater impact on altering microbial assemblage than genetic background in mice. In this study, 5 different inbred mouse strains, 4 genetic knockout strains relevant to host-microbe interactions (eg, ob/ob, NOD2, MyD88−/−, and Rag1−/−), and 200 outbred mice were placed on high-fat, high-sugar diets or diets rich in plant polysaccharides. In each experiment, the Western diet had profoundly altered community structure, regardless of strain differences or gene deficiencies. More recently, Sonnenburg and colleagues showed that diets low in microbe-accessible carbohydrate (MAC) and high in simple sugars result in loss of bacterial diversity and extinction of specific microbial groups that is compounded over generations. The generational loss of bacterial diversity could only be remedied with FMT from control mice maintained on the MAC-rich diet, but not by diet alone. This study provides a model for the rapid and drastic impact of the human food supply, containing readily available processed high-fat and high-sugar food, on the progressive loss of bacterial diversity over the past several decades. This theory postulates that human bodies are not equipped to reciprocate and adapt to the sudden insult on the gut microbiota, thereby leading to the development of obesity. Based on the results from this study, suitable therapies to combat the loss of bacterial diversity might include probiotic supplementation or FMT.

High-fat diets also transform the metagenomes of the bacteriophage community, also known as the phageome. It was shown by Howe and colleagues that high-fat diets can shift the phageome independent of observed alterations in the bacterial host pattern. The impact of diet on viral communities was also rapid, occurring within 24 hours. In addition, the change in the viral metagenomes by the high-fat diet was not reversible after washout, suggesting that diet-mediated changes in the phage community are persistent, similar to the aforementioned findings in bacteria. Further research in this area is needed to better understand the regulation and function of the phageome, its impact on gut microbial ecology, and more importantly consequences for the host.

Restructuring of Gut Microbiota in Bariatric Surgery

Surgical intervention, although largely invasive, is the most effective weight loss strategy for obesity. RYGB is the most common and the most effective, promoting a 20% to 40% weight loss compared with 15% to 30% loss of body weight with gastric banding. RYGB includes the formation of a small pouch, made of the upper stomach, that is then attached to a region of jejunum approximately 75 cm distal to the stomach (termed a gastrojejunostomy). The resulting limb (including the distal stomach) carries bile, gastric juice, and pancreatic juices alone, without nutrients, another 125 cm distal from the gastrojejunostomy, collectively delaying the mixture of digestive juices and nutrients for approximately 200 cm of the upper gastrointestinal (GI) tract. It is becoming increasingly apparent that bariatric surgery, particularly RYGB, may involve multiple mechanisms beyond simple physical restrictions to nutrient intake and absorption through reduced stomach size and decreased absorptive capacity. It is plausible that new treatments will be discovered based on the mechanisms underlying bariatric surgery efficaciousness. Intriguing data suggest that the mechanisms involved may include altered gut microbial function and interactions of the microbiome with the host’s bile acid pool.

Anatomic rearrangement triggers the dramatic restructuring of the intestinal microbiota and host-microbe interactions that may contribute to weight loss after bariatric surgery. For example, RYGB in mice resulted in the rapid restructuring of gut microbiota as early as 1 week compared with sham controls. The early changes in microbial composition occur within the same time frames as improvement in glucose tolerance and reduced insulin resistance, in contrast with body weight and adiposity changes that occur over weeks and months, suggesting that microbial alterations may be involved in the resetting of metabolic set points that are distinct from adiposity. Specifically, RYGB results in a decrease in the Firmicutes/Bacteroidetes ratio, which includes increases in Bacteroidales, Enterobacteriales, as well as increases in Gammaproteobacteria ( Escherichia coli ) and Verrucomicrobia as a relative percentage of the microbial community. Note that the Verrucomicrobia genus Akkermansia uses host secretion of mucin as a fuel source and has been inversely correlated with body weight. As previously discussed, oral administration of live A muciniphila restores insulin sensitivity in high-fat fed animals. Following RYGB in diabetic rodents, the level of A muciniphila in the small bowel increased significantly compared with sham obese controls. The increase in A muciniphila was positively related with the release of GLP-1, an important intestinal incretin, suggesting that this microbe could be modulating peripheral glucose handling through modulated insulin tolerance. In humans following RYGB, an inverse correlation in the relative percentages of E coli , Bacteroides , and Prevotella with circulating leptin levels was found, an important adipose factor released at higher levels in obesity. In addition, the increases in Proteobacteria observed following RYGB have reached 50-fold, and together with other models suggest that Proteobacteria may influence insulin sensitivity. A direct role for the microbial community in mediating host metabolism following RYGB was confirmed with FMT from bariatric surgery donors into recipients, which conferred protection from obesity. Altogether, these studies provide strong evidence that the gut microbiota may significantly contribute to the effectiveness of RYGB surgery, paving the way for focused investigations into altering the microbiota in a similar manner for the treatment of obesity.

The direct role for microbes in improving metabolism following RYGB remains under investigation, but other indirect roles include microbial changes to the bile acid composition; bile acid activation of the ileal and colonic bile acid receptors; and regulation of gut peptide enteroendocrine hormones, such as GLP-1 and peptide tyrosine tyrosine (PYY). Current evidence suggests that the composition of bile acids influences the microbiota assemblage through antimicrobial function, because bile acids are detergents and influence the membrane chemistry. Reciprocally, bacteria influence bile acid composition by deconjugation and fermentation of primary bile acids into secondary and tertiary bile acids, which have differential effects on host metabolism. Primary bile acids are associated with improved metabolism, whereas secondary bile acids are potentially carcinogenic and not associated with metabolic improvement. Therefore, bile acids and microbial compositions are inseparably associated and continually interacting in the gut. Novel work showed that bile acid–altered microbial communities in turn influence host metabolism, establishing a crosstalk between bile acids and the intestinal microbiome that influences host metabolism. In addition to altering bacterial viability and growth, and aiding in the absorption of luminal dietary lipids and lipid vitamins, bile acids directly modulate host metabolism through host bile acid receptors. Bile acid interactions with the G protein–coupled bile acid receptor 1 (GPBAR1 or TGR5) and farnesoid X receptor (FXR) regulate peripheral energy expenditure and counteract obesity and diabetes. On activation by bile acids, TGR5 specifically stimulates the release of GLP-1, GLP-2, and PYY from enteroendocrine cells as well as expression of various transport proteins and biosynthetics, resulting in improved glycemic control. Enteroendocrine cells also contain toll-like receptors and sense bacteria in the intestinal lumen. Following RYGB, increased circulating levels of GLP-1 and PYY are reported. PYY is normally released postprandially to increase energy expenditure and decrease food intake. In healthy individuals, PYY release following feeding is proportionate to caloric consumption, acting directly on the hypothalamus and vagal afferents to slow feeding behavior. It remains unclear whether increased PYY and GLP-1 levels following RYGB are in response to altered microbial populations, bile acid pools, or a combination. Regardless, changes in intestinal enteroendocrine signaling following RYGB have profound effects on host metabolism and multiple lines of evidence now strongly support the involvement of the microbiota.