In this study, we found preliminary evidence across four studies that race/ethnicity, or its correlates, may be associated with distinct gut microbiota subtypes of obesity. In all of the studies included here with NHW individuals, there was evidence of a low alpha diversity subtype of obesity, and the association between lower alpha diversity and higher BMI was most consistent and strongest among NHWs and in AG, which is a cohort of predominantly healthy individuals with moderate BMI and high socioeconomic status. This relationship was notably less consistent among black and Hispanic individuals. We additionally noted a novel subtype of obesity in which the gut microbiota composition was less “Western”, more similar to that of individuals from agrarian cultures and high in Prevotella. While we did see at least some evidence of this gut microbiota phenotype of obesity in three of four studies examined, and some indication of an association with race/ethnicity, it would need to be validated in larger and more diverse cohorts. It is notable, however, that we found some evidence of variation of the gut microbiota-obesity relationship with race/ethnicity in four very different cohorts in terms of the population characteristics: adult twins and their mothers from Missouri, a heterogeneous cohort of healthy highly educated Americans from across the country, teenagers from Colorado, and a cohort of HIV positive and control adults from Mexico City.

These results raise many important questions about the role of race/ethnicity, ancestry, and genetics in the gut microbiota-obesity relationship, as well as the influence of lifestyle factors, such as diet, socioeconomic status, and smoking, all of which demand larger more racially diverse studies to thoroughly address. As obesity is known to have a genetic component and a link with microbiota composition, it stands to reason that genes may impact microbiota composition in a manner that in turn influences susceptibility to obesity. This notion was supported in a study of the microbiota of >1000 fecal samples obtained from twins in the UK, where a co-occurring group of heritable bacteria were found to be enriched in individuals with low BMI; amendment of an obesity-associated microbiota with the heritable lean-associated species Christensenella minuta resulted in reduced weight gain when transplanted into germ-free mice.30 The demonstrated link between heritable bacteria and protection from obesity supports that varied rates of obesity in different ethnic/racial populations may be driven by genetic polymorphisms in those populations that in turn result in varied selections for different microbiotas. Links between microbiota composition and ethnicity across various body habitats, including stool, were also detected in the Human Microbiome Project (HMP), where the greatest number of differentially distributed microbiota features (taxa, gene families, and metabolic pathways) with subject attributes were by race/ethnicity.31 Similarly, recent analyses of HMP and AG found specific taxa consistently associated with ethnicity across these two studies, and many of these taxa also have prior evidence of high heritability.18 Likewise, in this study, we found that race/ethnicity were significant determinants of the overall gut microbiota composition in both of the cohorts that we examined with black and white participants, and both studies showed a significant interaction between race/ethnicity and overweight/obese status. The oral and vaginal microbiomes have also been shown to correlate strongly with race/ethnicity.32,33 Interestingly, one study found that BMI was significantly correlated with vaginal microbiota composition among African but not European Americans.34 However, it cannot be ruled out that these microbiota-correlates with race/ethnicity may be driven by environmental factors instead of genes; we saw that dietary intake correlates with race/ethnicity in these cohorts and the gut microbiota-obesity relationship varied with diet. Prior studies that have compared the diets in black and white Americans, as well as in African Americans and rural Africans, detected differences in dietary intake between populations that correlated with differences in both fecal bacteria and its metabolites.35,36 Another recent study of over 1000 individuals concluded that genetic ancestry played a limited role in shaping the gut microbiome relative to the environment.37 However, this cohort was Israeli with limited racial and ethnic diversity, specifically very few black individuals.37 Thus, there is still a substantial gap in our understanding about how genetic ancestry shapes the gut microbiota, how the relationship between the gut microbiota and disease varies with genetic ancestry, and how these relationships differ with self-described race, which likely reflects diet, culture, socioeconomic status and other aspects of the environment more strongly than genetic ancestry.

Our work suggests that ethnic/racial differences across populations may explain at least some discordance in the nature of associations between the microbiota and obesity reported in different studies.10,12 Our observation that low alpha diversity may correlate with high BMI more consistently in NHWs than in black or Hispanic populations is consistent with many studies that are either exclusively or predominantly in NHW populations.11,12,13 Socioeconomic and health status correlate with race/ethnicity, and it is difficult to untangle these effects; AG had a fairly consistent association between lower alpha diversity and BMI across racial and ethnic groups, and the AG cohort is predominantly healthy, highly educated, and fairly wealthy individuals since participants pay to submit their microbiota samples. A recent meta-analysis and re-analysis of numerous studies of obesity and the gut microbiome included two Hispanic populations; one Hispanic Mexican-American cohort showed a trend towards lower alpha diversity with higher BMI, while a Columbian cohort was one of only two populations examined (among 10) that showed no trend towards such an association.12 Hispanic ethnicity is a genetic admixture of European, Native American and African that varies in proportion across the United States and across different countries.38 Interestingly, Colombia is one of the most genetically diverse group of Hispanics in Latin America with many individuals having a high proportion of African ancestry.39

Our observation that the association between Prevotella and BMI was most pronounced among blacks and Hispanics is consistent with a study in which three morbidly obese individuals, one black, one Hispanic, and one white (Krajmalnik–Brown, R. personal communication), were compared to three lean individuals,14 but such an association was also been noted in a morbidly obese European individual and was not seen in Hispanic Americans living on the Texas–Mexico border.40,41 The Prevotella-Bacteroides ratio was also seen to predict fat loss during a fiber-rich dietary intervention in Danish individuals, suggesting that the our results may be driven more by diet than by race or ethnicity.40 Prevotella has been shown to be enriched in prevalence and in diversity in non-Westernized societies, particularly Prevotella copri, which is near ubiquitous in non-Westernized populations and includes four distinct clades that tend to co-occur but are generally absent in Westernized populations.42 Prevotella is a complex genus that has been linked both to health and disease, and may interact with diet in complex ways.19,24,42,43,44 For example, Prevotella-rich microbiomes have been linked with a dietary-fiber induced improvement in glucose metabolism,27 but also with insulin resistance through the production of branched chained amino acids in the context of a high fat diet.26 While our analyses mainly focus on Prevotella and BMI, our meta-analysis of Obese Twins and GG imply that the relationship between the gut microbiota and obesity is not fully reflected by Prevotella relative abundance alone.

Our findings should be taken in the context of certain limitations. Only two of the studies included in our analyses included black individuals, and many of the included studies had small sample sizes or small numbers of non-whites. In order to fully understand whether there are distinct gut microbiota phenotypes of obesity and their associations with individual characteristics, much larger sample sizes are needed. We did not find evidence of strong confounding or interaction effects by smoking, but the studies had relatively small numbers of smokers. Diet was measured in different ways across the studies, and we were unable to examine race-based differences in the effects of diet in AG due to limited numbers of Hispanics and blacks. Likewise, it is important to understand the role of genetic risk for obesity and genetic ancestry in the microbiota-obesity relationship. While there are numerous cohorts with both genetic and microbiome information, most of these cohorts are also lacking in racial and ethnic diversity.45

Individuals with obesity vary in the extent of adiposity and also in the extent to which they suffer from other adverse health outcomes, including metabolic complications, such as hyperlipidemia, hypertension, glucose intolerance, and diabetes.1,2 Since obesity is a heterogeneous disease, and since several unique mechanisms by which the microbiota may influence obesity susceptibility have been proposed,46 it is also not surprising that there may be multiple distinct microbiota types that associate with obesity and that these may differ in prevalence in different cohorts. In fact, obese individuals with a low-diversity microbiota type have been characterized by more marked adiposity, greater inflammation, and poorer metabolic health compared to a high-diversity type.11 Another interesting question is whether different types of obesity-associated microbiotas may drive obesity by diverse mechanisms. Experiments in gnotobiotic or humanized mice that use different types of obesity-associated microbiotas as donor samples could help to determine whether different mechanisms may be at play.6,14

Since obesity rates are particularly high in non-white populations, our observation that the microbiota-obesity relationship may vary in unique ways by race/ethnicity underscores an urgent need to evaluate links between the microbiota and obesity in diverse populations, while simultaneously evaluating the role of race-associated factors, such as diet and socioeconomic status. Research about obesity and the gut microbiota has been dominated by studies focused on NHWs (e.g., ref. 2,11,12), but there is growing awareness about the importance of race, ethnicity and geography in determining the gut microbiota,17,18 and there are large racially and ethnically diverse cohorts that have more recently collected gut microbiome samples and will likely shed more light on these issues in the future.47 As various treatments for obesity vary greatly in efficacy across individuals, experiments that test the effects of weight loss treatments, e.g., various diets, in obese populations may benefit from a deeper understanding about different microbiota types and how they vary with race/ethnicity. This could facilitate personalized interventions, where the most effective strategies can be predicted based on the composition of the microbiota. The gut microbiota may also offer opportunities to treat or prevent obesity through personalized probiotics. However, microbiota-based interventions that do not take into account the differences in the gut microbiota or microbiota-disease relationships across diverse populations may be less effective or even have unintended adverse consequences.17