South Asian Health: Inflammation, Infection, Exposure, and the Human Microbiome

Abstract

This paper presents the results of the literature review conducted for the working group topic on inflammation, infection, exposure, and the human microbiome. Infection and chronic inflammation can elevate risk for cardiovascular disease and cancer. Environmental exposures common among South Asian (SA) subgroups, such as arsenic exposure among Bangladeshis and particulate matter air pollution among taxi drivers, also pose risks. This review explores the effects of exposure to arsenic and particulate matter, as well as other infections common among SAs, including human papillomavirus (HPV) and hepatitis B/C infection. Emerging research on the human microbiome, and the effect of microbiome changes on obesity and diabetes risk among SAs are also explored.

Background

This paper presents the results of the literature review conducted for the working group topic on inflammation, infection, exposure, and the human microbiome. These topics are discussed together because infection, certain environmental exposures, and the microbiome all are related to chronic inflammation, which can elevate risk for both cardiovascular disease (CVD) and cancer. This review explores environmental exposures common among South Asian (SA) subgroups, such as arsenic exposure among Bangladeshis and particulate matter air pollution among taxi drivers, as well as infections common among SAs, including human papillomavirus (HPV) and hepatitis B/C infection. Emerging research on the human microbiome, and the effect of microbiome changes on obesity and diabetes risk among SAs are also explored. Gaps in research on SAs in the U.S. are noted by reviewing existing literature on research conducted both nationally and internationally. Findings from studies on SAs in their countries of origin or other non-U.S. diasporic countries (i.e. the United Kingdom) may inform research priorities to reduce CVD and cancer risk among SAs in the U.S. Recommended next steps and research priorities represent the culmination of discussions held among researchers and community members throughout the series of South Asian Health working group meetings, the day-long in-person convening, and the community-academic town halls.

Methods

For the literature review, a search of NCBI PubMed and Scopus databases using the following primary key terms was conducted: Arsenic OR Arsenic Poisoning OR Mercury OR Kohl OR Kajal OR Hepatitis B OR Hepatitis C OR Hepatitis C Chronic OR Hepatitis B Chronic OR HPV OR Human papillomavirus OR HPV 6 OR HPV 18 OR Particulate Matter OR Air Pollution OR PM OR Human Microbiome 0R South Asia(n) OR India(n) OR Bangladeshi(i) OR Pakistan(i) OR Sri Lanka(n). Additional articles were added based on Steering Committee and working group members’ suggestions and experiences. A total of 296 articles were found; articles were excluded from the review if they were not relevant to the working group theme. To determine recommended next steps to address the gaps identified in the literature, working group members met by conference call over a period of six months. Minutes from each meeting were summarized and then reviewed, and a set of preliminary research questions/topics and policy goals was developed. At the South Asian Health day-long convening and the community-academic town halls, these preliminary questions/goals were further discussed and a final summary of research and policy priorities was created.

Results of available literature

I. Arsenic

High levels of naturally-occurring arsenic can be found in several regions around the world including the U.S., Mexico, Argentina, Chile, Poland, China, Japan, Mongolia, and Vietnam [1, 2]. However, West Bengal (India) and Bangladesh have been the most affected by arsenic contamination [1]. Arsenic-contaminated water first started appearing in Bangladesh in the 1940’s as a result of a global initiative to provide “clean” water to the country’s rural communities by installing tube-wells. These wells were usually placed at a depth of 200 meters to eliminate contamination with illness-causing microorganisms [3]. However, in the early 1990’s the first evidence of arsenic contamination began surfacing [4]. Arsenic concentration in tube-well drinking water was >50 ug/L in many regions of Bangladesh (safe arsenic concentration is <10 ug/L, per WHO guidelines) [3]. It has since been estimated that areas with tube-well placement and arsenic contamination affect as many as 77 million people [3].

Although drinking contaminated water is the most common cause for arsenic exposure, there have been other identified sources of arsenic toxicity, such as eating crops irrigated with contaminated groundwater [5, 6]. Rice cultivated in South Asia, particularly the West Bengal area, has been shown to have high levels of arsenic contamination [7]. A 2008 analysis in Bengal found that inorganic arsenic ingestion from rice grains alone (2.32 µg/kg body wt./day) among Bengali participants exceeded the WHO’s recommended limit of 2.1 µg/kg body wt./day [5]. Arsenic exposure has been associated with rice intake in studies across diverse populations, including in China, Korea, Southeast Asia, Spain, Portugal, Argentina, and Uruguay [8].

The risk of excessive ingestion of arsenic due to rice products has also been studied in the U.S. [9, 10]. A 2012 Consumer Report analysis of rice grown in the U.S. as well as rice imported from South Asia found that many samples contained inorganic arsenic levels that exceeded the most protective state-level standard—New Jersey’s 5 parts per billion limit (no federal standard exists)[10]. Moreover, according to the Consumer Report analysis of federal health data, individuals who reported eating rice demonstrated 44% greater levels of arsenic than their counterparts [10]. The U.S. Food and Drug Administration released a statement in 2012 noting similar results [9]. Given that rice is a staple of the SA diet [5], SAs in the U.S. may face an increased risk of excessive arsenic ingestion through consumption of rice and rice products both grown in the U.S. and imported from South Asia .

Arsenic toxicity has been linked to high morbidity and mortality rates in South Asia, and arsenic-related disease risk factors identified among SAs in their countries of origin may apply to SAs in the U.S. Between 2000 and 2002, a cohort of over 11,000 individuals in Bangladesh was assessed prospectively through the HEALS study: Health Effects of Arsenic Longitudinal Study [11]. This study showed a significant hazard ratio (HR) for chronic-disease mortality in districts where arsenic well water levels were over 150 µg/L (1.68 HR), where arsenic dose was greater than 401 µg/day (1.58 HR) and where total arsenic levels in urine were over 352 µg/g (1.47 HR) [11].The study concluded that chronic arsenic exposure is associated with an increase in all-cause and chronic-disease mortality rates [11]. Below we discuss specific health consequences associated with arsenic exposure that have been identified in South Asia, including cancer and CVD.

Cancer

Chronic arsenic exposure and ingestion can lead to several forms of cancer [6]. Studies in Bangladesh and West Bengal have investigated arsenic-associated skin cancer, which is common and can be detected early from the distinctive skin lesions of melanosis and keratosis [12, 13]. There is a greater risk of arsenic-associated skin cancer for those who smoke, lack proper nutrition, and have greater exposure to sunlight [13]. Skin lesions can also be an indicator of arsenic-related lung cancer [14, 15]. Bladder cancer is also associated with arsenic exposure; one study in southwestern Taiwan has shown that bladder cancer risk is increased in poor arsenic metabolizers [16]. The HEALS study found that fatal cancer outcomes in Bangladesh disproportionately affected those with a history of chronic arsenic exposure [6]. The combined lung, liver and bladder cancer mortality rates of Bangladeshis chronically exposed to arsenic was over two times greater (229.6 per 100,000) than those for the overall Bangladeshi population (103.5 per 100,000)(6). There are not yet data on Bangladeshis living in the U.S.

Cardiovascular Disease

Arsenic exposure increases risk for coronary artery disease and peripheral arterial disease [17]. A study in West Bengal found that elevated exposure to arsenic led to increased levels of various markers of CVD (e.g. IL6 and IL8), liver damage (e.g. bilirubin), and inflammation and autoimmune disease (e.g. ANA) [18]. Other studies have shown a significant increase in mortality in both males and females from hypertensive heart disease in the U.S. (non-SA population) due to arsenic exposure [19]. Arsenic causes direct myocardial injury, cardiac arrhythmias, and cardiomyopathy [20–22].

II. Particulate Matter

Particulate matter (PM), one of the six most common air pollutants, is a widespread threat to health [23]. PM includes coarse particles, like sand and large dust particles (referred to as PM₁₀), and fine particles that stem from gases emitted from power plants, industries, and automobiles found in smoke and haze (referred to as PM_2.5) [24]. These particles can pass through the throat and nose and enter the lungs, and can cause serious health effects, such as CVD, cancer, and chronic obstructive pulmonary disease, with the severity of effects linked to smaller sized particles [23].

PM air pollution is a risk factor for CVD via mechanisms that likely include altered cardiovascular autonomic function. Associations have been seen between elevations in PM_2.5 and increases in systolic blood pressure [25], reduced heart rate variability [23, 26–32], inflammation, and accelerated atherosclerosis [33–36]. The Harvard Six Cities Study was the first large, prospective cohort study that demonstrated that chronic exposure to air pollutants is independently related to cardiovascular mortality [37]. The association between mortality with PM_2.5, sulfate particles, and sulfur dioxide (SO₂) was also illustrated in a study that demonstrated their role in increasing all-cause, cardiopulmonary, and lung cancer mortality[38, 39]. Several additional studies have linked PM exposure to lung cancer [40–42].

Air pollution has become a major concern in India in recent years, with a majority of the Indian urban population exposed to some of the highest pollutant levels in the world [43]. Acute respiratory infections (ARI), which are linked with PM and other air pollutant exposures, represent the largest single disease category in India, accounting for about 11% of the national disease burden [43]. Furthermore, there is use of open biomass stoves, which have been shown to contribute to poor air quality [43].

Air pollution is also a growing concern for certain SAs in the U.S., as recent research shows elevated PM exposure among occupations with disproportionate SA representation [44–48]. Professional taxicab driving is a common occupation among SAs, with over 40% of drivers in New York City, and approximately 20% in Chicago, San Francisco, and Washington DC originating from South Asia (India, Pakistan, Bangladesh, and Nepal) [45]. Taxi drivers work long hours (10–12 h/d shifts ∼6d/wk), most often in heavy traffic [45]. Thus, a large part of their day is spent inside a vehicle cabin where they are potentially exposed to high levels of traffic-related PM.

Taxi drivers are already at increased risk for CVD and cancer due to a number of factors, including poor diet and a sedentary lifestyle; exposure to PM exacerbates that risk [46–49]. Many studies (although none conducted among SAs in the U.S.) have demonstrated a high prevalence of lung cancer among taxi drivers, without known additional risk factors such as smoking (in a systematic review, SAs were less likely to smoke in their adopted countries versus their countries of origin [50], suggesting a possible association with PM [51, 52]. In a large population-based study of Danish male drivers, the odds ratio (OR) for lung cancer among taxi drivers was 1.6 (95% CI 1.2 – 2.2) after adjusting for socioeconomic status [51]. As the duration of driver employment increased, the lung cancer risk also increased significantly; the highest risk was found among long term taxi drivers with 10 years of lag time between lung cancer diagnosis and first employment (OR 3.0; 95% CI 1.2 – 6.8) [51]. A prospective study of drivers in Geneva found that professional drivers, including taxi drivers, had significant excess risk compared to the general population for all causes of death (standardized mortality ratio (SMR) 115, 90% CI 1.07–1.23) and for all cancers (SMR 125, 90% CI 1.12–1.40) [53]. Cause-specific analysis showed significant excesses for lung cancer (SMR 150, 90% CI 1.23–1.81) [53].

III. Human Papilloma Virus (HPV)

Human Papilloma Virus (HPV), the leading cause of cervical cancer worldwide, is becoming a growing health concern among SAs in their countries of origin and in SA diasporic countries, including the U.S. [54]. India has the highest number of cervical cancer cases worldwide, with 134,000 cases and 73,000 deaths in 2008, representing one fourth of the global burden of cervical cancer [54]. Bangladesh, Nepal, Cambodia, and India ranked among the countries with the highest cervical cancer mortality rates and incidence rates in Asia [54]. A review of dozens of case control studies worldwide that looked at the geographic variations in HPV type distribution in cervical cancer found that SA countries had the highest proportions (26%) of HPV type 18, one of the strains that is most closely associated with cervical cancer [55]. The authors noted that a vaccine against the 7 most common HPV types, including types 16, 18, 45, 31, 33, 52, and 58, would prevent 88.8% of cervical cancers in south Asia [55]. Current HPV vaccines confer protection against types 16 and 18 [56].

Though most commonly associated with cervical cancer, HPV has also been implicated in 19 out of 50 cancers of the upper aerodigestive tract, including cancers of the tonsil and pharynx [57]. In a U.S. study, including 284 individuals with cancer of the oral cavity and pharynx, HPV 16-DNA was detected more frequently in tonsillar carcinomas (34%) and oropharyngeal carcinomas (36%) compared with other cancer sites (<15%)[58]. In a worldwide study of cancers of the oral cavity and pharynx, rates of pharyngeal cancers among men in India were the second highest compared to rates in the 48 other areas across 5 continents that were included in this study [57]. The highest female incidence worldwide for oral cavity and pharynx cancers were observed in India, with rates in Madras of 10.2 and 3.2 per 100,000, respectively [57].

Women of SA origin may face barriers to preventive care for HPV and cervical cancer. Research on SA women’s health in the U.S. is lacking, but findings from several qualitative studies in other SA diasporic countries may reflect the experiences of SA immigrant women in the U.S. A study of White British, Pakistani, African Caribbean, and Indian women in the UK found that, overall, there is a lack of education around HPV transmission and testing [59]. In response to the possibility of testing positive for HPV, the women discussed sensitive topics related to trust, blame, and fidelity in their relationships [59]. Testing had the potential to force communication with one’s partner, family, and the wider community about trust and sexual behavior [59]. These concerns seemed especially pronounced for a subset of Indian and Pakistani women, for whom extramarital sex can be strongly forbidden [59].

A study of London-based Muslim women’s attitudes towards self-sampling for HPV in the context of cervical cancer screening found that participants were generally positive about cervical cancer screening but acknowledged that some women in their community were reluctant to be screened because of embarrassment, language difficulties, fear, or because they were unmarried and did not want to communicate implicit messages about being sexually active [60]. Women were concerned about not doing the test correctly, but thought that self-testing might overcome barriers to screening for some women [60]. In this same study, HPV testing itself was again thought to raise potentially difficult issues relating to trust and fidelity within marriages [60]. Although most women said they would prefer to continue to be screened by a health professional, if they were to perform self-sampling, there was overwhelming preference for the swab over the lavage kit [60].

IV. Hepatitis

Hepatitis B

Hepatitis B virus (HBV) infection can lead to serious liver damage, and without treatment, about 15–25% of people with HBV will die prematurely from cirrhosis, liver failure, or liver cancer [61]. Although many developed countries demonstrate low HBV endemicity, including the U.S. (<1%), infection among SAs continues to be a growing global concern [62, 63].

HBV is endemic in SA countries, with rates of current or past infection as high as 50–80% [64]. A retrospective study in England showed that among SAs, HBV incidence was 3.1 times higher than among non-SAs [65]. In this study, the estimated lifetime risk of infection was 1.4% in SAs and 0.4% in non-SAs, and of chronic infection was 0.8% in SAs and 0.02% in non-SAs [65]. SA blood donors also had a high frequency of new HBV infections, 4.3 times higher than among non-SAs [65]. Further, the adjusted incidence of acute HBV infection was 10 times higher in SA children than in non-SA children [65].

In the U.S., research has shown that hepatitis B infection remains a significant health concern for SAs, especially those who have recently emigrated from their countries of origin [62, 63, 66]. A review of literature on hepatitis B among Asian Americans found similarly high prevalence rates of the hepatitis B surface antigen (HBsAg) in first-generation Asian immigrants in the U.S. compared to Asians in their respective native countries. For example, among those of Indian descent, HBsAg rates are 1.4–3% in India and 1–6% in the U.S. [66].

In total, about 2 million Americans are chronically infected with HBV despite the availability of testing, vaccinations, and medications in the U.S. [61]. Two-thirds are unaware of being infected, as HBV symptoms may lay dormant for years [61]. There are various psychosocial, economic and environmental factors that affect an individual’s decision to undergo screening for HBV, including knowledge of HBV transmission and its consequences, language, stigma, high cost of screening and potential treatment, and a perception of the unavailability of treatment [61]. More education, outreach, and services are needed to improve prevention, increase screenings, and improve access to treatment. Additional logistical and socioeconomic barriers exist to testing and treatment. Patients may lack transportation or insurance to cover specialist care, and providers may lack relevant culturally responsive training and educational resources [61]. In addition to community-based outreach, legislative action can expand access to HBV screening and care [61, 62]. U.S. legislators are in the process of addressing mandatory screening for at-risk populations, including those who come from countries where the prevalence of HBV is greater than 2%, which includes SA nations [62]. More specifically, the National Hepatitis B Act would increase screening and vaccination efforts, as well as funding for HBV treatment, prioritizing those with limited healthcare access [62].

Hepatitis C

Like Hepatitis B, Hepatitis C (HCV) can lead to liver failure and cancer, cirrhosis, and heart disease [67]. Taken together, the few studies that have reviewed the epidemiology of HCV demonstrate endemicity of HCV in South Asia (<2% in India; 5% in Pakistan), and relatively low rates of infection among the total U.S. population (1.3%) [67]. However, recent surveys have revealed high rates of infection among U.S. SAs compared to other groups, suggesting that HCV remains a health concern for SAs both in their countries of origin and those to which they immigrate. Asians in developing countries commonly acquire HCV via medical treatment, such as through contaminated blood transfusions or non-sterilized medical equipment [67]. While high-income countries have implemented intensive screening of blood from donors, effective infection control, and safe-injection methods, mid to low income countries lag behind in such measures [68].

Hemodialysis is a major subgroup of nosocomial transmission of both HBV and HCV infection, as dialysis patients are exposed to blood and medical equipment over an extended period of time [69, 70]. One retrospective study found that some Indian patients living in Britain who returned to India for hemodialysis returned with HCV infection [71]. Of the 36 HCV positive patients at two hemodialysis units in Birmingham, over a nine year period 16 (44%) developed HCV infection while receiving hemodialysis in India [71]. A study in Scotland found that after holding HCV awareness groups at mosques and at a Pakistani women’s center in Dundee, out of 250 who attended meetings, 177 were tested at clinics (10% of Dundee’s Pakistani population) [72]. Of the 177, 7 (4.1%) were anti-HCV antibody positive, 5 (2.9%) had detectable HCV RNA by PCR, and one had chronic hepatitis B infection [72]. In New York, the Hepatitis Outreach Network (HONE), a community-engaged collaboration between Mount Sinai School of Medicine and the New York City Department of Health and Mental Hygiene, screens and treats communities with high rates of chronic hepatitis, including SAs [73]. In a study of over 1600 HONE participants, it was found that approximately 10% of those who were screened were diagnosed with HBV and/or HCV [73].

V. Human Microbiome

The human microbiota consists of more than 10,000 bacterial species that aid humans in normal physiological activities [74, 75]. Considered an organ in itself, the microbiota contains 10⁴ bacterial cells in just the intestine alone, which is ten times the number of cells in the human body [76]. The microbiota help to create an optimal internal environment via processes including the extraction of energy from food, the release of accessory growth factors, and the stimulation of both innate and adaptive immune systems [77]. Thus, the role bacteria play within humans offers advantageous biochemical support [76].

While the whole human species displays a vast range of microbiota, each individual houses a specific set of microorganisms [77]. Babies are born with a sterile GI tract, but immediately after birth, bacteria begin to colonize [77]. Throughout life, bacterial populations can change due to external factors such as geography, socioeconomic status, lifestyle, diet, hygiene, and the use of antibiotics [76, 78].

Antibiotics also have the potential to influence microbiota in a significant way. Not only can the microbiota change during one’s lifetime, Blaser, et al. suggest that it has changed over centuries as human ecology has evolved [74]. Diseases have come and gone as people moved to the cities, and industrialization, sanitation, and antibiotics developed. For example, due to sanitation measures and the use of antibiotics, Helicobacter pylori is no longer commonly found in the human microbiota [74]. Blaser believes that the rise of new “post-modern” diseases such as type II diabetes and obesity is connected to the changes in microbial composition [74]. Below we discuss evidence for the role of gut microbial changes in cancer, cardiovascular disease, and diabetes, and call for further exploration of these topics in SA populations in the U.S.

Cancer

While genetics and cellular processes lay the foundations for cancer, the environment plays a critical part in its initiation or advancement [79]. Evidence for the “alpha bug” hypothesis that certain microbiota are directly oncogenic point to a positive association between microbiota and cancer development [79]. At the same time, an “Asian enigma” (discussed further below) in current research and evidence for preventive effects of certain microbiota complicate researchers’ understandings of the relationship between microbiota and cancer [80]. The potential role of microbiota in cancer, whether protective or adverse, is of growing interest and warrants further investigation among SAs in the U.S.

Various modifications to cell surface receptors, the immune system, enzymes and metabolites, anatomy, and hormones can aid in cancer development [81]. The microflora can also affect immunity by aiding in inflammation, immune evasion, or immune suppression [81]. The microbiota are also involved in metabolic processes via conversions of hormones, kinases, and other biochemical compounds [81]. A bacterial enzyme, β-glucuronidase, hydrolyzes dietary compounds and other conjugates of activated metabolites that contain carcinogenic elements, which are then released into the body [79]. β-glucuronidase has been found in higher levels in colorectal cancer patients [79]. Oral microbiota can convert alcohol into acetaldehyde, a toxin and human carcinogen [82]. Oral microbiota can also activate carcinogenic elements in tobacco [82]. Enterococcus faecalis can make a superoxide that can in turn be made into hydrogen peroxide, which damages DNA [79]. Enterotoxigenic Bacterioides fragilies (ETBF) has a toxin that causes cleavage of E-cadherin, a tumor suppressor protein, and increases in cell proliferation proteins [79]. Anatomical changes occur with the growth of tumors. As a mass becomes hypoxic, aerobes move away and anaerobes gravitate toward it [81]. Microflora can also affect hormones, which cause growth and proliferation. Some can metabolize estrogen, which plays a key role in some female cancers [81].

In general, most research on the gut microflora and its impact on cancer has focused on colon cancer [83]. Colorectal or colon cancer (CRC) is the third leading cause of cancer in the developed world, with a mortality rate of 33% [84]. Fecal matter of CRC patients show significantly different proportions of bacterial species than that of healthy subjects [84]. For example, the family Lachnospiraceae, which may protect the intestine against cancer, is less commonly found in CRC patients [84]. Fusobacterium nucleatum is associated with CRC [85]. Despite the connection between the microbiome and cancer, no clear causal relation has been identified [86].

The relationship between H. pylori and cancer may be of special interest for SAs in the U.S. H. pylori, an ancient microorganism, was once the most dominant bacterial species in the stomach, yet now its prevalence in Western countries is generally low [74, 87]. In the U.S., H. pylori can be found in less than 10% of children [74]. However, immigrants in Western countries originating from locations with high H. pylori prevalence have demonstrated high rates of infection [74, 87, 88]. For example, one study in New York City reveals that East Asians have a significantly higher prevalence, with more than 70% of subjects harboring H. pylori [88]. Like East Asia, South Asia has a high prevalence of H. pylori. [89, 90]; therefore, prevalence among immigrants originating from SA countries also likely exceeds that of other populations in the U.S.

While H. pylori infection is often associated with the onset of gastric cancer, this relationship is not always clear. In South Asia, the prevalence of H. pylori is high, yet the incidence of gastric cancer is low [89, 90]. This is in contrast to certain East Asian countries, where the prevalence of H. pylori and incidence of gastric cancer is high [89, 90]. This “Asian enigma” has been refuted by Graham et al. (2009), who argue that the patterns of gastritis in each region can account for these different clinical outcomes [80]. A study by Matsuhisa and Aftab (2012) gives a further look into this phenomenon [80, 89]. Their study compared the gastric mucosa of patients who had endoscopies in Bangladesh and Japan [89]. Results showed that Bangladeshis had a higher prevalence of H. pylori infection (60.2%) than the Japanese (45.1%) [89]. Bangladeshis also had much less chronic inflammation [89]. Corpus-predominant was the prevailing form of gastritis amongst the Japanese, which increases risk of gastric cancer by 23.3 times [89]. Bangladeshis had antrum-predominant gastritis, which offers more protection from gastric cancer [89]. H. pylori has two known strains, Western and Eastern (East Asian) [89]. Eastern, which is common among Japanese and other East Asians, is more inflammatory in nature than the western strain found among Bangladeshis [89]. Ultimately the inflammatory factors contribute greatly to the risk of gastric cancer for those with the Eastern strain.

Gut microbiota undergo carbohydrate fermentation, which includes products such as lactate and short-chain fatty acids (SCFA) like acetate, propionate, and butyrate [91]. SCFA are important metabolic and immune cell regulators, acting as anti-inflammatory agents in monocytes and inhibiting cell proliferation in colon cells [91]. Diets high in carbohydrates and fiber, which are common among SA groups, offer the advantage that the microflora will produce such antiinflammatory and antiproliferative compounds [91]. In contrast, diets high in fat and protein lead to the production of potentially toxic nitrogen-containing compounds [92]. Research on the role of microbiota in aiding cancer prevention, specifically among SA groups, is lacking.

CVD and Diabetes

The potential association between microbiota and cardiovascular disease (CVD) and/or diabetes also warrants further exploration among SAs in the U.S. Recent research implicates the microflora in heart disease and its risk factors, particularly metabolic dysfunction [93]. Microbiota regulate fat storage and have been linked to metabolic dysfunction and low-grade inflammation, potential mechanisms leading to weight gain. In animal models, mice maintained in germ-free conditions are leaner compared to those maintained in an environment with microbiota; once gut microbiota are introduced to these mice, they gain fat mass and insulin resistance is increased [93].

Lipopolysaccarides (LPS), an endotoxin derived from gram-negative bacteria, have been identified as molecules of special interest among SAs with respect to CVD and diabetes. LPS are key molecules in the development of inflammation and metabolic diseases such as diabetes and obesity [93]. High levels of LPS have become a marker for cardiovascular risk [94]. A study in Italy that observed the relationship between LPS and heart failure saw that subjects with more than 50 pg/ml had a threefold risk of atherosclerosis [95]. Another study in a British multi-ethnic population showed that SAs. had the highest levels of LPS compared to whites and African Americans [96].

Another molecule that should be investigated more closely among U.S. SAs is trimethylamine-N-oxide (TMAO), a metabolite of microbiota that has been recently associated with elevated cardiovascular risk [97]. Experiments have shown that antibiotics decrease TMAO levels, but when antibiotics are removed, TMAO returns to higher levels, showing bacteria are directly involved with TMAO metabolism [97]. Research on the potential role of TMAO in CVD and diabetes across various ethnic and racial groups in the U.S., including SAs, is lacking.

Conclusions

Several themes and research priorities emerged as a result of the literature review process, the working group meetings, the in-person convening, and the community-academic town halls. As a whole, the available literature on inflammation, infection, exposure, and the human microbiome in relation to CVD and cancer risk among U.S. SAs (including subsequent diasporic generations) is limited. However, relevant preliminary findings and research conducted in South Asia and non-U.S. SA diasporic countries can inform future studies in the U.S.

Related to the topic of arsenic, recommended next steps include conducting more research on arsenic exposure (through hair or nail assessments) among U.S. SA immigrant populations. Special attention should be given to immigrants from Bangladesh, one of the most arsenic-contaminated regions in the world [1], because the detrimental effects of arsenic exposure in their homeland may carry over to their communities in the U.S. There are few studies on the long-term health effects of prior low to moderate levels of arsenic exposure among Bangladeshi immigrants in the U.S.

More studies also need to be done to further investigate the association between high levels of arsenic exposure and various cancers and CVD, especially among SAs in the U.S. Arsenic toxicity has been linked to CVD and cancer among SAs in their countries of origin, indicating that these risks are likely to apply to SAs in the U.S. as well. Future studies should also evaluate methods to mitigate risk among exposed SA populations. A likely source of arsenic exposure for SAs in the U.S. is rice, a usual staple of the SA diet that can be contaminated by arsenic-containing irrigation water [5]. More research should be conducted to evaluate arsenic levels in different brands of rice, both domestic and imported from South Asia.

Along with arsenic exposure, particulate matter (PM) exposure has also emerged as a serious health concern for certain SA groups in both the U.S. and their countries of origin. More research is needed on the health effects of air pollution, specifically PM exposure, among at-risk SA occupational groups, including taxi drivers, gas attendants, and restaurant workers, in the U.S. Next steps for future research should include: 1) quantifying levels of particulate matter exposure among taxi drivers and other at-risk occupational groups in the U.S; 2) gaining a better understanding of the relationship between PM/air pollution and inflammation, CVD, and cancer, as well as the contribution of oil fumes, among SA at-risk occupational groups; 3) assessing the potential of hybrid cars and/or air filters as an intervention to decrease PM exposure among taxi drivers; and 4) assessing residual risk in immigrants who had cooking stove exposures in their countries of origin.

The leading cause of cervical cancer, the Human Papilloma Virus (HPV), is another area where research is lacking among U.S. SA populations. The epidemiology of HPV-related infections and cancers, including cervical and of the upper aerodigestive tract, among both SA men and women in the U.S. is unknown. Studies from other SA diasporic countries, such as the United Kingdom, shed light on cultural barriers to HPV preventative care that may also be relevant among SA immigrants in the U.S. More research is needed on HPV screening rates and barriers to screening among U.S. SA women. The effectiveness of existing HPV vaccination programs should be evaluated as they relate to SAs, and educational outreach for girls and women about HPV transmission and cervical cancer testing should be considered as an intervention to increase HPV screening. Further, the potential link between HPV and oropharyngeal cancers among SAs in the U.S. should be further explored, particularly in the context of the influence of the microbiota and changes in the microbiota that may occur with migration.

Recent research shows that Hepatitis B and C infection remain significant health concerns for SAs in the U.S., despite the generally low prevalence nationwide. More research is needed to better understand the epidemiology of Hepatitis B and C in SAs in the U.S. and to implement surveillance, outreach, screening, and treatment interventions accordingly. Treatment outcomes among SAs also need to be further studied.

There is little literature on the microflora of the SA community, yet scientific studies have found associations between microbiota and the development of CVD, diabetes and common cancers. More research is needed to define the microbial compositions of SAs, to catalogue the associations between microbiota and common cancers and CVD risk among SAs, and to develop therapies and interventions that can mitigate the potentially harmful effects of microbiome imbalances.

A South Asian cohort study assessing infections, exposures, the microbiota, and biomarkers of inflammation, and the impact of these various factors on both CVD and cancer risk over time would be a significant next step in further elucidating this area of study. Further, intervention studies should be undertaken that examine the impact of changes in diet, lifestyle, and behavior (see “Cardiovascular Disease & Cancer Risk Among South Asians: Impact of Sociocultural Influcences on Lifestyle and Behavior” by Kandula N. et al. published in the Journal of Immigrant and Minority Health for a full discussion of lifestyle and behavior) on the microbiota as well as on exposures, and the resultant effect on modulating risk for CVD and cancer.