Obesity and the Human Microbiome

Gut Microbes and Endocrine Cells

The gut communicates with the brain using endocrine signals to coordinate energy intake and expenditure. Enteroendocrine cells respond to nutrient intake by secreting incretin hormones, including glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). GLP-1 stimulates insulin release from the pancreas, slows gastric emptying, and promotes satiety and weight loss;^[25•] GLP-2 stimulates intestinal glucose transport and reduces gut permeability.^[46] An earlier report indicated that gut microbiota can regulate enteroendocrine cells and influence the release of gut hormones.^[47] Furthermore, the presence of microbes is necessary for the full complement of enteroendocrine cells to be present in zebrafish.^[48] In a series of studies, Cani et al.^[49] have shown a connection between gut microbes and levels of both GLP-1 and GLP-2. In rats, oligofructose treatment (which increases the proportion of Bifidobacteria) has been associated with a greater number of GLP-1 secreting enteroendocrine cells (L cells) in the colon. Ob/ob mice treated with prebiotic carbohydrates had altered gut microbiotas and increased levels of GLP-1 and GLP-2.^[44] Thus, enteroendocrine cells represent a direct signaling pathway from gut microbes to host metabolism.

In yet another distinct pathway, gut microbes have been shown to stimulate gut hormones. Samuel et al.^[50] recently showed that enteroendocrine cells express a receptor for SCFAs, GPR41, which is necessary for the full metabolic effect of these microbial metabolites. Mice lacking Gpr41 had reduced levels of the gut hormone PYY, greater gut transit time, lower recovery of SCFAs from the diet, and lower fat accumulation in fat pads. SCFAs are products of bacterial fermentation of carbohydrates from the diet: thus, they function both as an energy source and as a signaling molecule, and their abundance and type (e.g., butyrate, propionate, acetate) are directly related to the species composition of the microbiota and their syntrophic interactions. Again, it will be interesting to see whether other signaling pathways (such as through the SCFA receptor GPR43 for example) are similarly involved in host energy balance and whether different microbial communities interact differently with these molecules.

Anecdotal evidence suggests that the gut microbes also affect gut hormones in humans. Gut hormones are implicated in the reduction of appetite and weight after Roux-en-Y gastric bypass surgery (RYGP).^[51,52] In RYGP, a small gastric pouch is created from the proximal stomach and the distal stomach and proximal small intestine are bypassed. In a study of the effects of RYGP on the fecal microbes, Zhang et al.^[14•] showed that members of the Gamma-Proteobacteria (and Verrucomicrobia) were enriched after gastric bypass, compared with lean and obese participants. In addition, the stomach chambers formed in RYGP surgery are colonized by bacteria to a greater extent than the normal stomach.^[53] Interestingly, the administration of probiotic microbes after the procedure has been shown to accelerate weight loss,^[54] supporting the notion that the gut bacteria may be modulating gut hormones.

Table 1. Human studies of gut microbial ecology in relation to body weight
Author	Participants	Method (sample type)	Finding
Ley et al.^[2]	12 obese participants on one of two diets, carbohydrate or fat-reduced, for 1 year; two lean controls	16S rRNA surveys by Sanger sequencing (feces)	Proportion of Bacteroidetes sequences increased over time, on average, and correlated with weight loss. No difference between diets
Turnbaugh et al.^[5••]	154 participants, MZ and DZ twins and mothers, obese or lean	16S by Sanger and 454 pyrosequencing, metagenomics (feces)	Reduced levels of diversity, and reduced levels of Bacteroidetes in obese participants; metagenomes of obese participants enriched in energy-harvesting genes
Schwiertz et al.^[6]	30 lean, 35 overweight, 33 obese participants	qPCR for Bacteroidetes, Actinobacteria, Archaea (feces)	More Bacteroidetes in overweight and obese vs. lean participants, and more Methanobrevibacter in lean participants
Collado et al.^[7]	Women before and during pregnancy, 18 overweight participants and 36 controls	FISH/flow cytometry and qPCR (feces)	Higher levels of Bacteroidetes and S. aureus in overweight, positive correlation between Bacteroides levels and weight gain over pregnancy
Sotos et al.^[8]	8 obese and overweight adolescents during weight loss	FISH (feces)	Enterobacteriaceae and sulfate-reducing bacteria reduced in group with greatest weight loss. Reduced levels of Roseburia–Eubacterium in those with less weight loss
Duncan et al.^[9]	Participants on weight loss diets over 8 weeks vs. weight maintenance	FISH counts (feces)	No difference in Bacteroidetes levels between groups; reduced levels of Roseburia and Eubacterium, and increased levels of Clostridium spp., correlate with reduced carbohydrate intake
Kalliomaki et al.^[10••]	Obese and overweight children (n=25) and normal weight children (n=24); prospective study	qRT-PCR and FISH/flow cytometry (feces)	Children remaining lean at age 7 had higher levels of Bifidobacteria and lower levels of S. aureus, as infants
Santacruz et al.^[11•]	36 adolescents on diet and physical activity, 10 weeks	qPCR (feces)	Bacteroides fragilis abundance correlated with carbohydrate intake. Levels of Bacteroides and Lactobacillus increased with weight loss
Nadal et al.^[12]	39 adolescents on diet and physical activity, 10 weeks	qPCR (feces)	Clostridium histolyticum and E. rectale–C. coccoides reduced with weight gain; increase in Bacteroides–Prevotella in high weight loss group
Sabate et al.^[13]	137 obese patients, 40 healthy controls	Glucose-hydrogen breath test (for H₂) and liver biopsy (breath, liver)	Bacterial overgrowth in small intestine more common in obese vs. lean participants
Zhang et al.^[14•]	3 lean, three obese, and three postgastric bypass participants	Sanger and 454 sequencing of 16S rDNAs, qPCR (feces)	Firmicutes more abundant in lean participants, lowest after gastric bypass. Gamma-Proteobacteria and Verrucomicrobia enriched after gastric bypass; higher Archaea in obese participants; overall communities of gastric bypass and obese participants more similar to each other than to lean participants

Table 1. Human studies of gut microbial ecology in relation to body weight

Author

Participants

Method (sample type)

Finding

Ley et al.^[2]

12 obese participants on one of two diets, carbohydrate or fat-reduced, for 1 year; two lean controls

16S rRNA surveys by Sanger sequencing (feces)

Proportion of Bacteroidetes sequences increased over time, on average, and correlated with weight loss. No difference between diets

Turnbaugh et al.^[5••]

154 participants, MZ and DZ twins and mothers, obese or lean

16S by Sanger and 454 pyrosequencing, metagenomics (feces)

Reduced levels of diversity, and reduced levels of Bacteroidetes in obese participants; metagenomes of obese participants enriched in energy-harvesting genes

Schwiertz et al.^[6]

30 lean, 35 overweight, 33 obese participants

qPCR for Bacteroidetes, Actinobacteria, Archaea (feces)

More Bacteroidetes in overweight and obese vs. lean participants, and more Methanobrevibacter in lean participants

Collado et al.^[7]

Women before and during pregnancy, 18 overweight participants and 36 controls

FISH/flow cytometry and qPCR (feces)

Higher levels of Bacteroidetes and S. aureus in overweight, positive correlation between Bacteroides levels and weight gain over pregnancy

Sotos et al.^[8]

8 obese and overweight adolescents during weight loss

FISH (feces)

Enterobacteriaceae and sulfate-reducing bacteria reduced in group with greatest weight loss. Reduced levels of Roseburia–Eubacterium in those with less weight loss

Duncan et al.^[9]

Participants on weight loss diets over 8 weeks vs. weight maintenance

FISH counts (feces)

No difference in Bacteroidetes levels between groups; reduced levels of Roseburia and Eubacterium, and increased levels of Clostridium spp., correlate with reduced carbohydrate intake

Kalliomaki et al.^[10••]

Obese and overweight children (n=25) and normal weight children (n=24); prospective study

qRT-PCR and FISH/flow cytometry (feces)

Children remaining lean at age 7 had higher levels of Bifidobacteria and lower levels of S. aureus, as infants

Santacruz et al.^[11•]

36 adolescents on diet and physical activity, 10 weeks

qPCR (feces)

Bacteroides fragilis abundance correlated with carbohydrate intake. Levels of Bacteroides and Lactobacillus increased with weight loss

Nadal et al.^[12]

39 adolescents on diet and physical activity, 10 weeks

qPCR (feces)

Clostridium histolyticum and E. rectale–C. coccoides reduced with weight gain; increase in Bacteroides–Prevotella in high weight loss group

Sabate et al.^[13]

137 obese patients, 40 healthy controls

Glucose-hydrogen breath test (for H₂) and liver biopsy (breath, liver)

Bacterial overgrowth in small intestine more common in obese vs. lean participants

Zhang et al.^[14•]

3 lean, three obese, and three postgastric bypass participants

Sanger and 454 sequencing of 16S rDNAs, qPCR (feces)

Firmicutes more abundant in lean participants, lowest after gastric bypass. Gamma-Proteobacteria and Verrucomicrobia enriched after gastric bypass; higher Archaea in obese participants; overall communities of gastric bypass and obese participants more similar to each other than to lean participants

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Obesity and the Human Microbiome

Gut Microbes and Endocrine Cells

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