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In the foregut hypothesis, exclusion of duodenal nutrient exposure is proposed to inhibit release of an unknown diabetogenic factor. This hypothesis is supported by several studies that have focused on duodenal bypass as being responsible for the weight loss-independent benefits immediately after RYGB Korner et al. On the other hand, the hindgut hypothesis posits that rapid delivery of nutrients to the distal intestine causes greater stimulation of L-cells and GLP-1 release, augmenting meal-stimulated insulin secretion and lowering prandial blood glucose.

We Isbell et al. Intriguingly, the increased GLP-1 at one month post-operative coincides with significant increases in total bile acids Albaugh et al. As the complex physiology of metabolism and body weight regulation is increasingly appreciated, contributions of both the foregut and hindgut hypotheses are likely at work in these patients and experimental models, though the search for a particular factor linking each of these hypotheses continues to be sought.

In this regard, bile acids appear to be uniquely suited to mediate a number of other metabolic changes in animals and humans that have been described following bariatric surgery. In recent years, bile acids have been implicated as potential mediators of the weight-independent effects of bariatric surgery with respect to glucose homeostasis and insulin sensitivity.

The mechanisms leading to these effects are currently of great interest and thus it is important to understand how bile acid metabolism and the enterohepatic circulation may be affected by bariatric operations. Both of these pathways include combinations of enzymatic conversions that modify a sterol backbone as well as the hydrocarbon side chain of cholesterol. Alternatively, cholesterol can be acted upon by sterol hydroxylase CYP27A1 that catalyzes the first committed reaction in the alternate pathway, which is highly expressed in peripheral tissues and macrophages Schwarz et al.

Both the classic and alternate pathways funnel into the two major precursors of human bile acid synthesis. The composition of the bile acid pool as well as the major primary bile acid species, can vary greatly among animal species. This is particularly important when studying the effects of animal models of bariatric operations and attempting to translate those results back to clinical medicine. The muricholic bile acids, which do not exist in humans, result from CDCA being additionally hydroxylated on the 6-position of the sterol backbone.

Aside from marked difference in primary bile acids, it is also noteworthy that the alternate pathway contributes to a much larger portion of the bile acid biosynthesis in rodents compared to humans Russell, Moreover, in many studies examining changes in bile acids following bariatric surgery, bile acids are lumped into broad categories e.

Newly synthesized bile acids are referred to as primary bile acids, while those same primary bile acids can be conjugated with either glycine or taurine in humans and can be referred to collectively as conjugated bile acids. Bile acids that have been chemically transformed by bacteria are referred to as secondary bile acids.

Differences in bile acid chemical structures can also lead to variation in the biologic effects that are intrinsic to each bile acid. The number and position of hydroxyl groups predominately determines the hydrophilic index of bile acids and this index differs greatly among individuals depending on disease phenotype Haeusler et al. Hydrophobic bile acids e. LCA have been shown to be cytotoxic and have been linked to a number of GI tract malignancies Ajouz et al. On the other hand, hydrophilic bile acids have been shown to have cytoprotective properties Amaral et al.

Gut microbiota metabolize nutrients and bile acids within the gastrointestinal tract, significantly affecting the intestinal environment. Bacterial transformation of bile acids is another factor that may be altered by bariatric surgery. This chemical transformation has been proposed to serve at least two purposes.

Bile acids also have intrinsic antimicrobial properties. Typically, bacteria can chemically transform the bacterially-toxic hydrophobic bile acids to less toxic species by a number of reactions. These reactions include deconjugation, oxidation, sulfation, and dehydroxylation generating secondary bile acids: deoxycholic acid DCA and lithocholic acid LCA Staels and Fonseca, Sulfation is the major detoxification pathway for hydrophobic bile acids Chiang, Without bacterial transformation there is a lack of bile acid diversity, as has been demonstrated in germ free mice Midtvedt, ; Ridlon et al.

Thus, it is clear that, microbiome-induced changes in bile acid diversity represent potential mechanisms linking bariatric surgery, bile acids, and metabolic improvements Kaska et al. Li et al. The discovery that bile acids could act as receptor ligands opened up a completely new field of biochemistry and biologic regulation Makishima et al. Bile acids play significant roles in lipid and glucose homeostasis Cariou and Staels, ; Jiao et al. Zhang et al. These metabolic effects have been linked to the primary bile acid receptor FXR Claudel et al.

FXR regulates bile acid synthesis Fu et al. Bile acid-FXR activation stimulates glycogen synthesis Li et al. In fact, transgenic mice overexpressing CYP7A1 in the liver were found to be resistant to high-fat diet HFD -induced obesity and to the development of fatty liver and insulin resistance T. Interestingly, the use of bile acid sequestrants e. TGR5 is not expressed in hepatocytes, but is localized to sinusoidal endothelial cells Keitel et al. Through kinase signaling pathways, TGR5 activation stimulates gallbladder filling T.

Metabolic activation of specific bile acid receptors, particularly involving FXR, vary with bile acid species. In contrast, FXR agonists decrease energy expenditure EE and induce obesity and insulin resistance in mice Watanabe et al. FXR is highly expressed in the liver and intestine and when bound to bile acids, activates complex transcription program to inhibit expression of Cyp7A1 and epithelial transport proteins that control the enterohepatic bile circulation Chiang, , ; Stroeve et al.

After bile acids are synthesized within the liver they are secreted into the biliary circulation, subsequently stored in gallbladder, and then eventually released into the duodenal lumen of the intestine in response to dietary intake Thomas et al. Bile is an electrolyte fluid enriched in bile acids, phospholipids lecithin , bilirubin and cholesterol, which facilitates the emulsification of dietary fat.

Bile acids are absorbed through both passive and active mechanisms in the small intestine Dawson et al. Passive bile acid absorption occurs throughout the length of intestinal lumen, but active transport of bile acids exclusively occurs in the ileum Einar Krag, ; Schiff et al.

Most bile acids are reabsorbed actively in the distal ileum by brush border apical sodium-dependent bile acid transporter ASBT and multi-drug resistance-associated protein 3 MRP3 Dawson et al. Bile acids that escape ileal uptake enter the colon, where commensal gut bacteria deconjugate, oxidize, and dehydroxylate primary bile acids into secondary bile acids. Several studies have examined how bile acid chemical species diversity and pool size vary across species, however, differences that specifically result from bariatric surgery or other intestinal manipulation have not been well studied.

Regardless, significant decreases in bile acid pool size likely exist among animal species, especially in mammals that lack a gallbladder e. Surgical removal of the gallbladder cholecystectomy in humans does not change the overall bile acid pool composition, but pool size is decreased Berr et al.

The decrease in pool size is attributed to the lack of the gallbladder, which is the major storage site in human and also due feedback inhibition of bile acid synthesis mediated through FXR-mediated inhibition of CYP7A1 in the classic synthetic pathway Kullak Ublick et al. Additionally, intestinal transit time may also affect the enterohepatic circulation and subsequently bile acid composition Duane, ; Duane et al.

Further, the changes in transit time may also influence the gut microbiome that accompany bariatric operations and alter bile acid diversity Fiorucci and Distrutti, ; Furet et al.

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The links among bile acids, energy expenditure Broeders et al. Several factors related to obesity, insulin sensitivity, diet and diet composition may impact bile acid homeostasis independent of bariatric surgery, and those factors are not currently well understood. It is clear from the literature that there are fundamental differences in bile acid metabolism regulated by total body adiposity between lean and obese individuals independent of insulin resistance. Several groups have shown decreased circulating concentrations of bile acids in obesity relative to leans Albaugh et al. Given that obesity and insulin resistance are generally highly correlated, this apparent disconnect between bile acid concentrations and body mass is paradoxical.

Further complicating the study of these phenomena in obesity are the confounders of age and sex Prinz et al.


Moreover, longitudinal data has actually showed that weight loss leads to lower bile acid concentrations in the plasma. Thus, it is clear that the metabolic abnormalities associated with obesity, insulin resistance and T2D exist on a spectrum and are not necessarily independent of one another, and may be a function of altered enterohepatic bile acid circulation Haeusler et al. Better understanding of the molecular basis for these improvements is an area of intense research Wewalka et al.

It is well-known from animal studies that high concentrations of glucose and insulin stimulate the expression of CYP7A1, the rate-limiting step of bile acid synthesis, to increase the bile acid pool T. Consistent with elevations in glucose, urinary bile acids that represent spill-over from the enterohepatic circulation to the periphery are associated with higher HgbA1c D. Taylor et al. Hepatic expression of the bile salt export bump BSEP as well as the sodium-taurocholate co-transporting polypeptide is also decreased in obese relative to lean subjects, Haeusler et al.

Caloric restriction and altered dietary composition are two factors that contribute to at least some of the metabolic improvements following bariatric surgery. While caloric restriction does not appear to affect bile acid pool size or composition in man Duane et al. Diet is known to induce changes in bile acid species and total bile acid pool Bisschop et al.

Finally, it is important to take into consideration the species differences while extrapolating differences between humans and rodents where changes in bile acid composition and concentration have been reported Ferland et al. The identification of bile acids as metabolic mediators has motivated some to pursue interventional studies examining potential off-target effects, but the number of those studies has been few.

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One interventional study showed that 6 weeks of oral tauro-ursodeoxycholic acid, a bile acid that has been shown to be elevated early after RYGB Albaugh et al. Over the last decade numerous clinical studies have reported changes in bile acids associated with bariatric surgery procedures Table 1. In large part, human studies have confirmed that fasting or postprandial total bile acid concentrations are increased following RYGB Ahmad et al.

The effects of VSG on bile acid levels is mixed with some showing increased plasma concentrations Jahansouz et al. As expected, studies examining adjustable gastric banding, known to be an exclusively restrictive procedure, show no changes in circulating bile acids Kohli et al. While most studies report a preoperative and then a single postoperative time point for comparison Coupaye et al.

These longitudinal studies, with repeated measures over time, have demonstrated that there are considerable fluctuations in plasma bile acids that may have biologic effects, the mechanisms of which have not yet been determined. In response to dietary fat, bile acids produced by the liver are released from the gallbladder into the lumen of the intestine.

Commensal gut bacteria deconjugate bile acids which are reabsorbed in the terminal ileum. In obese subjects prior to surgery circulating bile acid levels and insulin sensitivity are reduced compared to lean controls. In response to bile acid absorption and activation of the nuclear receptor FXR, fibroblast growth factor 19 FGF19 is released into portal circulation where it acts on the liver to inhibit bile acid synthesis.

Bile acids also stimulate the release of GLP-1 or GLP-2, hormones that act in an endocrine fashion to modulate insulin release and lipid absorption, respectively. The more rapid and enhanced delivery of bile acids to the terminal ileum is associated with improved glucose handling, enhanced energy expenditure in the periphery and altered gut microflora. Given the increased appreciation for the endocrine effects of bile acids, much research over the last decade has focused on describing the potential mechanism involved in the influence of bile acids on the overall metabolic improvements associated with bariatric surgical operations.

Early studies demonstrated that GI rearrangement or diversion of GI secretions was associated with changes in glucose homeostasis Ermini et al. Subsequent studies also noted that increased exposure of the distal intestine to proximal GI secretions enhanced bile acid absorption Tsuchiya et al. As mentioned above, the relevance of bile acids to the metabolic improvements after bariatric procedures was not fully appreciated until bile acids were recognized as endogenous hormones. Subsequently, a cross-sectional study demonstrated that individuals who had previously had RYGB had increased circulating concentrations of bile acids compared to weight-matched individuals Patti et al.

Regardless of what has been demonstrated clinically, no studies to date have shown unequivocally that changes in bile acid metabolism are necessary or sufficient for the metabolic benefits of bariatric surgery. Experimental models of metabolic and bariatric operations that have been developed over the last decade have provided a wealth of data on the mechanisms of these operations Table 2. The VSG and ileal interposition procedures have been most studied in rats and mice, given that they are technically simpler than the RYGB and bile diversion operations.

Similar to what is observed clinically, VSG increases total bile acids in rats B. One of the advantages of rodent models is the ability to isolate a particular portion of the bariatric operation in order to ask focused, hypothesis-driven questions. Ileal transposition, a procedure that interposes a segment of the distal ileum in a more proximal jejunal position, has been shown to improve insulin sensitivity and glucose tolerance Culnan et al.

Similar to the observed findings with ileal interposition, bile diversion operations Flynn et al. It is clear that the major common theme amongst these exploratory procedures — bile diversion, ileal interposition, and duodenal-jejunal bypass — is a paradoxical elevation of plasma bile acids. The mechanisms of why these animal models increase plasma bile acids remains unclear. In our recent publication Flynn et al. This area requires intense investigation, and may require examination of the various pathways involved in bile acid clearance, or even examining the involvement of the microbiome in influencing bile acid homeostasis.

In this regard, fecal bile acids have been reported as either decreased Kohli et al. Numerous studies have examined the kinetics of bile acid homeostasis, including the contributions of hepatic synthesis and clearance through fecal and urinary losses. Isotopic dilution techniques have been described in vivo Everson, ; Hulzebos et al. As bile acids have become recognized as receptor ligands, however, few studies have examined the impact of tissue accumulation of bile acids on the ensuing metabolic effects Swann et al.

Tissue specific changes in both receptors, FXR Ryan et al. However, receptor-knock out studies have failed to completely abrogate all the beneficial metabolic effects of bariatric surgery. Further studies of tissue-specific and whole-body knockout mice are necessary to understand which receptors drive specific metabolic effects on food intake, taste preference, glucose and lipid metabolism.

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As mentioned above, though, confirmatory human studies are necessary in any of these cases as rodent and human physiology differ significantly. There are a number of caveats to the experimental models of bariatric surgery that must be considered when attempting to translate the findings to humans. One of the most disputed areas relates to the discrepancies between the observed increased energy expenditure EE with RYGB in rodents Bueter et al. Our recent findings of similar observed increases in EE in mice following bile diversion Flynn et al.

The bile acid-induced increases in EE in mice are mediated by activation of brown adipose tissue deiodinase enzyme expression in both rodents Watanabe et al. Exogenous administration of chenodeoxycholic acid CDCA to 12 healthy female subjects for two days resulted in increased oxygen consumption and EE Broeders et al. Regardless, the bile acid induced changes in EE do not appear to play a significant role following bariatric surgical procedures in humans Carey et al.

A second factor that differs substantially between rodents and humans post-bariatric procedures relates to the degree of segmental intestinal partitioning of nutrient handling and their involvement in the metabolic improvements associated with bariatric surgery. The separation of bile and pancreatic secretions from enteral nutrient flow is associated with significant changes in intestinal reprogramming of nutrient handling. Stylopoulos et al. Interestingly, recent studies by Baud et al, demonstrated negligible glucose absorption in the bile-deprived alimentary limb AL ; glucose uptake in the AL was restored by the addition of bile Baud et al.

Despite these observations, there is concordance of observations demonstrating significant macronutrient malabsorption, primarily involving lipids, with RYGB and bile diversion in mice Flynn et al. No studies have yet addressed the effects of specific intestinal segment specific re-organization on fatty acid absorption in RYGB.

This may help explain the apparent bile acid-mediated stimulation of GLP-1 secretion in humans and rodents, when increasing the luminal bile acid concentration with bile acid sequestrants Beysen et al. Once believed to be apically-expressed, the location of TGR5 within the intestine has been disputed and has been suggested to be present on the basolateral membrane Brighton et al. Another important factor relates to intestinal villous hypertrophy, commonly observed in numerous rodent models of RYGB le Roux et al.

Similar findings of hypertrophy in the small intestines were previously described in bariatric patients Dudrick et al. While the mechanisms underlying these changes remain unknown, several studies have suggested a role for exposure to undigested food as a potential mechanism that is associated with increased EEC cell function le Roux et al. There are a number of physiologic and molecular processes that are altered by bariatric surgery that are associated with concomitant significant elevations of circulating bile acids.

Whether all these processes are being driven, or potentially modified, by bile acids is unknown, but this area of study remains ripe for identifying novel and better therapies for obesity and diabetes. Light Surgical Research Laboratory for advice and expertise. Disclosure Statement: The authors have nothing to disclose. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.

The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. National Center for Biotechnology Information , U. Mol Aspects Med. Author manuscript; available in PMC Aug 1. Vance L. Abumrad , 1 and Charles R. Naji N. Charles R. Author information Copyright and License information Disclaimer. Copyright notice. The publisher's final edited version of this article is available at Mol Aspects Med.

See other articles in PMC that cite the published article. Abstract Bariatric surgery, specifically Roux-en-Y gastric bypass RYGB and vertical sleeve gastrectomy VSG , are the most effective and durable treatments for morbid obesity and potentially a viable treatment for type 2 diabetes T2D. Introduction — The Obesity Epidemic The prevalence of obesity has continued to increase over the past 30 years and is associated with increased risk of numerous comorbid medical conditions, including insulin resistance, type 2 diabetes T2D , and cardiovascular disease.

Open in a separate window. Figure 1. Figure 2. What are the Mechanisms behind the Effectiveness of Bariatric Surgery? Weight Independent Numerous investigators have examined the short- and long-term changes after bariatric surgery. Figure 3. Body mass index and insulin resistance improve after bariatric surgery, but not at the same rate Representative data from bariatric surgical patients that have undergone Roux-en-Y gastric bypass over time. Bile Acids In recent years, bile acids have been implicated as potential mediators of the weight-independent effects of bariatric surgery with respect to glucose homeostasis and insulin sensitivity.

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Bile Acids and Obesity The links among bile acids, energy expenditure Broeders et al. Figure 4. Changes in bile acid enterohepatic circulation and metabolism after bariatric procedures In response to dietary fat, bile acids produced by the liver are released from the gallbladder into the lumen of the intestine. Table 1 Studies describing changes in plasma bile acids after bariatric procedures in humans. Fasting, Post-prandial Increased fasting and augmented prandial response Khan et al.

Fasting Minimal to no changes in bile acids, but decreased synthesis via surrogate marker Escalona et al. Post-prandial Increased rise in postprandial, only a trend for increased fasting Schmidt et al. Post-prandial Increased fasting, earlier postprandial rise De Giorgi et al.

Fasting Total increased Jansen et al. Table 2 Studies describing changes in plasma bile acids after bariatric procedures in rodents. Fasting Increased total, conjugated and unconjugated Ding et al. Fasting Increased total and conjugated Wu et al. Fasting Increased total Pierre et al. Fasting Increased total in both operations X.

Fasting Increased total, and some conjugated, and unconjugated Mencarelli et al. Fasting Increased total and conjugated B. Fasting No change in total trend for increase Ikezawa et al. Fasting Increased total Kohli et al. Fasting Increased total B. Fasting Increased total 3-fold elevation Strader et al.

Observations and Caveats from Experimental Models There are a number of caveats to the experimental models of bariatric surgery that must be considered when attempting to translate the findings to humans. Footnotes Disclosure Statement: The authors have nothing to disclose. Fischers Mastery of Surgery. Metabolic and Inflammatory Responses to Trauma and Infection; pp. Cancer and Obesity: Effect of Bariatric Surgery. World Journal of Surgery. Roux-en-Y gastric bypass normalizes the blunted postprandial bile acid excursion associated with obesity.

Int J Obes Lond ; 37 — Secondary bile acids: an underrecognized cause of colon cancer. World Journal of Surgical Oncology. J Clin Endocrinol Metab.

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Bile acids: regulation of apoptosis by ursodeoxycholic acid. J Lipid Res. Influence of fat-rich versus carbohydrate-rich diets on bile acid kinetics, biliary lipids, and net steroid balance in hyperlipidemic subjects. Altered bile acid profiles in duodenal bile and urine in diabetic subjects. Eur J Clin Invest. Obes Surg. Metabolic surgery and cancer. Bile acids in the colon, from healthy to cytotoxic molecules. Toxicol In Vitro. Cell Metabolism. Effects of cholecystectomy on the kinetics of primary and secondary bile acids. J Clin Invest. Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study.

Effect of Roux-en-Y gastric bypass surgery on bile acid metabolism in normal and obese diabetic rats. Low-fat, high-carbohydrate and high-fat, low-carbohydrate diets decrease primary bile acid synthesis in humans.

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Am J Clin Nutr. Effect of degree of weight loss on health benefits. Obes Res. Weight loss and incretin responsiveness improve glucose control independently after gastric bypass surgery. Journal of Diabetes. Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes. Nat Med. Bariatric surgery: a systematic review and meta-analysis. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. The American Journal of Medicine. Body composition and metabolic changes following bariatric surgery: effects on fat mass, lean mass and basal metabolic rate: six months to one-year follow-up.

Fasting plasma chenodeoxycholic acid and cholic acid concentrations are inversely correlated with insulin sensitivity in adults. FXR: a promising target for the metabolic syndrome? Trends in Pharmacological Sciences. The effect of bariatric surgery on intestinal absorption and transit time. Diabetes Care. Bile acid metabolism and signaling. Compr Physiol. Bile acids: regulation of synthesis. The Journal of Lipid Research. Effect of dietary energy restriction on glucose production and substrate utilization in type 2 diabetes. Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat.

N Engl J Med. Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice. Journal of Biological Chemistry. The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. Bile acid transporters. Pleiotropic Roles of Bile Acids in Metabolism. Long-term effects of Roux-en-Y gastric bypass on postprandial plasma lipid and bile acids kinetics in female non diabetic subjects: A cross-sectional pilot study. Clin Nutr. Gut hormones, early dumping and resting energy expenditure in patients with good and poor weight loss response after Roux-en-Y gastric bypass.

Simulation of the defect of bile acid metabolism associated with cholesterol cholelithiasis by sorbitol ingestion in man. J Lab Clin Med. Effects of fasting on bile acid metabolism and biliary lipid composition in man. Gastrointestinal adaptation following small bowel bypass for obesity. Ann Surg. Hepatic and peripheral insulin sensitivity and diabetes remission at 1 month after Roux-en-Y gastric bypass surgery in patients randomized to omentectomy. Journal of Clinical Investigation. The effects of bilio-jejunal diversion on streptozotocin diabetes in the rat.

Acta Diabetol Lat. Bile acids synthesis decreases after laparoscopic sleeve gastrectomy. Surgery for Obesity and Related Diseases. Steady-state kinetics of serum bile acids in healthy human subjects: single and dual isotope techniques using stable isotopes and mass spectrometry. Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults. Effect of aging and dietary restriction on bile acid metabolism in rats. Annual medical spending attributable to obesity: payer-and service-specific estimates. Health Aff Millwood ; 28 :w— Trends in Molecular Medicine.

Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery. Nat Commun. Does bariatric surgery improve adipose tissue function? Obes Rev. Henty and W. Kingston — Marsh wrote and published prolifically during the s and the early years of the 20th century. He died from heart disease in Haywards Heath in Sussex on 9 August Several of his novels were published posthumously.

Marsh's greatest commercial success was one of his earlier novels, The Beetle A story about a mysterious oriental person who pursues a British politician to London, where he wreaks havoc with his powers of hypnosis and shape-shifting , Marsh's novel is similar in some respects to certain other novels of the same period, such as Bram Stoker 's Dracula , George du Maurier 's Trilby , and Sax Rohmer 's Fu Manchu novels. Like Dracula and many of the sensation novels pioneered by Wilkie Collins and others during the s, The Beetle is narrated from the perspectives of multiple characters, a technique used in many late 19th-century novels those of Wilkie Collins and Stoker, for example to create suspense.

In the s the novel's story was made into a film, and adapted for the London stage. In addition to The Beetle , Marsh had several other successes in the genre of horror. Particularly notable among these are The Goddess: A Demon , in which an Indian sacrificial idol comes to life with murderous intent, and The Joss: A Reversion , in which an Englishman transforms himself into a hideous oriental idol.

In The Datchet Diamonds a young man who has lost his fortune by the stock market accidentally swaps bags with a diamond thief, only then to find himself pursued by both the robbers and the police. Marsh blends crime with science fiction in A Spoiler of Men , the gentleman-criminal villain of which renders people slaves to his will by means of a chemical injection. Current scholarly research describes Marsh as a writer with a good sense of the literary market but who often transcended the ideological and aesthetic boundaries that his contemporaries established.

Marsh was also adept in the genre of short stories, publishing in literary periodicals such as Household Words , Cornhill Magazine , The Strand Magazine , and Belgravia , as well as in a number of book collections. The stories The Seen and the Unseen , Marvels and Mysteries , Both Sides of the Veil and Between the Dark and the Daylight all feature an eclectic mix of humour, crime, romance and the occult. He also published serial short stories, developing characters whose adventures could be related in discrete stories in numerous editions of a magazine.