Effects of Obesity and Weight-Loss Surgery Shift the Microbiome and Impact Alloimmune Responses

Abstract

Purpose of review

Obesity is a worldwide health problem with increasing rates in both children and adults. Bariatric surgery (BS) represents the only effective long-term treatment. Beneficial effects of BS may be mediated through shifts of the gut microbiome. Here, we introduce data linking the microbiome to alloimmune responses.

Recent findings

The rapid development of microbiome sequencing technologies in addition to the availability of gnotobiotic facilities have enabled mechanistic investigations on modulations of alloimmune responses through microbiomes. Bariatric Surgery has been shown to improve comorbidities and chronic inflammation caused by obesity. Changes of microbiota and microbiota-related metabolites may play a role. Patients either listed or having received a transplant have undergone weight loss surgery, thus allowing to dissect mechanisms of microbial shifts to alloimmunity.

Summary

Weight loss and bariatric surgery have the potential to improve transplant outcomes by ameliorating alloimmune responses. Those effects may be carried out through alterations of the gut microbiome.

Introduction

Obesity has become a worldwide health problem with a rising incidence. Bariatric surgery (BS) induces rapid and durable weight loss while improving or resolving many obesity associated co-morbidities including cardiovascular diseases, type 2 diabetes mellitus, and non-alcoholic steatohepatitis [1]. Effects contributing to weight loss and metabolic improvements following BS are broad and include altered eating behavior, changes in energy metabolism and the absorption of nutrients, hormonal alterations, effects on bile acids, in addition to modifications of the gut microbiome.

Evidence has accumulated that the gut microbiota is an important environmental factor contributing to obesity by altering host energy extraction and storage [2-6]. Obesity, at the same time, has been associated with an altered composition of gut microbiota, compromised microbial- and genetic diversity [7,8]. Weight-loss interventions subsequent to BS have been shown to partially reverse obesity-associated microbial and metabolic alterations, suggesting the gut microbiome as a potential target for weight loss or metabolic interventions [9].

Microbial communities are important in protecting the host against pathogens [10,11]. Gut microbiota also play a role in the maturation of the host’s immune system through effects on the architecture of secondary lymphoid organs and the differentiation of innate and adaptive immune cells. There is also accumulating evidence suggesting that the gut microbiota can influence alloimmune responses [12-14]. Here, we summarize currently available data on BS-induced gut microbiome shifts and implications on organ transplantation (Figure 1).

Figure 1.

Obesity alters the microbiota. Bariatric surgery (BS) facilitates the listing of obese patients while improving outcomes after transplantation. BS also alters the gut microbiota, affecting alloimmune responses. Mechanisms proofing the causality between changes of the microbiome and altered alloimmune responses need to be detailed in further studies.

Bariatric surgery induced shifts of the gut microbiome

The most commonly performed bariatric surgery procedures include Roux-en-Y gastric bypass (RYGB), adjustable gastric banding (AGB) and sleeve gastrostomies (SG) [15]. Gut microbiota dysbiosis is increasingly recognized as an important consequence of obesity affecting the metabolic syndrome. The gut microbiome is a microbial ecosystem that is fragile and easily disturbed [16]. BS-induced weight loss, at the same time, is associated with alterations of the gut microbiome characterized by an augmented microbial gene diversity [17]. Microbiome changes have also been weight loss surgery specific and more pronounced after RYGB compared to AGB [18].

Ameta-analysis has shown an increase in Bacteroides and Proteobacteria and a decrease in Firmicutes subsequent to weight loss surgery [19]. In animal models, Akkermansia muciniphila increased after BS [20,21]. A clinical study, using linear mixed models and machine learning approaches, observed strikingly similar profiles of gut microbiota sequence data in both fecal microbiota composition and metabolic pathways ofpatients undergoing RYGB. Across multiple datasets, increasing amounts of Veillonella, Streptococcus, Gemella, Fusobacterium, Escherichia/Shigella, and Akkermansia have been detected while frequencies of Blautia had decreased [22].

Of note, fecal microbiota transplantation (FMT) from mice that underwent RYGB into naive germ-free mice resulted in weight loss [23], suggesting that the effects of BS had, at least in part, been caused by changes of the gut microbiome. In keeping with this observation, RYGB caused long-lasting effects on the composition and functional capacity of the human gut microbiota [24]. The same study also confirmed that germ-free mice colonized with stool from patients that underwent bariatric surgery altered microbiota promoted weight loss in recipient mice [24]. Importantly, antibiotic-mediated disruption of the intestinal microbiota greatly reduced the effectiveness of SG in experimental models [25]. These findings indicate a causal relationship between microbial alterations following gastric bypass surgery and weight reduction.

Although the role of gut microbiota and the beneficial effects of BS have been established, underlying mechanisms are not fully understood. Despite significantly improved metabolic comorbidities and weight loss, microbial gene richness was only partially rescued in selected patients post-BS [17].

Proteobacteria have proinflammatory capacitates [7] and are considered as a hallmark of gut microbiota dysbiosis [26]. Notably, BS reduces the frequency of Proteobacteria. Thus, future research is necessary to understand how the altered gut microbial activity after BS improves host metabolism and modulates alloimmunity. It is important to point out that other weight-loss interventions including caloric restriction can also impact gut bacterial abundance while restructure the gut microbiome [27].

Gut microbiome and Immune response

The microbiota ecosystem plays an important role in preventing pathogenic microbe colonization while aiding in the synthesis of vitamin K and the absorption of dietary lipid. Moreover, the system helps shaping local and systemic immune responses. Both, germ-free mice and those treated with antibiotics had reduced numbers of lacteals, blunt-ending, lymphatic-like structures located in the center of intestinal villi. Conventionalization of germ-free mice, on the other hand, restored lacteal maturation and integrity [28]. When germ-free mice had been colonized with Bacteroides fragilis, lymphoid organogenesis had been promoted while systemic T cell deficiencies and imbalances had been corrected [29]. Intestinal segmented filamentous bacterium (SFB) is known to confer resistance to the pathogenic Citrobacter rodentium [30], but has also been shown to promote T cell-dependent IgA responses. SFB has also been shown to contribute to Th1 and Th17 differentiation, promoting rheumatoid arthritis [30-32]. In addition, the gut microbiota may also help generating alloreactive memory T cells that mount critical responses during gastrointestinal infection [33]. There is also a link between the gut microbiota in supporting the development and maturation of mucosal and systemic natural killer T cells (NKTs) [34] In addition to lymphoid structures [35].

While several studies have shown that the modulation of gut microbiota impacts both, local and systemic immune responses [36-39], outstanding questions remain as to how gut-resident bacteria can impact immune responses at locations away from the gut. Moreover, further studies are required to delineate mechanisms that link microbial products or metabolites to immune cell migration or immune signal production.

The impact of microbiome on alloimmunity and transplant outcome

Taxonomic changes in the microbiome have been associated with acute and chronic rejection after organ transplantation [40-43]. Oral antibiotic treatment of donors and recipients prior to transplantation or transplants in germ-free mice prolonged skin and cardiac graft survival [37]. It has also been reported that alterations in gut microbiota by antibiotic pretreatment may improve lung transplant outcomes, characterized by reduced air way remodeling and fibrosis in experimental models [44]. Antibiotic pretreatment in mouse liver transplant recipients attenuates hepatic ischemia-reperfusion injury (IRI) and suppresses inflammatory responses, involving reduced endoplasmic reticulum stress and enhanced autophagy signaling. Moreover, clinical liver transplant recipients treated with antibiotics had an improved hepatocellular function and decreased incidence of early allograft dysfunction [45]. These studies demonstrate the capacity of microbiota in accelerating transplant rejection while demonstrating that certain microbial communities can affect transplant outcomes specifically.

In a clinical study, the intestinal microbiota of 12 patients has been prospectively analyzed prior and sequentially after liver transplantation. Those data have shown that patients with an infection had a substantial decrease of intestinal microbial diversity correlating with increased amounts of Bifidobacterium dentium [46]. A link between acute rejections has also been observed in clinical small bowel transplants with significantly reduced amounts of phylum Firmicutes and Lactobacillales while counts of phylum Proteobacteria, especially of the Enterobacteriaceae family were observed [40]. Likewise, kidney transplants recipients demonstrated a relative abundance of Proteobacteria in fecal specimens post-transplantation. Burkholderia, Corynebacterium and Staphylococcus were enriched, whereas anaerobes and normal oropharyngeal flora were less abundant during infection and inflammation in lung transplant recipients [47]. In both, murine and human recipients of allogeneic bone marrow transplantation (BMT), intestinal inflammation secondary to graft-versus-host disease (GVHD) has been associated with major shifts in the composition of the intestinal microbiota. Moreover, eliminating Lactobacillales from the flora of mice prior to BMT aggravated GVHD. In contrast, when reintroduced, Lactobacillus protected against GVHD [48]. Interestingly, the presence of Bifidobacterium pseudolongum correlated with the prolongation of graft survival while the oral administration of the same strain ameliorated cardiac allograft inflammation and fibrosis associated with lymph node structure remodeling [49]. While many of those studies are descriptive, they present the theoretical potential of modifying alloimmune responses through the administration of pro-or antibiotics.

Bariatric Surgery and Organ transplantation

Obesity is commonly associated with co-morbidities including cardiovascular- (coronary artery disease, atherosclerosis, hypertension), renal diseases (chronic kidney disease, immunoglobulin A nephritis), type 2 diabetes, and non-alcoholic steatohepatitis (NASH), conditions that can, in turn, promote end-stage organ failure. Approximately 30% of kidney transplant candidates and recipients in the US are obese [50]. The global prevalence of obesity among NASH patients was 81% [51]. In 2019, NASH was the second leading indication for liver transplantation in the US [52]. Obesity and associated comorbidities impact access to transplant, challenge surgical-technical aspects and compromise transplant outcomes. Body Mass Index (BMI) ≥35 kg/m² and BMI ≥40 kg/m² are generally considered relative and absolute contradictions by most transplant centers. BS has been shown to improve renal function while kidney transplant outcomes have improved [53], suggesting that weight loss surgery may ameliorate access to transplantation for morbidly obese candidates while enhancing transplant outcomes.

A systematic review and meta-analysis analyzing mortality and complications rates has detailed the efficacy and safety of BS in patients with end-stage kidney disease (ESKD). This analysis demonstrated an efficient and comparable weight loss in obese patients with and without ESKD. Of relevance, morbidity (7%) and mortality rates (2%) were higher than in the general population (morbidity rate 0.17% and mortality rate 0.18%) [54]. An additional retrospective single-center study showed a 90-day complication rate of 3% in the absence of mortality in CKD patients after sleeve gastrectomy (SG). Notably, 20 (63%) patients were subsequently listed for transplant while 14 (44%) underwent successful kidney transplantation in the year after SG [55]. These studies provide a rationale for morbidly obese patients to undergo bariatric surgery prior to transplantation.

Obesity may also occur in patients after transplantation linked to post-transplant diabetes with concurrent weight gain as a result of both corticosteroid therapy and the application of calcineurin inhibitors [56]. Transplant outcomes both, short-and long-term are significantly inferior in obese (BMI ≥ 30) recipients [57]. SG has provided effective weight loss in renal transplant recipients without adverse effects on graft function and immunosuppression [58]. Overall, BS (SG and Roux-en-Y gastric bypass) in transplant recipients with type 2 diabetes has been shown as safe with low rates of morbidity and mortality [59,60]. To our knowledge, BS-induced shifts of the gut microbiota and the impact on transplant outcomes have not been studied yet. Those investigations will be necessary to fully understand the mechanisms that BS sets in motion to improve transplant outcomes.

Microbiota and immunosuppression

Long-term antibiotics treatment is expected to affect microbiota composition. Of interest, a significant portion of drugs (24%) other than antibiotics inhibit the growth of at least one human gut bacterial strain [61]. Immunosuppressants have also been found to drive changes in the composition of the microbial community [62,63]. In view of the reported impact of gut microbial species on drug metabolism, fecal abundance of Faecalibacterium prausnitzii in renal transplant patients shortly after transplantation correlated with tacrolimus dosing early aftertransplantation, suggesting that the gut microbiota may impact tacrolimus drug absorption and/or metabolism[64].

It has previously been suggestedto develop strategies that control microbial communities through dietary interventions, anti- or probiotics. In animal models, it has been shown that high-salt diet or high-fat diet altered the microbiota whilepromoting graft rejection [65-68]. Fecal microbiota transplantation (FMT) represents a well-accepted strategy to treat recurrent Clostridium difficile infection-induced diarrhea [69]. Empiric third-party FMT after allogeneic hematopoietic cell transplantation appears to be feasible, safe, and associated with expansion of recipient microbiome diversity [70]. However, selection criteria for donors of FMT need to be carefully assessed as transfer of pathogens that have been asymptomatic in the donor may cause significant complications. Applying B. pseudolongum has been the only commensal so far that has been shown to improve transplant outcomes experimentally [49]. Clearly, detailed mechanistic in addition to translational studies are required to validate the therapeutic potential.

Conclusion

Alterations in the composition and activities of human gut microbiota have broad consequences. The impact of gut microbiota on transplant outcomes and alloimmunity has recently gained interest. While many relevant and interesting observations have become available, detailed mechanistic insights are needed to understand the complexity and to design efficient and safe treatments.