Visual omitted stimulus potentials are not retinotopic.

Omitted stimulus potentials (OSPs) are elicited in response to the omission of expected stimuli and are thought to reflect prediction errors. If prediction errors are signaled in the sensory cortex, OSPs are expected to be generated in the sensory cortex. The present study investigated the involvement of the early visual cortex in the generation of OSPs by testing whether omitted visual stimuli elicit brain responses in a spatially specific manner. Checkerboard pattern stimuli were presented alternately in the upper and lower visual fields, and the stimuli were omitted in 10 % of the trials. Event-related potentials were recorded from 33 participants. While a retinotopic C1 component was evoked by real visual stimuli, omitted stimuli did not produce any response reflecting retinotopy but did elicit a visual mismatch negativity, which was larger for omitted stimuli expected in the lower visual field than for those in the upper visual field. These results suggest that omitted visual stimuli are processed in a different pathway than actual stimuli.

Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis.

Inborn errors of bile acid metabolism (IEBAM) cause cholestasis during the neonatal period, and 8 types of IEBAM have been reported to date. IEBAM accounts for approximately 2% of cases of cholestasis of unknown cause. As only 10 patients have been identified in Japan, IEBAM presents diagnostic challenges due to the similarity of clinical symptoms with biliary atresia, thus necessitating precise differentiation to avoid unnecessary invasive procedures. Laboratory tests in IEBAM are characterized by normal γ-glutamyltransferase (GGT) and serum total bile acid (STBA) levels despite the presence of cholestasis; therefore, measuring STBA and GGT is essential to distinguishing biliary atresia from IEBAM. With suspected IEBAM, liquid chromatography-mass spectrometry (LC/MS) analysis of urinary bile acids is needed to optimize diagnostic and therapeutic efficacy and avoid open cholangiography and initiate treatment for primary bile acids such as cholic acid or chenodeoxycholic acid. This prospective report aims to increase awareness of IEBAM by highlighting the characteristics of general blood test and bile acid profiles from LC/MS analyses of blood, urine, and stool samples.

Rapid in vivo evaluation system for cholestasis-related genes in mice with humanized bile acid profiles.

BACKGROUND: Pediatric cholestatic liver diseases (Ped-CLD) comprise many ultrarare disorders with a genetic basis. Pharmacologic therapy for severe cases of Ped-CLD has not been established. Species differences in bile acid (BA) metabolism between humans and rodents contribute to the lack of phenocopy of patients with Ped-CLD in rodents and hinder the development of therapeutic strategies. We aimed to establish an efficient in vivo system to understand BA-related pathogenesis, such as Ped-CLD. METHODS: We generated mice that express spCas9 specifically in the liver (L-Cas9Tg/Tg [liver-specific Cas9Tg/Tg] mice) and designed recombinant adeno-associated virus serotype 8 encoding small-guide RNA (AAV8 sgRNA) targeting Abcc2, Abcb11, and Cyp2c70. In humans, ABCC2 and ABCB11 deficiencies cause constitutional hyperbilirubinemia and most severe Ped-CLD, respectively. Cyp2c70 encodes an enzyme responsible for the rodent-specific BA profile. Six-week-old L-Cas9Tg/Tg mice were injected with this AAV8 sgRNA and subjected to biochemical and histological analysis. RESULTS: Fourteen days after the injection with AAV8 sgRNA targeting Abcc2, L-Cas9Tg/Tg mice exhibited jaundice and phenocopied patients with ABCC2 deficiency. L-Cas9Tg/Tg mice injected with AAV8 sgRNA targeting Abcb11 showed hepatomegaly and cholestasis without histological evidence of liver injury. Compared to Abcb11 alone, simultaneous injection of AAV8 sgRNA for Abcb11 and Cyp2c70 humanized the BA profile and caused higher transaminase levels and parenchymal necrosis, resembling phenotypes with ABCB11 deficiency. CONCLUSIONS: This study provides proof of concept for efficient in vivo assessment of cholestasis-related genes in humanized bile acid profiles. Our platform offers a more time- and cost-effective alternative to conventional genetically engineered mice, increasing our understanding of BA-related pathogenesis such as Ped-CLD and expanding the potential for translational research.

Bile acid profiles in adult patients with biliary atresia who achieve native liver survival after portoenterostomy.

Bile acids have received increasing attention as a marker of the long-term prognosis and a potential therapeutic target in patients with biliary atresia, which is a progressive disease of the hepatobiliary system. A detailed analysis of serum and urinary bile acid compositions was conducted to assess the characteristics of bile acid profiles and the correlation between bile acid profiles and liver fibrosis markers in adult patients with biliary atresia who achieved bilirubin normalization. Serum total bile acids and glucuronide-conjugated (glyco- and tauro-) cholic acids (GCA and TCA) and chenodeoxycholic acids (GCDCA and TCDCA) were significantly higher in patients with biliary atresia than in healthy controls, whereas unconjugated CA and CDCA showed no significant difference. There were no significant differences in CA to CDCA ratios and glycine-to-taurine-conjugated ratios. Urinary glycocholic acid 3-sulfate (GCA-3S) was significantly higher in patients with biliary atresia. Serum GCDCA showed a strong positive correlation with Mac-2 binding protein glycosylation isomer (M2BPGi). These results demonstrate that bile acid congestion persists into adulthood in patients with biliary atresia, even after cholestasis has completely improved after Kasai portoenterostomy. These fundamental data on bile acid profiles also suggest the potential value of investigating bile acid profiles in patients with biliary atresia.

Effects of sensory modality and task relevance on omitted stimulus potentials.

Omitted stimulus potentials (OSPs) occur when a sensory stimulus is unexpectedly omitted. They are thought to reflect predictions about upcoming sensory events. The present study examined how OSPs differ across the sensory modalities of predicted stimuli. Twenty-nine university students were asked to press a mouse button at a regular interval of 1-2 s, which was immediately followed by either a visual or auditory stimulus in different blocks. The stimuli were sometimes omitted (p = 0.2), to which event-related potentials (ERPs) were recorded. The results showed that stimulus omissions in both modalities elicited ERP waveforms consisting of three components, oN1, oN2, and oP3. The peak latencies of these components were shorter in the auditory modality than in the visual modality. The amplitudes of OSPs were larger when participants were told that the omission indicated their poor performance (i.e., they pressed a button at an irregular interval) than when it was irrelevant to their performance. These findings suggest that OSPs occur from around 100 ms in a modality-specific manner and increase in amplitude depending on the task relevance of stimulus omissions.

Relationship between schematic and dynamic expectations of melodic patterns in music perception.

Prediction is fundamental in music listening. Two types of expectations have been proposed: schematic expectations, which arise from knowledge of tonal regularities (e.g., harmony and key) acquired through long-term plasticity and learning, and dynamic expectations, which arise from short-term regularity representations (e.g., rhythmic patterns and melodic contours) extracted from ongoing musical contexts. Although both expectations are indispensable in music listening, how they interact with each other in music prediction remains unclear. The present study examined the relationship between schematic and dynamic expectations in music processing using event-related potentials (ERPs). At the ending note of the melodies, the schematic expectation was violated by presenting a note with music-syntactic irregular (i.e., outof- key note), while the dynamic expectation was violated by presenting a contour deviant based on online statistical learning of melodic patterns. Schematic and dynamic expectations were manipulated to predict the same note. ERPs were recorded for the music-syntactic irregularity and the contour deviant, which occurred independently or simultaneously. The results showed that the music-syntactic irregularity elicited an early right anterior negativity (ERAN), reflecting the prediction error in the schematic expectation, while the contour deviant elicited a mismatch negativity (MMN), reflecting the prediction error in the dynamic expectation. Both components occurred within a similar latency range. Moreover, the ERP amplitude was multiplicatively increased when the irregularity and deviance occurred simultaneously. These findings suggest that schematic and dynamic expectations function concurrently in an interactive manner when both expectations predict the same note.

Effects of the cardiac cycle on auditory processing: A preregistered study on mismatch negativity.

The systolic and diastolic phases of the cardiac cycle are known to affect perception and cognition differently. Higher order processing tends to be facilitated at systole, whereas sensory processing of external stimuli tends to be impaired at systole compared to diastole. The current study aims to examine whether the cardiac cycle affects auditory deviance detection, as reflected in the mismatch negativity (MMN) of the event-related brain potential (ERP). We recorded the intensity deviance response to deviant tones (70 dB) presented among standard tones (60 or 80 dB, depending on blocks) and calculated the MMN by subtracting standard ERP waveforms from deviant ERP waveforms. We also assessed intensity-dependent N1 and P2 amplitude changes by subtracting ERPs elicited by soft standard tones (60 dB) from ERPs elicited by loud standard tones (80 dB). These subtraction methods were used to eliminate phase-locked cardiac-related electric artifacts that overlap auditory ERPs. The endogenous MMN was expected to be larger at systole, reflecting the facilitation of memory-based auditory deviance detection, whereas the exogenous N1 and P2 would be smaller at systole, reflecting impaired exteroceptive sensory processing. However, after the elimination of cardiac-related artifacts, there were no significant differences between systole and diastole in any ERP components. The intensity-dependent N1 and P2 amplitude changes were not obvious in either cardiac phase, probably because of the short interstimulus intervals. The lack of a cardiac phase effect on MMN amplitude suggests that preattentive auditory processing may not be affected by bodily signals from the heart.

Healthy Patients With AKR1D1 Mutation Not Requiring Primary Bile Acid Therapy: A Case Series.

Δ4-3-Oxosteroid 5ß-reductase (AKR1D1) deficiency typically causes severe cholestasis occurs in newborns, leading to death unless patients are treated with primary bile acids. However, we encountered an AKR1D1 deficiency patient treated with only ursodeoxycholic acid who had cholestasis until about 1 year of age but then grew up healthy without further treatment. We also have been following other healthy patients with AKR1D1 mutation who have never developed cholestasis and have not been treated. However, reports are few, involving 3 patients. To better understand and clinically manage a diverse group of patients with AKR1D1 mutation who do not develop potentially fatal cholestasis in the neonatal period, ongoing accumulation and study of informative cases is needed.

Dried blood spot-based newborn screening for bile acid synthesis disorders, Zellweger spectrum disorder, and Niemann-Pick type C1 by detection of bile acid metabolites.

OBJECTIVE: To examine whether it is possible to screen for bile acid synthesis disorders (BASDs) including peroxisome biogenesis disorder 1a (PBD1A) and Niemann-Pick type C1 (NPC1) at the time of newborn mass screening by measuring the intermediary metabolites of bile acid (BA) synthesis. METHODS: Patients with 3ß-hydroxy-ΔSuchy et al. (2021)5-C27-steroid dehydrogenase/isomerase (HSD3B7) deficiency (n = 2), 3-oxo-ΔPandak and Kakiyama (n.d.)4-steroid 5ß-reductase (SRD5B1) deficiency (n = 1), oxysterol 7α-hydroxylase (CYP7B1) deficiency (n = 1), PBD1A (n = 1), and NPC1 (n = 2) with available dried blood spot (DBS) samples collected in the neonatal period were included. DBSs from healthy neonates at 4 days of age (n = 1055) were also collected for the control. Disease specific BAs were measured by newly optimized liquid chromatography-tandem mass spectrometry with short run cycle (5-min/run). The results were validated by comparing with those obtained by the conventional condition with longer run cycle (76-min/run). RESULTS: In healthy specimens, taurocholic acid and cholic acid were the two major BAs which constituted approximately 80% in the measured BAs. The disease marker BAs presented <10%. In BASDs, the following BAs were determined for the disease specific markers: Glyco/tauro 3ß,7α,12α-trihydroxy-5-cholenoic acid 3-sulfate for HSD3B7 deficiency (>70%); glyco/tauro 7α,12α-dihydroxy-3-oxo-4-cholenoic acid for SRD5B1 deficiency (54%); tauro 3ß-hydroxy-5-cholenoic acid 3-sulfate for CYP7B1 deficiency (94%); 3α,7α,12α-trihydroxy-5ß-cholestanoic acid for PBD1A (78%); and tauro 3ß,7ß-dihydroxy-5-cholenoic acid 3-sulfate for NPC1 (26%). *The % in the parenthesis indicates the portion found in the patient's specimen. CONCLUSIONS: Early postnatal screening for BASDs, PBD1A and NPC1 is feasible with the described DBS-based method by measuring disease specific BAs. The present method is a quick and affordable test for screening for these inherited diseases.

Is two cuter than one? number and relationship effects on the feeling of kawaii toward social robots.

Kawaii, which is a Japanese word that means cute, lovely, and adorable, is an essential factor in promoting positive emotions in people. The characteristics of a target's appearance that induce such feelings of kawaii have been thoroughly investigated around the notion of Konrad Lorenz's famous baby schema. Such knowledge has been exploited to design the appearance of commercial products to increase their social acceptance and commercial appeal. However, the effects of the number of targets and showing their mutual relationships (like friendship) have not been investigated in the context of kawaii. Therefore, in this study, we conducted three web-based experiments and focused on how such factors contribute to feelings of kawaii toward social robots. In Experiment 1, the feelings of kawaii toward static images of targets were compared when they appeared alone or with another target: persons (twin boys/girls), non-human objects (cherries), and social robots. The results showed that the feeling of kawaii was stronger for two targets that displayed a mutual relationship (e.g., looking at each other and/or making physical contact) than for one target alone and for two-independent targets. In Experiment 2, these findings were replicated using video clips of robots. Two-related targets were rated as more kawaii than two-independent targets or a single target. These two experiments consistently show the advantage of multiple robots that display their mutual relationship for enhancing the viewer's feeling of kawaii. Experiment 3 examined the effect of the number of robots (from one to ten) and found that two robots induced the strongest feeling of kawaii. These results indicate that not only the physical characteristics of a target itself but also the number of targets and their perceived relationships affect feelings of kawaii.

Repeated response execution and inhibition alter subjective preferences but do not affect automatic approach and avoidance tendencies toward an object.

Background: Repeated action or inaction toward objects changes preferences for those objects. However, it remains unclear whether such training activates approach-avoidance motivation toward the objects, which leads to actual behavior. We conducted a pre-registered online experiment to examine whether approach and avoidance tendencies were affected by the experience of having executed or withheld a button-press response to a stimulus. Methods: Participants (N = 236) performed a Go/NoGo task in which they were asked to repeatedly execute a response to a picture of a mug (i.e., Go-primed stimulus) and suppress a response to another picture of a mug (i.e., NoGo-primed stimulus). They then received one of two manikin tasks, which were implicit association tests designed to assess approach-avoidance tendencies. One manikin task measured the reaction times of moving a manikin toward or away from the Go-primed stimulus and the other picture of a mug (i.e., unprimed stimulus). The other manikin task measured the reaction times of moving a manikin toward or away from the NoGo-primed stimulus and the unprimed stimulus. The participants then rated their preference for the Go-primed, NoGo-primed, and unprimed items. Results: The Go-primed item was evaluated as more highly preferable than the unprimed item in the Go condition, while the NoGo-primed item was evaluated as less preferable than the unprimed item in the NoGo condition. In contrast, the mean approach/avoidance reaction times in the manikin task showed no difference between the Go-primed and unprimed stimuli or between the NoGo-primed and unprimed stimuli. Conclusion: When participants repeatedly responded or inhibited their responses to an object, their explicit preference for the object increased or decreased, respectively. However, the effect did not occur in approach-avoidance behaviors toward the object.

Statistical Learning of Chord-Transition Regularities in a Novel Equitempered Scale: An MMN Study.

In music and language domains, it has been suggested that patterned transitions of sounds can be acquired implicitly through statistical learning. Previous studies have investigated the statistical learning of auditory regularities by recording early neural responses to a sequence of tones presented at high or low transition probabilities. However, it remains unclear whether the statistical learning of musical chord transitions is reflected in endogenous, regularity-dependent components of the event-related potential (ERP). The present study aimed to record the mismatch negativity (MMN) elicited by chord transitions that deviated from newly learned transitional regularities. Chords were generated in a novel 18 equal temperament pitch class scale to avoid interference from the existing tonal representations of the 12 equal temperament pitch class system. Thirty-six adults without professional musical training listened to a sequence of randomly inverted chords in which certain chords were presented with high (standard) or low (deviant) transition probabilities. An irrelevant timbre change detection task was assigned to make them attend to the sequence during the ERP recording. After that, a familiarity test was administered in which the participants were asked to choose the more familiar chord sequence out of two successive sequences. The results showed that deviant transitions elicited the MMN, although the participants could not recognize the standard transition beyond the level of chance. These findings suggest that humans can statistically learn new transitional regularities of chords in a novel musical scale, even though they did not recognize them explicitly. This study provides further evidence that music-syntactic regularities can be acquired implicitly through statistical learning.

Face inversion effect on perceived cuteness of infant faces.

Research has demonstrated that attractiveness evaluations of adult faces were less accurate when faces were inverted than upright. It remains unknown, however, whether a similar effect applies to perceived cuteness of infants, which is assumed to be based on elemental facial features called the "baby schema." In this research, we studied the face inversion effect on perceived cuteness of infant faces in a rating task and a two-alternative forced-choice (2AFC) task. We also examined beauty as a control dimension. Although the rating task revealed no inversion effect, the 2AFC task showed poorer discrimination performance with inverted faces than with upright faces in both evaluations. These results indicate that infant cuteness and beauty dimensions are correlated well with each other, and their perception not only relies on elemental features that are not strongly affected by inversion but is also affected by holistic facial configurations when a detailed comparison is required.

Insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease.

CYP7B1 catalyzes mitochondria-derived cholesterol metabolites such as (25R)26-hydroxycholesterol (26HC) and 3ß-hydroxy-5-cholesten-(25R)26-oic acid (3ßHCA) and facilitates their conversion to bile acids. Disruption of 26HC/3ßHCA metabolism in the absence of CYP7B1 leads to neonatal liver failure. Disrupted 26HC/3ßHCA metabolism with reduced hepatic CYP7B1 expression is also found in nonalcoholic steatohepatitis (NASH). The current study aimed to understand the regulatory mechanism of mitochondrial cholesterol metabolites and their contribution to onset of NASH. We used Cyp7b1-/- mice fed a normal diet (ND), Western diet (WD), or high-cholesterol diet (HCD). Serum and liver cholesterol metabolites as well as hepatic gene expressions were comprehensively analyzed. Interestingly, 26HC/3ßHCA levels were maintained at basal levels in ND-fed Cyp7b1-/- mice livers by the reduced cholesterol transport to mitochondria, and the upregulated glucuronidation and sulfation. However, WD-fed Cyp7b1-/- mice developed insulin resistance (IR) with subsequent 26HC/3ßHCA accumulation due to overwhelmed glucuronidation/sulfation with facilitated mitochondrial cholesterol transport. Meanwhile, Cyp7b1-/- mice fed an HCD did not develop IR or subsequent evidence of liver toxicity. HCD-fed mice livers revealed marked cholesterol accumulation but no 26HC/3ßHCA accumulation. The results suggest 26HC/3ßHCA-induced cytotoxicity occurs when increased cholesterol transport into mitochondria is coupled to decreased 26HC/3ßHCA metabolism driven with IR. Supportive evidence for cholesterol metabolite-driven hepatotoxicity is provided in a diet-induced nonalcoholic fatty liver mouse model and by human specimen analyses. This study uncovers an insulin-mediated regulatory pathway that drives the formation and accumulation of toxic cholesterol metabolites within the hepatocyte mitochondria, mechanistically connecting IR to cholesterol metabolite-induced hepatocyte toxicity which drives nonalcoholic fatty liver disease.

Personality descriptions influence perceived cuteness of children and nurturing motivation toward them.

The current empirical evidence regarding the effects of personality on physical attractiveness is limited to adult faces. In two preregistered studies, we demonstrated that personality descriptions influenced perceived cuteness, warmth, competence of young children, and female adults' nurturing motivation toward them. Study 1 showed that participants rated children accompanied by positive personality descriptions as cuter, friendlier, and more intelligent than their initial ratings. Negative personality descriptions reduced perceived cuteness in children, which in turn reduced nurturing motivation. Study 2 showed that negative personality descriptions consistently reduced perceived cuteness and warmth ratings after manipulation, regardless of the initial level of perceived cuteness. After one week, cuteness and warmth ratings in the positive personality condition tended to return to their initial ratings. However, the effect of negative personality descriptions on cuteness ratings persisted for all children. Together, our findings suggest that female adults' perception of cuteness and nurturing motivation are induced not only by children's appearance but also their personality.

Inborn errors of bile acid metabolism in Japan.

Bile acids are a category of steroids biosynthesized from cholesterol in the liver. Inborn errors of their metabolism are inherited in an autosomal recessive manner, resulting in enzyme deficiencies affecting the bile acid biosynthetic pathway. These defects in the pathway cause accumulation of unusual bile acids or bile alcohols. Unusual bile acids are highly cytotoxic, causing injury to the liver. These unusual bile acids damage hepatocytes, resulting in cholestatic liver injury beginning in infancy. Except for cerebrotendinous xanthomatosis and some secondary defects, various inborn errors of bile acid metabolism (IEBAM) have been reported from Japan, affecting eight patients including three with 3ß-hydroxy-Δ5 -C27 -steroid dehydrogenase/isomerase deficiency, three with Δ4 -3-oxosteroid 5ß-reductase deficiency, one with oxysterol 7α-hydroxylase deficiency, and one with bile acid-CoA: amino acid N-acyltransferase deficiency. Distinctive laboratory findings in patients with 3ß-hydroxy-Δ5 -C27 -steroid dehydrogenase/isomerase deficiency, Δ4 -3-oxosteroid 5ß-reductase deficiency, and oxysterol 7α-hydroxylase deficiency include normal serum γ-glutamyltransferase and total bile acids concentrations despite presence of cholestasis (elevated serum direct bilirubin) from infancy. Pediatricians and pediatric surgeons who suspect a case of IEBAM should obtain urinary and serum bile acid analyses using gas or liquid chromatography-mass spectrometry as well as genetic analyses. Available treatments include oral cholic acid, chenodeoxycholic acid, glycocholic acid, and ursodeoxycholic acid; fat-soluble vitamin supplementation; and liver transplantation. Early diagnosis and treatment can offer a good outcome.

Effects of respiratory phases on the processing of emotional and non-emotional visual stimuli.

The number of studies investigating the relationship between respiratory phases and cognitive/neural processing of external events has been increasing, but the findings remain controversial. This registered report examined the effect of the respiratory phase on the discrimination accuracy of visual stimuli in the emotional and non-emotional domains. Forty-two healthy young participants were asked to choose fearful over neutral facial expressions and to choose high-contrast over low-contrast Gabor patches during spontaneous nasal respiration. Event-related potentials (ERPs) were also recorded for each type of stimulus presented during each respiratory phase. It was hypothesized that discrimination accuracy would be higher when the stimuli were presented during inhalation than during exhalation. It was also hypothesized that the amplitudes of ERPs elicited by the stimuli would be greater during inhalation than during exhalation. For comparison, the effect of the cardiac phase was examined, with the expectation that discrimination accuracy would be higher when the stimuli were presented during systole than during diastole. It was also hypothesized that the amplitudes of ERPs elicited by the stimuli would be greater during systole than during diastole. As expected, the results indicated that fear discrimination accuracy was higher during inhalation than exhalation and during systole than diastole. However, this was not the case for contrast discrimination. No differences in ERPs were observed between respiratory phases in either task. These results suggest that natural breathing in through the nose facilitates the discrimination of emotional stimuli, possibly via subcortical processes.

Profiling of Urinary Glucuronidated Bile Acids across Age Groups.

We investigated the age-dependent changes in urinary excretion of glucuronidated bile acids at the C-3 position. Bile acid 3-glucuronides accounted for 0.5% of urinary bile acids in neonates, and the proportion of bile acid 3-glucuronides plateaued at 1-3 years of age. The 3-glucuronides of secondary bile acids were first secreted at 3 months of age, the same time as the establishment of the gut bacterial flora in infants. A considerable portion of bile acid 3-glucuronides were present as non-amidated forms. Our results indicate dynamic hepatic enzyme activity in which the levels of uridine 5'-diphospho-glucuronosyltransferases (UGTs) differ by age group, with higher glucuronidation activity of UGTs towards nonamidated bile acids than amidated bile acids.

Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes.

The gut microbiome of vertebrates is capable of numerous biotransformations of bile acids, which are responsible for intestinal lipid digestion and function as key nutrient-signaling molecules. The human liver produces bile acids from cholesterol predominantly in the A/B-cis orientation in which the sterol rings are "kinked", as well as small quantities of A/B-trans oriented "flat" stereoisomers known as "primary allo-bile acids". While the complex multi-step bile acid 7α-dehydroxylation pathway has been well-studied for conversion of "kinked" primary bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA) to deoxycholic acid (DCA) and lithocholic acid (LCA), respectively, the enzymatic basis for the formation of "flat" stereoisomers allo-deoxycholic acid (allo-DCA) and allo-lithocholic acid (allo-LCA) by Firmicutes has remained unsolved for three decades. Here, we present a novel mechanism by which Firmicutes generate the "flat" bile acids allo-DCA and allo-LCA. The BaiA1 was shown to catalyze the final reduction from 3-oxo-allo-DCA to allo-DCA and 3-oxo-allo-LCA to allo-LCA. Phylogenetic and metagenomic analyses of human stool samples indicate that BaiP and BaiJ are encoded only in Firmicutes and differ from membrane-associated bile acid 5α-reductases recently reported in Bacteroidetes that indirectly generate allo-LCA from 3-oxo-Δ4-LCA. We further map the distribution of baiP and baiJ among Firmicutes in human metagenomes, demonstrating an increased abundance of the two genes in colorectal cancer (CRC) patients relative to healthy individuals.